Expression of nociceptive ligands in canine osteosarcoma.

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Shor, S; Fadl-Alla, B A; Pondenis, H C; Zhang, X; Wycislo, K L; Lezmi, S; Fan, T M

2015-01-01

Canine osteosarcoma (OS) is associated with localized pain as a result of tissue injury from tumor infiltration and peritumoral inflammation. Malignant bone pain is caused by stimulation of peripheral pain receptors, termed nociceptors, which reside in the localized tumor microenvironment, including the periosteal and intramedullary bone cavities. Several nociceptive ligands have been determined to participate directly or indirectly in generating bone pain associated with diverse skeletal abnormalities. Canine OS cells actively produce nociceptive ligands with the capacity to directly or indirectly activate peripheral pain receptors residing in the bone tumor microenvironment. Ten dogs with appendicular OS. Expression of nerve growth factor, endothelin-1, and microsomal prostaglandin E synthase-1 was characterized in OS cell lines and naturally occurring OS samples. In 10 dogs with OS, circulating concentrations of nociceptive ligands were quantified and correlated with subjective pain scores and tumor volume in patients treated with standardized palliative therapies. Canine OS cells express and secrete nerve growth factor, endothelin-1, and prostaglandin E2. Naturally occurring OS samples uniformly express nociceptive ligands. In a subset of OS-bearing dogs, circulating nociceptive ligand concentrations were detectable but failed to correlate with pain status. Localized foci of nerve terminal proliferation were identified in a minority of primary bone tumor samples. Canine OS cells express nociceptive ligands, potentially permitting active participation of OS cells in the generation of malignant bone pain. Specific inhibitors of nociceptive ligand signaling pathways might improve pain control in dogs with OS. Copyright © 2015 The Authors. Journal of Veterinary Internal Medicine published by Wiley Periodicals, Inc. on behalf of American College of Veterinary Internal Medicine.

Control of somatic membrane potential in nociceptive neurons and its implications for peripheral nociceptive transmission

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Du, Xiaona; Hao, Han; Gigout, Sylvain; Huang, Dongyang; Yang, Yuehui; Li, Li; Wang, Caixue; Sundt, Danielle; Jaffe, David B.; Zhang, Hailin; Gamper, Nikita

2014-01-01

Peripheral sensory ganglia contain somata of afferent fibres conveying somatosensory inputs to the central nervous system. Growing evidence suggests that the somatic/perisomatic region of sensory neurons can influence peripheral sensory transmission. Control of resting membrane potential (Erest) is an important mechanism regulating excitability, but surprisingly little is known about how Erest is regulated in sensory neuron somata or how changes in somatic/perisomatic Erest affect peripheral sensory transmission. We first evaluated the influence of several major ion channels on Erest in cultured small-diameter, mostly capsaicin-sensitive (presumed nociceptive) dorsal root ganglion (DRG) neurons. The strongest and most prevalent effect on Erest was achieved by modulating M channels, K2P and 4-aminopiridine-sensitive KV channels, while hyperpolarization-activated cyclic nucleotide-gated, voltage-gated Na+, and T-type Ca2+ channels to a lesser extent also contributed to Erest. Second, we investigated how varying somatic/perisomatic membrane potential, by manipulating ion channels of sensory neurons within the DRG, affected peripheral nociceptive transmission in vivo. Acute focal application of M or KATP channel enhancers or a hyperpolarization-activated cyclic nucleotide-gated channel blocker to L5 DRG in vivo significantly alleviated pain induced by hind paw injection of bradykinin. Finally, we show with computational modelling how somatic/perisomatic hyperpolarization, in concert with the low-pass filtering properties of the t-junction within the DRG, can interfere with action potential propagation. Our study deciphers a complement of ion channels that sets the somatic Erest of nociceptive neurons and provides strong evidence for a robust filtering role of the somatic and perisomatic compartments of peripheral nociceptive neuron. PMID:25168672

Impact of behavioral control on the processing of nociceptive stimulation

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James W Grau

2012-08-01

Full Text Available How nociceptive signals are processed within the spinal cord, and whether these signals lead to behavioral signs of neuropathic pain, depends upon their relation to other events and behavior. Our work shows that these relations can have a lasting effect on spinal plasticity, inducing a form of learning that alters the effect of subsequent nociceptive stimuli. The capacity of lower spinal systems to adapt, in the absence of brain input, is examined in spinally transected rats that receive a nociceptive shock to the tibialis anterior muscle of one hind leg. If shock is delivered whenever the leg is extended (controllable stimulation, it induces an increase in flexion duration that minimizes net shock exposure. This learning is not observed in subjects that receive the same amount of shock independent of leg position (uncontrollable stimulation. These two forms of stimulation have a lasting, and divergent, effect on subsequent learning: Controllable stimulation enables learning whereas uncontrollable stimulation disables it (learning deficit. Uncontrollable stimulation also enhances mechanical reactivity (allodynia. We review evidence that training with controllable stimulation engages a BDNF-dependent process that can both prevent and reverse the consequences of uncontrollable shock. We relate these effects to changes in BDNF protein and TrkB signaling. Controllable stimulation is also shown to counter the effects of peripheral inflammation (from intradermal capsaicin. A model is proposed that assumes nociceptive input is gated at an early stage, within the dorsal horn. his gate is sensitive to current environmental relations (between proprioceptive and nociceptive input, allowing stimulation to be classified as controllable or uncontrollable. We further propose that the status of this gate is affected by past experience and that a history of uncontrollable stimulation will promote the development of neuropathic pain.

Impact of Behavioral Control on the Processing of Nociceptive Stimulation

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Grau, James W.; Huie, J. Russell; Garraway, Sandra M.; Hook, Michelle A.; Crown, Eric D.; Baumbauer, Kyle M.; Lee, Kuan H.; Hoy, Kevin C.; Ferguson, Adam R.

2012-01-01

How nociceptive signals are processed within the spinal cord, and whether these signals lead to behavioral signs of neuropathic pain, depends upon their relation to other events and behavior. Our work shows that these relations can have a lasting effect on spinal plasticity, inducing a form of learning that alters the effect of subsequent nociceptive stimuli. The capacity of lower spinal systems to adapt, in the absence of brain input, is examined in spinally transected rats that receive a nociceptive shock to the tibialis anterior muscle of one hind leg. If shock is delivered whenever the leg is extended (controllable stimulation), it induces an increase in flexion duration that minimizes net shock exposure. This learning is not observed in subjects that receive the same amount of shock independent of leg position (uncontrollable stimulation). These two forms of stimulation have a lasting, and divergent, effect on subsequent learning: controllable stimulation enables learning whereas uncontrollable stimulation disables it (learning deficit). Uncontrollable stimulation also enhances mechanical reactivity. We review evidence that training with controllable stimulation engages a brain-derived neurotrophic factor (BDNF)-dependent process that can both prevent and reverse the consequences of uncontrollable shock. We relate these effects to changes in BDNF protein and TrkB signaling. Controllable stimulation is also shown to counter the effects of peripheral inflammation (from intradermal capsaicin). A model is proposed that assumes nociceptive input is gated at an early sensory stage. This gate is sensitive to current environmental relations (between proprioceptive and nociceptive input), allowing stimulation to be classified as controllable or uncontrollable. We further propose that the status of this gate is affected by past experience and that a history of uncontrollable stimulation will promote the development of neuropathic pain. PMID:22934018

Markovian Analysis of the Sequential Behavior of the Spontaneous Spinal Cord Dorsum Potentials Induced by Acute Nociceptive Stimulation in the Anesthetized Cat

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Mario Martin

2017-05-01

Full Text Available In a previous study we developed a Machine Learning procedure for the automatic identification and classification of spontaneous cord dorsum potentials (CDPs. This study further supported the proposal that in the anesthetized cat, the spontaneous CDPs recorded from different lumbar spinal segments are generated by a distributed network of dorsal horn neurons with structured (non-random patterns of functional connectivity and that these configurations can be changed to other non-random and stable configurations after the noceptive stimulation produced by the intradermic injection of capsaicin in the anesthetized cat. Here we present a study showing that the sequence of identified forms of the spontaneous CDPs follows a Markov chain of at least order one. That is, the system has memory in the sense that the spontaneous activation of dorsal horn neuronal ensembles producing the CDPs is not independent of the most recent activity. We used this markovian property to build a procedure to identify portions of signals as belonging to a specific functional state of connectivity among the neuronal networks involved in the generation of the CDPs. We have tested this procedure during acute nociceptive stimulation produced by the intradermic injection of capsaicin in intact as well as spinalized preparations. Altogether, our results indicate that CDP sequences cannot be generated by a renewal stochastic process. Moreover, it is possible to describe some functional features of activity in the cord dorsum by modeling the CDP sequences as generated by a Markov order one stochastic process. Finally, these Markov models make possible to determine the functional state which produced a CDP sequence. The proposed identification procedures appear to be useful for the analysis of the sequential behavior of the ongoing CDPs recorded from different spinal segments in response to a variety of experimental procedures including the changes produced by acute nociceptive

Markovian Analysis of the Sequential Behavior of the Spontaneous Spinal Cord Dorsum Potentials Induced by Acute Nociceptive Stimulation in the Anesthetized Cat.

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Martin, Mario; Béjar, Javier; Esposito, Gennaro; Chávez, Diógenes; Contreras-Hernández, Enrique; Glusman, Silvio; Cortés, Ulises; Rudomín, Pablo

2017-01-01

In a previous study we developed a Machine Learning procedure for the automatic identification and classification of spontaneous cord dorsum potentials ( CDPs ). This study further supported the proposal that in the anesthetized cat, the spontaneous CDPs recorded from different lumbar spinal segments are generated by a distributed network of dorsal horn neurons with structured (non-random) patterns of functional connectivity and that these configurations can be changed to other non-random and stable configurations after the noceptive stimulation produced by the intradermic injection of capsaicin in the anesthetized cat. Here we present a study showing that the sequence of identified forms of the spontaneous CDPs follows a Markov chain of at least order one. That is, the system has memory in the sense that the spontaneous activation of dorsal horn neuronal ensembles producing the CDPs is not independent of the most recent activity. We used this markovian property to build a procedure to identify portions of signals as belonging to a specific functional state of connectivity among the neuronal networks involved in the generation of the CDPs . We have tested this procedure during acute nociceptive stimulation produced by the intradermic injection of capsaicin in intact as well as spinalized preparations. Altogether, our results indicate that CDP sequences cannot be generated by a renewal stochastic process. Moreover, it is possible to describe some functional features of activity in the cord dorsum by modeling the CDP sequences as generated by a Markov order one stochastic process. Finally, these Markov models make possible to determine the functional state which produced a CDP sequence. The proposed identification procedures appear to be useful for the analysis of the sequential behavior of the ongoing CDPs recorded from different spinal segments in response to a variety of experimental procedures including the changes produced by acute nociceptive stimulation. They

Effects of Parecoxib and Fentanyl on nociception-induced cortical activity

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Wang Ying-Wei

2010-01-01

Full Text Available Abstract Background Analgesics, including opioids and non-steroid anti-inflammatory drugs reduce postoperative pain. However, little is known about the quantitative effects of these drugs on cortical activity induced by nociceptive stimulation. The aim of the present study was to determine the neural activity in response to a nociceptive stimulus and to investigate the effects of fentanyl (an opioid agonist and parecoxib (a selective cyclooxygenase-2 inhibitor on this nociception-induced cortical activity evoked by tail pinch. Extracellular recordings (electroencephalogram and multi-unit signals were performed in the area of the anterior cingulate cortex while intracellular recordings were made in the primary somatosensory cortex. The effects of parecoxib and fentanyl on induced cortical activity were compared. Results Peripheral nociceptive stimulation in anesthetized rats produced an immediate electroencephalogram (EEG desynchronization resembling the cortical arousal (low-amplitude, fast-wave activity, while the membrane potential switched into a persistent depolarization state. The induced cortical activity was abolished by fentanyl, and the fentanyl's effect was reversed by the opioid receptor antagonist, naloxone. Parecoxib, on the other hand, did not significantly affect the neural activity. Conclusion Cortical activity was modulated by nociceptive stimulation in anesthetized rats. Fentanyl showed a strong inhibitory effect on the nociceptive-stimulus induced cortical activity while parecoxib had no significant effect.

Nociceptive TRP Channels: Sensory Detectors and Transducers in Multiple Pain Pathologies

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Aaron D. Mickle

2016-11-01

Full Text Available Specialized receptors belonging to the transient receptor potential (TRP family of ligand-gated ion channels constitute the critical detectors and transducers of pain-causing stimuli. Nociceptive TRP channels are predominantly expressed by distinct subsets of sensory neurons of the peripheral nervous system. Several of these TRP channels are also expressed in neurons of the central nervous system, and in non-neuronal cells that communicate with sensory nerves. Nociceptive TRPs are activated by specific physico-chemical stimuli to provide the excitatory trigger in neurons. In addition, decades of research has identified a large number of immune and neuromodulators as mediators of nociceptive TRP channel activation during injury, inflammatory and other pathological conditions. These findings have led to aggressive targeting of TRP channels for the development of new-generation analgesics. This review summarizes the complex activation and/or modulation of nociceptive TRP channels under pathophysiological conditions, and how these changes underlie acute and chronic pain conditions. Furthermore, development of small-molecule antagonists for several TRP channels as analgesics, and the positive and negative outcomes of these drugs in clinical trials are discussed. Understanding the diverse functional and modulatory properties of nociceptive TRP channels is critical to function-based drug targeting for the development of evidence-based and efficacious new generation analgesics.

Possible effects of mobilisation on acute post-operative pain and nociceptive function after total knee arthroplasty

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Lunn, T H; Kristensen, B B; Gaarn-Larsen, L

2012-01-01

anaesthesia and analgesia underwent an exercise (mobilisation) strategy on the first post-operative morning consisting of 25-m walking twice, with a 20-min interval. Pain was assessed at rest and during passive hip and knee flexion before, and 5 and 20 min after walk, as well as during walk. Nociceptive......BACKGROUND: Experimental studies in animals, healthy volunteers, and patients with chronic pain suggest exercise to provide analgesia in several types of pain conditions and after various nociceptive stimuli. To our knowledge, there is no data on the effects of exercise on pain and nociceptive...... function in surgical patients despite early mobilisation being an important factor to enhance recovery. We therefore investigated possible effects of mobilisation on post-operative pain and nociceptive function after total knee arthroplasty (TKA). METHODS: Thirty patients undergoing TKA under standardised...

Changes in thermal nociceptive responses in dairy cows following experimentally induced Escherichia coli mastitis

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Klaas Ilka C

2011-05-01

Full Text Available Abstract Background Mastitis is a high incidence disease in dairy cows. The acute stage is considered painful and inflammation can lead to hyperalgesia and thereby contribute to decreased welfare. The aim of this study was to examine changes in nociceptive responses toward cutaneous nociceptive laser stimulation (NLS in dairy cows with experimentally induced Escherichia coli mastitis, and correlate behavioral changes in nociceptive responses to clinical and paraclinical variables. Methods Seven Danish Holstein-Friesian cows were kept in tie-stalls, where the E. coli associated mastitis was induced and laser stimulations were conducted. Measurements of rectal temperature, somatic cell counts, white blood cell counts and E. coli counts were conducted. Furthermore, scores were given for anorexia, local udder inflammation and milk appearance to quantify the local and systemic disease response. In order to quantify the nociceptive threshold, behavioral responses toward cutaneous NLS applied to six skin areas at the tarsus/metatarsus and udder hind quarters were registered at evening milking on day 0 (control and days 1, 2, 3, 6 and 10 after experimental induction of mastitis. Results All clinical and paraclinical variables were affected by the induced mastitis. All cows were clinically ill on days 1 and 2. The cows responded behaviorally toward the NLS. For hind leg stimulation, the proportion of cows responding by stepping was higher on day 0 than days 3 and 6, and the frequency of leg movements after laser stimulation tended to decrease on day 1 compared to the other days. After udder stimulation, the proportion of cows responding by stepping was higher on day 1 than on all other days of testing. Significant correlations between the clinical and paraclinical variables of disease and the behavioral responses toward nociceptive stimulation were found. Conclusions Changes in behavioral responses coincide with peaks in local and systemic signs of E

Anti-nociceptive activity of Pereskia bleo Kunth. (Cactaceae) leaves extracts.

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Abdul-Wahab, Ikarastika Rahayu; Guilhon, Carolina Carvalho; Fernandes, Patricia Dias; Boylan, Fabio

2012-12-18

Local communities in Malaysia consume Pereskia bleo Kunth. (Cactaceae) leaves as raw vegetables or as a concoction and drink as a tea to treat diabetes, hypertension, rheumatism, cancer-related diseases, inflammation, gastric pain, ulcers, and for revitalizing the body. To evaluate anti-nociceptive activity of the extracts and vitexin, isolated for the first time in this species, in two analgesic models; formalin-induced licking and acetic acid-induced abdominal writhing. Three and a half kilos of P. bleo leaves were extracted using Soxhlet apparatus with ethanol for 72 h. The crude ethanol extract was treated with activated charcoal overnight and subjected to a liquid-liquid partition yielding hexane, dichloromethane, ethyl acetate and butanol extracts. All extracts, including the crude ethanol and vitexin isolated from the ethyl acetate partition were tested for peripheral anti-nociceptive activity using formalin test and acetic acid-induced abdominal writhing, besides having their acute toxicity assays performed. The phytochemical analyses resulted in the isolation of vitexin (1), β-sitosterol glucoside (2) and β-sitosterol (3) isolated from the ethyl acetate, dichloromethane and hexane extracts, respectively. This is the first time vitexin and β-sitosterol glucoside are isolated from this species. The anti-nociceptive activities for all extracts were only moderate. Vitexin, which was isolated from the ethyl acetate extract did not show any activity in all models tested when used alone at the same concentration as it appears in the extract. This study showed that all the extracts possess moderate anti-nociceptive activity. Vitexin is not the compound responsible for the anti-nociceptive effect in the ethyl acetate extract. Further investigations are needed to identify the compound(s) that might be responsible for the anti-nociceptive activity in this plant. Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.

Network dynamics in nociceptive pathways assessed by the neuronal avalanche model

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Wu José

2012-04-01

Full Text Available Abstract Background Traditional electroencephalography provides a critical assessment of pain responses. The perception of pain, however, may involve a series of signal transmission pathways in higher cortical function. Recent studies have shown that a mathematical method, the neuronal avalanche model, may be applied to evaluate higher-order network dynamics. The neuronal avalanche is a cascade of neuronal activity, the size distribution of which can be approximated by a power law relationship manifested by the slope of a straight line (i.e., the α value. We investigated whether the neuronal avalanche could be a useful index for nociceptive assessment. Findings Neuronal activity was recorded with a 4 × 8 multichannel electrode array in the primary somatosensory cortex (S1 and anterior cingulate cortex (ACC. Under light anesthesia, peripheral pinch stimulation increased the slope of the α value in both the ACC and S1, whereas brush stimulation increased the α value only in the S1. The increase in α values was blocked in both regions under deep anesthesia. The increase in α values in the ACC induced by peripheral pinch stimulation was blocked by medial thalamic lesion, but the increase in α values in the S1 induced by brush and pinch stimulation was not affected. Conclusions The neuronal avalanche model shows a critical state in the cortical network for noxious-related signal processing. The α value may provide an index of brain network activity that distinguishes the responses to somatic stimuli from the control state. These network dynamics may be valuable for the evaluation of acute nociceptive processes and may be applied to chronic pathological pain conditions.

Regulation of the Na,K-ATPase gamma-subunit FXYD2 by Runx1 and Ret signaling in normal and injured non-peptidergic nociceptive sensory neurons.

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Stéphanie Ventéo

Full Text Available Dorsal root ganglia (DRGs contain the cell bodies of sensory neurons which relay nociceptive, thermoceptive, mechanoceptive and proprioceptive information from peripheral tissues toward the central nervous system. These neurons establish constant communication with their targets which insures correct maturation and functioning of the somato-sensory nervous system. Interfering with this two-way communication leads to cellular, electrophysiological and molecular modifications that can eventually cause neuropathic conditions. In this study we reveal that FXYD2, which encodes the gamma-subunit of the Na,K-ATPase reported so far to be mainly expressed in the kidney, is induced in the mouse DRGs at postnatal stages where it is restricted specifically to the TrkB-expressing mechanoceptive and Ret-positive/IB4-binding non-peptidergic nociceptive neurons. In non-peptidergic nociceptors, we show that the transcription factor Runx1 controls FXYD2 expression during the maturation of the somato-sensory system, partly through regulation of the tyrosine kinase receptor Ret. Moreover, Ret signaling maintains FXYD2 expression in adults as demonstrated by the axotomy-induced down-regulation of the gene that can be reverted by in vivo delivery of GDNF family ligands. Altogether, these results establish FXYD2 as a specific marker of defined sensory neuron subtypes and a new target of the Ret signaling pathway during normal maturation of the non-peptidergic nociceptive neurons and after sciatic nerve injury.

Sensory processing of deep tissue nociception in the rat spinal cord and thalamic ventrobasal complex.

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Sikandar, Shafaq; West, Steven J; McMahon, Stephen B; Bennett, David L; Dickenson, Anthony H

2017-07-01

Sensory processing of deep somatic tissue constitutes an important component of the nociceptive system, yet associated central processing pathways remain poorly understood. Here, we provide a novel electrophysiological characterization and immunohistochemical analysis of neural activation in the lateral spinal nucleus (LSN). These neurons show evoked activity to deep, but not cutaneous, stimulation. The evoked responses of neurons in the LSN can be sensitized to somatosensory stimulation following intramuscular hypertonic saline, an acute model of muscle pain, suggesting this is an important spinal relay site for the processing of deep tissue nociceptive inputs. Neurons of the thalamic ventrobasal complex (VBC) mediate both cutaneous and deep tissue sensory processing, but in contrast to the lateral spinal nucleus our electrophysiological studies do not suggest the existence of a subgroup of cells that selectively process deep tissue inputs. The sensitization of polymodal and thermospecific VBC neurons to mechanical somatosensory stimulation following acute muscle stimulation with hypertonic saline suggests differential roles of thalamic subpopulations in mediating cutaneous and deep tissue nociception in pathological states. Overall, our studies at both the spinal (lateral spinal nucleus) and supraspinal (thalamic ventrobasal complex) levels suggest a convergence of cutaneous and deep somatosensory inputs onto spinothalamic pathways, which are unmasked by activation of muscle nociceptive afferents to produce consequent phenotypic alterations in spinal and thalamic neural coding of somatosensory stimulation. A better understanding of the sensory pathways involved in deep tissue nociception, as well as the degree of labeled line and convergent pathways for cutaneous and deep somatosensory inputs, is fundamental to developing targeted analgesic therapies for deep pain syndromes. © 2017 University College London. Physiological Reports published by Wiley Periodicals

Sympathetic β-adrenergic mechanism in pudendal inhibition of nociceptive and non-nociceptive reflex bladder activity.

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Kadow, Brian T; Lyon, Timothy D; Zhang, Zhaocun; Lamm, Vladimir; Shen, Bing; Wang, Jicheng; Roppolo, James R; de Groat, William C; Tai, Changfeng

2016-07-01

This study investigated the role of the hypogastric nerve and β-adrenergic mechanisms in the inhibition of nociceptive and non-nociceptive reflex bladder activity induced by pudendal nerve stimulation (PNS). In α-chloralose-anesthetized cats, non-nociceptive reflex bladder activity was induced by slowly infusing saline into the bladder, whereas nociceptive reflex bladder activity was induced by replacing saline with 0.25% acetic acid (AA) to irritate the bladder. PNS was applied at multiple threshold (T) intensities for inducing anal sphincter twitching. During saline infusion, PNS at 2T and 4T significantly (P reflex bladder activity. In addition to this peripheral mechanism, a central nervous system mechanism involving metabotropic glutamate 5 receptors also has a role in PNS inhibition. Copyright © 2016 the American Physiological Society.

Nociceptor-Enriched Genes Required for Normal Thermal Nociception

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Ken Honjo

2016-07-01

Full Text Available Here, we describe a targeted reverse genetic screen for thermal nociception genes in Drosophila larvae. Using laser capture microdissection and microarray analyses of nociceptive and non-nociceptive neurons, we identified 275 nociceptor-enriched genes. We then tested the function of the enriched genes with nociceptor-specific RNAi and thermal nociception assays. Tissue-specific RNAi targeted against 14 genes caused insensitive thermal nociception while targeting of 22 genes caused hypersensitive thermal nociception. Previously uncategorized genes were named for heat resistance (i.e., boilerman, fire dancer, oven mitt, trivet, thawb, and bunker gear or heat sensitivity (firelighter, black match, eucalyptus, primacord, jet fuel, detonator, gasoline, smoke alarm, and jetboil. Insensitive nociception phenotypes were often associated with severely reduced branching of nociceptor neurites and hyperbranched dendrites were seen in two of the hypersensitive cases. Many genes that we identified are conserved in mammals.

Nociceptive tuning by stem cell factor/c-Kit signaling.

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Milenkovic, Nevena; Frahm, Christina; Gassmann, Max; Griffel, Carola; Erdmann, Bettina; Birchmeier, Carmen; Lewin, Gary R; Garratt, Alistair N

2007-12-06

The molecular mechanisms regulating the sensitivity of sensory circuits to environmental stimuli are poorly understood. We demonstrate here a central role for stem cell factor (SCF) and its receptor, c-Kit, in tuning the responsiveness of sensory neurons to natural stimuli. Mice lacking SCF/c-Kit signaling displayed profound thermal hypoalgesia, attributable to a marked elevation in the thermal threshold and reduction in spiking rate of heat-sensitive nociceptors. Acute activation of c-Kit by its ligand, SCF, resulted in a reduced thermal threshold and potentiation of heat-activated currents in isolated small-diameter neurons and thermal hyperalgesia in mice. SCF-induced thermal hyperalgesia required the TRP family cation channel TRPV1. Lack of c-Kit signaling during development resulted in hypersensitivity of discrete mechanoreceptive neuronal subtypes. Thus, c-Kit can now be grouped with a small family of receptor tyrosine kinases, including c-Ret and TrkA, that control the transduction properties of sensory neurons.

Lion's Mane Medicinal Mushroom, Hericium erinaceus (Agaricomycetes), Modulates Purinoceptor-Coupled Calcium Signaling and Murine Nociceptive Behavior.

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Liu, Pei-Shan; Chueh, Sheau-Huei; Chen, Chin-Chu; Lee, Li-Ya; Shiu, Li-Yen

2017-01-01

Hericium erinaceus is well known for the neurotrophic effect it confers by promoting nerve growth factor biosynthesis. We discovered a novel bioactivity of H. erinaceus in its ability to suppress adenosine triphosphate (ATP)-induced calcium signaling in neuronal PC12 cells. ATP, known primarily as a neurotransmitter, also acts on purinoceptors (P2 purinergic receptor [P2R]) to generate the cellular calcium signaling and secretion that mediate P2R physiological manifestations, including pain. Chronic pain reduces quality of life. However, constant analgesic administration can cause liver and kidney injury, as well as loss of the analgesic effect because of desensitization. In this study we investigated the analgesic potential of H. erinaceus through measurements of ATP-induced Ca2+ signaling in cell lines and observation of pain behaviors in mice. In P2R-coupled Ca2+ signaling measurements, extracts of H. erinaceus mycelia (HEEs) blocked ATP-induced Ca2+ signaling in both rat PC12 cells and human HOS cells. HEEs completely blocked ATP-induced Ca2+ signaling in human HOS cells, suggesting that this effect of HEEs is exerted through the P2R subtypes present in HOS cells, which include the P2X4, P2X7, P2Y2, and P2Y4 subtypes. In observations of animal behavior during pain, HEEs significantly reduced heat-induced pain, including postponing both the tail-flick response to heat stimulation and the paw-lifting response to a hot plate. This study demonstrates novel characteristics of H. erinaceus in reducing nociceptive behavior and blocking the functional activity of P2R. Further studies are required to verify this linkage and its molecular mechanisms.

CGRPα within the Trpv1-Cre population contributes to visceral nociception.

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Spencer, Nick J; Magnúsdóttir, Elín I; Jakobsson, Jon E T; Kestell, Garreth; Chen, Bao Nan; Morris, David; Brookes, Simon J; Lagerström, Malin C

2018-02-01

The role of calcitonin gene-related peptide (CGRP) in visceral and somatic nociception is incompletely understood. CGRPα is highly expressed in sensory neurons of dorsal root ganglia and particularly in neurons that also express the transient receptor potential cation channel subfamily V member 1 (Trpv1). Therefore, we investigated changes in visceral and somatic nociception following deletion of CGRPα from the Trpv1-Cre population using the Cre/lox system. In control mice, acetic acid injection (0.6%, ip) caused significant immobility (time stationary), an established indicator of visceral pain. In CGRPα-mCherry lx/lx ;Trpv1-Cre mice, the duration of immobility was significantly less than controls, and the distance CGRPα-mCherry lx/lx ;Trpv1-Cre mice traveled over 20 min following acetic acid was significantly greater than controls. However, following acetic acid injection, there was no difference between genotypes in the writhing reflex, number of abdominal licks, or forepaw wipes of the cheek. CGRPα-mCherry lx/lx ;Trpv1-Cre mice developed more pronounced inflammation-induced heat hypersensitivity above baseline values compared with controls. However, analyses of noxious acute heat or cold transmission revealed no difference between genotypes. Also, odor avoidance test, odor preference test, and buried food test for olfaction revealed no differences between genotypes. Our findings suggest that CGRPα-mediated transmission within the Trpv1-Cre population plays a significant role in visceral nociceptive pathways underlying voluntary movement. Monitoring changes in movement over time is a sensitive parameter to identify differences in visceral nociception, compared with writhing reflexes, abdominal licks, or forepaw wipes of the cheek that were unaffected by deletion of CGRPα- from Trpv1-Cre population and likely utilize different mechanisms. NEW & NOTEWORTHY The neuropeptide calcitonin gene-related peptide (CGRP) is highly colocalized with transient receptor

Dopamine D3 receptor knockout mice exhibit abnormal nociception in a sex-different manner.

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Liu, Peng; Xing, Bo; Chu, Zheng; Liu, Fei; Lei, Gang; Zhu, Li; Gao, Ya; Chen, Teng; Dang, Yong-Hui

2017-07-01

Pain is a complex and subjective experience. Previous studies have shown that mice lacking the dopamine D3 receptor (D3RKO) exhibit hypoalgesia, indicating a role of the D3 receptor in modulation of nociception. Given that there are sex differences in pain perception, there may be differences in responses to nociceptive stimuli between male and female D3RKO mice. In the current study, we examined the role of the D3 receptor in modulating nociception in male and female D3RKO mice. Acute thermal pain was modeled by hot-plate test. This test was performed at different temperatures including 52°C, 55°C, and 58°C. The von Frey hair test was applied to evaluate mechanical pain. And persistent pain produced by peripheral tissue injury and inflammation was modeled by formalin test. In the hot-plate test, compared with wild-type (WT) mice, D3RKO mice generally exhibited longer latencies at each of the three temperatures. Specially, male D3RKO mice showed hypoalgesia compared with male WT mice when the temperature was 55°C, while for the female mice, there was a statistical difference between genotypes when the test condition was 52°C. In the von Frey hair test, both male and female D3RKO mice exhibited hypoalgesia. In the formalin test, the male D3RKO mice displayed a similar nociceptive behavior as their sex-matched WT littermates, whereas significantly depressed late-phase formalin-induced nociceptive behaviors were observed in the female mutants. These findings indicated that the D3 receptor affects nociceptive behaviors in a sex-specific manner and that its absence induces more analgesic behavior in the female knockout mice. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

Redox signaling in acute pancreatitis

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Pérez, Salvador; Pereda, Javier; Sabater, Luis; Sastre, Juan

2015-01-01

Acute pancreatitis is an inflammatory process of the pancreatic gland that eventually may lead to a severe systemic inflammatory response. A key event in pancreatic damage is the intracellular activation of NF-κB and zymogens, involving also calcium, cathepsins, pH disorders, autophagy, and cell death, particularly necrosis. This review focuses on the new role of redox signaling in acute pancreatitis. Oxidative stress and redox status are involved in the onset of acute pancreatitis and also in the development of the systemic inflammatory response, being glutathione depletion, xanthine oxidase activation, and thiol oxidation in proteins critical features of the disease in the pancreas. On the other hand, the release of extracellular hemoglobin into the circulation from the ascitic fluid in severe necrotizing pancreatitis enhances lipid peroxidation in plasma and the inflammatory infiltrate into the lung and up-regulates the HIF–VEGF pathway, contributing to the systemic inflammatory response. Therefore, redox signaling and oxidative stress contribute to the local and systemic inflammatory response during acute pancreatitis. PMID:25778551

Redox signaling in acute pancreatitis

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Salvador Pérez

2015-08-01

Full Text Available Acute pancreatitis is an inflammatory process of the pancreatic gland that eventually may lead to a severe systemic inflammatory response. A key event in pancreatic damage is the intracellular activation of NF-κB and zymogens, involving also calcium, cathepsins, pH disorders, autophagy, and cell death, particularly necrosis. This review focuses on the new role of redox signaling in acute pancreatitis. Oxidative stress and redox status are involved in the onset of acute pancreatitis and also in the development of the systemic inflammatory response, being glutathione depletion, xanthine oxidase activation, and thiol oxidation in proteins critical features of the disease in the pancreas. On the other hand, the release of extracellular hemoglobin into the circulation from the ascitic fluid in severe necrotizing pancreatitis enhances lipid peroxidation in plasma and the inflammatory infiltrate into the lung and up-regulates the HIF–VEGF pathway, contributing to the systemic inflammatory response. Therefore, redox signaling and oxidative stress contribute to the local and systemic inflammatory response during acute pancreatitis.

Substance P spinal signaling induces glial activation and nociceptive sensitization after fracture

OpenAIRE

Li, Wen-Wu; Guo, Tian-Zhi; Shi, Xiaoyou; Sun, Yuan; Wei, Tzuping; Clark, David J; Kingery, Wade S

2015-01-01

Tibia fracture in rodents induces substance P (SP)-dependent keratinocyte activation and inflammatory changes in the hindlimb, similar to those seen in complex regional pain syndrome (CRPS). In animal pain models spinal glial cell activation results in nociceptive sensitization. This study tested the hypothesis that limb fracture triggers afferent C-fiber SP release in the dorsal horn, resulting in chronic glia activation and central sensitization. At 4 weeks after tibia fracture and casting ...

Resveratrol engages AMPK to attenuate ERK and mTOR signaling in sensory neurons and inhibits incision-induced acute and chronic pain

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Tillu Dipti V

2012-01-01

Full Text Available Abstract Background Despite advances in our understanding of basic mechanisms driving post-surgical pain, treating incision-induced pain remains a major clinical challenge. Moreover, surgery has been implicated as a major cause of chronic pain conditions. Hence, more efficacious treatments are needed to inhibit incision-induced pain and prevent the transition to chronic pain following surgery. We reasoned that activators of AMP-activated protein kinase (AMPK may represent a novel treatment avenue for the local treatment of incision-induced pain because AMPK activators inhibit ERK and mTOR signaling, two important pathways involved in the sensitization of peripheral nociceptors. Results To test this hypothesis we used a potent and efficacious activator of AMPK, resveratrol. Our results demonstrate that resveratrol profoundly inhibits ERK and mTOR signaling in sensory neurons in a time- and concentration-dependent fashion and that these effects are mediated by AMPK activation and independent of sirtuin activity. Interleukin-6 (IL-6 is thought to play an important role in incision-induced pain and resveratrol potently inhibited IL-6-mediated signaling to ERK in sensory neurons and blocked IL-6-mediated allodynia in vivo through a local mechanism of action. Using a model of incision-induced allodynia in mice, we further demonstrate that local injection of resveratrol around the surgical wound strongly attenuates incision-induced allodynia. Intraplantar IL-6 injection and plantar incision induces persistent nociceptive sensitization to PGE2 injection into the affected paw after the resolution of allodynia to the initial stimulus. We further show that resveratrol treatment at the time of IL-6 injection or plantar incision completely blocks the development of persistent nociceptive sensitization consistent with the blockade of a transition to a chronic pain state by resveratrol treatment. Conclusions These results highlight the importance of signaling

Sex-dependent effects of restraint on nociception and pituitary-adrenal hormones in the rat.

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Aloisi, A M; Steenbergen, H L; van de Poll, N E; Farabollini, F

1994-05-01

The sex-dependent effects of acute restraint (RT) on nociceptive and pituitary-adrenal responses were investigated in the rat. In a first experiment, the effect of 30 min RT on pain sensitivity was evaluated through repeated use of the tail withdrawal test during and after treatment. RT induced an increase in the nociceptive threshold, i.e., analgesia, in males and females, but the duration and time-course of this effect varied between sexes. The latencies returned to approximately control values in females in the second half of RT, but in males they remained higher for the whole period of RT and immediately afterwards. Twenty-four hours later, males displayed longer latencies than controls in response to simple reexposure to the environment. In a second experiment, ACTH and corticosterone plasma levels were measured immediately after 15 or 30 min of RT. ACTH and corticosterone were higher in restrained animals than in controls after both periods of treatment, and in both sexes; however, females showed higher basal and stress corticosterone levels than males. The role played by corticosteroids in the nociceptive responses of the two sexes is discussed.

Calcitonin gene-related peptide modulates heat nociception in the human brain - An fMRI study in healthy volunteers

DEFF Research Database (Denmark)

Asghar, Mohammad Sohail; Becerra, Lino; Larsson, Henrik B.W.

2016-01-01

Background: Intravenous infusion of calcitonin-gene-related-peptide (CGRP) provokes headache and migraine in humans. Mechanisms underlying CGRP-induced headache are not fully clarified and it is unknown to what extent CGRP modulates nociceptive processing in the brain. To elucidate this we recorded...... cortex. Sumatriptan injection reversed these changes. Conclusion: The changes in BOLD-signals in the brain after CGRP infusion suggests that systemic CGRP modulates nociceptive transmission in the trigeminal pain pathways in response to noxious heat stimuli....

Potent analgesic effects of anticonvulsants on peripheral thermal nociception in rats

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Todorovic, Slobodan M; Rastogi, A J; Jevtovic-Todorovic, Vesna

2003-01-01

Anticonvulsant agents are commonly used to treat neuropathic pain conditions because of their effects on voltage- and ligand-gated channels in central pain pathways. However, their interaction with ion channels in peripheral pain pathways is poorly understood. Therefore, we studied the potential analgesic effects of commonly used anticonvulsant agents in peripheral nociception. We injected anticonvulsants intradermally into peripheral receptive fields of sensory neurons in the hindpaws of adult rats, and studied pain perception using the model of acute thermal nociception. Commonly used anticonvulsants such as voltage-gated Na+ channel blockers, phenytoin and carbamazepine, and voltage-gated Ca2+ channel blockers, gabapentin and ethosuximide, induced dose-dependent analgesia in the injected paw, with ED50 values of 0.30, 0.32 and 8, 410 μg per 100 μl, respectively. Thermal nociceptive responses were not affected in the contralateral, noninjected paws, indicating a lack of systemic effects with doses of anticonvulsants that elicited local analgesia. Hill slope coefficients for the tested anticonvulsants indicate that the dose–response curve was less steep for gabapentin than for phenytoin, carbamazepine and ethosuximide. Our data strongly suggest that cellular targets like voltage-gated Na+ and Ca2+ channels, similar to those that mediate the effects of anticonvulsant agents in the CNS, may exist in the peripheral nerve endings of rat sensory neurons. Thus, peripherally applied anticonvulsants that block voltage-gated Na+ and Ca2+ channels may be useful analgesics. PMID:12970103

Effect of Gmelina arborea Roxb in experimentally induced inflammation and nociception

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Yogesh A Kulkarni

2013-01-01

Full Text Available Background: Gmelina arborea Roxb (Verbenaceae, also known as "Gambhari", is an important medicinal plant in the Ayurveda. There are no meticulous scientific reports on effect of the plant on inflammation and pain. Objective: To study the anti-inflammatory and anti-nociceptive properties of aqueous extracts (AE and methanol extracts (ME of G. arborea. Materials and Methods: The AE and ME of stembark of G. arborea was prepared by cold maceration and Soxhlet extraction technique respectively. Anti-inflammatory activity was determined in Wistar albino rats in a model of acute plantar inflammation induced by carrageenan. The anti-nociceptive activity was evaluated by using hot plate test and writhing test in Swiss albino mice. Significant differences between the experimental groups were assessed by analysis of variance. Results: AE and ME at dose of 500 mg/kg showed maximum inhibition in carrageenan induced inflammation up to 30.15 and 31.21% respectively. In hot plate test, the AE and ME showed the maximum response of 8.8 ± 0.97 (P < 0.01 and 8.2 ± 1.24 (P < 0.01 respectively at dose of 500 mg/kg when compared with control. AE showed maximum inhibition of writhing response (84.3% as compared to ME (77.9% in writhing test at a dose of 500 mg/kg. Conclusion: The findings suggested that G. arborea possess significant anti-inflammatory and anti-nociceptive activities.

Molecular Basis of TRPA1 Regulation in Nociceptive Neurons. A Review

Czech Academy of Sciences Publication Activity Database

Kádková, Anna; Synytsya, Viktor; Krůšek, Jan; Zímová, Lucie; Vlachová, Viktorie

2017-01-01

Roč. 66, č. 3 (2017), s. 425-439 ISSN 0862-8408 R&D Projects: GA ČR(CZ) GA15-15839S; GA MZd(CZ) NV16-28784A Institutional support: RVO:67985823 Keywords : transient receptor potential ankyrin 1 * bradykinin * structure- function * nociception * post-translational modifications * signaling pathways Subject RIV: FH - Neurology OBOR OECD: Neurosciences (including psychophysiology Impact factor: 1.461, year: 2016

Suppression of thermal and chemical nociception in rats by methanol extract and its sub-fraction from lantana camara

International Nuclear Information System (INIS)

Simjee, S.U.; Perveen, H.; Zehra, S.Q.

2016-01-01

The traditional use of Lantana camara (Verbenaceae) is reported to include anti-nociceptive, antimicrobial, and immunosuppressant activity. To our knowledge no systematic study has been carried out on the anti-nociceptive activity of L. camara. The present study was designed to delineate the analgesic activity of L. camara extract and its fractions to elucidate the traditional belief in the painkilling effects. Experimental models employed were thermal and chemical-induced nociception assays. After initial screening of the methanol extract and its fractions prepared from the aerial parts of the plant, the dose of 50,100 and 200 mg/kg were selected and route of administration was i.p. The test samples were tested against a reference drug indomethacine (i.p. 5 mg/kg). The observations were made at 15, 30, 60, and 120 seconds following the administration of the samples or reference drug. Experiments on naloxone antagonism were conducted to determine involvement of opioid receptors. Compared to concurrent controls, a significant anti-nociceptive activity was observed in methanol extract LC (ED50 50 mg/kg, P < 0.002) and its sub-fractions LCEA-AQ (ED50 50 mg/kg, P < 0.004), LCEA (ED50 100 mg/kg, P < 0.004) and LCEA-PEI (ED50 100 mg/kg, P < 0.005). No apparent acute toxicity was observed in any test groups. The anti-nociceptive activity was not precipitated by naloxone antagonism indicating that these fractions do not act through opioid receptors. The methanol extract and active fractions of Lantana camara possess anti-nociceptive activity. Further investigations are needed to elucidate the mechanism of its action. (author)

Redox signaling in acute oxygen sensing

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Lin Gao

2017-08-01

Full Text Available Acute oxygen (O2 sensing is essential for individuals to survive under hypoxic conditions. The carotid body (CB is the main peripheral chemoreceptor, which contains excitable and O2-sensitive glomus cells with O2-regulated ion channels. Upon exposure to acute hypoxia, inhibition of K+ channels is the signal that triggers cell depolarization, transmitter release and activation of sensory fibers that stimulate the brainstem respiratory center to produce hyperventilation. The molecular mechanisms underlying O2 sensing by glomus cells have, however, remained elusive. Here we discuss recent data demonstrating that ablation of mitochondrial Ndufs2 gene selectively abolishes sensitivity of glomus cells to hypoxia, maintaining responsiveness to hypercapnia or hypoglycemia. These data suggest that reactive oxygen species and NADH generated in mitochondrial complex I during hypoxia are signaling molecules that modulate membrane K+ channels. We propose that the structural substrates for acute O2 sensing in CB glomus cells are “O2-sensing microdomains” formed by mitochondria and neighboring K+ channels in the plasma membrane. Keywords: Hypoxia, Acute oxygen sensing, Peripheral chemoreceptors, Carotid body, Adrenal medulla, Mitochondrial complex I, Reactive oxygen species (ROS, Pyridine nucleotides

Changes in the nitric oxide system in the shore crab Hemigrapsus sanguineus (Crustacea, Decapoda) CNS induced by a nociceptive stimulus.

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Dyuizen, Inessa V; Kotsyuba, Elena P; Lamash, Nina E

2012-08-01

Using NADPH-diaphorase (NADPH-d) histochemistry, inducible nitric oxide synthase (iNOS)-immunohistochemistry and immunoblotting, we characterized the nitric oxide (NO)-producing neurons in the brain and thoracic ganglion of a shore crab subjected to a nociceptive chemical stimulus. Formalin injection into the cheliped evoked specific nociceptive behavior and neurochemical responses in the brain and thoracic ganglion of experimental animals. Within 5-10 min of injury, the NADPH-d activity increased mainly in the neuropils of the olfactory lobes and the lateral antenna I neuropil on the side of injury. Later, the noxious-induced expression of NADPH-d and iNOS was detected in neurons of the brain, as well as in segmental motoneurons and interneurons of the thoracic ganglion. Western blotting analysis showed that an iNOS antiserum recognized a band at 120 kDa, in agreement with the expected molecular mass of the protein. The increase in nitrergic activity induced by nociceptive stimulation suggests that the NO signaling system may modulate nociceptive behavior in crabs.

Pharmacological effects of a synthetic quinoline, a hybrid of tomoxiprole and naproxen, against acute pain and inflammation in mice: a behavioral and docking study

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Hossein Hosseinzadeh

2017-04-01

Full Text Available Objective(s: In the present study, we investigated the potential anti-nociceptive activity and acute anti-inflammatory effect of a synthetic quinoline compound (2-(4-Methoxyphenylbenzo[h]quinoline-4-carboxylic acid, QC, possessing structural elements of both naproxen and tomoxiprole drugs. Materials and Methods: The anti-nociceptive activity of QC was evaluated using chemical- and thermal-induced nociception models and its acute anti-inflammatory effect was evaluated by xylene-induced ear edema test in mice. Results: QC displayed a dose dependent effect in both acute anti-nociceptive tests (writhing and hot plate. This compound at dose of 6.562 mg/kg showed a high anti-nociceptive effect near equal to  diclofenac 5 mg/kg. It also showed high anti-inflammatory effects (less than 6.562 mg/kg comparable to those of reference drugs diclofenac (5 mg/kg and celecoxib (100 mg/kg. Docking study showed that this quinoline derivative could inhibit COX-2 enzyme strongly. Conclusion: QC showed high anti-nociceptive and anti-inflammatory effects comparable to reference drugs and can exert its anti-nociceptive and anti-inflammatory activities through COX-2 inhibition.

Nociceptive Response to L-DOPA-Induced Dyskinesia in Hemiparkinsonian Rats.

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Nascimento, G C; Bariotto-Dos-Santos, K; Leite-Panissi, C R A; Del-Bel, E A; Bortolanza, M

2018-04-02

Non-motor symptoms are increasingly identified to present clinical and diagnostic importance for Parkinson's disease (PD). The multifactorial origin of pain in PD makes this symptom of great complexity. The dopamine precursor, L-DOPA (L-3,4-dihydroxyphenylalanine), the classic therapy for PD, seems to be effective in pain threshold; however, there are no studies correlating L-DOPA-induced dyskinesia (LID) and nociception development in experimental Parkinsonism. Here, we first investigated nociceptive responses in a 6-hydroxydopamine (6-OHDA)-lesioned rat model of Parkinson's disease to a hind paw-induced persistent inflammation. Further, the effect of L-DOPA on nociception behavior at different times of treatment was investigated. Pain threshold was determined using von Frey and Hot Plate/Tail Flick tests. Dyskinesia was measured by abnormal involuntary movements (AIMs) induced by L-DOPA administration. This data is consistent to show that 6-OHDA-lesioned rats had reduced nociceptive thresholds compared to non-lesioned rats. Additionally, when these rats were exposed to a persistent inflammatory challenge, we observed increased hypernociceptive responses, namely hyperalgesia. L-DOPA treatment alleviated pain responses on days 1 and 7 of treatment, but not on day 15. During that period, we observed an inverse relationship between LID and nociception threshold in these rats, with a high LID rate corresponding to a reduced nociception threshold. Interestingly, pain responses resulting from CFA-induced inflammation were significantly enhanced during established dyskinesia. These data suggest a pro-algesic effect of L-DOPA-induced dyskinesia, which is confirmed by the correlation founded here between AIMs and nociceptive indexes. In conclusion, our results are consistent with the notion that central dopaminergic mechanism is directly involved in nociceptive responses in Parkinsonism condition.

Steady-state evoked potentials to study the processing of tactile and nociceptive somatosensory input in the human brain.

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Colon, E; Legrain, V; Mouraux, A

2012-10-01

The periodic presentation of a sensory stimulus induces, at certain frequencies of stimulation, a sustained electroencephalographic response of corresponding frequency, known as steady-state evoked potentials (SS-EP). In visual, auditory and vibrotactile modalities, studies have shown that SS-EP reflect mainly activity originating from early, modality-specific sensory cortices. Furthermore, it has been shown that SS-EP have several advantages over the recording of transient event-related brain potentials (ERP), such as a high signal-to-noise ratio, a shorter time to obtain reliable signals, and the capacity to frequency-tag the cortical activity elicited by concurrently presented sensory stimuli. Recently, we showed that SS-EP can be elicited by the selective activation of skin nociceptors and that nociceptive SS-EP reflect the activity of a population of neurons that is spatially distinct from the somatotopically-organized population of neurons underlying vibrotactile SS-EP. Hence, the recording of SS-EP offers a unique opportunity to study the cortical representation of nociception and touch in humans, and to explore their potential crossmodal interactions. Here, (1) we review available methods to achieve the rapid periodic stimulation of somatosensory afferents required to elicit SS-EP, (2) review previous studies that have characterized vibrotactile and nociceptive SS-EP, (3) discuss the nature of the recorded signals and their relationship with transient event-related potentials and (4) outline future perspectives and potential clinical applications of this technique. Copyright © 2012 Elsevier Masson SAS. All rights reserved.

Comparative biology of pain: What invertebrates can tell us about how nociception works.

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Burrell, Brian D

2017-04-01

The inability to adequately treat chronic pain is a worldwide health care crisis. Pain has both an emotional and a sensory component, and this latter component, nociception, refers specifically to the detection of damaging or potentially damaging stimuli. Nociception represents a critical interaction between an animal and its environment and exhibits considerable evolutionary conservation across species. Using comparative approaches to understand the basic biology of nociception could promote the development of novel therapeutic strategies to treat pain, and studies of nociception in invertebrates can provide especially useful insights toward this goal. Both vertebrates and invertebrates exhibit segregated sensory pathways for nociceptive and nonnociceptive information, injury-induced sensitization to nociceptive and nonnociceptive stimuli, and even similar antinociceptive modulatory processes. In a number of invertebrate species, the central nervous system is understood in considerable detail, and it is often possible to record from and/or manipulate single identifiable neurons through either molecular genetic or physiological approaches. Invertebrates also provide an opportunity to study nociception in an ethologically relevant context that can provide novel insights into the nature of how injury-inducing stimuli produce persistent changes in behavior. Despite these advantages, invertebrates have been underutilized in nociception research. In this review, findings from invertebrate nociception studies are summarized, and proposals for how research using invertebrates can address questions about the fundamental mechanisms of nociception are presented. Copyright © 2017 the American Physiological Society.

Preferential distribution of nociceptive input to motoneurons with muscle units in the cranial portion of the upper trapezius muscle.

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Dideriksen, Jakob L; Holobar, Ales; Falla, Deborah

2016-08-01

Pain is associated with changes in the neural drive to muscles. For the upper trapezius muscle, surface electromyography (EMG) recordings have indicated that acute noxious stimulation in either the cranial or the caudal region of the muscle leads to a relative decrease in muscle activity in the cranial region. It is, however, not known if this adaption reflects different recruitment thresholds of the upper trapezius motor units in the cranial and caudal region or a nonuniform nociceptive input to the motor units of both regions. This study investigated these potential mechanisms by direct motor unit identification. Motor unit activity was investigated with high-density surface EMG signals recorded from the upper trapezius muscle of 12 healthy volunteers during baseline, control (intramuscular injection of isotonic saline), and painful (hypertonic saline) conditions. The EMG was decomposed into individual motor unit spike trains. Motor unit discharge rates decreased significantly from control to pain conditions by 4.0 ± 3.6 pulses/s (pps) in the cranial region but not in the caudal region (1.4 ± 2.8 pps; not significant). These changes were compatible with variations in the synaptic input to the motoneurons of the two regions. These adjustments were observed, irrespective of the location of noxious stimulation. These results strongly indicate that the nociceptive synaptic input is distributed in a nonuniform way across regions of the upper trapezius muscle. Copyright © 2016 the American Physiological Society.

Somatic modulation of spinal reflex bladder activity mediated by nociceptive bladder afferent nerve fibers in cats.

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Xiao, Zhiying; Rogers, Marc J; Shen, Bing; Wang, Jicheng; Schwen, Zeyad; Roppolo, James R; de Groat, William C; Tai, Changfeng

2014-09-15

The goal of the present study was to determine if supraspinal pathways are necessary for inhibition of bladder reflex activity induced by activation of somatic afferents in the pudendal or tibial nerve. Cats anesthetized with α-chloralose were studied after acute spinal cord transection at the thoracic T9/T10 level. Dilute (0.25%) acetic acid was used to irritate the bladder, activate nociceptive afferent C-fibers, and trigger spinal reflex bladder contractions (amplitude: 19.3 ± 2.9 cmH2O). Hexamethonium (a ganglionic blocker, intravenously) significantly (P reflex bladder contractions to 8.5 ± 1.9 cmH2O. Injection of lidocaine (2%, 1-2 ml) into the sacral spinal cord or transection of the sacral spinal roots and spinal cord further reduced the contraction amplitude to 4.2 ± 1.3 cmH2O. Pudendal nerve stimulation (PNS) at frequencies of 0.5-5 Hz and 40 Hz but not at 10-20 Hz inhibited reflex bladder contractions, whereas tibial nerve stimulation (TNS) failed to inhibit bladder contractions at all tested frequencies (0.5-40 Hz). These results indicate that PNS inhibition of nociceptive afferent C-fiber-mediated spinal reflex bladder contractions can occur at the spinal level in the absence of supraspinal pathways, but TNS inhibition requires supraspinal pathways. In addition, this study shows, for the first time, that after acute spinal cord transection reflex bladder contractions can be triggered by activating nociceptive bladder afferent C-fibers using acetic acid irritation. Understanding the sites of action for PNS or TNS inhibition is important for the clinical application of pudendal or tibial neuromodulation to treat bladder dysfunctions. Copyright © 2014 the American Physiological Society.

Notch signaling inhibitor DAPT provides protection against acute craniocerebral injury.

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Hong-Mei Zhang

Full Text Available Notch signaling pathway is involved in many physiological and pathological processes. The γ-secretase inhibitor DAPT inhibits Notch signaling pathway and promotes nerve regeneration after cerebral ischemia. However, neuroprotective effects of DAPT against acute craniocerebral injury remain unclear. In this study, we established rat model of acute craniocerebral injury, and found that with the increase of damage grade, the expression of Notch and downstream protein Hes1 and Hes5 expression gradually increased. After the administration of DAPT, the expression of Notch, Hes1 and Hes5 was inhibited, apoptosis and oxidative stress decreased, neurological function and cognitive function improved. These results suggest that Notch signaling can be used as an indicator to assess the severity of post-traumatic brain injury. Notch inhibitor DAPT can reduce oxidative stress and apoptosis after acute craniocerebral injury, and is a potential drug for the treatment of acute craniocerebral injury.

p-Cymene reduces orofacial nociceptive response in mice

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Michele F. Santana

2011-12-01

Full Text Available This study investigated the possible antinociceptive effect of p-cymene in different tests of orofacial nociception. The animals (mice were pretreated (i.p. with p-cymene (25, 50, 100 mg/kg, morphine (5 mg/kg, or vehicle (0.2% Tween 80+saline, and were then subsequently administered, subcutaneously into their upper lip: formalin, capsaicin, and glutamate. The nociceptive behavior response was characterized by the time in s that the mice remained rubbing the orofacial region, for a period of 40 min in the formalin test (first phase, 0-6 min; and second phase, 21-40 min, and for 42 and 15 min in the capsaicin and glutamate tests, respectively. To verify the possible opioid involvement in the antinociceptive effects, naloxone (i.p. was administered into the mice 15 min prior to the pretreatment with p-cymene (100 mg/kg. Finally, whether or not the p-cymene evoked any change in motor performance in the Rota-rod test was evaluated. The results showed that the treatment with p-cymene, at all doses, reduced (p<0.001 the nociceptive behavior in all nociception tests. The antinociceptive effect of p-cymene was antagonized by naloxone (1.5 mg/kg. Additionally, mice treated with p-cymene did not show any change in motor performance. In conclusion, p-cymene attenuated orofacial nociception, suggesting an involvement of the opioid system in this effect. Thus, p-cymene might represent an important biomolecule for management and/or treatment of orofacial pain.

Acute restraint stress induces hyperalgesia via non-adrenergic ...

African Journals Online (AJOL)

Analgesia or hyperalgesia has been reported to occur in animals under different stress conditions. This study examined the effect of acute restraint stress on nociception in rats. Acute restraint stress produced a time-dependant decrease in pain threshold; this hyperalgesia was not affected by prior administration of ...

Prediction of immediate postoperative pain using the analgesia/nociception index: a prospective observational study.

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Boselli, E; Bouvet, L; Bégou, G; Dabouz, R; Davidson, J; Deloste, J-Y; Rahali, N; Zadam, A; Allaouchiche, B

2014-04-01

The analgesia/nociception index (ANI) is derived from heart rate variability, ranging from 0 (maximal nociception) to 100 (maximal analgesia), to reflect the analgesia/nociception balance during general anaesthesia. This should be correlated with immediate postoperative pain in the post-anaesthesia care unit (PACU). The aim of this study was to evaluate the performance of ANI measured at arousal from general anaesthesia to predict immediate postoperative pain on arrival in PACU. Two hundred patients undergoing ear, nose, and throat or lower limb orthopaedic surgery with general anaesthesia using an inhalational agent and remifentanil were included in this prospective observational study. The ANI was measured immediately before tracheal extubation and pain intensity was assessed within 10 min of arrival in PACU using a 0-10 numerical rating scale (NRS). The relationship between ANI and NRS was assessed using linear regression. A receiver-operating characteristic (ROC) curve was used to evaluate the performance of ANI to predict NRS>3. A negative linear relationship was observed between ANI immediately before extubation and NRS on arrival in PACU. Using a threshold of 3 were both 86% with 92% negative predictive value, corresponding to an area under the ROC curve of 0.89. The measurement of ANI immediately before extubation after inhalation-remifentanil anaesthesia was significantly associated with pain intensity on arrival in PACU. The performance of ANI for the prediction of immediate postoperative pain is good and may assist physicians in optimizing acute pain management. ClinicalTrials.gov NCT01796249.

Specific involvement of atypical PKCζ/PKMζ in spinal persistent nociceptive processing following peripheral inflammation in rat

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Marchand Fabien

2011-11-01

Full Text Available Abstract Background Central sensitization requires the activation of various intracellular signalling pathways within spinal dorsal horn neurons, leading to a lowering of activation threshold and enhanced responsiveness of these cells. Such plasticity contributes to the manifestation of chronic pain states and displays a number of features of long-term potentiation (LTP, a ubiquitous neuronal mechanism of increased synaptic strength. Here we describe the role of a novel pathway involving atypical PKCζ/PKMζ in persistent spinal nociceptive processing, previously implicated in the maintenance of late-phase LTP. Results Using both behavioral tests and in vivo electrophysiology in rats, we show that inhibition of this pathway, via spinal delivery of a myristoylated protein kinase C-ζ pseudo-substrate inhibitor, reduces both pain-related behaviors and the activity of deep dorsal horn wide dynamic range neurons (WDRs following formalin administration. In addition, Complete Freund's Adjuvant (CFA-induced mechanical and thermal hypersensitivity was also reduced by inhibition of PKCζ/PKMζ activity. Importantly, this inhibition did not affect acute pain or locomotor behavior in normal rats and interestingly, did not inhibited mechanical allodynia and hyperalgesia in neuropathic rats. Pain-related behaviors in both inflammatory models coincided with increased phosphorylation of PKCζ/PKMζ in dorsal horn neurons, specifically PKMζ phosphorylation in formalin rats. Finally, inhibition of PKCζ/PKMζ activity decreased the expression of Fos in response to formalin and CFA in both superficial and deep laminae of the dorsal horn. Conclusions These results suggest that PKCζ, especially PKMζ isoform, is a significant factor involved in spinal persistent nociceptive processing, specifically, the manifestation of chronic pain states following peripheral inflammation.

Effect of a nitric oxide donor (glyceryl trinitrate) on nociceptive thresholds in man

DEFF Research Database (Denmark)

Thomsen, L L; Brennum, J; Iversen, Helle Klingenberg

1996-01-01

Several animal studies suggest that nitric oxide (NO) plays a role in central and peripheral modulation of nociception. Glyceryl trinitrate (GTN) exerts its physiological actions via donation of NO. The purpose of the present study was to examine the effect of this NO donor on nociceptive...... central facilitation of nociception by NO. However, we regard convergence of nociceptive input from pericranial myofascial tissue and from cephalic blood vessels dilated by NO as a more likely explanation of our findings....

Nociceptive flexion reflexes during analgesic neurostimulation in man.

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García-Larrea, L; Sindou, M; Mauguière, F

1989-11-01

Nociceptive flexion reflexes of the lower limbs (RIII responses) have been studied in 21 patients undergoing either epidural (DCS, n = 16) or transcutaneous (TENS, n = 5) analgesic neurostimulation (AN) for chronic intractable pain. Flexion reflex RIII was depressed or suppressed by AN in 11 patients (52.4%), while no modification was observed in 9 cases and a paradoxical increase during AN was evidenced in 1 case. In all but 2 patients, RIII changes were rapidly reversible after AN interruption. RIII depression was significantly associated with subjective pain relief, as assessed by conventional self-rating; moreover, in 2 patients it was possible to ameliorate the pain-suppressing effects of AN by selecting those stimulation parameters (intensity and frequency) that maximally depressed nociceptive reflex RIII. We recorded 2 cases of RIII attenuation after contralateral neurostimulation. AN appeared to affect nociceptive reflexes rather selectively, with no or very little effect on other cutaneous, non-nociceptive responses. Recording of RIII reflexes is relatively simple to implement as a routine paraclinical procedure. It facilitates the objective assessment of AN efficacy and may help to choose the most appropriate parameters of neurostimulation. In addition, RIII behavior in patients could be relevant to the understanding of some of the mechanisms involved in AN-induced pain relief.

BOLD fMRI of C-Fiber Mediated Nociceptive Processing in Mouse Brain in Response to Thermal Stimulation of the Forepaws.

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Simone C Bosshard

Full Text Available Functional magnetic resonance imaging (fMRI in rodents enables non-invasive studies of brain function in response to peripheral input or at rest. In this study we describe a thermal stimulation paradigm using infrared laser diodes to apply noxious heat to the forepaw of mice in order to study nociceptive processing. Stimulation at 45 and 46°C led to robust BOLD signal changes in various brain structures including the somatosensory cortices and the thalamus. The BOLD signal amplitude scaled with the temperature applied but not with the area irradiated by the laser beam. To demonstrate the specificity of the paradigm for assessing nociceptive signaling we administered the quaternary lidocaine derivative QX-314 to the forepaws, which due to its positive charge cannot readily cross biological membranes. However, upon activation of TRPV1 channels following the administration of capsaicin the BOLD signal was largely abolished, indicative of a selective block of the C-fiber nociceptors due to QX-314 having entered the cells via the now open TRPV1 channels. This demonstrates that the cerebral BOLD response to thermal noxious paw stimulation is specifically mediated by C-fibers.

Oral treatment with methanolic extract of the root bark of Condalia buxifolia Reissek alleviates acute pain and inflammation in mice: Potential interactions with PGE2, TRPV1/ASIC and PKA signaling pathways.

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Simões, Róli Rodrigues; Dos Santos Coelho, Igor; do Espírito Santo, Caroline Cunha; Morel, Ademir Farias; Zanchet, Eliane Maria; Santos, Adair Roberto Soares

2016-06-05

The Condalia buxifolia root bark infusion is used in traditional medicine in Brazil as antipyretic, anti-inflammatory and anti-dysentery. Previous data from our group showed that methanolic extract of Condalia buxifolia (MECb) produced a marked antinociceptive effect in animal models of acute pain. The purpose of this study was to investigate the mechanisms of MECb-induced antinociception as measured by nocifensive behavior in pain induced by endogenous (prostaglandin E2) or exogenous (TRPs and ASIC agonist, and protein kinase A and C activators) chemical stimuli, and the potential role of PKA signaling and capsaicin-sensitive central C-fiber afferents. The effect of MECb administered orally (0.1-300mg/kg, i.g.) to mice on nociception induced by capsaicin (TRPV1 agonist), cinnamaldehyde (TRPA1 agonist), menthol (TRPM8 agonist), acidified saline (ASIC agonist), PMA (protein kinase C activator), PGE2 and forskolin (protein kinase A activator) was assessed. Moreover, this study also investigated the role of C-fibers desensitizing mice with a high dose of intrathecal capsaicin. Furthermore, this study performed the western blot to PKA phosphorylated on nocifensive behavior induced by forskolin. MECb was able to reduce the nociception and paw edema induced by capsaicin, acidified saline, PMA, PGE2 and forskolin, but not by cinnamaldehyde or menthol. Western blot analyses showed that MECb reduced the levels of PKA phosphorylation induced by forskolin in hind paws. Finally, ablating central afferent C-fibers abolished MECb antinociception. In accordance with its use in traditional medicine, these findings provide new evidence indicating that Condalia buxifolia reduces the acute painful behavior of animals caused by chemical stimuli. The precise mechanism of MECb antinociceptive activity is not completely understood but the results suggest involvement of PGE2, TRPV1/ASIC and PKA signaling pathways, and require integrity of the capsaicin-sensitive central C-fiber afferents

Distinct brain mechanisms support spatial vs temporal filtering of nociceptive information.

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Nahman-Averbuch, Hadas; Martucci, Katherine T; Granovsky, Yelena; Weissman-Fogel, Irit; Yarnitsky, David; Coghill, Robert C

2014-12-01

The role of endogenous analgesic mechanisms has largely been viewed in the context of gain modulation during nociceptive processing. However, these analgesic mechanisms may play critical roles in the extraction and subsequent utilization of information related to spatial and temporal features of nociceptive input. To date, it remains unknown if spatial and temporal filtering of nociceptive information is supported by similar analgesic mechanisms. To address this question, human volunteers were recruited to assess brain activation with functional magnetic resonance imaging during conditioned pain modulation (CPM) and offset analgesia (OA). CPM provides one paradigm for assessing spatial filtering of nociceptive information while OA provides a paradigm for assessing temporal filtering of nociceptive information. CPM and OA both produced statistically significant reductions in pain intensity. However, the magnitude of pain reduction elicited by CPM was not correlated with that elicited by OA across different individuals. Different patterns of brain activation were consistent with the psychophysical findings. CPM elicited widespread reductions in regions engaged in nociceptive processing such as the thalamus, insula, and secondary somatosensory cortex. OA produced reduced activity in the primary somatosensory cortex but was associated with greater activation in the anterior insula, dorsolateral prefrontal cortex, intraparietal sulcus, and inferior parietal lobule relative to CPM. In the brain stem, CPM consistently produced reductions in activity, while OA produced increases in activity. Conjunction analysis confirmed that CPM-related activity did not overlap with that of OA. Thus, dissociable mechanisms support inhibitory processes engaged during spatial vs temporal filtering of nociceptive information. Copyright © 2014 International Association for the Study of Pain. Published by Elsevier B.V. All rights reserved.

Amygdala-prefrontal pathways and the dopamine system affect nociceptive responses in the prefrontal cortex

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Onozawa Kitaro

2011-11-01

Full Text Available Abstract Background We previously demonstrated nociceptive discharges to be evoked by mechanical noxious stimulation in the prefrontal cortex (PFC. The nociceptive responses recorded in the PFC are conceivably involved in the affective rather than the sensory-discriminative dimension of pain. The PFC receives dense projection from the limbic system. Monosynaptic projections from the basolateral nucleus of the amygdala (BLA to the PFC are known to produce long-lasting synaptic plasticity. We examined effects of high frequency stimulation (HFS delivered to the BLA on nociceptive responses in the rat PFC. Results HFS induced long lasting suppression (LLS of the specific high threshold responses of nociceptive neurons in the PFC. Microinjection of N-methyl-D-aspartic acid (NMDA receptor antagonists (2-amino-5-phosphonovaleric acid (APV, dizocilpine (MK-801 and also metabotropic glutamate receptor (mGluR group antagonists (α-methyl-4-carboxyphenylglycine (MCPG, and 2-[(1S,2S-2-carboxycyclopropyl]-3-(9H-xanthen-9-yl-D-alanine (LY341495, prevented the induction of LLS of nociceptive responses. We also examined modulatory effects of dopamine (DA on the LLS of nociceptive responses. With depletion of DA in response to 6-hydroxydopamine (6-OHDA injection into the ipsilateral forebrain bundle, LLS of nociceptive responses was decreased, while nociceptive responses were normally evoked. Antagonists of DA receptor subtypes D2 (sulpiride and D4 (3-{[4-(4-chlorophenyl piperazin-1-yl] methyl}-1H-pyrrolo [2, 3-b] pyridine (L-745,870, microinjected into the PFC, inhibited LLS of nociceptive responses. Conclusions Our results indicate that BLA-PFC pathways inhibited PFC nociceptive cell activities and that the DA system modifies the BLA-PFC regulatory function.

Citral reduces nociceptive and inflammatory response in rodents

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Lucindo J. Quintans-Júnior

2011-04-01

Full Text Available Citral (CIT, which contains the chiral enantiomers, neral (cis and geranial (trans, is the majority monoterpene from Lippia alba and Cymbopogon citratus. The present study aimed to evaluate CIT for antinociceptive and anti-inflammatory activities in rodents. Antinociceptive and anti-inflammatory effects were studied by measuring nociception through acetic acid and formalin tests, while inflammation was verified by inducing peritonitis and paw edema with carrageenan. All tested doses of CIT had significant protection (p<0.001 against acetic acid (0.8% induced nociceptive behavior and the effects were also similar to morphine while formalin induced nociception was significantly protected (p<0.05 only at higher dose (200 mg/kg of CIT in the first phase of the test. CIT significantly reduce (p<0.001 nociceptive behavior emanating from inflammation in second phase at all the doses.The pretreatment with CIT (100 and 200 mg/kg significantly reduced the paw edema induced by carrageenan. Moreover, systemic treatment with CIT (100 and 200 mg/kg significantly reduced (p<0.001 the leukocyte migration in the carrageenan-induced migration to the peritoneal cavity. Our investigation shows that CIT possess significant central and peripheral antinociceptive effects. It was also verified an anti-inflammatory activity. All together these results suggest that CIT might represent important tool for treatment of painful conditions.

Citral reduces nociceptive and inflammatory response in rodents

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Lucindo J. Quintans-Júnior

2011-06-01

Full Text Available Citral (CIT, which contains the chiral enantiomers, neral (cis and geranial (trans, is the majority monoterpene from Lippia alba and Cymbopogon citratus. The present study aimed to evaluate CIT for antinociceptive and anti-inflammatory activities in rodents. Antinociceptive and anti-inflammatory effects were studied by measuring nociception through acetic acid and formalin tests, while inflammation was verified by inducing peritonitis and paw edema with carrageenan. All tested doses of CIT had significant protection (p<0.001 against acetic acid (0.8% induced nociceptive behavior and the effects were also similar to morphine while formalin induced nociception was significantly protected (p<0.05 only at higher dose (200 mg/kg of CIT in the first phase of the test. CIT significantly reduce (p<0.001 nociceptive behavior emanating from inflammation in second phase at all the doses.The pretreatment with CIT (100 and 200 mg/kg significantly reduced the paw edema induced by carrageenan. Moreover, systemic treatment with CIT (100 and 200 mg/kg significantly reduced (p<0.001 the leukocyte migration in the carrageenan-induced migration to the peritoneal cavity. Our investigation shows that CIT possess significant central and peripheral antinociceptive effects. It was also verified an anti-inflammatory activity. All together these results suggest that CIT might represent important tool for treatment of painful conditions.

Assessment of anti-nociceptive efficacy of costus speciosus rhizome in swiss albino mice.

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Bhattacharya, Sanjib; Nagaich, Upendra

2010-01-01

Present study attempts to evaluate the anti-nociceptive activity of the aqueous and ethanol extracts of Costus speciosus rhizome (CPA and CPE) in Swiss albino mice. The maceration extracts were evaluated for anti-nociceptive activity by acetic acid-induced writhing and tail flick method in mice. The anti-nociceptive screening revealed significant peripheral anti-nociceptive actions of both extracts against acetic acid induced writhing in mice. Aqueous extract (CPA) significantly inhibited writhes at the dose of 75 and 150 mg/kg body weight, while ethanol extract (CPE) produced significant protection at the dose of 150 mg/kg body weight. However, in tail flick method only the ethanol extract (CPE) showed significant central analgesic action, while aqueous extract was totally ineffective. The present investigation demonstrates that the rhizome extracts of C. speciosus exhibited significant anti-nociceptive effects in Swiss albino mice.

Assessment of anti-nociceptive efficacy of Costus Speciosus rhizome in swiss albino mice

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Sanjib Bhattacharya

2010-01-01

Full Text Available Present study attempts to evaluate the anti-nociceptive activity of the aqueous and ethanol extracts of Costus speciosus rhizome (CPA and CPE in Swiss albino mice. The maceration extracts were evaluated for anti-nociceptive activity by acetic acid-induced writhing and tail flick method in mice. The anti-nociceptive screening revealed significant peripheral anti-nociceptive actions of both extracts against acetic acid induced writhing in mice. Aqueous extract (CPA significantly inhibited writhes at the dose of 75 and 150 mg/kg body weight, while ethanol extract (CPE produced significant protection at the dose of 150 mg/kg body weight. However, in tail flick method only the ethanol extract (CPE showed significant central analgesic action, while aqueous extract was totally ineffective. The present investigation demonstrates that the rhizome extracts of C. speciosus exhibited significant anti-nociceptive effects in Swiss albino mice.

Intraplantar injection of tetrahydrobiopterin induces nociception in mice

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Nasser, Arafat; Ali, Sawsan; Wilsbech, Signe

2015-01-01

was tested. Morphine served as a positive control. Intraplantar pre-injection of morphine dose-dependently inhibited BH4-induced nociception, while none of the other compounds showed any statistical significant antinociception. These results suggest that BH4 exhibits nociceptive properties at peripheral......Tetrahydrobiopterin (BH4) is implicated in the development and maintenance of chronic pain. After injury/inflammation, the biosynthesis of BH4 is markedly increased in sensory neurons, and the pharmacological and genetic inhibition of BH4 shows analgesic effects in pre-clinical animal pain models...

Nociception at the diabetic foot, an uncharted territory

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Chantelau, Ernst A

2015-01-01

The diabetic foot is characterised by painless foot ulceration and/or arthropathy; it is a typical complication of painless diabetic neuropathy. Neuropathy depletes the foot skin of intraepidermal nerve fibre endings of the afferent A-delta and C-fibres, which are mostly nociceptors and excitable by noxious stimuli only. However, some of them are cold or warm receptors whose functions in diabetic neuropathy have frequently been reported. Hence, it is well established by quantitative sensory testing that thermal detection thresholds at the foot skin increase during the course of painless diabetic neuropathy. Pain perception (nociception), by contrast, has rarely been studied. Recent pilot studies of pinprick pain at plantar digital skinfolds showed that the perception threshold was always above the upper limit of measurement of 512 mN (equivalent to 51.2 g) at the diabetic foot. However, deep pressure pain perception threshold at musculus abductor hallucis was beyond 1400 kPa (equivalent to 14 kg; limit of measurement) only in every fifth case. These discrepancies of pain perception between forefoot and hindfoot, and between skin and muscle, demand further study. Measuring nociception at the feet in diabetes opens promising clinical perspectives. A critical nociception threshold may be quantified (probably corresponding to a critical number of intraepidermal nerve fibre endings), beyond which the individual risk of a diabetic foot rises appreciably. Staging of diabetic neuropathy according to nociception thresholds at the feet is highly desirable as guidance to an individualised injury prevention strategy. PMID:25897350

Kv4 channels underlie the subthreshold-operating A-type K+-current in nociceptive dorsal root ganglion neurons

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Thanawath R Na Phuket

2009-07-01

Full Text Available The dorsal root ganglion (DRG contains heterogeneous populations of sensory neurons including primary nociceptive neurons and C-fibers implicated in pain signaling.  Recent studies have demonstrated DRG hyperexcitability associated with downregulation of A-type K+ channels; however, the molecular correlate of the corresponding A-type K+ current (IA has remained hypothetical.  Kv4 channels may underlie the IA in DRG neurons.  We combined electrophysiology, molecular biology (whole-tissue and single-cell RT-PCR and immunohistochemistry to investigate the molecular basis of the IA in acutely dissociated DRG neurons from 7-8 day-old rats.  Whole-cell recordings demonstrate a robust tetraethylammonium-resistant (20 mM and 4-aminopyridine-sensitive (5 mM IA.  Matching Kv4 channel properties, activation and inactivation of this IA occur in the subthreshold range of membrane potentials and the rate of recovery from inactivation is rapid and voltage-dependent.  Among Kv4 transcripts, the DRG expresses significant levels of Kv4.1 and Kv4.3 mRNAs.  Also, single small-medium diameter DRG neurons (~30 mm exhibit correlated frequent expression of mRNAs encoding Kv4.1 and Nav1.8, a known nociceptor marker.  In contrast, the expressions of Kv1.4 and Kv4.2 mRNAs at the whole-tissue and single-cell levels are relatively low and infrequent.  Kv4 protein expression in nociceptive DRG neurons was confirmed by immunohistochemistry, which demonstrates colocalization of Kv4.3 and Nav1.8, and negligible expression of Kv4.2.  Furthermore, specific dominant-negative suppression and overexpression strategies confirmed the contribution of Kv4 channels to IA in DRG neurons.  Contrasting the expression patterns of Kv4 channels in the central and peripheral nervous systems, we discuss possible functional roles of these channels in primary sensory neurons.

Cholinergic Nociceptive Mechanisms in Rat Meninges and Trigeminal Ganglia: Potential Implications for Migraine Pain.

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Shelukhina, Irina; Mikhailov, Nikita; Abushik, Polina; Nurullin, Leniz; Nikolsky, Evgeny E; Giniatullin, Rashid

2017-01-01

Parasympathetic innervation of meninges and ability of carbachol, acetylcholine (ACh) receptor (AChR) agonist, to induce headaches suggests contribution of cholinergic mechanisms to primary headaches. However, neurochemical mechanisms of cholinergic regulation of peripheral nociception in meninges, origin place for headache, are almost unknown. Using electrophysiology, calcium imaging, immunohistochemistry, and staining of meningeal mast cells, we studied effects of cholinergic agents on peripheral nociception in rat hemiskulls and isolated trigeminal neurons. Both ACh and carbachol significantly increased nociceptive firing in peripheral terminals of meningeal trigeminal nerves recorded by local suction electrode. Strong nociceptive firing was also induced by nicotine, implying essential role of nicotinic AChRs in control of excitability of trigeminal nerve endings. Nociceptive firing induced by carbachol was reduced by muscarinic antagonist atropine, whereas the action of nicotine was prevented by the nicotinic blocker d-tubocurarine but was insensitive to the TRPA1 antagonist HC-300033. Carbachol but not nicotine induced massive degranulation of meningeal mast cells known to release multiple pro-nociceptive mediators. Enzymes terminating ACh action, acetylcholinesterase (AChE) and butyrylcholinesterase, were revealed in perivascular meningeal nerves. The inhibitor of AChE neostigmine did not change the firing per se but induced nociceptive activity, sensitive to d-tubocurarine, after pretreatment of meninges with the migraine mediator CGRP. This observation suggested the pro-nociceptive action of endogenous ACh in meninges. Both nicotine and carbachol induced intracellular Ca 2+ transients in trigeminal neurons partially overlapping with expression of capsaicin-sensitive TRPV1 receptors. Trigeminal nerve terminals in meninges, as well as dural mast cells and trigeminal ganglion neurons express a repertoire of pro-nociceptive nicotinic and muscarinic AChRs, which

Sida cordifolia leaf extract reduces the orofacial nociceptive response in mice.

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Bonjardim, L R; Silva, A M; Oliveira, M G B; Guimarães, A G; Antoniolli, A R; Santana, M F; Serafini, M R; Santos, R C; Araújo, A A S; Estevam, C S; Santos, M R V; Lyra, A; Carvalho, R; Quintans-Júnior, L J; Azevedo, E G; Botelho, M A

2011-08-01

In this study, we describe the antinociceptive activity of the ethanol extract (EE), chloroform (CF) and methanol (MF) fractions obtained from Sida cordifolia, popularly known in Brazil as "malva branca" or "malva branca sedosa". Leaves of S. cordifolia were used to produce the crude ethanol extract and after CF and MF. Experiments were conducted on Swiss mice using the glutamate and formalin-induced orofacial nociception. In the formalin test, all doses of EE, CF and MF significantly reduced the orofacial nociception in the first (p < 0.001) and second phase (p < 0.001), which was also naloxone-sensitive. In the glutamate-induced nociception test, only CF and MF significantly reduced the orofacial nociceptive behavior with inhibition percentage values of 48.1% (100 mg/kg, CF), 56.1% (200 mg/kg, CF), 66.4% (400 mg/kg, CF), 48.2 (200 mg/kg, MF) and 60.1 (400 mg/kg, MF). Furthermore, treatment of the animals with EE, CF and MF was not able to promote motor activity changes. These data demonstrate that S. cordifolia has a pronounced antinociceptive activity on orofacial nociception. However, pharmacological and chemical studies are necessary in order to characterize the responsible mechanisms for this antinociceptive action and also to identify other bioactive compounds present in S. cordifolia. Copyright © 2011 John Wiley & Sons, Ltd.

Nociceptive sensations evoked from 'spots' in the skin by mild cooling and heating.

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Green, Barry G; Roman, Carolyn; Schoen, Kate; Collins, Hannah

2008-03-01

It was recently found that nociceptive sensations (stinging, pricking, or burning) can be evoked by cooling or heating the skin to innocuous temperatures (e.g., 29 and 37 degrees C). Here, we show that this low-threshold thermal nociception (LTN) can be traced to sensitive 'spots' in the skin equivalent to classically defined warm spots and cold spots. Because earlier work had shown that LTN is inhibited by simply touching a thermode to the skin, a spatial search procedure was devised that minimized tactile stimulation by sliding small thermodes (16 and 1mm(2)) set to 28 or 36 degrees C slowly across the lubricated skin of the forearm. The procedure uncovered three types of temperature-sensitive sites (thermal, bimodal, and nociceptive) that contained one or more thermal, nociceptive, or (rarely) bimodal spots. Repeated testing indicated that bimodal and nociceptive sites were less stable over time than thermal sites, and that mechanical contact differentially inhibited nociceptive sensations. Intensity ratings collected over a range of temperatures showed that LTN increased monotonically on heat-sensitive sites but not on cold-sensitive sites. These results provide psychophysical evidence that stimulation from primary afferent fibers with thresholds in the range of warm fibers and cold fibers is relayed to the pain pathway. However, the labile nature of LTN implies that these low-threshold nociceptive inputs are subject to inhibitory controls. The implications of these findings for the roles of putative temperature receptors and nociceptors in innocuous thermoreception and thermal pain are discussed.

Modulatory Mechanism of Nociceptive Neuronal Activity by Dietary Constituent Resveratrol

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Mamoru Takeda

2016-10-01

Full Text Available Changes to somatic sensory pathways caused by peripheral tissue, inflammation or injury can result in behavioral hypersensitivity and pathological pain, such as hyperalgesia. Resveratrol, a plant polyphenol found in red wine and various food products, is known to have several beneficial biological actions. Recent reports indicate that resveratrol can modulate neuronal excitability, including nociceptive sensory transmission. As such, it is possible that this dietary constituent could be a complementary alternative medicine (CAM candidate, specifically a therapeutic agent. The focus of this review is on the mechanisms underlying the modulatory effects of resveratrol on nociceptive neuronal activity associated with pain relief. In addition, we discuss the contribution of resveratrol to the relief of nociceptive and/or pathological pain and its potential role as a functional food and a CAM.

Learned control over spinal nociception in patients with chronic back pain.

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Krafft, S; Göhmann, H-D; Sommer, J; Straube, A; Ruscheweyh, R

2017-10-01

Descending pain inhibition suppresses spinal nociception, reducing nociceptive input to the brain. It is modulated by cognitive and emotional processes. In subjects with chronic pain, it is impaired, possibly contributing to pain persistence. A previously developed feedback method trains subjects to activate their descending inhibition. Participants are trained to use cognitive-emotional strategies to reduce their spinal nociception, as quantified by the nociceptive flexor reflex (RIII reflex), under visual feedback about their RIII reflex size. The aim of the present study was to test whether also subjects with chronic back pain can achieve a modulation of their descending pain inhibition under RIII feedback. In total, 33 subjects with chronic back pain received either true (n = 18) or sham RIII feedback (n = 15), 15 healthy control subjects received true RIII feedback. All three groups achieved significant RIII suppression, largest in controls (to 76 ± 26% of baseline), intermediate in chronic back pain subjects receiving true feedback (to 82 ± 13%) and smallest in chronic back pain subjects receiving sham feedback (to 89 ± 14%, all p chronic pain subjects receiving true feedback significantly improved their descending inhibition over the feedback training, quantified by the conditioned pain modulation effect (test pain reduction of baseline before training: to 98 ± 26%, after: to 80 ± 21%, p chronic back pain can achieve a reduction of their spinal nociception and improve their descending pain inhibition under RIII feedback training. Subjects with chronic back pain can learn to control their spinal nociception, quantified by the RIII reflex, when they receive feedback about the RIII reflex. © 2017 European Pain Federation - EFIC®.

CORTICAL RESPONSES TO SALIENT NOCICEPTIVE AND NOT NOCICEPTIVE STIMULI IN VEGETATIVE AND MINIMAL CONSCIOUS STATE

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MARINA eDE TOMMASO

2015-01-01

Full Text Available Aims Questions regarding perception of pain in non-communicating patients and the management of pain continue to raise controversy both at a clinical and ethical level. The aim of this study was to examine the cortical response to salient multimodal visual, acoustic, somatosensory electric non nociceptive and nociceptive laser stimuli and their correlation with the clinical evaluation.Methods: Five Vegetative State (VS, 4 Minimally Conscious State (MCS patients and 11 age- and sex-matched controls were examined. Evoked responses were obtained by 64 scalp electrodes, while delivering auditory, visual, non-noxious electrical and noxious laser stimulation, which were randomly presented every 10 sec. Laser, somatosensory, auditory and visual evoked responses were identified as a negative-positive (N2-P2 vertex complex in the 500 msec post-stimulus time. We used Nociception Coma Scale-Revised (NCS-R and Coma Recovery Scale (CRS-R for clinical evaluation of pain perception and consciousness impairment.Results: The laser evoked potentials (LEPs were recognizable in all cases. Only one MCS patient showed a reliable cortical response to all the employed stimulus modalities. One VS patient did not present cortical responses to any other stimulus modality. In the remaining participants, auditory, visual and electrical related potentials were inconstantly present. Significant N2 and P2 latency prolongation occurred in both VS and MCS patients. The presence of a reliable cortical response to auditory, visual and electric stimuli was able to correctly classify VS and MCS patients with 90% accuracy. Laser P2 and N2 amplitudes were not correlated with the CRS-R and NCS-R scores, while auditory and electric related potentials amplitude were associated with the motor response to pain and consciousness recovery. Discussion: pain arousal may be a primary function also in vegetative state patients while the relevance of other stimulus modalities may indicate the

(-)-α-Bisabolol reduces orofacial nociceptive behavior in rodents.

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Melo, Luana Torres; Duailibe, Mariana Araújo Braz; Pessoa, Luciana Moura; da Costa, Flávio Nogueira; Vieira-Neto, Antonio Eufrásio; de Vasconcellos Abdon, Ana Paula; Campos, Adriana Rolim

2017-02-01

The purposes of this study were to evaluate the anti-nociceptive effect of oral and topical administration of (-)-α-bisabolol (BISA) in rodent models of formalin- or cinnamaldehyde-induced orofacial pain and to explore the inhibitory mechanisms involved. Orofacial pain was induced by injecting 1.5% formalin into the upper lip of mice (20 μL) or into the temporomandibular joint (TMJ) of rats (50 μL). In another experiment, orofacial pain was induced with cinnamaldehyde (13.2 μg/lip). Nociceptive behavior was proxied by time (s) spent rubbing the injected area and by the incidence of head flinching. BISA (100, 200, or 400 mg/kg p.o. or 50, 100, or 200 mg/mL topical) or vehicle was administered 60 min before pain induction. The two formulations (lotion and syrup) were compared with regard to efficacy. The effect of BISA remained after incorporation into the formulations, and nociceptive behavior decreased significantly in all tests. The high binding affinity observed for BISA and TRPA1 in the molecular docking study was supported by in vivo experiments in which HC-030031 (a TRPA1 receptor antagonist) attenuated pain in a manner qualitatively and quantitatively similar to that of BISA. Blockers of opioid receptors, NO synthesis, and K + ATP channels did not affect orofacial pain, nor inhibit the effect of BISA. In conclusion, BISA had a significant anti-nociceptive effect on orofacial pain. The effect may in part be due to TRPA1 antagonism. The fact that the effect of BISA remained after incorporation into oral and topical formulations suggests that the compound may be a useful adjuvant in the treatment of orofacial pain.

17β-Estradiol Enhances ASIC Activity in Primary Sensory Neurons to Produce Sex Difference in Acidosis-Induced Nociception.

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Qu, Zu-Wei; Liu, Ting-Ting; Ren, Cuixia; Gan, Xiong; Qiu, Chun-Yu; Ren, Ping; Rao, Zhiguo; Hu, Wang-Ping

2015-12-01

Sex differences have been reported in a number of pain conditions. Women are more sensitive to most types of painful stimuli than men, and estrogen plays a key role in the sex differences in pain perception. However, it is unclear whether there is a sex difference in acidosis-evoked pain. We report here that both male and female rats exhibit nociceptive behaviors in response to acetic acid, with females being more sensitive than males. Local application of exogenous 17β-estradiol (E2) exacerbated acidosis-evoked nociceptive response in male rats. E2 and estrogen receptor (ER)-α agonist 1,3,5-Tris(4-hydroxyphenyl)-4-propyl-1H-pyrazole, but not ERβ agonist 2,3-bis(4-hydroxyphenyl)-propionitrile, replacement also reversed attenuation of the acetic acid-induced nociceptive response in ovariectomized females. Moreover, E2 can exert a rapid potentiating effect on the functional activity of acid-sensing ion channels (ASICs), which mediated the acidosis-induced events. E2 dose dependently increased the amplitude of ASIC currents with a 42.8 ± 1.6 nM of EC50. E2 shifted the concentration-response curve for proton upward with a 50.1% ± 6.2% increase of the maximal current response to proton. E2 potentiated ASIC currents via an ERα and ERK1/2 signaling pathway. E2 also altered acidosis-evoked membrane excitability of dorsal root ganglia neurons and caused a significant increase in the amplitude of the depolarization and the number of spikes induced by acidic stimuli. E2 potentiation of the functional activity of ASICs revealed a peripheral mechanism underlying this sex difference in acetic acid-induced nociception.

A study of the reliability of the Nociception Coma Scale.

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Riganello, F; Cortese, M D; Arcuri, F; Candelieri, A; Guglielmino, F; Dolce, G; Sannita, W G; Schnakers, C

2015-04-01

In this study, we investigated the reliability of the Nociception Coma Scale which has recently been developed to assess nociception in non-communicative, severely brain-injured patients. Prospective cross-sequential study. Semi-intensive care unit and long-term brain injury care. Forty-four patients diagnosed as being in a vegetative state (n=26) or in a minimally conscious state (n=18). Patients were assessed by two experts (rater A and rater B) on two consecutive weeks to measure inter-rater agreement and test-retest reliability. Total scores and subscores of the Nociception Coma Scale. We performed a total of 176 assessments. The inter-rater agreement was moderate for the total scores (k = 0.57) and fair to substantial for the subscores (0.33 ≤ k ≤ 0.62) on week 2. The test-retest reliability was substantial for the total scores (k = 0.66) and moderate to almost perfect for the subscores (0.53 ≤ k ≤ 0.96) for rater A. The inter-rater agreement was weaker on week 1, whereas the test-retest reliability was lower for the least experienced rater (rater B). This study provides further evidence of the psychometric qualities of the Nociception Coma Scale. Future studies should assess the impact of practical experience and background on administration and scoring of the scale. © The Author(s) 2014.

Aberrant Signaling Pathways in T-Cell Acute Lymphoblastic Leukemia

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Bongiovanni, Deborah; Saccomani, Valentina

2017-01-01

T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive disease caused by the malignant transformation of immature progenitors primed towards T-cell development. Clinically, T-ALL patients present with diffuse infiltration of the bone marrow by immature T-cell blasts high blood cell counts, mediastinal involvement, and diffusion to the central nervous system. In the past decade, the genomic landscape of T-ALL has been the target of intense research. The identification of specific genomic alterations has contributed to identify strong oncogenic drivers and signaling pathways regulating leukemia growth. Notwithstanding, T-ALL patients are still treated with high-dose multiagent chemotherapy, potentially exposing these patients to considerable acute and long-term side effects. This review summarizes recent advances in our understanding of the signaling pathways relevant for the pathogenesis of T-ALL and the opportunities offered for targeted therapy. PMID:28872614

Urethane anesthesia depresses activities of thalamocortical neurons and alters its response to nociception in terms of dual firing modes

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Yeowool eHuh

2013-10-01

Full Text Available Anesthetics are often used to characterize the activity of single neurons in-vivo for its advantages such as reduced noise level and convenience in noxious stimulations. Of the anesthetics, urethane had been widely used in some thalamic studies under the assumption that sensory signals are still relayed to the thalamus under urethane anesthesia and that thalamic response would therefore reflect the response of the awake state. We tested whether this assumption stands by comparing thalamic activity in terms of tonic and burst firing modes during ‘the awake state’ or under ‘urethane anesthesia’ utilizing the extracellular single unit recording technique. First we have tested how thalamic relay neurons respond to the introduction of urethane and then tested how urethane influences thalamic discharges under formalin-induced nociception. Urethane significantly depressed overall firing rates of thalamic relay neurons, which was sustained despite the delayed increase of burst activity over the 4 hour recording period. Thalamic response to nociception under anesthesia was also similar overall except for the slight and transient increase of burst activity. Overall, results demonstrated that urethane suppresses the activity of thalamic relay neurons and that, despite the slight fluctuation of burst firing, formalin-induced nociception cannot significantly change the firing pattern of thalamic relay neurons that was caused by urethane.

Top-Down Effect of Direct Current Stimulation on the Nociceptive Response of Rats.

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Luiz Fabio Dimov

Full Text Available Transcranial direct current stimulation (tDCS is an emerging, noninvasive technique of neurostimulation for treating pain. However, the mechanisms and pathways involved in its analgesic effects are poorly understood. Therefore, we investigated the effects of direct current stimulation (DCS on thermal and mechanical nociceptive thresholds and on the activation of the midbrain periaqueductal gray (PAG and the dorsal horn of the spinal cord (DHSC in rats; these central nervous system areas are associated with pain processing. Male Wistar rats underwent cathodal DCS of the motor cortex and, while still under stimulation, were evaluated using tail-flick and paw pressure nociceptive tests. Sham stimulation and naive rats were used as controls. We used a randomized design; the assays were not blinded to the experimenter. Immunoreactivity of the early growth response gene 1 (Egr-1, which is a marker of neuronal activation, was evaluated in the PAG and DHSC, and enkephalin immunoreactivity was evaluated in the DHSC. DCS did not change the thermal nociceptive threshold; however, it increased the mechanical nociceptive threshold of both hind paws compared with that of controls, characterizing a topographical effect. DCS decreased the Egr-1 labeling in the PAG and DHSC as well as the immunoreactivity of spinal enkephalin. Altogether, the data suggest that DCS disinhibits the midbrain descending analgesic pathway, consequently inhibiting spinal nociceptive neurons and causing an increase in the nociceptive threshold. This study reinforces the idea that the motor cortex participates in the neurocircuitry that is involved in analgesia and further clarifies the mechanisms of action of tDCS in pain treatment.

Measuring cutaneous thermal nociception in group-housed pigs using laser technique - effects of laser power output

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Herskin, Mette S.; Ladevig, Jan; Arendt-Nielsen, Lars

2009-01-01

Nociceptive testing is a valuable tool in the development of pharmaceutical products, for basic nociceptive research, and for studying changes in pain sensitivity is investigated after inflammatory states or nerve injury. However, in pigs only very limited knowledge about nociceptive processes...... nociceptive stimulation from a computer-controlled CO2-laser beam applied to either the caudal part of the metatarsus on the hind legs or the shoulder region of gilts. In Exp. 1, effects of laser power output (0, 0.5, 1, 1.5 and 2 W) on nociceptive responses toward stimulation on the caudal aspects...... of the metatarsus were examined using 15 gilts kept in one group and tested in individual feeding stalls after feeding. Increasing the power output led to gradually decreasing latency to respond (P 

In vivo and in vitro anti-inflammatory and anti-nociceptive activities of lovastatin in rodents

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D.O. Gonçalves

2011-02-01

Full Text Available Statins are among the most prescribed drugs in recent clinical practice. They are also known for their pleiotropic actions, which are independent of their lipid-lowering properties. The effect of lovastatin was investigated against carrageenan-induced paw edema in male Wistar rats (200-250 g and on leukocyte migration, as measured by carrageenan-induced peritonitis in male Swiss mice (20-25 g, which are models of acute inflammation. Lovastatin (administered 1 h prior to carrageenan, at oral doses of 2, 5, and 10 mg/kg, markedly attenuated paw edema formation in rats at the 4th hour after carrageenan injection (25, 43, and 37% inhibition, respectively. Inhibitions of 20, 45 and 80% were observed in the leukocyte migration, as evaluated by carrageenan-induced peritonitis in mice with lovastatin doses of 0.5, 1 and 5 mg/kg, as compared to controls. Furthermore, lovastatin (administered 1 h before initiation reduced the nociceptive effect of the formalin test in mice, at both phases, at doses of 2, 5, and 10 mg/kg: first phase (51, 65, and 70%, respectively and second phase (73, 57, and 66% inhibition of licking time, respectively. The anti-nociceptive activity of lovastatin was inhibited by naloxone (3 mg/kg, sc. Lovastatin (0.01, 0.1, and 1 µg/mL inhibited by 23, 79, and 86%, respectively, the release of myeloperoxidase from human neutrophils. Leukocyte (predominantly neutrophils infiltration was almost completely reduced by lovastatin treatment, as observed in the model of acute paw edema with hematoxylin and eosin staining. In addition, lovastatin decreased the number of cells expressing tumor necrosis factor-α (TNF-α and the inducible form of nitric oxide synthase (iNOS activity. Therefore, the alterations in leukocyte activity and cytokine release could contribute to the anti-inflammatory activity of lovastatin.

Cortical responses to salient nociceptive and not nociceptive stimuli in vegetative and minimal conscious state

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de Tommaso, Marina; Navarro, Jorge; Lanzillotti, Crocifissa; Ricci, Katia; Buonocunto, Francesca; Livrea, Paolo; Lancioni, Giulio E.

2015-01-01

Aims: Questions regarding perception of pain in non-communicating patients and the management of pain continue to raise controversy both at a clinical and ethical level. The aim of this study was to examine the cortical response to salient visual, acoustic, somatosensory electric non-nociceptive and nociceptive laser stimuli and their correlation with the clinical evaluation. Methods: Five Vegetative State (VS), 4 Minimally Conscious State (MCS) patients and 11 age- and sex-matched controls were examined. Evoked responses were obtained by 64 scalp electrodes, while delivering auditory, visual, non-noxious electrical and noxious laser stimulation, which were randomly presented every 10 s. Laser, somatosensory, auditory and visual evoked responses were identified as a negative-positive (N2-P2) vertex complex in the 500 ms post-stimulus time. We used Nociception Coma Scale-Revised (NCS-R) and Coma Recovery Scale (CRS-R) for clinical evaluation of pain perception and consciousness impairment. Results: The laser evoked potentials (LEPs) were recognizable in all cases. Only one MCS patient showed a reliable cortical response to all the employed stimulus modalities. One VS patient did not present cortical responses to any other stimulus modality. In the remaining participants, auditory, visual and electrical related potentials were inconstantly present. Significant N2 and P2 latency prolongation occurred in both VS and MCS patients. The presence of a reliable cortical response to auditory, visual and electric stimuli was able to correctly classify VS and MCS patients with 90% accuracy. Laser P2 and N2 amplitudes were not correlated with the CRS-R and NCS-R scores, while auditory and electric related potentials amplitude were associated with the motor response to pain and consciousness recovery. Discussion: pain arousal may be a primary function also in vegetative state patients while the relevance of other stimulus modalities may indicate the degree of cognitive and motor

Differential Efficacy of Ketamine in the Acute versus Chronic Stages of Complex Regional Pain Syndrome in Mice

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Tajerian, Maral; Leu, David; Yang, Phillip; Huang, Ting Ting; Kingery, Wade S; Clark, J David

2015-01-01

Background Complex regional pain syndrome (CRPS) is a painful, disabling and often chronic condition, where many patients transition from an acute phase with prominent peripheral neurogenic inflammation to a chronic phase with evident central nervous system (CNS) changes. Ketamine is a centrally-acting agent believed to work through blockade of N-methyl-D-aspartate (NMDA) receptors and is being increasingly used for the treatment of refractory CRPS, although the basis for the drug’s effects and efficacy at different stages of the syndrome remain unclear. Methods We used a mouse model of CRPS (n=8–12/group) involving tibia fracture/cast immobilization to test the efficacy of ketamine (2 mg/kg/day; 7 days) or vehicle infusion during acute (3weeks [3w] post-fracture) and chronic (7w post-fracture) stages. Results Acute phase fracture mice displayed elevated limb temperature, edema and nociceptive sensitization that were not reduced by ketamine. Fracture mice treated with ketamine during the chronic phase showed reduced nociceptive sensitization that persisted beyond completion of the infusion. During this chronic phase, ketamine also reduced latent nociceptive sensitization and improved motor function at 18 weeks post-fracture. No side effects of the infusions were identified. These behavioral changes were associated with altered spinal astrocyte activation and expression of pain-related proteins including NMDA receptor 2b (NR2b), Ca2+/calmodulin-dependent protein kinase ii (CaMK2), and brain-derived neurotrophic factor (BNDF). Conclusions Collectively, these results demonstrate that ketamine is efficacious in the chronic, but not acute stages of CRPS, suggesting that the centrally-acting drug is relatively ineffective in early CRPS when peripheral mechanisms are more critical for supporting nociceptive sensitization. PMID:26492479

Anti-nociceptive, anti-hyperalgesic and anti-arthritic activity of amides and extract obtained from Piper amalago in rodents.

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da Silva Arrigo, Jucicléia; Balen, Eloise; Júnior, Ubirajara Lanza; da Silva Mota, Jonas; Iwamoto, Renan Donomae; Barison, Andersson; Sugizaki, Mario Mateus; Leite Kassuya, Cândida Aparecida

2016-02-17

amides obtained seemed to be the active component(s) present in the EEPA because they proved to be anti-nociceptive and anti-hyperalgesic in models of acute pain. Considering that few drugs are currently available for the treatment of chronic pain, especially neuropathic pain, the present results may have clinical relevance and open new possibilities for the development of new anti-hyperalgesic and anti-arthritic agents from P. amalago. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Synaptic Plasticity and Nociception

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ChenJianguo

2004-01-01

Synaptic plasticity is one of the fields that progresses rapidly and has a lot of success in neuroscience. The two major types of synaptie plasticity: long-term potentiation ( LTP and long-term depression (LTD are thought to be the cellular mochanisms of learning and memory. Recently, accumulating evidence suggests that, besides serving as a cellular model for learning and memory, the synaptic plasticity involves in other physiological or pathophysiological processes, such as the perception of pain and the regulation of cardiovascular system. This minireview will focus on the relationship between synaptic plasticity and nociception.

Anti-nociceptive effects of Tanshinone IIA (TIIA) in a rat model of complete Freund's adjuvant (CFA)-induced inflammatory pain.

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Sun, Shukai; Yin, Yue; Yin, Xin; Cao, Fale; Luo, Daoshu; Zhang, Ting; Li, Yunqing; Ni, Longxing

2012-09-01

Inflammatory pain is an important clinical symptom. The levels of extracellular signal-regulated kinases (ERKs) and the levels of cytokines such as interleukin 1β (IL-1β), interleukin 6 (IL-6) and tumor necrosis factor-alpha (TNF-α) play important roles in inflammatory pain. Tanshinone IIA (TIIA) is an important component of Danshen, a traditional Chinese medicine that has been commonly used to treat cardiovascular disease. In this study, we investigated the potential anti-inflammatory nociceptive effects of TIIA on complete Freund's adjuvant (CFA)-induced inflammation and inflammatory pain in rats. The effects of TIIA on CFA-induced thermal and mechanical hypersensitivity were investigated using behavioral tests. The levels of ERKs, nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) and transient receptor potential vanilloid 1 (TRPV1) in the fifth segment of the lumbar spinal cord (L5) ganglia were detected by Western blot, and the levels of mRNA and protein production of IL1-β, IL-6 and TNF-α were detected by real-time reverse transcription polymerase chain reaction (RT-PCR) and enzyme-linked immuno sorbent assay (ELISA). In this study, we found that TIIA attenuates the development of CFA-induced mechanical and thermal hypersensitivity. In addition, p-ERK and NF-κB expression levels were inhibited by TIIA, and the levels of the pro-inflammatory cytokines IL-1β, IL-6 and TNF-α were reduced. Finally, we found that the expression level of TRPV1 was significantly decreased after TIIA injection. This study demonstrated that TIIA has significant anti-nociceptive effects in a rat model of CFA-induced inflammatory pain. TIIA can inhibit the activation of ERK signaling pathways and the expression of pro-inflammatory cytokines. These results suggest that TIIA may be a potential anti-inflammatory and anti-nociceptive drug. Copyright © 2012 Elsevier Inc. All rights reserved.

The nociceptive and anti-nociceptive effects of bee venom injection and therapy: a double-edged sword.

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Chen, Jun; Lariviere, William R

2010-10-01

Bee venom injection as a therapy, like many other complementary and alternative medicine approaches, has been used for thousands of years to attempt to alleviate a range of diseases including arthritis. More recently, additional theraupeutic goals have been added to the list of diseases making this a critical time to evaluate the evidence for the beneficial and adverse effects of bee venom injection. Although reports of pain reduction (analgesic and antinociceptive) and anti-inflammatory effects of bee venom injection are accumulating in the literature, it is common knowledge that bee venom stings are painful and produce inflammation. In addition, a significant number of studies have been performed in the past decade highlighting that injection of bee venom and components of bee venom produce significant signs of pain or nociception, inflammation and many effects at multiple levels of immediate, acute and prolonged pain processes. This report reviews the extensive new data regarding the deleterious effects of bee venom injection in people and animals, our current understanding of the responsible underlying mechanisms and critical venom components, and provides a critical evaluation of reports of the beneficial effects of bee venom injection in people and animals and the proposed underlying mechanisms. Although further studies are required to make firm conclusions, therapeutic bee venom injection may be beneficial for some patients, but may also be harmful. This report highlights key patterns of results, critical shortcomings, and essential areas requiring further study. Copyright 2010 Elsevier Ltd. All rights reserved.

Blockade of NMDA receptors decreased spinal microglia activation in bee venom induced acute inflammatory pain in rats.

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Li, Li; Wu, Yongfang; Bai, Zhifeng; Hu, Yuyan; Li, Wenbin

2017-03-01

Microglial cells in spinal dorsal horn can be activated by nociceptive stimuli and the activated microglial cells release various cytokines enhancing the nociceptive transmission. However, the mechanisms underlying the activation of spinal microglia during nociceptive stimuli have not been well understood. In order to define the role of NMDA receptors in the activation of spinal microglia during nociceptive stimuli, the present study was undertaken to investigate the effect of blockade of NMDA receptors on the spinal microglial activation induced by acute peripheral inflammatory pain in rats. The acute inflammatory pain was induced by subcutaneous bee venom injection to the plantar surface of hind paw of rats. Spontaneous pain behavior, thermal withdrawal latency and mechanical withdrawal threshold were rated. The expression of specific microglia marker CD11b/c was assayed by immunohistochemistry and western blot. After bee venom treatment, it was found that rats produced a monophasic nociception characterized by constantly lifting and licking the injected hind paws, decreased thermal withdrawal latency and mechanical withdrawal threshold; immunohistochemistry displayed microglia with enlarged cell bodies, thickened, extended cellular processes with few ramifications, small spines, and intensive immunostaining; western blot showed upregulated expression level of CD11b/c within the period of hyperalgesia. Prior intrathecal injection of MK-801, a selective antagonist of NMDA receptors, attenuated the pain behaviors and suppressed up-regulation of CD11b/c induced by bee venom. It can be concluded that NMDA receptors take part in the mediation of spinal microglia activation in bee venom induced peripheral inflammatory pain and hyperalgesia in rats.

Innocuous cooling can produce nociceptive sensations that are inhibited during dynamic mechanical contact.

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Green, Barry G; Pope, Jennifer V

2003-02-01

In a previous study of the heat grill illusion, sensations of burning and stinging were sometimes reported when the skin was cooled by as little as 2 degrees C. Informal tests subsequently indicated that these nociceptive sensations were experienced if cooling occurred when the stimulating thermode rested on the skin, but not when the thermode was cooled and then touched to the skin. In experiment 1 subjects judged the intensity of thermal (cold/warm) and nociceptive (burning/stinging) sensations when the volar surface of the forearm was cooled to 25 degrees C (1) via a static thermode (Static condition), or (2) via a cold thermode touched to the skin (Dynamic condition). The total area of stimulation was varied from 2.6 to 10.4 cm(2) to determine if the occurrence of nociceptive sensations depended upon stimulus size. Burning/stinging was rated 10.3 times stronger in the Static condition than in the Dynamic condition, and this difference did not vary significantly with stimulus size. In experiment 2, thermal and nociceptive sensations were measured during cooling to just 31 degrees, 29 degrees or 27 degrees C, and data were obtained on the frequency at which different sensation qualities were experienced. Stinging was the most frequently reported nociceptive quality in the Static condition, and stinging and burning were both markedly reduced in the Dynamic condition. In experiment 3 we tested the possibility that dynamic contact might have inhibited burning and stinging not because of mechanical contact per se, but rather because dynamic contact caused higher rates of cooling. However, varying cooling rate over a tenfold range (-0.5 degrees to -5.0 degrees /s) had no appreciable effect on the frequency of stinging and burning. Overall, the data show that mild cooling can produce nociceptive sensations that are suppressed under conditions of dynamic mechanical contact. The latter observation suggests that cold is perceived differently during active contact with

Thermal nociception as a measure of non-steroidal anti-inflammatory drug effectiveness in broiler chickens with articular pain☆

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Caplen, Gina; Baker, Laurence; Hothersall, Becky; McKeegan, Dorothy E.F.; Sandilands, Victoria; Sparks, Nick H.C.; Waterman-Pearson, Avril E.; Murrell, Joanna C.

2013-01-01

Pain associated with poultry lameness is poorly understood. The anti-nociceptive properties of two non-steroidal anti-inflammatory drugs (NSAIDs) were evaluated using threshold testing in combination with an acute inflammatory arthropathy model. Broilers were tested in six groups (n = 8 per group). Each group underwent a treatment (saline, meloxicam (3 or 5 mg/kg) or carprofen (15 or 25 mg/kg)) and a procedure (Induced (arthropathy-induction) or sham (sham-handling)) prior to testing. Induced groups had Freund’s complete adjuvant injected intra-articularly into the left intertarsal joint (hock). A ramped thermal stimulus (1 °C/s) was applied to the skin of the left metatarsal. Data were analysed using random-intercept multi-level models. Saline-induced birds had a significantly higher skin temperature (± SD) than saline-sham birds (37.6 ± 0.8 °C vs. 36.5 ± 0.5 °C; Z = −3.47, P carprofen: Z = 2.58, P = 0.010) in induced birds. Saline-induced birds also had significantly lower TT than saline-sham birds (Z = −2.17, P = 0.030). This study found direct evidence of an association between inflammatory arthropathies and thermal hyperalgesia, and showed that NSAID treatment maintained baseline thermal sensitivity (via anti-nociception). Quantification of nociceptive responsiveness in a predictable broiler pain model identified thermal anti-hyperalgesic properties of two NSAIDs, which suggested that therapeutically effective treatment was provided at the doses administered. Such validation of analgesic strategies will increase the understanding of pain associated with specific natural broiler lameness types. PMID:24129110

Anti-Inflammatory and Antinociceptive Effects of Salbutamol on Acute and Chronic Models of Inflammation in Rats: Involvement of an Antioxidant Mechanism

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Hulya Uzkeser

2012-01-01

Full Text Available The possible role of β-2 adrenergic receptors in modulation of inflammatory and nociceptive conditions suggests that the β-2 adrenergic receptor agonist, salbutamol, may have beneficial anti-inflammatory and analgesic effects. Therefore, in this study, we induced inflammatory and nociceptive responses with carrageenan-induced paw edema or cotton-pellet-induced granuloma models, both of which result in oxidative stress. We hypothesized that salbutamol would prevent inflammatory and nociceptive responses by stimulating β-2 adrenergic receptors and the prevention of generation of ROS during the acute inflammation process in rats. Both doses of salbutamol used in the study (1 and 2 mg/kg effectively blocked the acute inflammation and inflammatory nociception induced by carrageenan. In the cotton-pellet-induced granuloma test, both doses of salbutamol also significantly decreased the weight of granuloma tissue on the cotton pellets when compared to the control. Anti-inflammatory and analgesic effects of salbutamol were found to be comparable with those of indomethacin. Salbutamol decreased myeloperoxidase (MPO activity and lipid peroxidation (LPO level and increased the activity of superoxide dismutase (SOD and level of glutathione (GSH during the acute phase of inflammation. In conclusion, salbutamol can decrease acute and chronic inflammation, possibly through the stimulation of β-2 adrenergic receptors. This anti-inflammatory effect may be of significance in asthma treatment, where inflammation also takes part in the etiopathology. This study reveals that salbutamol has significant antioxidative effects, which at least partially explain its anti-inflammatory capabilities. These findings presented here may also shed light on the roles of β-2 adrenergic receptors in inflammatory and hyperalgesic conditions.

Oxytocin Modulates Nociception as an Agonist of Pain-Sensing TRPV1

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Yelena Nersesyan

2017-11-01

Full Text Available Oxytocin is a hormone with various actions. Oxytocin-containing parvocellular neurons project to the brainstem and spinal cord. Oxytocin release from these neurons suppresses nociception of inflammatory pain, the molecular mechanism of which remains unclear. Here, we report that the noxious stimulus receptor TRPV1 is an ionotropic oxytocin receptor. Oxytocin elicits TRPV1 activity in native and heterologous expression systems, regardless of the presence of the classical oxytocin receptor. In TRPV1 knockout mice, DRG neurons exhibit reduced oxytocin sensitivity relative to controls, and oxytocin injections significantly attenuate capsaicin-induced nociception in in vivo experiments. Furthermore, oxytocin potentiates TRPV1 in planar lipid bilayers, supporting a direct agonistic action. Molecular modeling and simulation experiments provide insight into oxytocin-TRPV1 interactions, which resemble DkTx. Together, our findings suggest the existence of endogenous regulatory pathways that modulate nociception via direct action of oxytocin on TRPV1, implying its analgesic effect via channel desensitization.

Early Postoperative Nociceptive Threshold and Production of Brain-Derived Neurotrophic Factor Induced by Plantar Incision Are Not Influenced with Minocycline in a Rat: Role of Spinal Microglia

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Eiji Masaki

2016-03-01

Full Text Available Background: Brain-derived neurotrophic factor (BDNF from spinal microglia is crucial for aberrant nociceptive signaling in several pathological pain conditions, including postoperative pain. We assess the contribution of spinal microglial activation and associated BDNF overexpression to the early post-incisional nociceptive threshold. Methods: Male Sprague-Dawley rats were implanted with an intrathecal catheter. A postoperative pain model was established by plantar incision. Thermal and mechanical nociceptive responses were assessed by infrared radiant heat and von Frey filaments before and after plantar incision. Rats were injected intrathecally the microglial activation inhibitor minocycline before incision, 24 h after incision, or both. Other groups were subjected to the same treatments and the L4-L5 spinal cord segment removed for immunohistochemical analysis of microglia activation and BNDF expression. Results: Plantar incision reduced both thermal latency and mechanical threshold, indicating thermal hypersensitivity and mechanical allodynia. Minocycline temporally reduced thermal withdrawal latency but had no effect on mechanical withdrawal threshold, spinal microglial activity, or dorsal horn BDNF overexpression during the early post-incision period. Conclusion: These results suggest that spinal microglia does not contribute substantially to post-incisional nociceptive threshold. The BDNF overexpression response that may contribute to postoperative hyperalgesia and allodynia is likely derived from other sources.

Chronic intrathecal cannulation enhances nociceptive responses in rats

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Almeida F.R.C.

2000-01-01

Full Text Available The influence of a chronically implanted spinal cannula on the nociceptive response induced by mechanical, chemical or thermal stimuli was evaluated. The hyperalgesia in response to mechanical stimulation induced by carrageenin or prostaglandin E2 (PGE2 was significantly increased in cannulated (Cn rats, compared with naive (Nv or sham-operated (Sh rats. Only Cn animals presented an enhanced nociceptive response in the first phase of the formalin test when low doses were used (0.3 and 1%. The withdrawal latency to thermal stimulation of a paw inflamed by carrageenin was significantly reduced in Cn rats but not in Nv or Sh rats. In contrast to Nv and Sh rats, injection in Cn animals of a standard non-steroid anti-inflammatory drug, indomethacin, either intraperitoneally or into the spinal cord via an implanted cannula or by direct puncture of the intrathecal space significantly blocked the intensity of the hyperalgesia induced by PGE2. Cannulated animals treated with indomethacin also showed a significant inhibition of second phase formalin-induced paw flinches. Histopathological analysis of the spinal cord showed an increased frequency of mononuclear inflammatory cells in the Cn groups. Thus, the presence of a chronically implanted cannula seems to cause nociceptive spinal sensitization to mechanical, chemical and thermal stimulation, which can be blocked by indomethacin, thus suggesting that it may result from the spinal release of prostaglandins due to an ongoing mild inflammation.

Neuropathic pain in experimental autoimmune neuritis is associated with altered electrophysiological properties of nociceptive DRG neurons.

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Taha, Omneya; Opitz, Thoralf; Mueller, Marcus; Pitsch, Julika; Becker, Albert; Evert, Bernd Oliver; Beck, Heinz; Jeub, Monika

2017-11-01

Guillain-Barré syndrome (GBS) is an acute, immune-mediated polyradiculoneuropathy characterized by rapidly progressive paresis and sensory disturbances. Moderate to severe and often intractable neuropathic pain is a common symptom of GBS, but its underlying mechanisms are unknown. Pathology of GBS is classically attributed to demyelination of large, myelinated peripheral fibers. However, there is increasing evidence that neuropathic pain in GBS is associated with impaired function of small, unmyelinated, nociceptive fibers. We therefore examined the functional properties of small DRG neurons, the somata of nociceptive fibers, in a rat model of GBS (experimental autoimmune neuritis=EAN). EAN rats developed behavioral signs of neuropathic pain. This was accompanied by a significant shortening of action potentials due to a more rapid repolarization and an increase in repetitive firing in a subgroup of capsaicin-responsive DRG neurons. Na + current measurements revealed a significant increase of the fast TTX-sensitive current and a reduction of the persistent TTX-sensitive current component. These changes of Na + currents may account for the significant decrease in AP duration leading to an overall increase in excitability and are therefore possibly directly linked to pathological pain behavior. Thus, like in other animal models of neuropathic and inflammatory pain, Na + channels seem to be crucially involved in the pathology of GBS and may constitute promising targets for pain modulating pharmaceuticals. Copyright © 2017 Elsevier Inc. All rights reserved.

Neurochemical dynamics of acute orofacial pain in the human trigeminal brainstem nuclear complex.

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de Matos, Nuno M P; Hock, Andreas; Wyss, Michael; Ettlin, Dominik A; Brügger, Mike

2017-11-15

The trigeminal brainstem sensory nuclear complex is the first central relay structure mediating orofacial somatosensory and nociceptive perception. Animal studies suggest a substantial involvement of neurochemical alterations at such basal CNS levels in acute and chronic pain processing. Translating this animal based knowledge to humans is challenging. Human related examining of brainstem functions are challenged by MR related peculiarities as well as applicability aspects of experimentally standardized paradigms. Based on our experience with an MR compatible human orofacial pain model, the aims of the present study were twofold: 1) from a technical perspective, the evaluation of proton magnetic resonance spectroscopy at 3 T regarding measurement accuracy of neurochemical profiles in this small brainstem nuclear complex and 2) the examination of possible neurochemical alterations induced by an experimental orofacial pain model. Data from 13 healthy volunteers aged 19-46 years were analyzed and revealed high quality spectra with significant reductions in total N-acetylaspartate (N-acetylaspartate + N-acetylaspartylglutamate) (-3.7%, p = 0.009) and GABA (-10.88%, p = 0.041) during the pain condition. These results might reflect contributions of N-acetylaspartate and N-acetylaspartylglutamate in neuronal activity-dependent physiologic processes and/or excitatory neurotransmission, whereas changes in GABA might indicate towards a reduction in tonic GABAergic functioning during nociceptive signaling. Summarized, the present study indicates the applicability of 1 H-MRS to obtain neurochemical dynamics within the human trigeminal brainstem sensory nuclear complex. Further developments are needed to pave the way towards bridging important animal based knowledge with human research to understand the neurochemistry of orofacial nociception and pain. Copyright © 2017 Elsevier Inc. All rights reserved.

Factors affecting mechanical (nociceptive) thresholds in piglets.

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Janczak, Andrew M; Ranheim, Birgit; Fosse, Torunn K; Hild, Sophie; Nordgreen, Janicke; Moe, Randi O; Zanella, Adroaldo J

2012-11-01

To evaluate the stability and repeatability of measures of mechanical (nociceptive) thresholds in piglets and to examine potentially confounding factors when using a hand held algometer. Descriptive, prospective cohort. Forty-four piglets from four litters, weighing 4.6 ± 1.0 kg (mean ± SD) at 2 weeks of age. Mechanical thresholds were measured twice on each of 2 days during the first and second week of life. Data were analyzed using a repeated measures design to test the effects of behavior prior to testing, sex, week, day within week, and repetition within day. The effect of body weight and the interaction between piglet weight and behaviour were also tested. Piglet was entered into the model as a random effect as an additional test of repeatability. The effect of repeated testing was used to test the stability of measures. Pearson correlations between repeated measures were used to test the repeatability of measures. Variance component analysis was used to describe the variability in the data. Variance component analysis indicated that piglet explained only 17% of the variance in the data. All variables in the model (behaviour prior to testing, sex, week, day within week, repetition within day, body weight, the interaction between body weight and behaviour, piglet identity) except sex had a significant effect (p testing and measures changed with repeated testing and increased with increasing piglet weight, indicating that time (age) and animal body weight should be taken into account when measuring mechanical (nociceptive) thresholds in piglets. Mechanical (nociceptive) thresholds can be used both for testing the efficacy of anaesthetics and analgesics, and for assessing hyperalgesia in chronic pain states in research and clinical settings. © 2012 The Authors. Veterinary Anaesthesia and Analgesia. © 2012 Association of Veterinary Anaesthetists and the American College of Veterinary Anesthesiologists.

Long-term potentiation in spinal nociceptive pathways as a novel target for pain therapy

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Liu Xian-Guo

2011-03-01

Full Text Available Abstract Long-term potentiation (LTP in nociceptive spinal pathways shares several features with hyperalgesia and has been proposed to be a cellular mechanism of pain amplification in acute and chronic pain states. Spinal LTP is typically induced by noxious input and has therefore been hypothesized to contribute to acute postoperative pain and to forms of chronic pain that develop from an initial painful event, peripheral inflammation or neuropathy. Under this assumption, preventing LTP induction may help to prevent the development of exaggerated postoperative pain and reversing established LTP may help to treat patients who have an LTP component to their chronic pain. Spinal LTP is also induced by abrupt opioid withdrawal, making it a possible mechanism of some forms of opioid-induced hyperalgesia. Here, we give an overview of targets for preventing LTP induction and modifying established LTP as identified in animal studies. We discuss which of the various symptoms of human experimental and clinical pain may be manifestations of spinal LTP, review the pharmacology of these possible human LTP manifestations and compare it to the pharmacology of spinal LTP in rodents.

D-Aspartate Modulates Nociceptive-Specific Neuron Activity and Pain Threshold in Inflammatory and Neuropathic Pain Condition in Mice

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Serena Boccella

2015-01-01

Full Text Available D-Aspartate (D-Asp is a free D-amino acid found in the mammalian brain with a temporal-dependent concentration based on the postnatal expression of its metabolizing enzyme D-aspartate oxidase (DDO. D-Asp acts as an agonist on NMDA receptors (NMDARs. Accordingly, high levels of D-Asp in knockout mice for Ddo gene (Ddo−/− or in mice treated with D-Asp increase NMDAR-dependent processes. We have here evaluated in Ddo−/− mice the effect of high levels of free D-Asp on the long-term plastic changes along the nociceptive pathway occurring in chronic and acute pain condition. We found that Ddo−/− mice show an increased evoked activity of the nociceptive specific (NS neurons of the dorsal horn of the spinal cord (L4–L6 and a significant decrease of mechanical and thermal thresholds, as compared to control mice. Moreover, Ddo gene deletion exacerbated the nocifensive responses in the formalin test and slightly reduced pain thresholds in neuropathic mice up to 7 days after chronic constriction injury. These findings suggest that the NMDAR agonist, D-Asp, may play a role in the regulation of NS neuron electrophysiological activity and behavioral responses in physiological and pathological pain conditions.

Has central sensitization become independent of nociceptive input in chronic pancreatitis patients who fail thoracoscopic splanchnicectomy?

NARCIS (Netherlands)

Bouwense, S.A.W.; Buscher, H.C.J.L.; Goor, H. van; Wilder-Smith, O.H.G.

2011-01-01

BACKGROUND AND OBJECTIVES: : Central sensitization due to visceral pancreatic nociceptive input may be important in chronic pancreatitis pain. We investigated whether bilateral thoracoscopic splanchnicectomy (BTS) to reduce nociceptive input in chronic pancreatitis patients (CPP) with poor pain

Cellular mechanisms of nociception in the frog

Czech Academy of Sciences Publication Activity Database

Kuffler, D. P.; Lyfenko, Alla; Vyklický st., Ladislav; Vlachová, Viktorie

2002-01-01

Roč. 88, č. 4 (2002), s. 1843-1850 ISSN 0022-3077 R&D Projects: GA ČR GA305/00/1639; GA MŠk LN00B122 Grant - others:NATO(XX) Grant 977062 Institutional research plan: CEZ:AV0Z5011922 Keywords : cellular mechanisms of nociception * frog Subject RIV: FH - Neurology Impact factor: 3.743, year: 2002

Acute fluoride poisoning alters myocardial cytoskeletal and AMPK signaling proteins in rats.

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Panneerselvam, Lakshmikanthan; Raghunath, Azhwar; Perumal, Ekambaram

2017-02-15

Our previous findings revealed that increased oxidative stress, apoptosis and necrosis were implicated in acute fluoride (F - ) induced cardiac dysfunction apart from hypocalcemia and hyperkalemia. Cardiac intermediate filaments (desmin and vimentin) and cytoskeleton linker molecule vinculin plays an imperative role in maintaining the architecture of cardiac cytoskeleton. In addition, AMPK is a stress activated kinase that regulates the energy homeostasis during stressed state. The present study was aimed to examine the role of cytoskeletal proteins and AMPK signaling molecules in acute F - induced cardiotoxicity in rats. In order to study this, male Wistar rats were treated with single oral doses of 45 and 90mg/kgF - for 24h. Acute F - intoxicated rats showed declined cytoskeletal protein expression of desmin, vimentin and vinculin in a dose dependent manner compared to control. A significant increase in phosphorylation of AMPKα (Thr172), AMPKß1 (Ser108) and Acetyl-coA carboxylase (ACC) (Ser79) in the myocardium and associated ATP deprivation were found in acute F - intoxicated rats. Further, ultra-structural studies confirmed myofibril lysis with interruption of Z lines, dilated sarcoplasmic reticulum and damaged mitochondrion were observed in both the groups of F - intoxicated rats. Taken together, these findings reveal that acute F - exposure causes sudden heart failure by altering the expression of cytoskeletal proteins and AMPK signaling molecules. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Mechanisms of G Protein-Coupled Estrogen Receptor-Mediated Spinal Nociception

DEFF Research Database (Denmark)

Deliu, Elena; Brailoiu, G. Cristina; Arterburn, Jeffrey B.

2012-01-01

. Cytosolic calcium concentration elevates faster and with higher amplitude following G-1 intracellular microinjections compared to extracellular exposure, suggesting subcellular GPER functionality. Thus, GPER activation results in spinal nociception, and the downstream mechanisms involve cytosolic calcium......Human and animal studies suggest that estrogens are involved in the processing of nociceptive sensory information and analgesic responses in the central nervous system. Rapid pronociceptive estrogenic effects have been reported, some of which likely involve G protein-coupled estrogen receptor (GPER......) activation. Membrane depolarization and increases in cytosolic calcium and reactive oxygen species (ROS) levels are markers of neuronal activation, underlying pain sensitization in the spinal cord. Using behavioral, electrophysiological, and fluorescent imaging studies, we evaluated GPER involvement...

Nociceptive afferents to the premotor neurons that send axons simultaneously to the facial and hypoglossal motoneurons by means of axon collaterals.

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Yulin Dong

Full Text Available It is well known that the brainstem premotor neurons of the facial nucleus and hypoglossal nucleus coordinate orofacial nociceptive reflex (ONR responses. However, whether the brainstem PNs receive the nociceptive projection directly from the caudal spinal trigeminal nucleus is still kept unclear. Our present study focuses on the distribution of premotor neurons in the ONR pathways of rats and the collateral projection of the premotor neurons which are involved in the brainstem local pathways of the orofacial nociceptive reflexes of rat. Retrograde tracer Fluoro-gold (FG or FG/tetramethylrhodamine-dextran amine (TMR-DA were injected into the VII or/and XII, and anterograde tracer biotinylated dextran amine (BDA was injected into the caudal spinal trigeminal nucleus (Vc. The tracing studies indicated that FG-labeled neurons receiving BDA-labeled fibers from the Vc were mainly distributed bilaterally in the parvicellular reticular formation (PCRt, dorsal and ventral medullary reticular formation (MdD, MdV, supratrigeminal nucleus (Vsup and parabrachial nucleus (PBN with an ipsilateral dominance. Some FG/TMR-DA double-labeled premotor neurons, which were observed bilaterally in the PCRt, MdD, dorsal part of the MdV, peri-motor nucleus regions, contacted with BDA-labeled axonal terminals and expressed c-fos protein-like immunoreactivity which induced by subcutaneous injection of formalin into the lip. After retrograde tracer wheat germ agglutinated horseradish peroxidase (WGA-HRP was injected into VII or XII and BDA into Vc, electron microscopic study revealed that some BDA-labeled axonal terminals made mainly asymmetric synapses on the dendritic and somatic profiles of WGA-HRP-labeled premotor neurons. These data indicate that some premotor neurons could integrate the orofacial nociceptive input from the Vc and transfer these signals simultaneously to different brainstem motonuclei by axonal collaterals.

Effect of detomidine on visceral and somatic nociception and duodenal motility in conscious adult horses.

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Elfenbein, Johanna R; Sanchez, L Chris; Robertson, Sheilah A; Cole, Cynthia A; Sams, Richard

2009-03-01

To evaluate the effects of detomidine on visceral and somatic nociception, heart and respiratory rates, sedation, and duodenal motility and to correlate these effects with serum detomidine concentrations. Nonrandomized, experimental trial. Five adult horses, each with a permanent gastric cannula weighing 534 +/- 46 kg. Visceral nociception was evaluated by colorectal (CRD) and duodenal distension (DD). The duodenal balloon was used to assess motility. Somatic nociception was assessed via thermal threshold (TT). Nose-to-ground (NTG) height was used as a measure of sedation. Serum was collected for pharmacokinetic analysis. Detomidine (10 or 20 microg kg(-1)) was administered intravenously. Data were analyzed by means of a three-factor anova with fixed factors of treatment and time and random factor of horse. When a significant time x treatment interaction was detected, differences were compared with a simple t-test or Bonferroni t-test. Significance was set at p Detomidine produced a significant, dose-dependent decrease in NTG height, heart rate, and skin temperature and a significant, nondose-dependent decrease in respiratory rate. Colorectal distension threshold was significantly increased with 10 microg kg(-1) for 15 minutes and for at least 165 minutes with 20 microg kg(-1). Duodenal distension threshold was significantly increased at 15 minutes for the 20 microg kg(-1) dose. A significant change in TT was not observed at either dose. A marked, immediate decrease in amplitude of duodenal contractions followed detomidine administration at both doses for 50 minutes. Detomidine caused a longer period of visceral anti-nociception as determined by CRD but a shorter period of anti-nociception as determined by DD than has been previously reported. The lack of somatic anti-nociception as determined by TT testing may be related to the marked decrease in skin temperature, likely caused by peripheral vasoconstriction and the low temperature cut-off of the testing device.

Linkage between increased nociception and olfaction via a SCN9A haplotype.

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Dirk Heimann

Full Text Available BACKGROUND AND AIMS: Mutations reducing the function of Nav1.7 sodium channels entail diminished pain perception and olfactory acuity, suggesting a link between nociception and olfaction at ion channel level. We hypothesized that if such link exists, it should work in both directions and gain-of-function Nav1.7 mutations known to be associated with increased pain perception should also increase olfactory acuity. METHODS: SCN9A variants were assessed known to enhance pain perception and found more frequently in the average population. Specifically, carriers of SCN9A variants rs41268673C>A (P610T; n = 14 or rs6746030C>T (R1150W; n = 21 were compared with non-carriers (n = 40. Olfactory function was quantified by assessing odor threshold, odor discrimination and odor identification using an established olfactory test. Nociception was assessed by measuring pain thresholds to experimental nociceptive stimuli (punctate and blunt mechanical pressure, heat and electrical stimuli. RESULTS: The number of carried alleles of the non-mutated SCN9A haplotype rs41268673C/rs6746030C was significantly associated with the comparatively highest olfactory threshold (0 alleles: threshold at phenylethylethanol dilution step 12 of 16 (n = 1, 1 allele: 10.6±2.6 (n = 34, 2 alleles: 9.5±2.1 (n = 40. The same SCN9A haplotype determined the pain threshold to blunt pressure stimuli (0 alleles: 21.1 N/m(2, 1 allele: 29.8±10.4 N/m(2, 2 alleles: 33.5±10.2 N/m(2. CONCLUSIONS: The findings established a working link between nociception and olfaction via Nav1.7 in the gain-of-function direction. Hence, together with the known reduced olfaction and pain in loss-of-function mutations, a bidirectional genetic functional association between nociception and olfaction exists at Nav1.7 level.

Comparison of voiding function and nociceptive behavior in two rat models of cystitis induced by cyclophosphamide or acetone

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Saitoh, Chikashi; Yokoyama, Hitoshi; Chancellor, Michael B.; de Groat, William C.; Yoshimura, Naoki

2009-01-01

Aims Nociceptive behavior and its relationship with bladder dysfunction were investigated in two cystitis models, which were induced by intraperitoneal (ip) injection of cyclophosphamide (CYP) or intravesical instillation of acetone, using freely moving, non-catheterized conscious rats. Methods Female Sprague-Dawley rats were used. Cystitis was induced by ip injection of CYP (100 and 200mg/kg) or intravesical instillation of acetone (10, 30 and 50%) via a polyethylene catheter temporarily inserted into the bladder through the urethra. Then the incidence of nociceptive behavior (immobility with decreased breathing rates) was scored. Voided urine was collected simultaneously and continuously to measure bladder capacity. The plasma extravasation in the bladder was quantified by an evans blue (EB) dye leakage technique. Results CYP (100mg/kg, ip) induced nociceptive behavior without affecting bladder capacity or EB concentration in the bladder. A higher dose of CYP (200mg/kg, ip) decreased bladder capacity and increased EB levels as well as nociceptive behavior. In contrast, intravesical instillation of acetone (30%) decreased bladder capacity and increased EB levels, but evoked nociceptive behavior less frequently compared with CYP-treated animals. In capsaicin pretreated rats, nociceptive behavior induced by CYP or acetone was reduced; however, the overall effects of CYP or acetone on bladder capacity and bladder EB levels were unaffected. Conclusions These results suggest that there is a difference in the induction process of nociceptive behavior and small bladder capacity after two different types of bladder irritation and that C-fiber sensitization is more directly involved in pain sensation than reduced bladder capacity. PMID:19618450

Nociceptive Effects of Locally Treated Metoprolol

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Nursima Cukadar

2015-06-01

Results: Metoprolol, an antagonist, significantly decreased the thermal latency and mechanical thresholds with dose and time dependent manner. However, dobutamine, an agonist, enhanced the latency and thresholds dose and time dependent. Conclusions: This results suggest that in contrast to dobutamine, locally treated metoprolol may cause hyperalgesic and allodynic actions. In addition, our results can demonstrate that peripheral beta-adrenergic receptors can play important roles in nociceptive process. [Cukurova Med J 2015; 40(2.000: 258-266

Antioxidant and orofacial anti-nociceptive activities of the stem bark aqueous extract of Anadenanthera colubrina (Velloso) Brenan (Fabaceae).

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Damascena, N P; Souza, M T S; Almeida, A F; Cunha, R S; Damascena, N P; Curvello, R L; Lima, A C B; Almeida, E C V; Santos, C C S; Dias, A S; Paixão, M S; Souza, L M A; Quintans Júnior, L J; Estevam, C S; Araujo, B S

2014-01-01

The anti-nociceptive and antioxidant activities of the Anadenantheracolubrina stem bark aqueous extract (AEAC) were investigated. AEAC (30 μg/mL) reduced 94.8% of 2,2-diphenyl-1-picrylhydrazyl radical and prevented 64% (200 μg/mL) of lipid peroxidation caused by 2,2'-azobis(2-methylpropionamidine) dihydrochloride-induced peroxyl radicals. AEAC treatment (200 and 400 mg/kg) significantly (p < 0.001) reduced mice orofacial nociception in the first (61.4% and 62.6%, respectively) and second (48.9% and 61.9%, respectively) phases of the formalin test. Nociception caused by glutamate was significantly (p < 0.001) reduced by up to 79% at 400 mg/kg, while 56-60% of the nociceptive behaviour induced by capsaicin was significantly inhibited by AEAC (100-400 mg/kg). Mice treated with AEAC did not show changes in motor performance in the Rota-rod apparatus. It appears that AEAC is of pharmacological importance in treating pain due to its anti-nociceptive effects, which were shown to be mediated by central and peripheral mechanisms.

Anti-inflammatory and anti-nociceptive activities of methanol extract from aerial part of Phlomis younghusbandii Mukerjee.

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Qiu-Shi Wang

Full Text Available This study was designed to investigate the anti-inflammatory and anti-nociceptive activity of the methanol extract from the aerial part of Phlomis younghusbandii (MEAP and to explore the possible related mechanisms. Anti-inflammatory effects of MEAP were evaluated by using the ear edema test induced by dimethylbenzene and vascular permeability test induced by acetic acid. Anti-nociceptive activities of MEAP were evaluated by the chemical nociception in models of acetic acid-induced writhing and formalin-induced hind paw licking, and by the thermal nociception in hot plate tests. Mechanisms of MEAP activities also were explored by evaluating expression levels of TNF-α, IL-6 and iNOS induced by LPS using real-time fluorogenic PCR and expression of COX-2 using Western blotting and an open-field test. The results indicated that the MEAP administered orally could significantly decrease ear edema induced by dimethylbenzene and increase vascular permeability induced by acetic acid. Additionally, the nociceptions induced by acetic acid and formalin were significantly inhibited. The anti-nociceptive effect could not be decreased by naloxone in the formalin test, and MEAP did not affect the normal autonomic activities of mice. Expression levels of pro-inflammatory cytokines (TNF-α, IL-6, iNOS induced by LPS were decreased obviously by treatment with MEAP. Furthermore, COX-2 expression in the spinal dorsal horns of the pain model mice induced by formalin was significantly down-regulated by MEAP. In conclusion, MEAP has significant anti-inflammatory and antinociceptive activities, and the mechanisms may be related to the down-regulated expression of TNF-α, IL-6, iNOS and COX-2.

Is there a reasonable excuse for not providing post-operative analgesia when using animal models of peripheral neuropathic pain for research purposes?

DEFF Research Database (Denmark)

Hestehave, Sara; Munro, Gordon; Christensen, Rie

2017-01-01

INTRODUCTION: The induction of neuropathic pain-like behaviors in rodents often requires surgical intervention. This engages acute nociceptive signaling events that contribute to pain and stress post-operatively that from a welfare perspective demands peri-operative analgesic treatment. However...

Nociceptive and inflammatory mediator upregulation in a mouse model of chronic prostatitis.

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Schwartz, Erica S; Xie, Amy; La, Jun-Ho; Gebhart, G F

2015-08-01

Chronic nonbacterial prostatitis, characterized by genitourinary pain in the pelvic region in the absence of an identifiable cause, is common in adult males. Surprisingly, the sensory innervation of the prostate and mediators that sensitize its innervation have received little attention. We thus characterized a mouse model of chronic prostatitis, focusing on the prostate innervation and how organ inflammation affects gene expression of putative nociceptive markers in prostate afferent somata in dorsal root ganglia (DRG) and mediators in the prostate. Retrograde tracing (fast blue) from the prostate revealed that thoracolumbar and lumbosacral DRG are the principal sources of somata of prostate afferents. Nociceptive markers (eg, transient receptor potential, TREK, and P2X channels) were upregulated in fast blue-labeled thoracolumbar and lumbosacral somata for up to four weeks after inflaming the prostate (intraprostate injection of zymosan). Prostatic inflammation was evident histologically, by monocyte infiltration and a significant increase in mast cell tryptase activity 14, 21, and 28 days after zymosan injection. Interleukin 10 and NGF were also significantly upregulated in the prostate throughout the 4 weeks of inflammation. Open-field pain-related behaviors (eg, rearing) were unchanged in prostate-inflamed mice, suggesting the absence of ongoing nociception, but withdrawal thresholds to lower abdominal pressure were significantly reduced. The increases in IL-10, mast cell tryptase, and NGF in the inflamed prostate were cotemporaneous with reduced thresholds to probing of the abdomen and upregulation of nociceptive markers in DRG somata innervating the prostate. The results provide insight and direction for the study of mechanisms underlying pain in chronic prostatitis.

Borneol, a Bicyclic Monoterpene Alcohol, Reduces Nociceptive Behavior and Inflammatory Response in Mice

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Jackson Roberto Guedes da Silva Almeida

2013-01-01

Full Text Available Borneol, a bicyclic monoterpene, has been evaluated for antinociceptive and anti-inflammatory activities. Antinociceptive and anti-inflammatory activities were studied by measuring nociception by acetic acid, formalin, hot plate, and grip strength tests, while inflammation was prompted by carrageenan-induced peritonitis. The rotarod test was used to evaluate motor coordination. Borneol produced a significant (P<0.01 reduction of the nociceptive behavior at the early and late phases of paw licking and reduced the writhing reflex in mice (formalin and writhing tests, resp.. When the hot plate test was conducted, borneol (in higher dose produced an inhibition (P<0.05 of the nociceptive behavior. Such results were unlikely to be provoked by motor abnormality. Additionally, borneol-treated mice reduced the carrageenan-induced leukocytes migration to the peritoneal cavity. Together, our results suggest that borneol possess significant central and peripheral antinociceptive activity; it has also anti-inflammatory activity. In addition, borneol did not impair motor coordination.

Estradiol-induced antinociceptive responses on formalin-induced nociception are independent of COX and HPA activation.

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Hunter, Deirtra A; Barr, Gordon A; Amador, Nicole; Shivers, Kai-Yvonne; Kemen, Lynne; Kreiter, Christopher M; Jenab, Shirzad; Inturrisi, Charles E; Quinones-Jenab, Vanya

2011-07-01

Estrogen modulates pain perception but how it does so is not fully understood. The aim of this study was to determine if estradiol reduces nociceptive responses in part via hypothalamic-pituitary-adrenal (HPA) axis regulation of cyclooxygenase (COX)-1/COX-2 activity. The first study examined the effects of estradiol (20%) or vehicle with concurrent injection nonsteroidal antiinflammatory drugs (NSAIDs) on formalin-induced nociceptive responding (flinching) in ovariectomized (OVX) rats. The drugs were ibuprofen (COX-1 and COX-2 inhibitor), SC560 (COX-1 inhibitor), or NS398 (COX-2 inhibitor). In a second study, estradiol's effects on formalin-induced nociception were tested in adrenalectomized (ADX), OVX, and ADX+OVX rats. Serum levels of prostaglandins (PG) PGE(2) and corticosterone were measured. Estradiol significantly decreased nociceptive responses in OVX rats with effects during both the first and the second phase of the formalin test. The nonsteroidal antiinflammatory drugs (NSAIDs) did not alter nociception at the doses used here. Adrenalectomy neither altered flinching responses in female rats nor reversed estradiol-induced antinociceptive responses. Estradiol alone had no effect on corticosterone (CORT) or prostaglandin levels after the formalin test, dissociating the effects of estradiol on behavior and these serum markers. Ibuprofen and NS398 significantly reduced PGE2 levels. CORT was not decreased by OVX surgery or by estradiol below that of ADX. Only IBU significantly increased corticosterone levels. Taken together, our results suggest that estradiol-induced antinociception in female rats is independent of COX activity and HPA axis activation. Copyright © 2010 Wiley-Liss, Inc.

Trigeminal nociception-induced, cerebral Fos expression in the conscious rat

NARCIS (Netherlands)

Ter Horst, GJ; Meijler, WJ; Korf, J; Kemper, RHA

2001-01-01

Little is known about trigeminal nociception-induced cerebral activity and involvement of cerebral structures in pathogenesis of trigeminovascular headaches such as migraine. Neuroimaging has demonstrated cortical, hypothalamic and brainstem activation during the attack and after abolition with

Application of a handheld Pressure Application Measurement device for the characterisation of mechanical nociceptive thresholds in intact pig tails

DEFF Research Database (Denmark)

Di Giminiani, Pierpaolo; Sandercock, Dale A.; Malcolm, Emma M.

2016-01-01

The assessment of nociceptive thresholds is employed in animals and humans to evaluate changes in sensitivity potentially arising from tissue damage. Its application on the intact pig tail might represent a suitable method to assess changes in nociceptive thresholds arising from tail injury...... to the body was observed (P knowledge, no other...... nociceptive threshold in pig tails. This methodological approach is possibly suitable for assessing changes in tail stump MNTs after tail injury caused by tail docking and biting....

DNA Methylation Modulates Nociceptive Sensitization after Incision.

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Yuan Sun

Full Text Available DNA methylation is a key epigenetic mechanism controlling DNA accessibility and gene expression. Blockade of DNA methylation can significantly affect pain behaviors implicated in neuropathic and inflammatory pain. However, the role of DNA methylation with regard to postoperative pain has not yet been explored. In this study we sought to investigate the role of DNA methylation in modulating incisional pain and identify possible targets under DNA methylation and contributing to incisional pain. DNA methyltranferase (DNMT inhibitor 5-Aza-2'-deoxycytidine significantly reduced incision-induced mechanical allodynia and thermal sensitivity. Aza-2'-deoxycytidine also reduced hindpaw swelling after incision, suggesting an anti-inflammatory effect. Global DNA methylation and DNMT3b expression were increased in skin after incision, but none of DNMT1, DNMT3a or DNMT3b was altered in spinal cord or DRG. The expression of proopiomelanocortin Pomc encoding β-endorphin and Oprm1 encoding the mu-opioid receptor were upregulated peripherally after incision; moreover, Oprm1 expression was further increased under DNMT inhibitor treatment. Finally, local peripheral injection of the opioid receptor antagonist naloxone significantly exacerbated incision-induced mechanical hypersensitivity. These results suggest that DNA methylation is functionally relevant to incisional nociceptive sensitization, and that mu-opioid receptor signaling might be one methylation regulated pathway controlling sensitization after incision.

Cognitive aspects of nociception and pain: bridging neurophysiology with cognitive psychology.

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Legrain, V; Mancini, F; Sambo, C F; Torta, D M; Ronga, I; Valentini, E

2012-10-01

The event-related brain potentials (ERPs) elicited by nociceptive stimuli are largely influenced by vigilance, emotion, alertness, and attention. Studies that specifically investigated the effects of cognition on nociceptive ERPs support the idea that most of these ERP components can be regarded as the neurophysiological indexes of the processes underlying detection and orientation of attention toward the eliciting stimulus. Such detection is determined both by the salience of the stimulus that makes it pop out from the environmental context (bottom-up capture of attention) and by its relevance according to the subject's goals and motivation (top-down attentional control). The fact that nociceptive ERPs are largely influenced by information from other sensory modalities such as vision and proprioception, as well as from motor preparation, suggests that these ERPs reflect a cortical system involved in the detection of potentially meaningful stimuli for the body, with the purpose to respond adequately to potential threats. In such a theoretical framework, pain is seen as an epiphenomenon of warning processes, encoded in multimodal and multiframe representations of the body, well suited to guide defensive actions. The findings here reviewed highlight that the ERPs elicited by selective activation of nociceptors may reflect an attentional gain apt to bridge a coherent perception of salient sensory events with action selection processes. Copyright © 2012 Elsevier Masson SAS. All rights reserved.

Anti-nociceptive effect of total alkaloids isolated from the seeds of ...

African Journals Online (AJOL)

pretreatment of the animals with naloxone (2 mg/kg) was performed to investigate whether the anti- nociceptive effect .... detecting the absorbance at 618 nm. Arecoline ..... attenuates food allergic responses in ovalbumin- sensitized mice.

Anti-nociceptive and anti-inflammatory properties of the ethanolic ...

African Journals Online (AJOL)

Anti-nociceptive and anti-inflammatory properties of the ethanolic extract of Lagenaria breviflora whole fruit in rat and mice. ... Its effect was comparable especially at 200mg/kg body weight to those of diclofenac, indomethacin and ibuprofen. It could be suggested from the findings of this experiment that the extract may be ...

The role of Drosophila Piezo in mechanical nociception.

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Kim, Sung Eun; Coste, Bertrand; Chadha, Abhishek; Cook, Boaz; Patapoutian, Ardem

2012-02-19

Transduction of mechanical stimuli by receptor cells is essential for senses such as hearing, touch and pain. Ion channels have a role in neuronal mechanotransduction in invertebrates; however, functional conservation of these ion channels in mammalian mechanotransduction is not observed. For example, no mechanoreceptor potential C (NOMPC), a member of transient receptor potential (TRP) ion channel family, acts as a mechanotransducer in Drosophila melanogaster and Caenorhabditis elegans; however, it has no orthologues in mammals. Degenerin/epithelial sodium channel (DEG/ENaC) family members are mechanotransducers in C. elegans and potentially in D. melanogaster; however, a direct role of its mammalian homologues in sensing mechanical force has not been shown. Recently, Piezo1 (also known as Fam38a) and Piezo2 (also known as Fam38b) were identified as components of mechanically activated channels in mammals. The Piezo family are evolutionarily conserved transmembrane proteins. It is unknown whether they function in mechanical sensing in vivo and, if they do, which mechanosensory modalities they mediate. Here we study the physiological role of the single Piezo member in D. melanogaster (Dmpiezo; also known as CG8486). Dmpiezo expression in human cells induces mechanically activated currents, similar to its mammalian counterparts. Behavioural responses to noxious mechanical stimuli were severely reduced in Dmpiezo knockout larvae, whereas responses to another noxious stimulus or touch were not affected. Knocking down Dmpiezo in sensory neurons that mediate nociception and express the DEG/ENaC ion channel pickpocket (ppk) was sufficient to impair responses to noxious mechanical stimuli. Furthermore, expression of Dmpiezo in these same neurons rescued the phenotype of the constitutive Dmpiezo knockout larvae. Accordingly, electrophysiological recordings from ppk-positive neurons revealed a Dmpiezo-dependent, mechanically activated current. Finally, we found that Dmpiezo

On the use of information theory for the analysis of synchronous nociceptive withdrawal reflexes and somatosensory evoked potentials elicited by graded electrical stimulation.

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Arguissain, Federico G; Biurrun Manresa, José A; Mørch, Carsten D; Andersen, Ole K

2015-01-30

To date, few studies have combined the simultaneous acquisition of nociceptive withdrawal reflexes (NWR) and somatosensory evoked potentials (SEPs). In fact, it is unknown whether the combination of these two signals acquired simultaneously could provide additional information on somatosensory processing at spinal and supraspinal level compared to individual NWR and SEP signals. By using the concept of mutual information (MI), it is possible to quantify the relation between electrical stimuli and simultaneous elicited electrophysiological responses in humans based on the estimated stimulus-response signal probability distributions. All selected features from NWR and SEPs were informative in regard to the stimulus when considered individually. Specifically, the information carried by NWR features was significantly higher than the information contained in the SEP features (pinformation carried by the combination of features showed an overall redundancy compared to the sum of the individual contributions. Comparison with existing methods MI can be used to quantify the information that single-trial NWR and SEP features convey, as well as the information carried jointly by NWR and SEPs. This is a model-free approach that considers linear and non-linear correlations at any order and is not constrained by parametric assumptions. The current study introduces a novel approach that allows the quantification of the individual and joint information content of single-trial NWR and SEP features. This methodology could be used to decode and interpret spinal and supraspinal interaction in studies modulating the responsiveness of the nociceptive system. Copyright © 2014 Elsevier B.V. All rights reserved.

Identifying brain nociceptive information transmission in patients with chronic somatic pain

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Don A. Davis

2016-10-01

Conclusion:. Collectively, the results suggest that, across 2 types of chronic pain, nociceptive-specific information is relayed through the spinothalamic pathway to the lateral thalamus, potentiated by pronociceptive descending modulation, and interrupting cortical cognitive processes.

High-throughput profiling of signaling networks identifies mechanism-based combination therapy to eliminate microenvironmental resistance in acute myeloid leukemia.

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Zeng, Zhihong; Liu, Wenbin; Tsao, Twee; Qiu, YiHua; Zhao, Yang; Samudio, Ismael; Sarbassov, Dos D; Kornblau, Steven M; Baggerly, Keith A; Kantarjian, Hagop M; Konopleva, Marina; Andreeff, Michael

2017-09-01

The bone marrow microenvironment is known to provide a survival advantage to residual acute myeloid leukemia cells, possibly contributing to disease recurrence. The mechanisms by which stroma in the microenvironment regulates leukemia survival remain largely unknown. Using reverse-phase protein array technology, we profiled 53 key protein molecules in 11 signaling pathways in 20 primary acute myeloid leukemia samples and two cell lines, aiming to understand stroma-mediated signaling modulation in response to the targeted agents temsirolimus (MTOR), ABT737 (BCL2/BCL-XL), and Nutlin-3a (MDM2), and to identify the effective combination therapy targeting acute myeloid leukemia in the context of the leukemia microenvironment. Stroma reprogrammed signaling networks and modified the sensitivity of acute myeloid leukemia samples to all three targeted inhibitors. Stroma activated AKT at Ser473 in the majority of samples treated with single-agent ABT737 or Nutlin-3a. This survival mechanism was partially abrogated by concomitant treatment with temsirolimus plus ABT737 or Nutlin-3a. Mapping the signaling networks revealed that combinations of two inhibitors increased the number of affected proteins in the targeted pathways and in multiple parallel signaling, translating into facilitated cell death. These results demonstrated that a mechanism-based selection of combined inhibitors can be used to guide clinical drug selection and tailor treatment regimens to eliminate microenvironment-mediated resistance in acute myeloid leukemia. Copyright© 2017 Ferrata Storti Foundation.

Retinoid receptor signaling and autophagy in acute promyelocytic leukemia.

LENUS (Irish Health Repository)

Orfali, Nina

2014-05-15

Retinoids are a family of signaling molecules derived from vitamin A with well established roles in cellular differentiation. Physiologically active retinoids mediate transcriptional effects on cells through interactions with retinoic acid (RARs) and retinoid-X (RXR) receptors. Chromosomal translocations involving the RARα gene, which lead to impaired retinoid signaling, are implicated in acute promyelocytic leukemia (APL). All-trans-retinoic acid (ATRA), alone and in combination with arsenic trioxide (ATO), restores differentiation in APL cells and promotes degradation of the abnormal oncogenic fusion protein through several proteolytic mechanisms. RARα fusion-protein elimination is emerging as critical to obtaining sustained remission and long-term cure in APL. Autophagy is a degradative cellular pathway involved in protein turnover. Both ATRA and ATO also induce autophagy in APL cells. Enhancing autophagy may therefore be of therapeutic benefit in resistant APL and could broaden the application of differentiation therapy to other cancers. Here we discuss retinoid signaling in hematopoiesis, leukemogenesis, and APL treatment. We highlight autophagy as a potential important regulator in anti-leukemic strategies.

Citral reduces nociceptive and inflammatory response in rodents

OpenAIRE

Quintans-Júnior, Lucindo J.; Guimarães, Adriana G.; Santana, Marilia T. de; Araújo, Bruno E.S.; Moreira, Flávia V.; Bonjardim, Leonardo R.; Araújo, Adriano A. S.; Siqueira, Jullyana S.; Antoniolli, Ângelo R.; Botelho, Marco A.; Almeida, Jackson R. G. S.; Santos, Márcio R. V.

2011-01-01

Citral (CIT), which contains the chiral enantiomers, neral (cis) and geranial (trans), is the majority monoterpene from Lippia alba and Cymbopogon citratus. The present study aimed to evaluate CIT for antinociceptive and anti-inflammatory activities in rodents. Antinociceptive and anti-inflammatory effects were studied by measuring nociception through acetic acid and formalin tests, while inflammation was verified by inducing peritonitis and paw edema with carrageenan. All tested doses of CIT...

The Role of PPK26 in Drosophila Larval Mechanical Nociception

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Yanmeng Guo

2014-11-01

Full Text Available In Drosophila larvae, the class IV dendritic arborization (da neurons are polymodal nociceptors. Here, we show that ppk26 (CG8546 plays an important role in mechanical nociception in class IV da neurons. Our immunohistochemical and functional results demonstrate that ppk26 is specifically expressed in class IV da neurons. Larvae with mutant ppk26 showed severe behavioral defects in a mechanical nociception behavioral test but responded to noxious heat stimuli comparably to wild-type larvae. In addition, functional studies suggest that ppk26 and ppk (also called ppk1 function in the same pathway, whereas piezo functions in a parallel pathway. Consistent with these functional results, we found that PPK and PPK26 are interdependent on each other for their cell surface localization. Our work indicates that PPK26 and PPK might form heteromeric DEG/ENaC channels that are essential for mechanotransduction in class IV da neurons.

Role of spinal metabotropic glutamate receptor 5 in pudendal inhibition of the nociceptive bladder reflex in cats.

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Reese, Jeremy N; Rogers, Marc J; Xiao, Zhiying; Shen, Bing; Wang, Jicheng; Schwen, Zeyad; Roppolo, James R; de Groat, William C; Tai, Changfeng

2015-04-15

This study examined the role of spinal metabotropic glutamate receptor 5 (mGluR5) in the nociceptive C-fiber afferent-mediated spinal bladder reflex and in the inhibtion of this reflex by pudendal nerve stimulation (PNS). In α-chloralose-anesthetized cats after spinal cord transection at the T9/T10 level, intravesical infusion of 0.25% acetic acid irritated the bladder, activated nociceptive C-fiber afferents, and induced spinal reflex bladder contractions of low amplitude (reflexes were responsible for a major component of the contractions. This study shows that spinal mGluR5 plays an important role in the nociceptive C-fiber afferent-mediated spinal bladder reflex and in pudendal inhibition of this spinal reflex. Copyright © 2015 the American Physiological Society.

Effects of magnetic field exposure on open field behaviour and nociceptive responses in mice.

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Del Seppia, Cristina; Mezzasalma, Lorena; Choleris, Elena; Luschi, Paolo; Ghione, Sergio

2003-09-15

Results of previous studies have shown that nociceptive sensitivity in male C57 mice is enhanced by exposure to a regular 37 Hz or an irregularly varying (field. In order to test whether these fields affect more generally mouse behaviour, we placed Swiss CD-1 mice in a novel environment (open field test) and exposed them for 2 h to these two different magnetic field conditions. Hence, we analysed how duration and time course of various behavioural patterns (i.e. exploration, rear, edge chew, self-groom, sit, walk and sleep) and nociceptive sensitivity had been affected by such exposure. Nociceptive sensitivity was significantly greater in magnetically treated mice than in controls. The overall time spent in exploratory activities was significantly shorter in both magnetically treated groups (time), than in controls (42%). Conversely, the time spent in sleeping was markedly longer in the treated groups (both 27% of total time) than in controls (11%). These results suggest that exposure to altered magnetic fields induce a more rapid habituation to a novel environment.

Synaptic Conversion of Chloride-Dependent Synapses in Spinal Nociceptive Circuits: Roles in Neuropathic Pain

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Mark S. Cooper

2011-01-01

Full Text Available Electrophysiological conversion of chloride-dependent synapses from inhibitory to excitatory function, as a result of aberrant neuronal chloride homeostasis, is a known mechanism for the genesis of neuropathic pain. This paper examines theoretically how this type of synaptic conversion can disrupt circuit logic in spinal nociceptive circuits. First, a mathematical scaling factor is developed to represent local aberration in chloride electrochemical driving potential. Using this mathematical scaling factor, electrophysiological symbols are developed to represent the magnitude of synaptic conversion within nociceptive circuits. When inserted into a nociceptive circuit diagram, these symbols assist in understanding the generation of neuropathic pain associated with the collapse of transmembrane chloride gradients. A more generalized scaling factor is also derived to represent the interplay of chloride and bicarbonate driving potentials on the function of GABAergic and glycinergic synapses. These mathematical and symbolic representations of synaptic conversion help illustrate the critical role that anion driving potentials play in the transduction of pain. Using these representations, we discuss ramifications of glial-mediated synaptic conversion in the genesis, and treatment, of neuropathic pain.

SDF1-CXCR4 Signaling Contributes to the Transition from Acute to Chronic Pain State.

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Yang, Fei; Sun, Wei; Luo, Wen-Jun; Yang, Yan; Yang, Fan; Wang, Xiao-Liang; Chen, Jun

2017-05-01

Emerging evidence has demonstrated the involvement of stromal cell-derived factor 1 (SDF1, also known as CXCL12)-CXCR4 signaling in a variety of pain state. However, the underlying mechanisms of SDF1-CXCR4 signaling leading to the maintenance of chronic pain states are poorly understood. In the present study, we sought to explore the role of SDF1-CXCR4 signaling in the forming of neuroplasticity by applying a model of the transition from acute to chronic pain state, named as hyperalgesic priming. Utilizing intraplantar bee venom (BV) injection, we successfully established hyperalgesic priming state and found that peripheral treating with AMD3100, a CXCR4 antagonist, or knocking down CXCR4 by intraganglionar CXCR4 small interfering RNA (siRNA) injection could prevent BV-induced primary mechanical hyperalgesia and hyperalgesic priming. Moreover, we showed that single intraplantar active SDF1 protein injection is sufficient to induce acute mechanical hyperalgesia and hyperalgesic priming through CXC4. Intraplantar coinjection of ERK inhibitor, U0126, and PI3K inhibitor, LY294002, as well as two protein translation inhibitors, temsirolimus and cordycepin, prevented the development of SDF1-induced acute mechanical hyperalgesia and hyperalgesic priming. Finally, on the models of complete Freund's adjuvant (CFA)-induced chronic inflammatory pain and spared nerve injury (SNI)-induced chronic neuropathic pain, we observed that knock-down of CXCR4 could both prevent the development and reverse the maintenance of chronic pain state. In conclusion, our present data suggested that through regulating ERK and PI3K-AKT pathways-mediated protein translation SDF1-CXCR4 signaling mediates the transition from acute pain to chronic pain state and finally contributes to the development and maintenance of chronic pain.

Corticostriatal Regulation of Acute Pain

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Erik Martinez

2017-05-01

Full Text Available The mechanisms for acute pain regulation in the brain are not well understood. The prefrontal cortex (PFC provides top-down control of emotional processes, and it projects to the nucleus accumbens (NAc. This corticostriatal projection forms an important regulatory pathway within the brain’s reward system. Recently, this projection has been suggested to control both sensory and affective phenotypes specifically associated with chronic pain. As this projection is also known to play a role in the transition from acute to chronic pain, we hypothesized that this corticostriatal circuit can also exert a modulatory function in the acute pain state. Here, we used optogenetics to specifically target the projection from the PFC to the NAc. We tested sensory pain behaviors with Hargreaves’ test and mechanical allodynia, and aversive pain behaviors with conditioned place preference (CPP test. We found that the activation of this corticostriatal circuit gave rise to bilateral relief from peripheral nociceptive inputs. Activation of this circuit also provided important control for the aversive response to transient noxious stimulations. Hence, our results support a novel role for corticostriatal circuitry in acute pain regulation.

Neonatal morphine enhances nociception and decreases analgesia in young rats.

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Zhang, Guo Hua; Sweitzer, Sarah M

2008-03-14

The recognition of the impact of neonatal pain experience on subsequent sensory processing has led to the increased advocacy for the use of opioids for pain relief in infants. However, following long-term opioid exposure in intensive care units more than 48% of infants exhibited behaviors indicative of opioid abstinence syndrome, a developmentally equivalent set of behaviors to opioid withdrawal as seen in adults. Little is known about the long-term influence of repeated neonatal morphine exposure on nociception and analgesia. To investigate this, we examined mechanical and thermal nociception on postnatal days 11, 13, 15, 19, 24, 29, 39 and 48 following subcutaneous administration of morphine (3 mg/kg) once daily on postnatal days 1-9. The cumulative morphine dose-response was assessed on postnatal days 20 and 49, and stress-induced analgesia was assessed on postnatal days 29 and 49. Both basal mechanical and thermal nociception in neonatal, morphine-exposed rats were significantly lower than those in saline-exposed, handled-control rats and naive rats until P29. A rightward-shift of cumulative dose-response curves for morphine analgesia upon chronic neonatal morphine was observed both on P20 and P49. The swim stress-induced analgesia was significantly decreased in neonatal morphine-exposed rats on P29, but not on P49. These data indicate that morphine exposure equivalent to the third trimester of gestation produced prolonged pain hypersensitivity, decreased morphine antinociception, and decreased stress-induced analgesia. The present study illustrates the need to examine the long-term influence of prenatal morphine exposure on pain and analgesia in the human pediatric population.

Evidence for spinal N-methyl-d-aspartate receptor involvement in prolonged chemical nociception in the rat.

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Haley, Jane E; Dickenson, Anthony H

2016-08-15

We used in vivo electrophysiology and a model of more persistent nociceptive inputs to monitor spinal cord neuronal activity in anaesthetised rats to reveal the pharmacology of enhanced pain signalling. The study showed that all responses were blocked by non-selective antagonism of glutamate receptors but a selective and preferential role of the N-methyl-d-aspartate (NMDA) receptor in the prolonged plastic responses was clearly seen. The work lead to many publications, initially preclinical but increasingly from patient studies, showing the importance of the NMDA receptor in central sensitisation within the spinal cord and how this could relate to persistent pain states. This article is part of a Special Issue entitled SI:50th Anniversary Issue. Copyright © 2016 Elsevier B.V. All rights reserved.

Validation of a thermal threshold nociceptive model in bearded dragons (Pogona vitticeps).

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Couture, Émilie L; Monteiro, Beatriz P; Aymen, Jessica; Troncy, Eric; Steagall, Paulo V

2017-05-01

To validate a thermal threshold (TT) nociceptive model in bearded dragons (Pogona vitticeps) and to document TT changes after administration of morphine. A two-part randomized, blinded, controlled, experimental study. Five adult bearded dragons (242-396 g). A TT device delivered a ramped nociceptive stimulus (0.6 °C second -1 ) to the medial thigh until a response (leg kick/escape behavior) was observed or maximum (cut-off) temperature of 62 °C was reached. In phase I, period 1, six TT readings were determined at 20 minute intervals for evaluation of repeatability. Two of these readings were randomly assigned to be sham to assess specificity of the behavioral response. The same experiment was repeated 2 weeks later (period 2) to test reproducibility. In phase II, animals were administered either intramuscular morphine (10 mg kg -1 ) or saline 0.9%. TTs (maximum 68 °C) were determined before and 2, 4, 8, 12 and 24 hours after treatment administration. Data were analyzed using one-way anova (temporal changes and repeatability) and paired t tests (reproducibility and treatment comparisons) using Bonferroni correction (p dragons. TT nociceptive testing detected morphine administration and may be suitable for studying opioid regimens in bearded dragons. Copyright © 2017 Association of Veterinary Anaesthetists and American College of Veterinary Anesthesia and Analgesia. Published by Elsevier Ltd. All rights reserved.

Consequences of a human TRPA1 genetic variant on the perception of nociceptive and olfactory stimuli.

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Michael Schütz

Full Text Available BACKGROUND: TRPA1 ion channels are involved in nociception and are also excited by pungent odorous substances. Based on reported associations of TRPA1 genetics with increased sensitivity to thermal pain stimuli, we therefore hypothesized that this association also exists for increased olfactory sensitivity. METHODS: Olfactory function and nociception was compared between carriers (n = 38 and non-carriers (n = 43 of TRPA1 variant rs11988795 G>A, a variant known to enhance cold pain perception. Olfactory function was quantified by assessing the odor threshold, odor discrimination and odor identification, and by applying 200-ms pulses of H2S intranasal. Nociception was assessed by measuring pain thresholds to experimental nociceptive stimuli (blunt pressure, electrical stimuli, cold and heat stimuli, and 200-ms intranasal pulses of CO2. RESULTS: Among the 11 subjects with moderate hyposmia, carriers of the minor A allele (n = 2 were underrepresented (34 carriers among the 70 normosmic subjects; p = 0.049. Moreover, carriers of the A allele discriminated odors significantly better than non-carriers (13.1±1.5 versus 12.3±1.6 correct discriminations and indicated a higher intensity of the H2S stimuli (29.2±13.2 versus 21±12.8 mm VAS, p = 0.006, which, however, could not be excluded to have involved a trigeminal component during stimulation. Finally, the increased sensitivity to thermal pain could be reproduced. CONCLUSIONS: The findings are in line with a previous association of a human TRPA1 variant with nociceptive parameters and extend the association to the perception of odorants. However, this addresses mainly those stimulants that involve a trigeminal component whereas a pure olfactory effect may remain disputable. Nevertheless, findings suggest that future TRPA1 modulating drugs may modify the perception of odorants.

Deregulated WNT signaling in childhood T-cell acute lymphoblastic leukemia

International Nuclear Information System (INIS)

Ng, O H; Erbilgin, Y; Firtina, S; Celkan, T; Karakas, Z; Aydogan, G; Turkkan, E; Yildirmak, Y; Timur, C; Zengin, E; Dongen, J J M van; Staal, F J T; Ozbek, U; Sayitoglu, M

2014-01-01

WNT signaling has been implicated in the regulation of hematopoietic stem cells and plays an important role during T-cell development in thymus. Here we investigated WNT pathway activation in childhood T-cell acute lymphoblastic leukemia (T-ALL) patients. To evaluate the potential role of WNT signaling in T-cell leukomogenesis, we performed expression analysis of key components of WNT pathway. More than 85% of the childhood T-ALL patients showed upregulated β-catenin expression at the protein level compared with normal human thymocytes. The impact of this upregulation was reflected in high expression of known target genes (AXIN2, c-MYC, TCF1 and LEF). Especially AXIN2, the universal target gene of WNT pathway, was upregulated at both mRNA and protein levels in ∼40% of the patients. When β-CATENIN gene was silenced by small interfering RNA, the cancer cells showed higher rates of apoptosis. These results demonstrate that abnormal WNT signaling activation occurs in a significant fraction of human T-ALL cases independent of known T-ALL risk factors. We conclude that deregulated WNT signaling is a novel oncogenic event in childhood T-ALL

Effect of butorphanol on thermal nociceptive threshold in healthy pony foals.

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McGowan, K T; Elfenbein, J R; Robertson, S A; Sanchez, L C

2013-07-01

Pain management is an important component of foal nursing care, and no objective data currently exist regarding the analgesic efficacy of opioids in foals. To evaluate the somatic antinociceptive effects of 2 commonly used doses of intravenous (i.v.) butorphanol in healthy foals. Our hypothesis was that thermal nociceptive threshold would increase following i.v. butorphanol in a dose-dependent manner in both neonatal and older pony foals. Seven healthy neonatal pony foals (age 1-2 weeks), and 11 healthy older pony foals (age 4-8 weeks). Five foals were used during both age periods. Treatments, which included saline (0.5 ml), butorphanol (0.05 mg/kg bwt) and butorphanol (0.1 mg/kg bwt), were administered i.v. in a randomised crossover design with at least 2 days between treatments. Response variables included thermal nociceptive threshold, skin temperature and behaviour score. Data within each age period were analysed using a 2-way repeated measures ANOVA, followed by a Holm-Sidak multiple comparison procedure if warranted. There was a significant (P<0.05) increase in thermal threshold, relative to Time 0, following butorphanol (0.1 mg/kg bwt) administration in both age groups. No significant time or treatment effects were apparent for skin temperature. Significant time, but not treatment, effects were evident for behaviour score in both age groups. Butorphanol (0.1 mg/kg bwt, but not 0.05 mg/kg bwt) significantly increased thermal nociceptive threshold in neonatal and older foals without apparent adverse behavioural effects. Butorphanol shows analgesic potential in foals for management of somatic painful conditions. © 2012 EVJ Ltd.

Pruritic and Nociceptive Sensations and Dysesthesias From a Spicule of Cowhage

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LaMotte, R. H.; Shimada, S. G.; Green, B. G.; Zelterman, D.

2009-01-01

Although the trichomes (spicules) of a pod of cowhage (Mucuna pruriens) are known to evoke a histamine-independent itch that is mediated by a cysteine protease, little is known of the itch and accompanying nociceptive sensations evoked by a single spicule and the enhanced itch and pain that can occur in the surrounding skin. The tip of a single spicule applied to the forearm of 45 subjects typically evoked 1) itch accompanied by nociceptive sensations (NS) of pricking/stinging and, to a lesser extent, burning, and 2) one or more areas of cutaneous dysesthesia characterized by hyperknesis (enhanced itch to pricking) with or without alloknesis (itch to stroking) and/or hyperalgesia (enhanced pricking pain). Itch could occur in the absence of NS or one or more dysesthesias but very rarely the reverse. The peak magnitude of sensation was positively correlated for itch and NS and increased (exhibited spatial summation) as the number of spicules was increased within a spatial extent of 6 cm but not 1 cm. The areas of dysesthesia did not exhibit spatial summation. We conclude that itch evoked by a punctate chemical stimulus can co-exist with NS and cutaneous dysesthesias as may occur in clinical pruritus. However, cowhage itch was not always accompanied by NS or dysesthesia nor was a momentary change in itch necessarily accompanied by a similar change in NS or vice versa. Thus there may be separate neural coding mechanisms for itch, nociceptive sensations, and each type of dysesthesia. PMID:19144738

Chemogenetic and Optogenetic Activation of Gαs Signaling in the Basolateral Amygdala Induces Acute and Social Anxiety-Like States.

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Siuda, Edward R; Al-Hasani, Ream; McCall, Jordan G; Bhatti, Dionnet L; Bruchas, Michael R

2016-07-01

Anxiety disorders are debilitating psychiatric illnesses with detrimental effects on human health. These heightened states of arousal are often in the absence of obvious threatening cues and are difficult to treat owing to a lack of understanding of the neural circuitry and cellular machinery mediating these conditions. Activation of noradrenergic circuitry in the basolateral amygdala is thought to have a role in stress, fear, and anxiety, and the specific cell and receptor types responsible is an active area of investigation. Here we take advantage of two novel cellular approaches to dissect the contributions of G-protein signaling in acute and social anxiety-like states. We used a chemogenetic approach utilizing the Gαs DREADD (rM3Ds) receptor and show that selective activation of generic Gαs signaling is sufficient to induce acute and social anxiety-like behavioral states in mice. Second, we use a recently characterized chimeric receptor composed of rhodopsin and the β2-adrenergic receptor (Opto-β2AR) with in vivo optogenetic techniques to selectively activate Gαs β-adrenergic signaling exclusively within excitatory neurons of the basolateral amygdala. We found that optogenetic induction of β-adrenergic signaling in the basolateral amygdala is sufficient to induce acute and social anxiety-like behavior. These findings support the conclusion that activation of Gαs signaling in the basolateral amygdala has a role in anxiety. These data also suggest that acute and social anxiety-like states may be mediated through signaling pathways identical to β-adrenergic receptors, thus providing support that inhibition of this system may be an effective anxiolytic therapy.

Ovariectomy results in variable changes in nociception, mood and depression in adult female rats.

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Li-Hong Li

Full Text Available Decline in the ovarian hormones with menopause may influence somatosensory, cognitive, and affective processing. The present study investigated whether hormonal depletion alters the nociceptive, depressive-like and learning behaviors in experimental rats after ovariectomy (OVX, a common method to deplete animals of their gonadal hormones. OVX rats developed thermal hyperalgesia in proximal and distal tail that was established 2 weeks after OVX and lasted the 7 weeks of the experiment. A robust mechanical allodynia was also occurred at 5 weeks after OVX. In the 5th week after OVX, dilute formalin (5%-induced nociceptive responses (such as elevating and licking or biting during the second phase were significantly increased as compared to intact and sham-OVX females. However, chronic constriction injury (CCI of the sciatic nerve-induced mechanical allodynia did not differ as hormonal status (e.g. OVX and ovarian intact. Using formalin-induced conditioned place avoidance (F-CPA, which is believed to reflect the pain-related negative emotion, we further found that OVX significantly attenuated F-CPA scores but did not alter electric foot-shock-induced CPA (S-CPA. In the open field and forced swimming test, there was an increase in depressive-like behaviors in OVX rats. There was no detectable impairment of spatial performance by Morris water maze task in OVX rats up to 5 weeks after surgery. Estrogen replacement retrieved OVX-induced nociceptive hypersensitivity and depressive-like behaviors. This is the first study to investigate the impacts of ovarian removal on nociceptive perception, negative emotion, depressive-like behaviors and spatial learning in adult female rats in a uniform and standard way.

Anti-nociceptive effects of calcitonin gene-related peptide in nucleus raphe magnus of rats: an effect attenuated by naloxone.

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Huang, Y; Brodda-Jansen, G; Lundeberg, T; Yu, L C

2000-08-04

The present study investigated the role of calcitonin gene-related peptide (CGRP) on nociception in nucleus raphe magnus (NRM) and the interaction between CGRP and opioid peptides in NRM of rats. CGRP-like immunoreactivity was found at a concentration of 6.0+/-0. 77 pmol/g in NRM tissue of ten samples of rats, suggesting that it may contribute to physiological responses orchestrated by the NRM. The hindpaw withdrawal latency (HWL) to thermal and mechanical stimulation increased significantly after intra-NRM administration of 0.5 or 1 nmol of CGRP in rats, but not 0.25 nmol. The anti-nociceptive effect induced by CGRP was antagonized by following intra-NRM injection of 1 nmol of the CGRP receptor antagonist CGRP8-37. Furthermore, the CGRP-induced anti-nociceptive effect was attenuated by following intra-NRM administration of 6 nmol of naloxone. The results indicate that CGRP and its receptors play an important role in anti-nociception, and there is a possible interaction between CGRP and opioid peptides in NRM of rats.

Neonatal bee venom exposure induces sensory modality-specific enhancement of nociceptive response in adult rats.

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Li, Mengmeng; Chen, Huisheng; Tang, Jiaguang; Chen, Jun

2014-06-01

Previous studies have shown that inflammatory pain at the neonatal stage can produce long-term structural and functional changes in nociceptive pathways, resulting in altered pain perception in adulthood. However, the exact pattern of altered nociceptive response and associated neurochemical changes in the spinal cord in this process is unclear. In this study, we used an experimental paradigm in which each rat first received intraplantar bee venom (BV) or saline injection on postnatal day 1, 4, 7, 14, 21, or 28. This was followed 2 months later by a second intraplantar bee venom injection in the same rats to examine the difference in nociceptive responses. We found that neonatal inflammatory pain induced by the first BV injection significantly reduced baseline paw withdrawal mechanical threshold, but not baseline paw withdrawal thermal latency, when rats were examined 2 months from the first BV injection. Neonatal inflammatory pain also exacerbated mechanical, but not thermal, hyperalgesia in response to the second BV injection in these same rats. Rats exposed to neonatal inflammation also showed up-regulation of spinal NGF, TrkA receptor, BDNF, TrkB receptor, IL-1β, and COX-2 expression following the second BV injection, especially with prior BV exposure on postnatal day 21 or 28. These results indicate that neonatal inflammation produces sensory modality-specific changes in nociceptive behavior and alters neurochemistry in the spinal cord of adult rats. These results also suggest that a prior history of inflammatory pain during the developmental period might have an impact on clinical pain in highly susceptible adult patients. Wiley Periodicals, Inc.

Interactions between superficial and deep dorsal horn spinal cord neurons in the processing of nociceptive information.

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Petitjean, Hugues; Rodeau, Jean-Luc; Schlichter, Rémy

2012-12-01

In acute rat spinal cord slices, the application of capsaicin (5 μm, 90 s), an agonist of transient receptor potential vanilloid 1 receptors expressed by a subset of nociceptors that project to laminae I-II of the spinal cord dorsal horn, induced an increase in the frequency of spontaneous excitatory and spontaneous inhibitory postsynaptic currents in about half of the neurons in laminae II, III-IV and V. In the presence of tetrodotoxin, which blocks action potential generation and polysynaptic transmission, capsaicin increased the frequency of miniature excitatory postsynaptic currents in only 30% of lamina II neurons and had no effect on the frequency of miniature excitatory postsynaptic currents in laminae III-V or on the frequency of miniature inhibitory postsynaptic currents in laminae II-V. When the communication between lamina V and more superficial laminae was interrupted by performing a mechanical section between laminae IV and V, capsaicin induced an increase in spontaneous excitatory postsynaptic current frequency in laminae II-IV and an increase in spontaneous inhibitory postsynaptic current frequency in lamina II that were similar to those observed in intact slices. However, in laminae III-IV of transected slices, the increase in spontaneous inhibitory postsynaptic current frequency was virtually abolished. Our results indicate that nociceptive information conveyed by transient receptor potential vanilloid 1-expressing nociceptors is transmitted from lamina II to deeper laminae essentially by an excitatory pathway and that deep laminae exert a 'feedback' control over neurons in laminae III-IV by increasing inhibitory synaptic transmission in these laminae. Moreover, we provide evidence that laminae III-IV might play an important role in the processing of nociceptive information in the dorsal horn. © 2012 The Authors. European Journal of Neuroscience © 2012 Federation of European Neuroscience Societies and Blackwell Publishing Ltd.

Vagus nerve stimulation inhibits trigeminal nociception in a rodent model of episodic migraine

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Jordan L. Hawkins

2017-12-01

Conclusion:. Our findings demonstrate that nVNS inhibits mechanical nociception and represses expression of proteins associated with peripheral and central sensitization of trigeminal neurons in a novel rodent model of episodic migraine.

Increased BOLD Signals Elicited by High Gamma Auditory Stimulation of the Left Auditory Cortex in Acute State Schizophrenia

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Hironori Kuga, M.D.

2016-10-01

We acquired BOLD responses elicited by click trains of 20, 30, 40 and 80-Hz frequencies from 15 patients with acute episode schizophrenia (AESZ, 14 symptom-severity-matched patients with non-acute episode schizophrenia (NASZ, and 24 healthy controls (HC, assessed via a standard general linear-model-based analysis. The AESZ group showed significantly increased ASSR-BOLD signals to 80-Hz stimuli in the left auditory cortex compared with the HC and NASZ groups. In addition, enhanced 80-Hz ASSR-BOLD signals were associated with more severe auditory hallucination experiences in AESZ participants. The present results indicate that neural over activation occurs during 80-Hz auditory stimulation of the left auditory cortex in individuals with acute state schizophrenia. Given the possible association between abnormal gamma activity and increased glutamate levels, our data may reflect glutamate toxicity in the auditory cortex in the acute state of schizophrenia, which might lead to progressive changes in the left transverse temporal gyrus.

Impact of carprofen administration on stress and nociception responses of calves to cautery dehorning.

Science.gov (United States)

Stock, M L; Barth, L A; Van Engen, N K; Millman, S T; Gehring, R; Wang, C; Voris, E A; Wulf, L W; Labeur, Léa; Hsu, W H; Coetzee, J F

2016-02-01

The objective of this study was to investigate the effects of carprofen administered immediately before cautery dehorning on nociception and stress. Forty Holstein calves aged approximately 6 to 8 wk old were either placebo treated and sham dehorned ( = 10) or cautery dehorned following administration of carprofen (1.4 mg/kg) subcutaneously ( = 10) or orally ( = 10) or a subcutaneous and oral placebo ( = 10) in a randomized, controlled trial. All animals were given a cornual nerve block using lidocaine before dehorning. Response variables including mechanical nociception threshold, ocular temperature, heart rate, and respiratory rate were measured before and following cautery dehorning for 96 h. Blood samples were also collected over 96 h following dehorning and analyzed for plasma cortisol and substance P concentrations by RIA. Plasma carprofen concentration and ex vivo PGE concentrations were also determined for this time period. Average daily gain was calculated for 7 d after dehorning. Data were analyzed using a linear mixed effects model with repeated measures, controlling for baseline values by their inclusion as a covariate in addition to planned contrasts. Dehorning was associated with decreased nociception thresholds throughout the study and a stress response immediately after dehorning, following the loss of local anesthesia, and 48 h after dehorning compared with sham-dehorned calves. Carprofen was well absorbed after administration and reached concentrations that inhibited ex vivo PGE concentrations for 72 h (subcutaneous) and 96 h (oral) compared with placebo-treated calves ( Carprofen-treated calves tended to be less sensitive ( = 0.097) to nociceptive threshold tests. Overall, at the dosing regimen studied, the effect of carprofen on sensitivity and stress following cautery dehorning was minimal. Consideration of route of administration and dose determination studies may be warranted.

Retinoid receptor signaling and autophagy in acute promyelocytic leukemia

International Nuclear Information System (INIS)

Orfali, Nina; McKenna, Sharon L.; Cahill, Mary R.; Gudas, Lorraine J.; Mongan, Nigel P.

2014-01-01

Retinoids are a family of signaling molecules derived from vitamin A with well established roles in cellular differentiation. Physiologically active retinoids mediate transcriptional effects on cells through interactions with retinoic acid (RARs) and retinoid-X (RXR) receptors. Chromosomal translocations involving the RARα gene, which lead to impaired retinoid signaling, are implicated in acute promyelocytic leukemia (APL). All-trans-retinoic acid (ATRA), alone and in combination with arsenic trioxide (ATO), restores differentiation in APL cells and promotes degradation of the abnormal oncogenic fusion protein through several proteolytic mechanisms. RARα fusion-protein elimination is emerging as critical to obtaining sustained remission and long-term cure in APL. Autophagy is a degradative cellular pathway involved in protein turnover. Both ATRA and ATO also induce autophagy in APL cells. Enhancing autophagy may therefore be of therapeutic benefit in resistant APL and could broaden the application of differentiation therapy to other cancers. Here we discuss retinoid signaling in hematopoiesis, leukemogenesis, and APL treatment. We highlight autophagy as a potential important regulator in anti-leukemic strategies. - Highlights: • Normal and aberrant retinoid signaling in hematopoiesis and leukemia is reviewed. • We suggest a novel role for RARα in the development of X-RARα gene fusions in APL. • ATRA therapy in APL activates transcription and promotes onco-protein degradation. • Autophagy may be involved in both onco-protein degradation and differentiation. • Pharmacologic autophagy induction may potentiate ATRA's therapeutic effects

Retinoid receptor signaling and autophagy in acute promyelocytic leukemia

Energy Technology Data Exchange (ETDEWEB)

Orfali, Nina [Cork Cancer Research Center, University College Cork, Cork (Ireland); Department of Pharmacology, Weill Cornell Medical College, New York, NY 10065, USA. (United States); McKenna, Sharon L. [Cork Cancer Research Center, University College Cork, Cork (Ireland); Cahill, Mary R. [Department of Hematology, Cork University Hospital, Cork (Ireland); Gudas, Lorraine J., E-mail: ljgudas@med.cornell.edu [Department of Pharmacology, Weill Cornell Medical College, New York, NY 10065, USA. (United States); Mongan, Nigel P., E-mail: nigel.mongan@nottingham.ac.uk [Faculty of Medicine and Health Science, School of Veterinary Medicine and Science, University of Nottingham, LE12 5RD (United Kingdom); Department of Pharmacology, Weill Cornell Medical College, New York, NY 10065, USA. (United States)

2014-05-15

Retinoids are a family of signaling molecules derived from vitamin A with well established roles in cellular differentiation. Physiologically active retinoids mediate transcriptional effects on cells through interactions with retinoic acid (RARs) and retinoid-X (RXR) receptors. Chromosomal translocations involving the RARα gene, which lead to impaired retinoid signaling, are implicated in acute promyelocytic leukemia (APL). All-trans-retinoic acid (ATRA), alone and in combination with arsenic trioxide (ATO), restores differentiation in APL cells and promotes degradation of the abnormal oncogenic fusion protein through several proteolytic mechanisms. RARα fusion-protein elimination is emerging as critical to obtaining sustained remission and long-term cure in APL. Autophagy is a degradative cellular pathway involved in protein turnover. Both ATRA and ATO also induce autophagy in APL cells. Enhancing autophagy may therefore be of therapeutic benefit in resistant APL and could broaden the application of differentiation therapy to other cancers. Here we discuss retinoid signaling in hematopoiesis, leukemogenesis, and APL treatment. We highlight autophagy as a potential important regulator in anti-leukemic strategies. - Highlights: • Normal and aberrant retinoid signaling in hematopoiesis and leukemia is reviewed. • We suggest a novel role for RARα in the development of X-RARα gene fusions in APL. • ATRA therapy in APL activates transcription and promotes onco-protein degradation. • Autophagy may be involved in both onco-protein degradation and differentiation. • Pharmacologic autophagy induction may potentiate ATRA's therapeutic effects.

New Insights in Trigeminal Anatomy: A Double Orofacial Tract for Nociceptive Input

NARCIS (Netherlands)

Henssen, D.J.H.A.; Kurt, E.; Kozicz, L.T.; Dongen, R.T.M. van; Bartels, R.H.M.A.; Cappellen van Walsum, A.M. van

2016-01-01

Orofacial pain in patients relies on the anatomical pathways that conduct nociceptive information, originating from the periphery towards the trigeminal sensory nucleus complex (TSNC) and finally, to the thalami and the somatosensorical cortical regions. The anatomy and function of the so-called

The Inhibitory Effect of Somatostatin Receptor Activation on Bee Venom-Evoked Nociceptive Behavior and pCREB Expression in Rats

Directory of Open Access Journals (Sweden)

Li Li

2014-01-01

Full Text Available The present study examined nociceptive behaviors and the expression of phosphorylated cAMP response element-binding protein (pCREB in the dorsal horn of the lumbar spinal cord and the dorsal root ganglion (DRG evoked by bee venom (BV. The effect of intraplantar preapplication of the somatostatin analog octreotide on nociceptive behaviors and pCREB expression was also examined. Subcutaneous injection of BV into the rat unilateral hindpaw pad induced significant spontaneous nociceptive behaviors, primary mechanical allodynia, primary thermal hyperalgesia, and mirror-thermal hyperalgesia, as well as an increase in pCREB expression in the lumbar spinal dorsal horn and DRG. Octreotide pretreatment significantly attenuated the BV-induced lifting/licking response and mechanical allodynia. Local injection of octreotide also significantly reduced pCREB expression in the lumbar spinal dorsal horn and DRG. Furthermore, pretreatment with cyclosomatostatin, a somatostatin receptor antagonist, reversed the octreotide-induced inhibition of the lifting/licking response, mechanical allodynia, and the expression of pCREB. These results suggest that BV can induce nociceptive responses and somatostatin receptors are involved in mediating the antinociception, which provides new evidence for peripheral analgesic action of somatostatin in an inflammatory pain state.

Thrombopoietin/MPL participates in initiating and maintaining RUNX1-ETO acute myeloid leukemia via PI3K/AKT signaling

NARCIS (Netherlands)

J.A. Pulikkan (John); D. Madera (Dmitri); L. Xue (Liting); P. Bradley (Paul); S.F. Landrette (Sean Francis); Y.-H. Kuo (Ya-Huei); S. Abbas (Saman); L.J. Zhu (Lihua Julie); P.J.M. Valk (Peter); L.H. Castilla (Lucio)

2012-01-01

textabstractOncogenic mutations in components of cytokine signaling pathways elicit ligand-independent activation of downstream signaling, enhancing proliferation and survival in acute myeloid leukemia (AML). The myeloproliferative leukemia virus oncogene, MPL, a homodimeric receptor activated by

Response characteristics of pruriceptive and nociceptive trigeminoparabrachial tract neurons in the rat

NARCIS (Netherlands)

N.A. Jansen (Nico A.); G.J. Giesler (Glenn J.)

2015-01-01

textabstractWe tested the possibility that the trigeminoparabrachial tract (VcPbT), a projection thought to be importantly involved in nociception, might also contribute to sensation of itch. In anesthetized rats, 47 antidromically identified VcPbT neurons with receptive fields involving the cheek

Pain sensation and nociceptive reflex excitability in surgical patients and human volunteers

DEFF Research Database (Denmark)

Dahl, J B; Erichsen, C J; Fuglsang-Frederiksen, A

1992-01-01

Pain threshold, nociceptive flexion reflex (NFR) threshold and responses to suprathreshold stimulation were investigated in 15 female patients (mean age 32 yr (range 22-48 yr)) before and 68 (range 48-96) h after gynaecological laparotomy. Control measurements were performed in 17 healthy human v...

Type III Nrg1 back signaling enhances functional TRPV1 along sensory axons contributing to basal and inflammatory thermal pain sensation.

Science.gov (United States)

Canetta, Sarah E; Luca, Edlira; Pertot, Elyse; Role, Lorna W; Talmage, David A

2011-01-01

Type III Nrg1, a member of the Nrg1 family of signaling proteins, is expressed in sensory neurons, where it can signal in a bi-directional manner via interactions with the ErbB family of receptor tyrosine kinases (ErbB RTKs). Type III Nrg1 signaling as a receptor (Type III Nrg1 back signaling) can acutely activate phosphatidylinositol-3-kinase (PtdIns3K) signaling, as well as regulate levels of α7* nicotinic acetylcholine receptors, along sensory axons. Transient receptor potential vanilloid 1 (TRPV1) is a cation-permeable ion channel found in primary sensory neurons that is necessary for the detection of thermal pain and for the development of thermal hypersensitivity to pain under inflammatory conditions. Cell surface expression of TRPV1 can be enhanced by activation of PtdIns3K, making it a potential target for regulation by Type III Nrg1. We now show that Type III Nrg1 signaling in sensory neurons affects functional axonal TRPV1 in a PtdIns3K-dependent manner. Furthermore, mice heterozygous for Type III Nrg1 have specific deficits in their ability to respond to noxious thermal stimuli and to develop capsaicin-induced thermal hypersensitivity to pain. Cumulatively, these results implicate Type III Nrg1 as a novel regulator of TRPV1 and a molecular mediator of nociceptive function.

Type III Nrg1 back signaling enhances functional TRPV1 along sensory axons contributing to basal and inflammatory thermal pain sensation.

Directory of Open Access Journals (Sweden)

Sarah E Canetta

Full Text Available Type III Nrg1, a member of the Nrg1 family of signaling proteins, is expressed in sensory neurons, where it can signal in a bi-directional manner via interactions with the ErbB family of receptor tyrosine kinases (ErbB RTKs. Type III Nrg1 signaling as a receptor (Type III Nrg1 back signaling can acutely activate phosphatidylinositol-3-kinase (PtdIns3K signaling, as well as regulate levels of α7* nicotinic acetylcholine receptors, along sensory axons. Transient receptor potential vanilloid 1 (TRPV1 is a cation-permeable ion channel found in primary sensory neurons that is necessary for the detection of thermal pain and for the development of thermal hypersensitivity to pain under inflammatory conditions. Cell surface expression of TRPV1 can be enhanced by activation of PtdIns3K, making it a potential target for regulation by Type III Nrg1. We now show that Type III Nrg1 signaling in sensory neurons affects functional axonal TRPV1 in a PtdIns3K-dependent manner. Furthermore, mice heterozygous for Type III Nrg1 have specific deficits in their ability to respond to noxious thermal stimuli and to develop capsaicin-induced thermal hypersensitivity to pain. Cumulatively, these results implicate Type III Nrg1 as a novel regulator of TRPV1 and a molecular mediator of nociceptive function.

Clinical, nociceptive and psychological profiling to predict acute pain after total knee arthroplasty

DEFF Research Database (Denmark)

Luna, I E; Kehlet, H; Petersen, M A

2017-01-01

BACKGROUND: Pre-operative identification of high-pain responders for acute pain after total knee arthroplasty (TKA) could lead to targeted analgesic trials and individualized analgesic strategies to improve recovery and potentially reduce the risk of persistent post-surgical pain. The aim...

Evaluation of signalment, clinical, and laboratory variables as prognostic indicators in dogs with acute abdominal syndrome

OpenAIRE

SIMEONOVA, Galina; DINEV, Dinko; CHAPRAZOV, Tzvetan; ROYDEV, Rumen

2013-01-01

The aim of the study was to identify predictors of mortality and to propose a new severity scoring system in dogs with acute abdominal syndrome. A retrospective study was carried out on 58 dogs presented with acute abdominal syndrome with American Society of Anesthesiologists grades III-IV and treated surgically by exploratory laparotomy. Medical records were reviewed and information regarding dog signalment, history, clinical, and laboratory data; surgical findings; and outcome was collected...

Electrophysiological assessment of nociception in patients with Parkinson's disease : A multi-methods approach

NARCIS (Netherlands)

Priebe, Janosch A.; Kunz, Miriam; Morcinek, Christian; Rieckmann, Peter; Lautenbacher, Stefan

2016-01-01

Objective: Nociceptive abnormalities indicating increased pain sensitivity have been reported in patients with Parkinson's disease (PD). The disturbances are mostly responsive to dopaminergic (DA) treatment; yet, there are conflicting results. The objective of the present study was to investigate

Hydro-ethanolic leaf extract of Ziziphus abyssinica Hochst Ex A. Rich (Rhamnaceae) exhibits anti-nociceptive effects in murine models.

Science.gov (United States)

Boakye-Gyasi, Eric; Henneh, Isaac Tabiri; Abotsi, Wonder Kofi Mensah; Ameyaw, Elvis Ofori; Woode, Eric

2017-04-26

Despite substantial advances in pain research and treatment, millions of people continue to suffer from pain and this has been attributed mainly to the unavailability of effective and safer analgesics. The use of plants as medicines is still widespread and plants constitute a large source of novel phytocompounds that might become leads for the discovery of newer, effective and safer alternatives. Various parts of Ziziphus abyssinica have been used in folk medicine in several African countries as painkillers. However, there is no report on the possible anti-nociceptive effects of this plant especially the leaves, hence the need for this current study. The possible anti-nociceptive activity of hydro-ethanolic leaf extract of Ziziphus abyssinica (EthE) was assessed in rodents using chemical (acetic acid, formalin and glutamate), thermal (tail-immersion test) and mechanical/inflammatory (carrageenan) models of nociception. EthE (30-300 mg/kg, p.o.) dose-dependently and significantly inhibited chemical-induced nociception with a maximum inhibition of 86.29 ± 2.27%, 76.34 ± 5.67%, 84.97 ± 5.35%, and 82.81 ± 5.97% respectively for acetic acid, formalin (phase 1), formalin (phase 2) and glutamate tests at its highest dose. EthE also dose-dependently and significantly increased reaction times in both tail-immersion and carrageenan-induced hypernociceptive tests. The activities of the extract in the various models were comparable with the effect of morphine hydrochloride and diclofenac sodium used as standard analgesic drugs. Oral administration of hydro-ethanolic leaf extract of Ziziphus abyssinica ameliorates nocifensive behaviours associated with chemical-, thermal- and mechanical/inflammatory - induced nociceptive pain.

Stress activates pronociceptive endogenous opioid signalling in DRG neurons during chronic colitis.

Science.gov (United States)

Guerrero-Alba, Raquel; Valdez-Morales, Eduardo E; Jimenez-Vargas, Nestor N; Lopez-Lopez, Cintya; Jaramillo-Polanco, Josue; Okamoto, Takanobu; Nasser, Yasmin; Bunnett, Nigel W; Lomax, Alan E; Vanner, Stephen J

2017-12-01

Psychological stress accompanies chronic inflammatory diseases such as IBD, and stress hormones can exacerbate pain signalling. In contrast, the endogenous opioid system has an important analgesic action during chronic inflammation. This study examined the interaction of these pathways. Mouse nociceptive dorsal root ganglia (DRG) neurons were incubated with supernatants from segments of inflamed colon collected from patients with chronic UC and mice with dextran sodium sulfate (cDSS)-induced chronic colitis. Stress effects were studied by adding stress hormones (epinephrine and corticosterone) to dissociated neurons or by exposing cDSS mice to water avoidance stress. Changes in excitability of colonic DRG nociceptors were measured using patch clamp and Ca 2+ imaging techniques. Supernatants from patients with chronic UC and from colons of mice with chronic colitis caused a naloxone-sensitive inhibition of neuronal excitability and capsaicin-evoked Ca 2+ responses. Stress hormones decreased signalling induced by human and mouse supernatants. This effect resulted from stress hormones signalling directly to DRG neurons and indirectly through signalling to the immune system, leading to decreased opioid levels and increased acute inflammation. The net effect of stress was a change endogenous opioid signalling in DRG neurons from an inhibitory to an excitatory effect. This switch was associated with a change in G protein-coupled receptor excitatory signalling to a pathway sensitive to inhibitors of protein kinase A-protein, phospholipase C-protein and G protein βϒ subunits. Stress hormones block the inhibitory actions of endogenous opioids and can change the effect of opioid signalling in DRG neurons to excitation. Targeting these pathways may prevent heavy opioid use in IBD. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.

Different pain responses to chronic and acute pain in various ethnic/racial groups.

Science.gov (United States)

Rahavard, Behnoosh B; Candido, Kenneth D; Knezevic, Nebojsa Nick

2017-09-01

Our goal in this study was to review the similarities and differences among ethnic groups and their respective responses to acute and chronic clinically related and experimentally induced pain. In this review, the PUBMED and Google-Scholar databases were searched to analyze articles that have assessed the variations in both acute and chronic pain responses among different ethnic/racial groups. According to the results from 42 reviewed articles, significant differences exist among ethnic-racial groups for pain prevalence as well as responses to acute and chronic pain. Compared with Caucasians, other ethnic groups are more susceptible to acute pain responses to nociceptive stimulation and to the development of long-term chronic pain. These differences need to be addressed and assessed more extensively in the future in order to minimize the pain management disparities among various ethnic-racial groups and also to improve the relationship between pain management providers and their patients.

Differential Contribution of TRPA1, TRPV4 and TRPM8 to Colonic Nociception in Mice.

Directory of Open Access Journals (Sweden)

Sonja M Mueller-Tribbensee

Full Text Available Various transient receptor potential (TRP channels in sensory neurons contribute to the transduction of mechanical stimuli in the colon. Recently, even the cold-sensing menthol receptor TRPM(melastatin8 was suggested to be involved in murine colonic mechano-nociception.To analyze the roles of TRPM8, TRPA1 and TRPV4 in distension-induced colonic nociception and pain, TRP-deficient mice and selective pharmacological blockers in wild-type mice (WT were used. Visceromotor responses (VMR to colorectal distension (CRD in vivo were recorded and distension/pressure-induced CGRP release from the isolated murine colon ex vivo was measured by EIA.Distension-induced colonic CGRP release was markedly reduced in TRPA1-/- and TRPV4-/- mice at 90/150 mmHg compared to WT. In TRPM8-deficient mice the reduction was only distinct at 150 mmHg. Exposure to selective pharmacological antagonists (HC030031, 100 μM; RN1734, 10 μM; AMTB, 10 μM showed corresponding effects. The unselective TRP blocker ruthenium red (RR, 10 μM was as efficient in inhibiting distension-induced CGRP release as the unselective antagonists of mechanogated DEG/ENaC (amiloride, 100 μM and stretch-activated channels (gadolinium, 50 μM. VMR to CRD revealed prominent deficits over the whole pressure range (up to 90 mmHg in TRPA1-/- and TRPV4-/- but not TRPM8-/- mice; the drug effects of the TRP antagonists were again highly consistent with the results from mice lacking the respective TRP receptor gene.TRPA1 and TRPV4 mediate colonic distension pain and CGRP release and appear to govern a wide and congruent dynamic range of distensions. The role of TRPM8 seems to be confined to signaling extreme noxious distension, at least in the healthy colon.

Differential inhibitory effect on human nociceptive skin senses induced by local stimulation of thin cutaneous fibers.

Science.gov (United States)

Nilsson, H J; Schouenborg, J

1999-03-01

It is known that stimulation of thin cutaneous nerve fibers can induce long lasting analgesia through both supraspinal and segmental mechanisms, the latter often exhibiting restricted receptive fields. On this basis, we recently developed a new method, termed cutaneous field stimulation (CFS), for localized stimulation of A delta and C fibers in the superficial part of the skin. In the present study, we have evaluated the effects of CFS on non-nociceptive and nociceptive skin senses. We compared the effects of CFS with those of conventional transcutaneous electrical nerve stimulation (TENS), known to preferentially activate coarse myelinated fibers. A battery of sensory tests were made on the right volar forearm of 20 healthy subjects. CFS (16 electrodes, 4 Hz per electrode, 1 ms, up to 0.8 mA) and TENS (100 Hz, 0.2 ms, up to 26 mA) applied either on the right volar forearm (homotopically), or on the lower right leg (heterotopically) were used as conditioning stimulation for 25 min. The tactile threshold was not affected by either homo- or heterotopical CFS or TENS. The mean thresholds for detecting warming or cooling of the skin were increased by 0.4-0.9 degrees C after homo- but not heterotopical CFS and TENS. Regarding nociceptive skin senses, homo- but not heterotopical CFS, markedly reduced CO2-laser evoked A delta- and C fiber mediated heat pain to 75 and 48% of control, respectively, and mechanically evoked pain to 73% of control. Fabric evoked prickle, was not affected by CFS. Neither homo- nor heterotopical TENS induced any marked analgesic effects. It is concluded that different qualities of nociception can be differentially controlled by CFS.

Nurses assessing pain with the Nociception Coma Scale: interrater reliability and validity

NARCIS (Netherlands)

Vink, Peter; Eskes, Anne Maria; Lindeboom, Robert; van den Munckhof, Pepijn; Vermeulen, Hester

2014-01-01

The Nociception Coma Scale (NCS) is a pain observation tool, developed for patients with disorders of consciousness (DOC) due to acquired brain injury (ABI). The aim of this study was to assess the interrater reliability of the NCS and NCS-R among nurses for the assessment of pain in ABI patients

Nociceptive DRG neurons express muscle lim protein upon axonal injury.

Science.gov (United States)

Levin, Evgeny; Andreadaki, Anastasia; Gobrecht, Philipp; Bosse, Frank; Fischer, Dietmar

2017-04-04

Muscle lim protein (MLP) has long been regarded as a cytosolic and nuclear muscular protein. Here, we show that MLP is also expressed in a subpopulation of adult rat dorsal root ganglia (DRG) neurons in response to axonal injury, while the protein was not detectable in naïve cells. Detailed immunohistochemical analysis of L4/L5 DRG revealed ~3% of MLP-positive neurons 2 days after complete sciatic nerve crush and maximum ~10% after 4-14 days. Similarly, in mixed cultures from cervical, thoracic, lumbar and sacral DRG ~6% of neurons were MLP-positive after 2 days and maximal 17% after 3 days. In both, histological sections and cell cultures, the protein was detected in the cytosol and axons of small diameter cells, while the nucleus remained devoid. Moreover, the vast majority could not be assigned to any of the well characterized canonical DRG subpopulations at 7 days after nerve injury. However, further analysis in cell culture revealed that the largest population of MLP expressing cells originated from non-peptidergic IB4-positive nociceptive neurons, which lose their ability to bind the lectin upon axotomy. Thus, MLP is mostly expressed in a subset of axotomized nociceptive neurons and can be used as a novel marker for this population of cells.

Evaluation of Postoperative Anti-nociceptive Efficacy of Intrathecal Dexketoprofen in Rats

OpenAIRE

Birol Muhammet Er; İsmail Serhat Kocamanoğlu; Ayhan Bozkurt; Sırrı Bilge; Erhan Çetin Çetinoğlu

2016-01-01

Background: Some studies have suggested that the intrathecal use of cyclooxygenase enzyme inhibitors provides an anti-nociceptive effect. Therefore, the occurrence of side effects seen in systemic usage can be eliminated. Aims: The primary objective of this experimental, randomized, controlled trial was to test the hypothesis asserting that intrathecal dexketoprofen trometamol would demonstrate an analgesic effect during postoperative period. Study Design: Animal experimentation. ...

[Changes in ingestive behavior during growth affects the functional maturation of temporomandibular joint nociceptive neurons of rats].

Science.gov (United States)

Hiranuma, Maya

2013-03-01

Temporomandibular joint (TMJ) loading during development promotes its growth and maintains normal structure/function. Continuous change in diet consistency is related to development and maturation of the peripheral nervous system, including the nociceptive system. However, the functional modulation of TMJ-nociceptive neurons under different ingestive behavior is unclear. We fed growing rats a liquid diet to investigate the effects of low TMJ loading on the response properties of neurons in the trigeminal spinal tract subnucleus caudalis (Sp5C). Forty 2-week-old male rats were used. They were fed chow pellets (n = 20, C group) or a liquid diet (n = 20, LD group) soon after weaning. Firing activities of single sensory units in response to TMJ pressure stimuli were recorded at 4, 5, 7 and 9 weeks. In TMJ-nociceptive neurons, the firing threshold (FT) in the LD group was significantly lower than that in the C group at each recording age. The FT in the C group remained unchanged throughout the recording period, whereas that in the LD group was the highest at 4 weeks, and gradually decreased. On the other hand, the initial firing frequency (IFF) was significantly higher in the LD group than in the C group at each recording age. The IFF in the C group remained unchanged throughout the experimental period, whereas that in the LD group was at its lowest at 4 weeks, and gradually increased. Based on these findings, ingestive behavior that results from continuous changes in the physical consistency of the diet during growth may affect the functional maturation of TMJ-nociceptive neurons.

Atorvastatin attenuates experimental contrast-induced acute kidney injury: a role for TLR4/MyD88 signaling pathway.

Science.gov (United States)

Yue, Rongzheng; Zuo, Chuan; Zeng, Jing; Su, Baihai; Tao, Ye; Huang, Songmin; Zeng, Rui

2017-11-01

To investigate the protective effect of different atorvastatin doses on contrast-induced acute kidney injury and the related mechanism. Healthy male Sprague-Dawley (SD) rats were randomly divided into the blank control group, experimental control group and different-dose atorvastatin groups. A rat model of contrast-induced acute kidney injury was established. We detected changes in serum creatinine (Scr) and blood urea nitrogen (BUN) before and after model establishment, observed and scored renal tubular injury, analyzed rat renal cell apoptosis, and measure the expression of signal pathway proteins and downstream inflammatory factors. After contrast agent injection, the Scr and BUN levels of the experimental control group were significantly increased, the different doses applied in the atorvastatin group significantly reduced the Scr and BUN levels (p atorvastatin doses have protective effects on contrast-induced acute renal tubular injury in rats, possibly by targeting TLR4, suppressing TLR4 expression, regulating the TLR4/Myd88 signaling pathway, and inhibiting the expression of downstream inflammatory factors.

Scaling Up Cortical Control Inhibits Pain

Directory of Open Access Journals (Sweden)

Jahrane Dale

2018-05-01

Full Text Available Summary: Acute pain evokes protective neural and behavioral responses. Chronic pain, however, disrupts normal nociceptive processing. The prefrontal cortex (PFC is known to exert top-down regulation of sensory inputs; unfortunately, how individual PFC neurons respond to an acute pain signal is not well characterized. We found that neurons in the prelimbic region of the PFC increased firing rates of the neurons after noxious stimulations in free-moving rats. Chronic pain, however, suppressed both basal spontaneous and pain-evoked firing rates. Furthermore, we identified a linear correlation between basal and evoked firing rates of PFC neurons, whereby a decrease in basal firing leads to a nearly 2-fold reduction in pain-evoked response in chronic pain states. In contrast, enhancing basal PFC activity with low-frequency optogenetic stimulation scaled up prefrontal outputs to inhibit pain. These results demonstrate a cortical gain control system for nociceptive regulation and establish scaling up prefrontal outputs as an effective neuromodulation strategy to inhibit pain. : Dale et al. find that acute pain increases activity levels in the prefrontal cortex. Chronic pain reduces both basal spontaneous and pain-evoked activity in this region, whereas neurostimulation to restore basal activities can in turn enhance nociception-evoked prefrontal activities to inhibit pain. Keywords: chronic pain, neuromodulation, prefrontal cortex, PFC, cortical gain control

G-CSF maintains controlled neutrophil mobilization during acute inflammation by negatively regulating CXCR2 signaling

Science.gov (United States)

Bajrami, Besnik; Zhu, Haiyan; Zhang, Yu C.

2016-01-01

Cytokine-induced neutrophil mobilization from the bone marrow to circulation is a critical event in acute inflammation, but how it is accurately controlled remains poorly understood. In this study, we report that CXCR2 ligands are responsible for rapid neutrophil mobilization during early-stage acute inflammation. Nevertheless, although serum CXCR2 ligand concentrations increased during inflammation, neutrophil mobilization slowed after an initial acute fast phase, suggesting a suppression of neutrophil response to CXCR2 ligands after the acute phase. We demonstrate that granulocyte colony-stimulating factor (G-CSF), usually considered a prototypical neutrophil-mobilizing cytokine, was expressed later in the acute inflammatory response and unexpectedly impeded CXCR2-induced neutrophil mobilization by negatively regulating CXCR2-mediated intracellular signaling. Blocking G-CSF in vivo paradoxically elevated peripheral blood neutrophil counts in mice injected intraperitoneally with Escherichia coli and sequestered large numbers of neutrophils in the lungs, leading to sterile pulmonary inflammation. In a lipopolysaccharide-induced acute lung injury model, the homeostatic imbalance caused by G-CSF blockade enhanced neutrophil accumulation, edema, and inflammation in the lungs and ultimately led to significant lung damage. Thus, physiologically produced G-CSF not only acts as a neutrophil mobilizer at the relatively late stage of acute inflammation, but also prevents exaggerated neutrophil mobilization and the associated inflammation-induced tissue damage during early-phase infection and inflammation. PMID:27551153

Phytochemical Screening and Anti-nociceptive Properties of the Ethanolic Leaf Extract of Trema Cannabina Lour

Directory of Open Access Journals (Sweden)

Hira Arpona

2013-02-01

Full Text Available Purpose: The present study was designed to investigate the anti-nociceptive activity of ethanolic leaf extract of Trema cannabina Lour (family: Cannabaceae in experimental animal models. Methods: The anti-nociceptive action was carried out against two types of noxious stimuli, thermal (hot plate and tail immersion tests and chemical (acetic acid-induced writhing in mice. Results: Phytochemical analysis of crude extract indicated the presence of reducing sugar, tannins, steroid and alkaloid types of secondary metabolites. Crude extract of T. cannabina (500 mg/kg dose showed maximum time needed for the response against thermal stimuli (6.79±0.15 seconds which is comparable to diclofenac sodium (8.26±0.14 seconds in the hot plate test. Hot tail immersion test also showed similar results as in hot plate test. At the dose of 250 and 500 mg/kg body weight, the extract showed significantly and in a dose-dependent (p<0.001 reduction in acetic acid induced writhing in mice with a maximum effect of 47.56% reduction at 500 mg/kg dose comparable to that of diclofenac sodium (67.07% at 25 mg/kg. Conclusion: The obtained results tend to suggest the Anti-nociceptive activity of ethanolic leaf extract of Trema cannabina and thus provide the scientific basis for the traditional uses of this plant part as a remedy for pain.

CREBBP knockdown enhances RAS/RAF/MEK/ERK signaling in Ras pathway mutated acute lymphoblastic leukemia but does not modulate chemotherapeutic response.

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Dixon, Zach A; Nicholson, Lindsay; Zeppetzauer, Martin; Matheson, Elizabeth; Sinclair, Paul; Harrison, Christine J; Irving, Julie A E

2017-04-01

Relapsed acute lymphoblastic leukemia is the most common cause of cancer-related mortality in young people and new therapeutic strategies are needed to improve outcome. Recent studies have shown that heterozygous inactivating mutations in the histone acetyl transferase, CREBBP , are particularly frequent in relapsed childhood acute lymphoblastic leukemia and associated with a hyperdiploid karyotype and KRAS mutations. To study the functional impact of CREBBP haploinsufficiency in acute lymphoblastic leukemia, RNA interference was used to knock down expression of CREBBP in acute lymphoblastic leukemia cell lines and various primagraft acute lymphoblastic leukemia cells. We demonstrate that attenuation of CREBBP results in reduced acetylation of histone 3 lysine 18, but has no significant impact on cAMP-dependent target gene expression. Impaired induction of glucocorticoid receptor targets was only seen in 1 of 4 CREBBP knockdown models, and there was no significant difference in glucocorticoid-induced apoptosis, sensitivity to other acute lymphoblastic leukemia chemotherapeutics or histone deacetylase inhibitors. Importantly, we show that CREBBP directly acetylates KRAS and that CREBBP knockdown enhances signaling of the RAS/RAF/MEK/ERK pathway in Ras pathway mutated acute lymphoblastic leukemia cells, which are still sensitive to MEK inhibitors. Thus, CREBBP mutations might assist in enhancing oncogenic RAS signaling in acute lymphoblastic leukemia but do not alter response to MEK inhibitors. Copyright© Ferrata Storti Foundation.

Slack KNa Channels Influence Dorsal Horn Synapses and Nociceptive Behavior.

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Evely, Katherine M; Pryce, Kerri D; Bausch, Anne E; Lukowski, Robert; Ruth, Peter; Haj-Dahmane, Samir; Bhattacharjee, Arin

2017-01-01

The sodium-activated potassium channel Slack (Kcnt1, Slo2.2) is highly expressed in dorsal root ganglion neurons where it regulates neuronal firing. Several studies have implicated the Slack channel in pain processing, but the precise mechanism or the levels within the sensory pathway where channels are involved remain unclear. Here, we furthered the behavioral characterization of Slack channel knockout mice and for the first time examined the role of Slack channels in the superficial, pain-processing lamina of the dorsal horn. We performed whole-cell recordings from spinal cord slices to examine the intrinsic and synaptic properties of putative inhibitory and excitatory lamina II interneurons. Slack channel deletion altered intrinsic properties and synaptic drive to favor an overall enhanced excitatory tone. We measured the amplitudes and paired pulse ratio of paired excitatory post-synaptic currents at primary afferent synapses evoked by electrical stimulation of the dorsal root entry zone. We found a substantial decrease in the paired pulse ratio at synapses in Slack deleted neurons compared to wildtype, indicating increased presynaptic release from primary afferents. Corroborating these data, plantar test showed Slack knockout mice have an enhanced nociceptive responsiveness to localized thermal stimuli compared to wildtype mice. Our findings suggest that Slack channels regulate synaptic transmission within the spinal cord dorsal horn and by doing so establishes the threshold for thermal nociception.

Insulin signaling is acutely required for long-term memory in Drosophila.

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Chambers, Daniel B; Androschuk, Alaura; Rosenfelt, Cory; Langer, Steven; Harding, Mark; Bolduc, Francois V

2015-01-01

Memory formation has been shown recently to be dependent on energy status in Drosophila. A well-established energy sensor is the insulin signaling (InS) pathway. Previous studies in various animal models including human have revealed the role of insulin levels in short-term memory but its role in long-term memory remains less clear. We therefore investigated genetically the spatial and temporal role of InS using the olfactory learning and long-term memory model in Drosophila. We found that InS is involved in both learning and memory. InS in the mushroom body is required for learning and long-term memory whereas long-term memory specifically is impaired after InS signaling disruption in the ellipsoid body, where it regulates the level of p70s6k, a downstream target of InS and a marker of protein synthesis. Finally, we show also that InS is acutely required for long-term memory formation in adult flies.

Reliability and validity of a brief method to assess nociceptive flexion reflex (NFR) threshold.

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Rhudy, Jamie L; France, Christopher R

2011-07-01

The nociceptive flexion reflex (NFR) is a physiological tool to study spinal nociception. However, NFR assessment can take several minutes and expose participants to repeated suprathreshold stimulations. The 4 studies reported here assessed the reliability and validity of a brief method to assess NFR threshold that uses a single ascending series of stimulations (Peak 1 NFR), by comparing it to a well-validated method that uses 3 ascending/descending staircases of stimulations (Staircase NFR). Correlations between the NFR definitions were high, were on par with test-retest correlations of Staircase NFR, and were not affected by participant sex or chronic pain status. Results also indicated the test-retest reliabilities for the 2 definitions were similar. Using larger stimulus increments (4 mAs) to assess Peak 1 NFR tended to result in higher NFR threshold estimates than using the Staircase NFR definition, whereas smaller stimulus increments (2 mAs) tended to result in lower NFR threshold estimates than the Staircase NFR definition. Neither NFR definition was correlated with anxiety, pain catastrophizing, or anxiety sensitivity. In sum, a single ascending series of electrical stimulations results in a reliable and valid estimate of NFR threshold. However, caution may be warranted when comparing NFR thresholds across studies that differ in the ascending stimulus increments. This brief method to assess NFR threshold is reliable and valid; therefore, it should be useful to clinical pain researchers interested in quickly assessing inter- and intra-individual differences in spinal nociceptive processes. Copyright © 2011 American Pain Society. Published by Elsevier Inc. All rights reserved.

Sensitization of the nociceptive system in patients with low back pain and sickness absence: Disc degeneration disease or pain syndrome

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Jensen, Ole Kudsk; Nielsen, Claus Vinther; Stengaard-Pedersen, Kristian

SENSITIZATION OF THE NOCICEPTIVE SYSTEM IN PATIENTS WITH LOW BACK PAIN AND SICKNESS ABSENCE O.K. Jensen1, C.V. Nielsen2, K. Stengaard-Pedersen3 1The Spine Center, Department of Internal Medicine, Region Hospital Silkeborg, 2Department of Clinical Social Medicine, University of Aarhus, and 3...... characterized by sensitization of the nociceptive system. Purpose: To assess sensitization of the nociceptive system in low back pain (LBP) patients by means of TP examination and measure of Pressure Pain Threshold (PPT) on the thumb nails. To search for associations between the number of TPs and structural...... = 1.35, p = 0.017) and mental distress (anxiety) in men (OR = 1.39, p = 0.003). After adjustment for age and sex, a positive association between LBP score and DDS was found only in patients with less than six TPs (OR = 1.21 (1.0-1.47), p = 0.043). Low PPT on the thumb nails was associated with DDS...

Sertraline inhibits formalin-induced nociception and cardiovascular responses

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Santuzzi, C.H. [Departamento de Ciências Fisiológicas, Centro de Ciências da Saúde, Universidade Federal do Espírito Santo, Vitória, ES (Brazil); Futuro Neto, H.A. [Departamento de Morfologia, Centro de Ciências da Saúde, Universidade Federal do Espírito Santo, Vitória, ES (Brazil); Escola de Medicina da Empresa Brasileira de Ensino, Pesquisa e Extensão, Vitória, ES (Brazil); Escola Superior de Ciências da Saúde, Santa Casa de Misericórdia de Vitória, Vitória, ES (Brazil); Pires, J.G.P. [Escola de Medicina da Empresa Brasileira de Ensino, Pesquisa e Extensão, Vitória, ES (Brazil); Centro Universitário do Espírito Santo, Colatina, ES (Brazil); Gonçalves, W.L.S. [Centro Universitário do Espírito Santo, Colatina, ES (Brazil); Tiradentes, R.V.; Gouvea, S.A.; Abreu, G.R. [Departamento de Ciências Fisiológicas, Centro de Ciências da Saúde, Universidade Federal do Espírito Santo, Vitória, ES (Brazil)

2011-11-18

The objective of the present study was to determine the antihyperalgesic effect of sertraline, measured indirectly by the changes of sciatic afferent nerve activity, and its effects on cardiorespiratory parameters, using the model of formalin-induced inflammatory nociception in anesthetized rats. Serum serotonin (5-HT) levels were measured in order to test their correlation with the analgesic effect. Male Wistar rats (250-300 g) were divided into 4 groups (N = 8 per group): sertraline-treated group (Sert + Saline (Sal) and Sert + Formalin (Form); 3 mg·kg{sup −1}·day{sup −1}, ip, for 7 days) and saline-treated group (Sal + Sal and Sal + Form). The rats were injected with 5% (50 µL) formalin or saline into the right hind paw. Sciatic nerve activity was recorded using a silver electrode connected to a NeuroLog apparatus, and cardiopulmonary parameters (mean arterial pressure, heart rate and respiratory frequency), assessed after arterial cannulation and tracheotomy, were monitored using a Data Acquisition System. Blood samples were collected from the animals and serum 5-HT levels were determined by ELISA. Formalin injection induced the following changes: sciatic afferent nerve activity (+50.8 ± 14.7%), mean arterial pressure (+1.4 ± 3 mmHg), heart rate (+13 ± 6.8 bpm), respiratory frequency (+4.6 ± 5 cpm) and serum 5-HT increased to 1162 ± 124.6 ng/mL. Treatment with sertraline significantly reduced all these parameters (respectively: +19.8 ± 6.9%, -3.3 ± 2 mmHg, -13.1 ± 10.8 bpm, -9.8 ± 5.7 cpm) and serum 5-HT level dropped to 634 ± 69 ng/mL (P < 0.05). These results suggest that sertraline plays an analgesic role in formalin-induced nociception probably through a serotonergic mechanism.

Effect of riluzole on acute pain and hyperalgesia in humans

DEFF Research Database (Denmark)

Hammer, N A; Lillesø, J; Pedersen, J L

1999-01-01

Riluzole modulates several transmitter systems which may be involved in nociception. Antinociceptive effects have been shown in animal studies, but there are no human data. Therefore, we have examined the acute analgesic effect of riluzole in a human model of inflammatory pain induced by a thermal...... injury on the distal leg (47 degrees C, 7 min, 12.5 cm2) in 20 healthy volunteers. Hyperalgesia to mechanical and heat stimuli were examined by von Frey hairs and thermodes. We used a randomized, double-blind, placebo-controlled design, and subjects received riluzole 100 mg or placebo for 2 days...

Functional significance of M-type potassium channels in nociceptive cutaneous sensory endings

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Passmore, Gayle M.; Reilly, Joanne M.; Thakur, Matthew; Keasberry, Vanessa N.; Marsh, Stephen J.; Dickenson, Anthony H.; Brown, David A.

2012-01-01

M-channels carry slowly activating potassium currents that regulate excitability in a variety of central and peripheral neurons. Functional M-channels and their Kv7 channel correlates are expressed throughout the somatosensory nervous system where they may play an important role in controlling sensory nerve activity. Here we show that Kv7.2 immunoreactivity is expressed in the peripheral terminals of nociceptive primary afferents. Electrophysiological recordings from single afferents in vitro showed that block of M-channels by 3 μM XE991 sensitized Aδ- but not C-fibers to noxious heat stimulation and induced spontaneous, ongoing activity at 32°C in many Aδ-fibers. These observations were extended in vivo: intraplantar injection of XE991 selectively enhanced the response of deep dorsal horn (DH) neurons to peripheral mid-range mechanical and higher range thermal stimuli, consistent with a selective effect on Aδ-fiber peripheral terminals. These results demonstrate an important physiological role of M-channels in controlling nociceptive Aδ-fiber responses and provide a rationale for the nocifensive behaviors that arise following intraplantar injection of the M-channel blocker XE991. PMID:22593734

Functional significance of M-type potassium channels in nociceptive cutaneous sensory endings

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Gayle M. Passmore

2012-05-01

Full Text Available M-channels carry slowly activating potassium currents that regulate excitability in a variety of central and peripheral neurons. Functional M-channels and their Kv7 channel correlates are expressed throughout the somatosensory nervous system where they may play an important role in controlling sensory nerve activity. Here we show that Kv7.2 immunoreactivity is expressed in the peripheral terminals of nociceptive primary afferents. Electrophysiological recordings from single afferents in vitro showed that block of M-channels by 3 µM XE991 sensitised Adelta- but not C-fibres to noxious heat stimulation and induced spontaneous, ongoing activity at 32ºC in many Adelta-fibres. These observations were extended in vivo: intraplantar injection of XE991 selectively enhanced the response of deep dorsal horn neurons to peripheral mid-range mechanical and higher range thermal stimuli, consistent with a selective effect on Adelta-fibre peripheral terminals. These results demonstrate an important physiological role of M-channels in controlling nociceptive Adelta-fibre responses and provide a rationale for the nocifensive behaviours that arise following intraplantar injection of the M-channel blocker XE991.

Sensitization of the Nociceptive System in Complex Regional Pain Syndrome

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Diedrichs, Carolina; Baron, Ralf; Gierthmühlen, Janne

2016-01-01

Background Complex regional pain syndrome type I (CRPS-I) is characterized by sensory, motor and autonomic abnormalities without electrophysiological evidence of a nerve lesion. Objective Aims were to investigate how sensory, autonomic and motor function change in the course of the disease. Methods 19 CRPS-I patients (17 with acute, 2 with chronic CRPS, mean duration of disease 5.7±8.3, range 1–33 months) were examined with questionnaires (LANSS, NPS, MPI, Quick DASH, multiple choice list of descriptors for sensory, motor, autonomic symptoms), motor and autonomic tests as well as quantitative sensory testing according to the German Research Network on Neuropathic Pain at two visits (baseline and 36±10.6, range 16–53 months later). Results CRPS-I patients had an improvement of sudomotor and vasomotor function, but still a great impairment of sensory and motor function upon follow-up. Although pain and mechanical detection improved upon follow-up, thermal and mechanical pain sensitivity increased, including the contralateral side. Increase in mechanical pain sensitivity and loss of mechanical detection were associated with presence of ongoing pain. Conclusions The results demonstrate that patients with CRPS-I show a sensitization of the nociceptive system in the course of the disease, for which ongoing pain seems to be the most important trigger. They further suggest that measured loss of function in CRPS-I is due to pain-induced hypoesthesia rather than a minimal nerve lesion. In conclusion, this article gives evidence for a pronociceptive pain modulation profile developing in the course of CRPS and thus helps to assess underlying mechanisms of CRPS that contribute to the maintenance of patients’ pain and disability. PMID:27149519

Sensitization of the Nociceptive System in Complex Regional Pain Syndrome.

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Maren Reimer

Full Text Available Complex regional pain syndrome type I (CRPS-I is characterized by sensory, motor and autonomic abnormalities without electrophysiological evidence of a nerve lesion.Aims were to investigate how sensory, autonomic and motor function change in the course of the disease.19 CRPS-I patients (17 with acute, 2 with chronic CRPS, mean duration of disease 5.7±8.3, range 1-33 months were examined with questionnaires (LANSS, NPS, MPI, Quick DASH, multiple choice list of descriptors for sensory, motor, autonomic symptoms, motor and autonomic tests as well as quantitative sensory testing according to the German Research Network on Neuropathic Pain at two visits (baseline and 36±10.6, range 16-53 months later.CRPS-I patients had an improvement of sudomotor and vasomotor function, but still a great impairment of sensory and motor function upon follow-up. Although pain and mechanical detection improved upon follow-up, thermal and mechanical pain sensitivity increased, including the contralateral side. Increase in mechanical pain sensitivity and loss of mechanical detection were associated with presence of ongoing pain.The results demonstrate that patients with CRPS-I show a sensitization of the nociceptive system in the course of the disease, for which ongoing pain seems to be the most important trigger. They further suggest that measured loss of function in CRPS-I is due to pain-induced hypoesthesia rather than a minimal nerve lesion. In conclusion, this article gives evidence for a pronociceptive pain modulation profile developing in the course of CRPS and thus helps to assess underlying mechanisms of CRPS that contribute to the maintenance of patients' pain and disability.

Cortical and spinal assessment - a comparative study using encephalography and the nociceptive withdrawal reflex

DEFF Research Database (Denmark)

Fischer, I W; Gram, M; Hansen, T M

2017-01-01

solution in randomized order. The electroencephalogram (EEG) was recorded during rest and during immersion of the hand into ice-water. Electrical stimulation of the sole of the foot was used to elicit the nociceptive withdrawal reflex and the reflex amplitude was recorded. RESULTS: Data from thirty...

Are MRI high-signal changes of alar and transverse ligaments in acute whiplash injury related to outcome?

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Eide Geir E

2010-11-01

Full Text Available Abstract Background Upper neck ligament high-signal changes on magnetic resonance imaging (MRI have been found in patients with whiplash-associated disorders (WAD but also in non-injured controls. The clinical relevance of such changes is controversial. Their prognostic role has never been evaluated. The purpose of this study was to examine if alar and transverse ligament high-signal changes on MRI immediately following the car accident are related to outcome after 12 months for patients with acute WAD grades 1-2. Methods Within 13 days after a car accident, 114 consecutive acute WAD1-2 patients without prior neck injury or prior neck problems underwent upper neck high-resolution proton-weighted MRI. High-signal changes of the alar and transverse ligaments were graded 0-3. A questionnaire including the impact of event scale for measuring posttraumatic stress response and questions on patients' expectations of recovery provided clinical data at injury. At 12 months follow-up, 111 (97.4% patients completed the Neck Disability Index (NDI and an 11-point numeric rating scale (NRS-11 on last week neck pain intensity. Factors potentially related to these outcomes were assessed using multiple logistic regression analyses. Results Among the 111 responders (median age 29.8 years; 63 women, 38 (34.2% had grades 2-3 alar ligament changes and 25 (22.5% had grades 2-3 transverse ligament changes at injury. At 12 months follow-up, 49 (44.1% reported disability (NDI > 8 and 23 (20.7% neck pain (NRS-11 > 4. Grades 2-3 ligament changes in the acute phase were not related to disability or neck pain at 12 months. More severe posttraumatic stress response increased the odds for disability (odds ratio 1.46 per 10 points on the impact of event scale, p = 0.007 and so did low expectations of recovery (odds ratio 4.66, p = 0.005. Conclusions High-signal changes of the alar and transverse ligaments close after injury did not affect outcome for acute WAD1-2 patients

STING Signaling Promotes Inflammation in Experimental Acute Pancreatitis.

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Zhao, Qinglan; Wei, Yi; Pandol, Stephen J; Li, Lingyin; Habtezion, Aida

2018-05-01

Acute pancreatitis (AP) is characterized by severe inflammation and acinar cell death. Transmembrane protein 173 (TMEM173 or STING) is a DNA sensor adaptor protein on immune cells that recognizes cytosolic nucleic acids and transmits signals that activate production of interferons and the innate immune response. We investigated whether leukocyte STING signaling mediates inflammation in mice with AP. We induced AP in C57BL/6J mice (control) and C57BL/6J-Tmem173gt/J mice (STING-knockout mice) by injection of cerulein or placement on choline-deficient DL-ethionine supplemented diet. In some mice, STING signaling was induced by administration of a pharmacologic agonist. AP was also induced in C57BL/6J mice with bone marrow transplants from control or STING-knockout mice and in mice with disruption of the cyclic GMP-AMP synthase (Cgas) gene. Pancreata were collected, analyzed by histology, and acini were isolated and analyzed by flow cytometry, quantitative polymerase chain reaction, immunoblots, and enzyme-linked immunosorbent assay. Bone-marrow-derived macrophages were collected from mice and tested for their ability to detect DNA from dying acinar cells in the presence and absence of deoxyribonuclease (DNaseI). STING signaling was activated in pancreata from mice with AP but not mice without AP. STING-knockout mice developed less severe AP (less edema, inflammation, and markers of pancreatic injury) than control mice, whereas mice given a STING agonist developed more severe AP than controls. In immune cells collected from pancreata, STING was expressed predominantly in macrophages. Levels of cGAS were increased in mice with vs without AP, and cGAS-knockout mice had decreased edema, inflammation, and other markers of pancreatic injury upon induction of AP than control mice. Wild-type mice given bone marrow transplants from STING-knockout mice had less pancreatic injury and lower serum levels of lipase and pancreatic trypsin activity following induction of AP than

microRNAs in nociceptive circuits as predictors of future clinical applications

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Michaela eKress

2013-10-01

Full Text Available Neuro-immune alterations in the peripheral and central nervous system play a role in the pathophysiology of chronic pain, and non-coding RNAs (ncRNAs – and microRNAs (miRNAs in particular - regulate both immune and neuronal processes. Specifically, miRNAs control macromolecular complexes in neurons, glia and immune cells and regulate signals used for neuro-immune communication in the pain pathway. Therefore, miRNAs may be hypothesised as critically important master switches modulating chronic pain. In particular, understanding the concerted function of miRNA in the regulation of nociception and endogenous analgesia and defining the importance of miRNAs in the circuitries and cognitive, emotional and behavioural components involved in pain is expected to shed new light on the enigmatic pathophysiology of neuropathic pain, migraine and complex regional pain syndrome (CRPS. Specific miRNAs may evolve as new druggable molecular targets for pain prevention and relief. Furthermore, predisposing miRNA expression patterns and inter-individual variations and polymorphisms in miRNAs and/or their binding sites may serve as biomarkers for pain and help to predict individual risks for certain types of pain and responsiveness to analgesic drugs. miRNA-based diagnostics are expected to develop into hands-on tools that allow better patient stratification, improved mechanism-based treatment, and targeted prevention strategies for high risk individuals.

Acute stress-induced antinociception is cGMP-dependent but heme oxygenase-independent

International Nuclear Information System (INIS)

Carvalho-Costa, P.G.; Branco, L.G.S.; Leite-Panissi, C.R.A.

2014-01-01

Endogenous carbon monoxide (CO), which is produced by the enzyme heme oxygenase (HO), participates as a neuromodulator in physiological processes such as thermoregulation and nociception by stimulating the formation of 3′,5′-cyclic guanosine monophosphate (cGMP). In particular, the acute physical restraint-induced fever of rats can be blocked by inhibiting the enzyme HO. A previous study reported that the HO-CO-cGMP pathway plays a key phasic antinociceptive role in modulating noninflammatory acute pain. Thus, this study evaluated the involvement of the HO-CO-cGMP pathway in antinociception induced by acute stress in male Wistar rats (250-300 g; n=8/group) using the analgesia index (AI) in the tail flick test. The results showed that antinociception induced by acute stress was not dependent on the HO-CO-cGMP pathway, as neither treatment with the HO inhibitor ZnDBPG nor heme-lysinate altered the AI. However, antinociception was dependent on cGMP activity because pretreatment with the guanylate cyclase inhibitor 1H-[1,2,4] oxadiazolo [4,3-a] quinoxaline-1-one (ODQ) blocked the increase in the AI induced by acute stress

Acute stress-induced antinociception is cGMP-dependent but heme oxygenase-independent

Energy Technology Data Exchange (ETDEWEB)

Carvalho-Costa, P.G. [Programa de Graduação em Psicobiologia, Faculdade de Filosofia, Ciências e Letras de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto, SP (Brazil); Branco, L.G.S. [Departamento de Morfologia, Fisiologia e Patologia Básica, Faculdade de Odontologia de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto, SP (Brazil); Leite-Panissi, C.R.A. [Programa de Graduação em Psicobiologia, Faculdade de Filosofia, Ciências e Letras de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto, SP (Brazil); Departamento de Morfologia, Fisiologia e Patologia Básica, Faculdade de Odontologia de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto, SP (Brazil)

2014-09-19

Endogenous carbon monoxide (CO), which is produced by the enzyme heme oxygenase (HO), participates as a neuromodulator in physiological processes such as thermoregulation and nociception by stimulating the formation of 3′,5′-cyclic guanosine monophosphate (cGMP). In particular, the acute physical restraint-induced fever of rats can be blocked by inhibiting the enzyme HO. A previous study reported that the HO-CO-cGMP pathway plays a key phasic antinociceptive role in modulating noninflammatory acute pain. Thus, this study evaluated the involvement of the HO-CO-cGMP pathway in antinociception induced by acute stress in male Wistar rats (250-300 g; n=8/group) using the analgesia index (AI) in the tail flick test. The results showed that antinociception induced by acute stress was not dependent on the HO-CO-cGMP pathway, as neither treatment with the HO inhibitor ZnDBPG nor heme-lysinate altered the AI. However, antinociception was dependent on cGMP activity because pretreatment with the guanylate cyclase inhibitor 1H-[1,2,4] oxadiazolo [4,3-a] quinoxaline-1-one (ODQ) blocked the increase in the AI induced by acute stress.

Effects of awareness and nociception on heart rate variability during general anaesthesia

International Nuclear Information System (INIS)

Huhle, R; Zaunseder, S; Malberg, H; Burghardt, M; Koch, T; Heller, A R; Wessel, N

2012-01-01

During anaesthesia awareness and nociception are serious complications that may further lead to haemodynamic instability. Specific monitoring of depth of hypnosis and depth of analgesia based on heart rate variability (HRV) analysis is eligible to improve patient safety and reduce efforts in post-operative care. Consequently, in this analysis we assess the applicability of HRV parameters during surgical interventions with standardized intravenous propofol-remifentanil-anaesthesia. Peri-operative electrocardiograms were recorded from cardiovascular stable patients (ASA Score I/II, N = 32, age: 36.4 ± 11.23 a, BMI: 25.2 ± 3.16) scheduled for trauma and dentofacial surgery. HRV time- and frequency-domain parameters, measures of complexity and nonlinear dynamics were compared by analysing longitudinally distributed 300 s intervals preceding/following induction of anaesthesia (BL–I1), intubation (I1–I2) and extubation (E1–E2). Mean value (meanNN) and standard deviation (sdNN) of the heart rate are influenced in BL–I1 (p < 0.001), I1–I2 (p < 0.05) and E1–E2 (p < 0.001). The number of forbidden words of symbolic dynamics changes significantly for BL–I1 (p < 0.001) and not for I1–I2 and E1–E2 (p > 0.05). Probability of low-variability POLVAR10 is significantly altered in all comparisons (BL–I1: Δ = 0.032, p < 0.01, I1–I2: Δ = 0.12, p < 0.05, E1–E2: Δ = 0.169, p < 0.01) but especially during nociception. While standard time-domain parameters lacked selectivity, parameters of symbolic dynamics appear to be specifically influenced by changes in depth of hypnosis and nociception, respectively. However, the lack of steady-state ventilation/breathing in this study needs to be considered in future research. To be used for clinical anaesthesia monitoring our results have to be prospectively validated in clinical studies. (paper)

Acute effects of different diet compositions on skeletal muscle insulin signalling in obese individuals during caloric restriction

Science.gov (United States)

Wang, Cecilia C.L.; Adochio, Rebecca L.; Leitner, J. Wayne; Abeyta, Ian M.; Draznin, Boris; Cornier, Marc-Andre

2012-01-01

Objective The cellular effects of restricting fat versus carbohydrate during a low-calorie diet are unclear. The aim of this study was to examine acute effects of energy and macronutrient restriction on skeletal muscle insulin signalling in obesity. Materials/Methods Eighteen obese individuals without diabetes underwent euglycemic-hyperinsulinemic clamp and skeletal muscle biopsy after: (a) 5 days of eucaloric diet (30% fat, 50% carbohydrate), and (b) 5 days of a 30% calorie-restricted diet, either low fat/high carbohydrate (LF/HC: 20% fat, 60% carbohydrate) or high-fat/low carbohydrate (HF/LC: 50% fat, 30% carbohydrate). Results Weight, body composition, and insulin sensitivity were similar between groups after eucaloric diet. Weight loss was similar between groups after hypocaloric diet, 1.3 ± 1.3 kg (pdiet. Skeletal muscle of the LF/HC group had increased insulin-stimulated tyrosine phosphorylation of IRS-1, decreased insulin-stimulated Ser 307 phosphorylation of IRS-1, and increased IRS-1-associated phosphatidylinositol (PI)3-kinase activity. Conversely, insulin stimulation of tyrosine phosphorylated IRS-1 was absent and serine 307 phosphorylation of IRS-1 was increased on HF/LC, with blunting of IRS-1-associated PI3-kinase activity. Conclusion Acute caloric restriction with a LF/HC diet alters skeletal muscle insulin signalling in a way that improves insulin sensitivity, while acute caloric restriction with a HF/LC diet induces changes compatible with insulin resistance. In both cases, ex vivo changes in skeletal muscle insulin signalling appear prior to changes in whole body insulin sensitivity. PMID:23174405

Biophysical parameters of erythrocyte membranes and mechanisms of interaction with non-opioid analgesics under acute pain syndrome

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Yu. I. Gubskyi

2014-06-01

Full Text Available Methods of fluorescent probing, spectrophotometry and microcalorimetry were applied to investigate the alterations in biophysical parameters of erythrocytes membranes, and specifically microviscosity, surface charge, molecular organization of lipid bilayer and lipid-protein interactions under conditions of acute pain syndrome produced by experimental chemical lesion. The distinctive features of non-opiod analgesics interactions and binding to the erythrocytes membranes of rats subjected to acute nociceptive pain accompanied with oxidative stress development were investigated. The abilities of analgesics under research, and namely paracetamol, aspirin, phenazone, ketorolac, pyrodazole, ketoprofenum, natrium mefenaminate, indometacin, nimesulide to make up physico-chemical complexes with lipoperoxidation modified erythrocytes surface and protein-lipid bilayer showed marked changes. The significance of oxidative damage of biophase under conditions of acute pain syndrome for analgesics effective pharmacodynamics and pharmacokinetics realization is under consideration.

Fish oil concentrate delays sensitivity to thermal nociception in mice

Science.gov (United States)

Veigas, Jyothi M.; Williams, Paul J.; Halade, Ganesh; Rahman, Mizanur M.; Yoneda, Toshiyuki; Fernandes, Gabriel

2011-01-01

Fish oil has been used to alleviate pain associated with inflammatory conditions such as rheumatoid arthritis. The anti-inflammatory property of fish oil is attributed to the n-3 fatty acids docosahexaenoic acid and eicosapentaenoic acid. Contrarily, vegetable oils such as safflower oil are rich in n-6 fatty acids which are considered to be mediators of inflammation. This study investigates the effect of n-3 and n-6 fatty acids rich oils as dietary supplements on the thermally induced pain sensitivity in healthy mice. C57Bl/6J mice were fed diet containing regular fish oil, concentrated fish oil formulation (CFO) and safflower oil (SO) for 6 months. Pain sensitivity was measured by plantar test and was correlated to the expression of acid sensing ion channels (ASICs), transient receptor potential vanilloid 1 (TRPV1) and c-fos in dorsal root ganglion cells. Significant delay in sensitivity to thermal nociception was observed in mice fed CFO compared to mice fed SO (p<0.05). A significant diminution in expression of ion channels such as ASIC1a (64%), ASIC13 (37%) and TRPV1 (56%) coupled with reduced expression of c-fos, a marker of neuronal activation, was observed in the dorsal root ganglion cells of mice fed CFO compared to that fed SO. In conclusion, we describe here the potential of fish oil supplement in reducing sensitivity to thermal nociception in normal mice. PMID:21345372

Recent studies of cutaneous nociception in atopic and non-atopic subjects.

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Heyer, G R; Hornstein, O P

1999-02-01

Itching reflects a distinct quality of cutaneous nociception elicited by chemical or other stimuli to neuronal receptors at the superficial layers of the skin and muco-cutaneous orifices. Although recent experimental studies of the conduction and perception of itch have yielded deeper insight into the physiology of this sensory quality, little is known about the neuromechanisms involved in pruritus accompanying many inflammatory skin diseases, in particular, in atopic eczema. Previous case-control studies of our research group with patients suffering from atopic eczema (AE) revealed significantly diminished itch perception after iontophoretic application of different doses of histamine as well as substance P (i.c. injected). Further experiments using acetylcholine (ACh, i.c.) clearly demonstrated that ACh elicits pruritus instead of pain in patients with AE. The first part of the present review deals with the results of our most recent case-control studies on histamine-induced itch perception in atopics devoid of eczema as well as in patients with urticaria or psoriasis compared to atopics with or without manifest eczema. We demonstrated that both focal itch and perifocal alloknesis (i.e., itch elicited by a slight mechanical, otherwise non-itching stimulus) were significantly reduced in eczema-free atopics yet were normal in non-atopics suffering from urticaria or psoriasis. In further studies using ACh i.c. injected into the uninvolved skin of patients with AE, lichen ruber, psoriasis, type IV contact eczema, or non-specific nummular eczema (n = 10/each group), all the atopics and 6/10 psoriatics felt itch instead of burning pain, but none of the others did. Different doses of vasoactive intestinal peptide (VIP) i.c. applied to the controls and the atopics with or without eczema did not markedly increase the intensity of nociceptive sensations. However, ACh induced pain in the controls, pure pruritus in the atopics with acute eczema, and a 'mixture' of pain and

Forebrain Mechanisms of Nociception and Pain: Analysis through Imaging

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Casey, Kenneth L.

1999-07-01

Pain is a unified experience composed of interacting discriminative, affective-motivational, and cognitive components, each of which is mediated and modulated through forebrain mechanisms acting at spinal, brainstem, and cerebral levels. The size of the human forebrain in relation to the spinal cord gives anatomical emphasis to forebrain control over nociceptive processing. Human forebrain pathology can cause pain without the activation of nociceptors. Functional imaging of the normal human brain with positron emission tomography (PET) shows synaptically induced increases in regional cerebral blood flow (rCBF) in several regions specifically during pain. We have examined the variables of gender, type of noxious stimulus, and the origin of nociceptive input as potential determinants of the pattern and intensity of rCBF responses. The structures most consistently activated across genders and during contact heat pain, cold pain, cutaneous laser pain or intramuscular pain were the contralateral insula and anterior cingulate cortex, the bilateral thalamus and premotor cortex, and the cerebellar vermis. These regions are commonly activated in PET studies of pain conducted by other investigators, and the intensity of the brain rCBF response correlates parametrically with perceived pain intensity. To complement the human studies, we developed an animal model for investigating stimulus-induced rCBF responses in the rat. In accord with behavioral measures and the results of human PET, there is a progressive and selective activation of somatosensory and limbic system structures in the brain and brainstem following the subcutaneous injection of formalin. The animal model and human PET studies should be mutually reinforcing and thus facilitate progress in understanding forebrain mechanisms of normal and pathological pain.

Pre-test habituation improves the reliability of a handheld test of mechanical nociceptive threshold in dairy cows

DEFF Research Database (Denmark)

Raundal, P. M.; Andersen, P. H.; Toft, Nils

2015-01-01

Mechanical nociceptive threshold (MNT) testing has been used to investigate aspects of painful states in bovine claws. We investigated a handheld tool, where the applied stimulation force was monitored continuously relative to a pre-encoded based target force. The effect on MNT of two pre-testing...... habituation procedures was performed in two different experiments comprising a total of 88 sound Holsteins dairy cows kept either inside or outside their home environment. MNT testing was performed using five consecutive mechanical nociceptive stimulations per cow per test at a fixed pre-encoded target rate...... of 2.1 N/s. The habituation procedure performed in dairy cows kept in their home environment led to lowered intra-individual coefficient of variation of MNT (P test...

Occlusal splint versus modified nociceptive trigeminal inhibition splint in bruxism therapy: a randomized, controlled trial using surface electromyography.

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Dalewski, B; Chruściel-Nogalska, M; Frączak, B

2015-12-01

An occlusal splint and a modified nociceptive trigeminal inhibition splint (AMPS, anterior deprogrammer, Kois deprogrammer, Lucia jig, etc.) are commonly and quite frequently used in the treatment of masticatory muscle disorders, although their sustainable and long-lasting effect on these muscles' function is still not very well known. Results of scant surface electromyography studies in patients with temporomandibular disorders have been contradictory. The aim of this study was to evaluate both devices in bruxism therapy; EMG activity levels during postural activity and maximum voluntary contraction of the superficial temporal and masseter muscles were compared before and after 30 days of treatment. Surface electromyography of the examined muscles was performed in two groups of bruxers (15 patients each). Patients in the first group used occlusal splints, while those in the second used modified nociceptive trigeminal inhibition splints. The trial was randomized, controlled and semi-blind. Neither device affected the asymmetry index or postural activity/maximum voluntary contraction ratio after 1 month of treatment. Neither the occlusal nor the nociceptive trigeminal inhibition splint showed any significant influence on the examined muscles. Different scientific methods should be considered in clinical applications that require either direct influence on the muscles' bioelectrical activity or a quantitative measurement of the treatment quality. © 2015 Australian Dental Association.

Nociception contributes to the formation of myogenic contracture in the early phase of adjuvant-induced arthritis in a rat knee.

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Kaneguchi, Akinori; Ozawa, Junya; Moriyama, Hideki; Yamaoka, Kaoru

2017-07-01

It is unknown how joint contracture is generated in inflamed joints. This study aimed to clarify the role of nociception on the formation of joint contracture secondary to arthritis. Monoarthritis was induced by intra-articular injections of complete Freund's adjuvant (CFA) into rat knees. On day 5 after CFA injection, the passive extension range of motion (ROM) of knee joints were measured, both before and after myotomy of knee flexors, to evaluate the extent of muscular contribution to CFA-induced joint contracture. The steroidal anti-inflammatory drug dexamethasone could prevent ROM restrictions completely, both before and after myotomy. On the other hand, the opioid analgesic drug morphine did not prevent the development of restricted ROM observed after myotomy, while it did before myotomy. This indicates that nociception contributes to joint contracture through alterations in muscular structure (myogenic factors). Next, we tested the hypothesis that nociception-induced reflexive flexor muscle contractions cause myogenic contracture in arthritic joints. To do this, chemical denervation was performed by Botulinum toxin type A (BTX-A) injections into knee flexor muscles, simultaneously with CFA injections into the knee. As expected, BTX-A could alleviate ROM restrictions observed before myotomy. These findings suggest that nociceptive-related muscle contractions play an essential role in the formation of joint contracture. Thus, our study indicates that analgesic management during an early stage of joint arthritis is an essential mean to prevent the formation of joint contracture. © 2016 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 35:1404-1413, 2017. © 2016 Orthopaedic Research Society. Published by Wiley Periodicals, Inc.

Elevated peritoneal expression and estrogen regulation of nociceptive ion channels in endometriosis.

Science.gov (United States)

Greaves, Erin; Grieve, Kelsey; Horne, Andrew W; Saunders, Philippa T K

2014-09-01

Ovarian suppression is a common treatment for endometriosis-associated pelvic pain. Its exact mechanism of action is poorly understood, although it is assumed to reflect reduced production/action of estrogens. The objective of the study was to measure the expression of mRNAs encoded by nociceptive genes in the peritoneum of women with chronic pelvic pain (CPP) with or without endometriosis and to investigate whether estrogens alter nociceptive gene expression in human sensory neurons. The study was performed using human tissue analysis and cell culture. The study was conducted at a university research institute. Peritoneal biopsies were obtained from women with CPP and endometriosis (n = 12), CPP and no endometriosis (n = 10), and no pain or endometriosis (n = 5). Endometriosis lesions were obtained from women with endometriosis (n = 18). mRNAs encoding ion channels (P2RX3, SCN9A, SCN11A, TRPA1, TRPV1) and the neurotransmitter TAC1 were measured in human tissue samples and in human embryonic stem cell-derived sensory neurons treated with estrogens. TRPV1, TRPA1, and SCN11A mRNAs were significantly higher in the peritoneum from women with endometriosis (P endometriosis lesions (P endometriosis (P endometriosis-associated pain. Strategies directly targeting ion channels may offer an alternative option for the management of CPP.

Characterization of nociceptive response to chemical, mechanical, and thermal stimuli in adolescent rats with neonatal dopamine depletion.

Science.gov (United States)

Ogata, M; Noda, K; Akita, H; Ishibashi, H

2015-03-19

Rats with dopamine depletion caused by 6-hydroxydopamine (6-OHDA) treatment during adulthood and the neonatal period exhibit akinetic motor activity and spontaneous motor hyperactivity during adolescence, respectively, indicating that the behavioral effects of dopamine depletion depend on the period of lesion development. Dopamine depletion during adulthood induces hyperalgesic response to mechanical, thermal, and/or chemical stimuli, whereas the effects of neonatal dopamine depletion on nociceptive response in adolescent rats are yet to be examined. The latter aspect was addressed in this study, and behavioral responses were examined using von-Frey, tail flick, and formalin tests. The formalin test revealed that rats with neonatal dopamine depletion exhibited a significant increase in nociceptive response during interphase (6-15min post formalin injection) and phase 2 (16-75min post formalin injection). This increase in nociceptive response to the formalin injection was not reversed by pretreatment with methamphetamine, which ameliorates motor hyperactivity observed in adolescent rats with neonatal 6-OHDA treatment. The von-Frey filament and tail flick tests failed to reveal significant differences in withdrawal thresholds between neonatal 6-OHDA-treated and vehicle-treated rats. The spinal neuronal response to the formalin injection into the rat hind paw was also examined through immunohistochemical analysis of c-Fos protein. Significantly increased numbers of c-Fos-immunoreactive cells were observed in laminae I-II and V-VI of the ipsilateral spinal cord to the site of the formalin injection in rats with neonatal dopamine depletion compared with vehicle-treated rats. These results suggest that the dopaminergic neural system plays a crucial role in the development of a neural network for tonic pain, including the spinal neural circuit for nociceptive transmission, and that the mechanism underlying hyperalgesia to tonic pain is not always consistent with that of

Methanol extract of Xanthium strumarium L. possesses anti-inflammatory and anti-nociceptive activities.

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Kim, In-Tae; Park, Young-Mi; Won, Jong-Heon; Jung, Hyun-Ju; Park, Hee-Juhn; Choi, Jong-Won; Lee, Kyung-Tae

2005-01-01

As an attempt to identify bioactive natural products with anti-inflammatory activity, we evaluated the effects of the methanol extract of the semen of Xanthium strumarium L. (MEXS) on lipopolysaccharide (LPS)-induced nitric oxide (NO), prostaglandin E2 (PGE2) and tumor necrosis factor-alpha (TNF-alpha) production in RAW 264.7 cells. Our data indicate that MEXS is a potent inhibitor of NO, PGE2 and TNF-alpha production. Consistent with these findings, the expression levels of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) protein and iNOS, COX-2 and TNF-alpha mRNA were down-regulated in a concentration-dependent manner. Furthermore, MEXS inhibited nuclear factor kappa B (NF-kappaB) DNA binding activity and the translocation of NF-kappaB to the nucleus by blocking the degradation of inhibitor of kappa B-alpha (IkappaB-alpha). We further evaluated the anti-inflammatory and anti-nociceptive activities of MEXS in vivo. MEXS (100, 200 mg/kg/d, p.o.) reduced acute paw edema induced by carrageenin in rats, and showed analgesic activities in an acetic acid-induced abdominal constriction test and a hot plate test in mice. Thus, our study suggests that the inhibitions of iNOS, COX-2 expression, and TNF-alpha release by the methanol extract of the semen of Xanthium strumarium L. are achieved by blocking NF-kappaB activation, and that this is also responsible for its anti-inflammatory effects.

3,6-Dimethoxy-6″,6″-Dimethyl-(7,8,2″,3″)-Chromeneflavone, a Flavonoid Isolated from Lonchocarpus Araripensis Benth. (Fabaceae), Reduces Nociceptive Behaviour in Mice.

Science.gov (United States)

Almeida, Jackson R G S; Silva, Juliane C; Guimarães, Amanda L; Oliveira, Ana P; Souza, Grasielly R; Oliveira-Júnior, Raimundo G; Lima-Saraiva, Sarah R G; Barbosa-Filho, José M; Braz-Filho, Raimundo; Queiroz, Dinalva Brito; Botelho, Marco Antônio

2015-10-01

Lonchocarpus araripensis Benth. is largely distributed in the northeast region of Brazil. It is popularly known as 'sucupira'. Recent studies have shown that some species of Lonchocarpus have interesting pharmacological activities. In this study, we evaluated the antinociceptive effect of a flavone isolated from L. araripensis. The chemical examination resulted in the isolation of 3,6-dimethoxy-6″,6″-dimethyl-(7,8,2″,3″)-chromeneflavone (DDF). The structure of the compound was established by spectral analysis. Antinociceptive activity of DDF was evaluated by measuring nociception by acetic acid, formalin and hot plate tests. The rota rod test was used to evaluate motor coordination. The results demonstrated that DDF was able to prevent acetic-acid-writhing-induced nociception (p < 0.001) in mice. Furthermore, DDF produced a significant reduction of the nociceptive behaviour at the early and late phases of paw licking in the formalin test. Also, DDF produced an inhibition of the nociceptive behaviour during a hot-plate test. No alteration in motor coordination was observed. These results confirm the hypothesis that DDF reduces the nociceptive behaviour in mice, probably through central mechanisms, but without compromising the motor coordination of animals. Copyright © 2015 John Wiley & Sons, Ltd.

Delayed onset of changes in soma action potential genesis in nociceptive A-beta DRG neurons in vivo in a rat model of osteoarthritis

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Henry James L

2009-09-01

Full Text Available Abstract Background Clinical data on osteoarthritis (OA suggest widespread changes in sensory function that vary during the progression of OA. In previous studies on a surgically-induced animal model of OA we have observed that changes in structure and gene expression follow a variable trajectory over the initial days and weeks. To investigate mechanisms underlying changes in sensory function in this model, the present electrophysiological study compared properties of primary sensory nociceptive neurons at one and two months after model induction with properties in naïve control animals. Pilot data indicated no difference in C- or Aδ-fiber associated neurons and therefore the focus is on Aβ-fiber nociceptive neurons. Results At one month after unilateral derangement of the knee by cutting the anterior cruciate ligament and removing the medial meniscus, the only changes observed in Aβ-fiber dorsal root ganglion (DRG neurons were in nociceptor-like unresponsive neurons bearing a hump on the repolarization phase; these changes consisted of longer half width, reflecting slowed dynamics of AP genesis, a depolarized Vm and an increased AP amplitude. At two months, changes observed were in Aβ-fiber high threshold mechanoreceptors, which exhibited shorter AP duration at base and half width, shorter rise time and fall time, and faster maximum rising rate/maximum falling rate, reflecting accelerated dynamics of AP genesis. Conclusion These data indicate that Aβ nociceptive neurons undergo significant changes that vary in time and occur later than changes in structure and in nociceptive scores in this surgically induced OA model. Thus, if changes in Aβ-fiber nociceptive neurons in this model reflect a role in OA pain, they may relate to mechanisms underlying pain associated with advanced OA.

Risperidone reverses the spatial object recognition impairment and hippocampal BDNF-TrkB signalling system alterations induced by acute MK-801 treatment

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Chen, Guangdong; Lin, Xiaodong; Li, Gongying; Jiang, Diego; Lib, Zhiruo; Jiang, Ronghuan; Zhuo, Chuanjun

2017-01-01

The aim of the present study was to investigate the effects of a commonly-used atypical antipsychotic, risperidone, on alterations in spatial learning and in the hippocampal brain-derived neurotrophic factor (BDNF)-tyrosine receptor kinase B (TrkB) signalling system caused by acute dizocilpine maleate (MK-801) treatment. In experiment 1, adult male Sprague-Dawley rats subjected to acute treatment of either low-dose MK801 (0.1 mg/kg) or normal saline (vehicle) were tested for spatial object recognition and hippocampal expression levels of BDNF, TrkB and the phophorylation of TrkB (p-TrkB). We found that compared to the vehicle, MK-801 treatment impaired spatial object recognition of animals and downregulated the expression levels of p-TrkB. In experiment 2, MK-801- or vehicle-treated animals were further injected with risperidone (0.1 mg/kg) or vehicle before behavioural testing and sacrifice. Of note, we found that risperidone successfully reversed the deleterious effects of MK-801 on spatial object recognition and upregulated the hippocampal BDNF-TrkB signalling system. Collectively, the findings suggest that cognitive deficits from acute N-methyl-D-aspartate receptor blockade may be associated with the hypofunction of hippocampal BDNF-TrkB signalling system and that risperidone was able to reverse these alterations. PMID:28451387

The TRIF-dependent signaling pathway is not required for acute cerebral ischemia/reperfusion injury in mice

International Nuclear Information System (INIS)

Hua, Fang; Wang, Jun; Sayeed, Iqbal; Ishrat, Tauheed; Atif, Fahim; Stein, Donald G.

2009-01-01

TIR domain-containing adaptor protein (TRIF) is an adaptor protein in Toll-like receptor (TLR) signaling pathways. Activation of TRIF leads to the activation of interferon regulatory factor 3 (IRF3) and nuclear factor kappa B (NF-κB). While studies have shown that TLRs are implicated in cerebral ischemia/reperfusion (I/R) injury and in neuroprotection against ischemia afforded by preconditioning, little is known about TRIF's role in the pathological process following cerebral I/R. The present study investigated the role that TRIF may play in acute cerebral I/R injury. In a mouse model of cerebral I/R induced by transient middle cerebral artery occlusion, we examined the activation of NF-κB and IRF3 signaling in ischemic cerebral tissue using ELISA and Western blots. Neurological function and cerebral infarct size were also evaluated 24 h after cerebral I/R. NF-κB activity and phosphorylation of the inhibitor of kappa B (IκBα) increased in ischemic brains, but IRF3, inhibitor of κB kinase complex-ε (IKKε), and TANK-binding kinase1 (TBK1) were not activated after cerebral I/R in wild-type (WT) mice. Interestingly, TRIF deficit did not inhibit NF-κB activity or p-IκBα induced by cerebral I/R. Moreover, although cerebral I/R induced neurological and functional impairments and brain infarction in WT mice, the deficits were not improved and brain infarct size was not reduced in TRIF knockout mice compared to WT mice. Our results demonstrate that the TRIF-dependent signaling pathway is not required for the activation of NF-κB signaling and brain injury after acute cerebral I/R.

Evaluation of Postoperative Anti-nociceptive Efficacy of Intrathecal Dexketoprofen in Rats.

Science.gov (United States)

Birol Muhammet, Er; Kocamanoğlu, İsmail Serhat; Bozkurt, Ayhan; Bilge, Sırrı; Çetinoğlu, Erhan Çetin

2016-05-01

Some studies have suggested that the intrathecal use of cyclooxygenase enzyme inhibitors provides an anti-nociceptive effect. Therefore, the occurrence of side effects seen in systemic usage can be eliminated. The primary objective of this experimental, randomized, controlled trial was to test the hypothesis asserting that intrathecal dexketoprofen trometamol would demonstrate an analgesic effect during postoperative period. Animal experimentation. Forty rats were randomized into 4 groups 7 days after intrathecal catheterization; the following drugs were given through catheter lumens: Group Lidocaine (Group L): Lidocaine 20 μg; Group Lidocaine-Morphine (Group LM): Lidocaine 20 μg and morphine 0.5 μgr; Group Lidocaine-Dexketoprofen (Group LD): Lidocaine 20 μg and dexketoprofen trometamol 100 μg; and Group Dexketoprofen (Group D): Dexketoprofen trometamol 100 μg. Paw incision was achieved under ether inhalation. To measure analgesic potential, hot plate and tail immersion tests were used as nociceptive tests during the postoperative period. The mean reaction times detected in groups during hot plate and tail immersion tests were shortest in Group L at 15, 30, 45, 60, 75, 90, 105, and 120 minutes after start of surgery (pdexketoprofen, as in the morphine group, longer reaction times were detected than in the lidocaine group at all measurement times except 120 minutes (pdexketoprofen in the optimal perioperative pain management is effective, and can be administered as an adjuvant in clinics after neurotoxicity studies in animals, and effective dose studies in volunteers.

Anti-nociceptive and anti-hyperprolactinemia activities of Fructus Viticis and its effective fractions and chemical constituents.

Science.gov (United States)

Hu, Y; Xin, H-L; Zhang, Q-Y; Zheng, H-C; Rahman, K; Qin, L-P

2007-10-01

Vitex rotundifolia L. is widely distributed along the sea coast of China. The aim of this study was to investigate the anti-nociceptive and anti-hyperprolactinemia activities of substances isolated from Fructus Viticis (the fruit of Vitex rotundifolia), which may be effective in the treatment of pre-menstrual symptoms, using acetic-acid-induced writhing and metoclopramide-dihydrochloride-induced hyperprolactinemia in mice. The fractions effective in terms of anti-nociceptive and anti-hyperprolactinemia activities were obtained from Fructus Viticis by elution through macro-porous resin, and polyamide and silica gel column chromatography. The standardization of the fractions obtained from the separation procedures was carried out by means of high-performance liquid chromatography (HPLC)-fingerprint. In this study, the flavone-enriched fraction (Fraction 6) showed a higher inhibitory rate than indomethacin (69.4% vs. 56.4%) at a dose of 50 mg/kg body wt., and significantly reduced the prolactin level as compared to HPRL-treated mice (8.2 ng/ml vs. 25.5 ng/ml). Furthermore, this fraction showed anti-nociceptive activity in a dose-dependent manner (10-50 mg/kg body wt., i.g.). On further purification with silica gel, Casticin was isolated from this fraction and it decreased abnormal serum levels of prolactin by approximately 50% (p screening methods, our results indicate that the presence of flavonoids such as Casticin in this plant may be responsible for the activity effects. Casticin has potent analgesic and anti-hyperprolactinaemia properties, is likely to be one of the active components of Fructus Viticis, and may have a role in treating PMS (premenstrual syndrom).

The Discriminative validity of "nociceptive," "peripheral neuropathic," and "central sensitization" as mechanisms-based classifications of musculoskeletal pain.

LENUS (Irish Health Repository)

Smart, Keith M

2012-02-01

OBJECTIVES: Empirical evidence of discriminative validity is required to justify the use of mechanisms-based classifications of musculoskeletal pain in clinical practice. The purpose of this study was to evaluate the discriminative validity of mechanisms-based classifications of pain by identifying discriminatory clusters of clinical criteria predictive of "nociceptive," "peripheral neuropathic," and "central sensitization" pain in patients with low back (+\\/- leg) pain disorders. METHODS: This study was a cross-sectional, between-patients design using the extreme-groups method. Four hundred sixty-four patients with low back (+\\/- leg) pain were assessed using a standardized assessment protocol. After each assessment, patients\\' pain was assigned a mechanisms-based classification. Clinicians then completed a clinical criteria checklist indicating the presence\\/absence of various clinical criteria. RESULTS: Multivariate analyses using binary logistic regression with Bayesian model averaging identified a discriminative cluster of 7, 3, and 4 symptoms and signs predictive of a dominance of "nociceptive," "peripheral neuropathic," and "central sensitization" pain, respectively. Each cluster was found to have high levels of classification accuracy (sensitivity, specificity, positive\\/negative predictive values, positive\\/negative likelihood ratios). DISCUSSION: By identifying a discriminatory cluster of symptoms and signs predictive of "nociceptive," "peripheral neuropathic," and "central" pain, this study provides some preliminary discriminative validity evidence for mechanisms-based classifications of musculoskeletal pain. Classification system validation requires the accumulation of validity evidence before their use in clinical practice can be recommended. Further studies are required to evaluate the construct and criterion validity of mechanisms-based classifications of musculoskeletal pain.

Sphingosine kinase 2-deficiency mediated changes in spinal pain processing

Directory of Open Access Journals (Sweden)

Jastrow eCanlas

2015-08-01

Full Text Available Chronic pain is one of the most burdensome health issues facing the planet (as costly as diabetes and cancer combined, and in desperate need for new diagnostic targets leading to better therapies. The bioactive lipid sphingosine 1-phosphate (S1P and its receptors have recently been shown to modulate nociceptive signalling at the level of peripheral nociceptors and central neurons. However, the exact role of S1P generating enzymes, in particular sphingosine kinase 2 (Sphk2, in nociception remains unknown. We found that both sphingosine kinases, Sphk1 and Sphk2, were expressed in spinal cord with higher levels of Sphk2 mRNA compared to Sphk1. All three Sphk2 mRNA-isoforms were present with the Sphk2.1 mRNA showing the highest relative expression. Mice deficient in Sphk2 (Sphk2-/- showed in contrast to mice deficient in Sphk1 (Sphk1-/- substantially lower spinal S1P levels compared to wild-type C57BL/6 mice. In the formalin model of acute peripheral inflammatory pain, Sphk2-/- mice showed facilitation of nociceptive transmission during the late response, whereas responses to early acute pain, and the number of c-Fos immunoreactive dorsal horn neurons were not different between Sphk2-/- and wild-type mice. Chronic peripheral inflammation (CPI caused a bilateral increase in mechanical sensitivity in Sphk2-/- mice. Additionally, CPI increased the relative mRNA expression of P2X4 receptor, brain-derived neurotrophic factor and inducible nitric oxide synthase in the ipsilateral spinal cord of wild-type but not Sphk2-/- mice. Similarly, Sphk2-/- mice showed in contrast to wild-type no CPI-dependent increase in areas of the dorsal horn immunoreactive for the microglia marker Iba-1 and the astrocyte marker GFAP. Our results suggest that the tightly regulated cell signalling enzyme Sphk2 may be a key component for facilitation of nociceptive circuits in the CNS leading to central sensitization and pain memory formation.

Tramadol effects on clinical variables and the mechanical nociceptive threshold in horses

OpenAIRE

Franco,Leandro Guimarães; Moreno,Juan Carlos Duque; Teixeira Neto,Antônio Raphael; Souza,Moisés Caetano e; Silva,Luiz Antônio Franco da

2014-01-01

This study assessed the clinical effects and the mechanical antinociceptive potential of intravenous (IV) tramadol in horses.A blinded and randomized study was designed with 7 horses treated with 1 (Tr1), 2 (Tr2) or 3 (Tr3) mg kg-1 of tramadol IV. The heart rate, respiratory rate (fR), arterial pressure, degree of sedation, gastrointestinal motility (GI), behavior changes and the mechanical nociceptive threshold (MNT) were evaluated. The MNT was determined with von Frey device method.Tr3 had ...

D2-like receptors in the descending dopaminergic pathway are not involved in the decreased postoperative nociceptive threshold induced by plantar incision in adult rats.

Science.gov (United States)

Ohtani, Norimasa; Masaki, Eiji

2016-01-01

Approximately half of all patients who undergo surgery develop postoperative pain, the mechanisms of which are not well understood by anesthesiologists. D2-like receptors in the descending dopaminergic pathway play an important role in regulation of pain transmission in the spinal cord. Impairment of inhibitory neurons in the spinal cord is suggested as part of the mechanism for neuropathic pain, which is one component of postoperative pain. The purpose of this study was to investigate whether impairment of D2-like receptors in the descending dopaminergic pathway in the spinal cord is involved in the decreased postoperative nociceptive threshold in rats. Male Sprague-Dawley rats (250-300 g) were anesthetized with sevoflurane and an intrathecal (IT) catheter was implanted. Six days later, a plantar incision was made. On the following day, saline, a D2-like receptor agonist (quinpirole), or a D2-like receptor antagonist (sulpiride) was administered intrathecally. Thermal and mechanical nociceptive responses were assessed by exposure to infrared radiant heat and the von Frey filament test before and after plantar incision. Plantar incision decreased both thermal latency and the mechanical nociceptive threshold. IT administration of quinpirole inhibited the nociceptive responses induced by plantar incision, but sulpiride had no effect. A D2-like receptor agonist had antinociceptive effects on the hypersensitivity response triggered by a surgical incision, but a D2-like receptor antagonist had no effect on this response. These results suggest that impairment and/or modification of D2-like receptors in the descending dopaminergic pathway in the spinal cord is not involved in the postoperative decrease in nociceptive threshold.

Distinct brain systems mediate the effects of nociceptive input and self-regulation on pain.

Directory of Open Access Journals (Sweden)

Choong-Wan Woo

2015-01-01

Full Text Available Cognitive self-regulation can strongly modulate pain and emotion. However, it is unclear whether self-regulation primarily influences primary nociceptive and affective processes or evaluative ones. In this study, participants engaged in self-regulation to increase or decrease pain while experiencing multiple levels of painful heat during functional magnetic resonance imaging (fMRI imaging. Both heat intensity and self-regulation strongly influenced reported pain, but they did so via two distinct brain pathways. The effects of stimulus intensity were mediated by the neurologic pain signature (NPS, an a priori distributed brain network shown to predict physical pain with over 90% sensitivity and specificity across four studies. Self-regulation did not influence NPS responses; instead, its effects were mediated through functional connections between the nucleus accumbens and ventromedial prefrontal cortex. This pathway was unresponsive to noxious input, and has been broadly implicated in valuation, emotional appraisal, and functional outcomes in pain and other types of affective processes. These findings provide evidence that pain reports are associated with two dissociable functional systems: nociceptive/affective aspects mediated by the NPS, and evaluative/functional aspects mediated by a fronto-striatal system.

Metformin induces differentiation in acute promyelocytic leukemia by activating the MEK/ERK signaling pathway

International Nuclear Information System (INIS)

Huai, Lei; Wang, Cuicui; Zhang, Cuiping; Li, Qihui; Chen, Yirui; Jia, Yujiao; Li, Yan; Xing, Haiyan; Tian, Zheng; Rao, Qing; Wang, Min; Wang, Jianxiang

2012-01-01

Highlights: ► Metformin induces differentiation in NB4 and primary APL cells. ► Metformin induces activation of the MEK/ERK signaling pathway in APL cells. ► Metformin synergizes with ATRA to trigger maturation of NB4 and primary APL cells. ► Metformin induces the relocalization and degradation of the PML-RARα fusion protein. ► The study may be applicable for new differentiation therapy in cancer treatment. -- Abstract: Recent studies have shown that metformin, a widely used antidiabetic agent, may reduce the risk of cancer development. In this study, we investigated the antitumoral effect of metformin on both acute myeloid leukemia (AML) and acute promyelocytic leukemia (APL) cells. Metformin induced apoptosis with partial differentiation in an APL cell line, NB4, but only displayed a proapoptotic effect on several non-M3 AML cell lines. Further analysis revealed that a strong synergistic effect existed between metformin and all-trans retinoic acid (ATRA) during APL cell maturation and that metformin induced the hyperphosphorylation of extracellular signal-regulated kinase (ERK) in APL cells. U0126, a specific MEK/ERK activation inhibitor, abrogated metformin-induced differentiation. Finally, we found that metformin induced the degradation of the oncoproteins PML-RARα and c-Myc and activated caspase-3. In conclusion, these results suggest that metformin treatment may contribute to the enhancement of ATRA-induced differentiation in APL, which may deepen the understanding of APL maturation and thus provide insight for new therapy strategies.

The TRIF-dependent signaling pathway is not required for acute cerebral ischemia/reperfusion injury in mice

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Hua, Fang, E-mail: fhua2@emory.edu [Department of Emergency Medicine, Brain Research Laboratory, Emory University School of Medicine, 1365B Clifton Road, Suite 5100, Atlanta, GA 30322 (United States); Wang, Jun; Sayeed, Iqbal; Ishrat, Tauheed; Atif, Fahim; Stein, Donald G. [Department of Emergency Medicine, Brain Research Laboratory, Emory University School of Medicine, 1365B Clifton Road, Suite 5100, Atlanta, GA 30322 (United States)

2009-12-18

TIR domain-containing adaptor protein (TRIF) is an adaptor protein in Toll-like receptor (TLR) signaling pathways. Activation of TRIF leads to the activation of interferon regulatory factor 3 (IRF3) and nuclear factor kappa B (NF-{kappa}B). While studies have shown that TLRs are implicated in cerebral ischemia/reperfusion (I/R) injury and in neuroprotection against ischemia afforded by preconditioning, little is known about TRIF's role in the pathological process following cerebral I/R. The present study investigated the role that TRIF may play in acute cerebral I/R injury. In a mouse model of cerebral I/R induced by transient middle cerebral artery occlusion, we examined the activation of NF-{kappa}B and IRF3 signaling in ischemic cerebral tissue using ELISA and Western blots. Neurological function and cerebral infarct size were also evaluated 24 h after cerebral I/R. NF-{kappa}B activity and phosphorylation of the inhibitor of kappa B (I{kappa}B{alpha}) increased in ischemic brains, but IRF3, inhibitor of {kappa}B kinase complex-{epsilon} (IKK{epsilon}), and TANK-binding kinase1 (TBK1) were not activated after cerebral I/R in wild-type (WT) mice. Interestingly, TRIF deficit did not inhibit NF-{kappa}B activity or p-I{kappa}B{alpha} induced by cerebral I/R. Moreover, although cerebral I/R induced neurological and functional impairments and brain infarction in WT mice, the deficits were not improved and brain infarct size was not reduced in TRIF knockout mice compared to WT mice. Our results demonstrate that the TRIF-dependent signaling pathway is not required for the activation of NF-{kappa}B signaling and brain injury after acute cerebral I/R.

Acute swelling of the limbs: magnetic resonance pictorial review of fascial and muscle signal changes

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Revelon, Geraldine [Department of Radiology, Centre Hospitalo-Universitaire Henri Mondor, 51 Avenue du Marechal De Lattre De Tassigny, 94000 Creteil (France); Rahmouni, Alain [Department of Radiology, Centre Hospitalo-Universitaire Henri Mondor, 51 Avenue du Marechal De Lattre De Tassigny, 94000 Creteil (France); Jazaerli, Nedal [Department of Radiology, Centre Hospitalo-Universitaire Henri Mondor, 51 Avenue du Marechal De Lattre De Tassigny, 94000 Creteil (France); Godeau, Bertrand [Department of Internal Medicine, Centre Hospitalo-Universitaire Henri Mondor, 51 Avenue du Marechal De Lattre De Tassigny, 94000 Creteil (France); Chosidow, Olivier [Department of Dermatology, Centre Hospitalo-Universitaire Henri Mondor, 51 Avenue du Marechal De Lattre De Tassigny, 94000 Creteil (France); Authier, Jerome [Department of Pathology, Centre Hospitalo-Universitaire Henri Mondor, 51 Avenue du Marechal De Lattre De Tassigny, 94000 Creteil (France); Mathieu, Didier [Department of Radiology, Centre Hospitalo-Universitaire Henri Mondor, 51 Avenue du Marechal De Lattre De Tassigny, 94000 Creteil (France); Roujeau, Jean-Claude [Department of Dermatology, Centre Hospitalo-Universitaire Henri Mondor, 51 Avenue du Marechal De Lattre De Tassigny, 94000 Creteil (France); Vasile, Norbert [Department of Radiology, Centre Hospitalo-Universitaire Henri Mondor, 51 Avenue du Marechal De Lattre De Tassigny, 94000 Creteil (France)

1999-04-01

Objective: This pictorial review analyzes the magnetic resonance (MR) fascial/muscular changes in 69 patients referred as emergencies with acute swelling of the limbs (ASL) from various causes. Methods and material: A prospective MR imaging (MRI) study of 69 patients referred as emergencies for ASL was performed. Our population consisted of 45 patients with skin and soft-tissue infections (cellulitis and necrotizing fasciitis, and pyomyositis), six patients with soft-tissue inflammatory diseases (dermatomyositis, graft-versus-host disease), 11 patients with acute deep venous thrombosis, three patients with rhabdomyolysis, one patient with acute denervation and three other patients with rare diseases. Hematomas, tumorous or infectious bone involvement and soft-tissue tumors were excluded. All studies included spin echo T1-weighted images and spin echo T2-weighted images. Gadolinium-enhanced spin echo T1-weighted images were obtained when an abscess was suspected on T2-weighted images. Selective fat-saturated T1- and T2-weighted sequences were also used. MRI analysis was performed to obtain a compartmentalized anatomical approach according to the location of signal abnormalities in subcutaneous fat, superficial and deep fascia and muscle. Results: In all patients with ASL, MRI demonstrated soft-tissue abnormalities involving subcutaneous fat, superficial fascia, deep fascia, or muscle. Although MR findings were non-specific, MRI appears sensitive for detecting subtle fascial and muscle signal changes. Conclusions: In skin and soft-tissue infections, MRI can be helpful for therapeutic management by determining the depth of soft-tissue involvement, particularly within fasciae and muscles, which is partly related to the severity of cellulitis with severe systemic manifestations. MRI can also aid the surgeon in diagnosing abscesses. In inflammatory diseases, MRI can determine the best site for biopsy and also monitor therapeutic response.

Determination of the temperature causing a nociceptive response in the tail of albino BALB/c mice.

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Aguirre Siancas, E E; Lam Figueroa, N M; Delgado Rios, J C; Ruiz Ramirez, E; Portilla Flores, O S; Crispín Huamaní, L J; Alarcón Velásquez, L

2018-06-08

Designs for determining nociceptive response in rodents are of great use in neurology and experimental neuroscience. Immersing mice's tails in warm water is one of the most widely used procedures to evaluate this response; however, a wide range of temperatures are used in different studies. Knowing the temperature that produces a powerful nociceptive response in the tail of BALB/c mice is extremely useful. Eight 2-month-old male BALB/c mice were used. A 14-cm high beaker was filled with water up to 13 cm. The animals' tails were immersed in the container with a starting temperature of 36°C. The water temperature was raised in 1°C increments until we identified the temperatures that produced nociceptive responses. That response was determined by counting the time taken before the mouse shook its tail to remove it from the water. Six of the 8 mice began shaking their tails at the temperature of 51°C. All animals removed their tails from the water at the temperatures of 54°C, 55°C, and 56°C, taking a mean time of 8.54, 7.99, and 5.33seconds, respectively. ANOVA applied to the response times for each of the 3 temperatures indicated revealed a value of F=2.8 (P=.123). The response time was statistically similar for the temperatures of 54°C, 55°C, and 56°C; however, the data were less dispersed for the latter temperature. Copyright © 2018 Sociedad Española de Neurología. Publicado por Elsevier España, S.L.U. All rights reserved.

Evaluation of Postoperative Anti-nociceptive Efficacy of Intrathecal Dexketoprofen in Rats

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Birol Muhammet Er

2016-06-01

Full Text Available Background: Some studies have suggested that the intrathecal use of cyclooxygenase enzyme inhibitors provides an anti-nociceptive effect. Therefore, the occurrence of side effects seen in systemic usage can be eliminated. Aims: The primary objective of this experimental, randomized, controlled trial was to test the hypothesis asserting that intrathecal dexketoprofen trometamol would demonstrate an analgesic effect during postoperative period. Study Design: Animal experimentation. Methods: Forty rats were randomized into 4 groups 7 days after intrathecal catheterization; the following drugs were given through catheter lumens: Group Lidocaine (Group L: Lidocaine 20 μg; Group Lidocaine-Morphine (Group LM: Lidocaine 20 μg and morphine 0.5 μgr; Group Lidocaine-Dexketoprofen (Group LD: Lidocaine 20 μg and dexketoprofen trometamol 100 μg; and Group Dexketoprofen (Group D: Dexketoprofen trometamol 100 μg. Paw incision was achieved under ether inhalation. To measure analgesic potential, hot plate and tail immersion tests were used as nociceptive tests during the postoperative period. Results: The mean reaction times detected in groups during hot plate and tail immersion tests were shortest in Group L at 15, 30, 45, 60, 75, 90, 105, and 120 minutes after start of surgery (p<0.01, all others. In the groups using dexketoprofen, as in the morphine group, longer reaction times were detected than in the lidocaine group at all measurement times except 120 minutes (p<0.01. Conclusion: Intrathecal dexketoprofen in the optimal perioperative pain management is effective, and can be administered as an adjuvant in clinics after neurotoxicity studies in animals, and effective dose studies in volunteers.

Advanced glycation end-products (AGEs acutely impair Ca2+ signalling in bovine aortic endothelial cells

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Nadim eNaser

2013-03-01

Full Text Available Post-translational modification of proteins in diabetes, including formation of advanced glycation end products (AGEs are believed to contribute to vascular dysfunction and disease. Impaired function of the endothelium is an early indicator of vascular dysfunction in diabetes and as many endothelial cell processes are dependent upon intracellular [Ca2+] and Ca2+ signalling, the aim of this study was to examine the acute effects of AGEs on Ca2+ signalling in bovine aortic endothelial cells (BAEC. Ca2+ signalling was studied using the fluorescent indicator dye Fura2-AM. AGEs were generated by incubating bovine serum albumin with 0 - 250 mM glucose or glucose-6-phosphate for 0 to 120 days at 37ºC. Under all conditions, the main AGE species generated was carboxymethyl lysine (CML as assayed using both GC-MS and HPLC. In Ca2+-replete solution, exposure of BAEC to AGEs for 5 min caused an elevation in basal [Ca2+] and attenuated the increase in intracellular [Ca2+] caused by ATP (100 µM. In the absence of extracellular Ca2+, exposure of BAEC to AGEs for 5 min caused an elevation in basal [Ca2+] and attenuated subsequent intracellular Ca2+ release caused by ATP, thapsigargin (0.1 µM and ionomycin (3 µM, but AGEs did not affect extracellular Ca2+ entry induced by the re-addition of Ca2+ to the bathing solution in the presence of any of these agents. The anti-oxidant α-lipoic acid (2 µM and NAD(PH oxidase inhibitors apocynin (500 µM and diphenyleneiodonium (DPI, 1 µM abolished these effects of AGEs on BAECs, as did the IP3 receptor antagonist xestospongin C (1 µM. In summary, AGEs caused an acute depletion of Ca2+ from the intracellular store in BAECs, such that the Ca2+ signal stimulated by the subsequent application other agents acting upon this store is reduced. The mechanism may involve generation of ROS from NAD(PH oxidase and possible activation of the IP3 receptor.

Anti-inflammatory and anti-nociceptive activities of methanolic leaf extract of Indigofera cassioides Rottl. Ex. DC.

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Raju Senthil Kumar

2013-01-01

Conclusions: All the results obtained revealed that the extract MEIC showed potent anti-inflammatory and anti-nociceptive activity against all the tested models and the results obtained were comparable with the standards used. The activity of the extract may be due to the presence of terpenoids, flavonoids and other phytochemicals.

D2-like receptors in the descending dopaminergic pathway are not involved in the decreased postoperative nociceptive threshold induced by plantar incision in adult rats

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Ohtani N

2016-10-01

Full Text Available Norimasa Ohtani, Eiji Masaki Division of Dento-oral Anesthesiology, Tohoku University Graduate School of Dentistry, Sendai, Miyagi, Japan Background: Approximately half of all patients who undergo surgery develop postoperative pain, the mechanisms of which are not well understood by anesthesiologists. D2-like receptors in the descending dopaminergic pathway play an important role in regulation of pain transmission in the spinal cord. Impairment of inhibitory neurons in the spinal cord is suggested as part of the mechanism for neuropathic pain, which is one component of postoperative pain. The purpose of this study was to investigate whether impairment of D2-like receptors in the descending dopaminergic pathway in the spinal cord is involved in the decreased postoperative nociceptive threshold in rats.Methods: Male Sprague-Dawley rats (250–300 g were anesthetized with sevoflurane and an intrathecal (IT catheter was implanted. Six days later, a plantar incision was made. On the following day, saline, a D2-like receptor agonist (quinpirole, or a D2-like receptor antagonist (sulpiride was administered intrathecally. Thermal and mechanical nociceptive responses were assessed by exposure to infrared radiant heat and the von Frey filament test before and after plantar incision.Results: Plantar incision decreased both thermal latency and the mechanical nociceptive threshold. IT administration of quinpirole inhibited the nociceptive responses induced by plantar incision, but sulpiride had no effect.Conclusion: A D2-like receptor agonist had antinociceptive effects on the hypersensitivity response triggered by a surgical incision, but a D2-like receptor antagonist had no effect on this response. These results suggest that impairment and/or modification of D2-like receptors in the descending dopaminergic pathway in the spinal cord is not involved in the postoperative decrease in nociceptive threshold. Keywords: postoperative pain, descending pathway

Acute inhibition of central c-Jun N-terminal kinase restores hypothalamic insulin signalling and alleviates glucose intolerance in diabetic mice.

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Benzler, J; Ganjam, G K; Legler, K; Stöhr, S; Krüger, M; Steger, J; Tups, A

2013-05-01

The hypothalamus has been identified as a main insulin target tissue for regulating normal body weight and glucose metabolism. Recent observations suggest that c-Jun-N-terminal kinase (JNK)-signalling plays a crucial role in the development of obesity and insulin resistance because neuronal JNK-1 ablation in the mouse prevented high-fat diet-induced obesity (DIO) and increased energy expenditure, as well as insulin sensitivity. In the present study, we investigated whether central JNK inhibition is associated with sensitisation of hypothalamic insulin signalling in mice fed a high-fat diet for 3 weeks and in leptin-deficient mice. We determined whether i.c.v. injection of a pharmacological JNK-inhibitor (SP600125) improved impaired glucose homeostasis. By immunohistochemistry, we first observed that JNK activity was increased in the arcuate nucleus (ARC) and the ventromedial hypothalamus (VMH) in both mouse models, relative to normoglycaemic controls. This suggests that up-regulation of JNK in these regions is associated with glucose intolerance and obesity, independent of leptin levels. Acute i.c.v. injection of SP600125 ameliorated glucose tolerance within 30 min in both leptin-deficient and DIO mice. Given the acute nature of i.c.v. injections, these effects cannot be attributed to changes in food intake or energy balance. In a hypothalamic cell line, and in the ARC and VMH of leptin-deficient mice, JNK inhibition by SP600125 consistently improved impaired insulin signalling. This was determined by a reduction of phospho-insulin receptor substrate-1 [IRS-1(Ser612)] protein in a hypothalamic cell line and a decline in the number of pIRS-1(Ser612) immunoreactive cells in the ARC and VMH. Serine 612 phosphorylation of IRS-1 is assumed to negatively regulate insulin signalling. In leptin-deficient mice, in both nuclei, central inhibition of JNK increased the number of cells immunoreactive for phospho-Akt (Ser473) and phospho-GSK-3β (Ser9), which are important

Pseudomonas aeruginosa forms Biofilms in Acute InfectionIndependent of Cell-to-Cell Signaling

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Schaber, J. Andy; Triffo, W.J.; Suh, Sang J.; Oliver, Jeffrey W.; Hastert, Mary C.; Griswold, John A.; Auer, Manfred; Hamood, Abdul N.; Rumbaugh, Kendra P.

2006-09-20

Biofilms are bacterial communities residing within a polysaccharide matrix that are associated with persistence and antibiotic resistance in chronic infections. We show that the opportunistic pathogen Pseudomonas aeruginosa forms biofilms within 8 hours of infection in thermally-injured mice, demonstrating that biofilms contribute to bacterial colonization in acute infections. P. aeruginosa biofilms were visualized within burned tissue surrounding blood vessels and adipose cells. Although quorum sensing (QS), a bacterial signaling mechanism, coordinates differentiation of biofilms in vitro, wild type and QS-deficient P. aeruginosa formed similar biofilms in vivo. Our findings demonstrate that P. aeruginosa forms biofilms on specific host tissues independent of QS.

Influence of dental correction on nociceptive test responses, fecal appearance, body condition score, and apparent digestibility coefficient for dry matter of Zamorano-leones donkeys (Equus asinus).

Science.gov (United States)

Rodrigues, J B; Ferreira, L M; Bastos, E; San Roman, F; Viegas, C; Santos, A S

2013-10-01

The influence of dental correction on nociceptive (pressure) test responses, fecal appearance, BCS, and apparent digestibility coefficient for DM was studied in 18 Zamorano-Leonés donkeys, an endangered local breed from the Zamora province in Spain. For this purpose, donkeys were divided into 2 homogeneous control and treatment groups, based on age, BCS, and dental findings. On d 1, 45, 90, and 135, BCS and nociceptive test responses were evaluated in all donkeys. Feed and fecal samples were collected from all donkeys for 3 consecutive days, starting at each of the aforementioned days. Apparent digestibility coefficient for DM was estimated, using ADL as an internal marker. A progressive decrease of positive nociceptive test responses was observed from d 1 up to 90 (P donkeys but also the equid population, in general, to improve their welfare.

Interaction of corneal nociceptive stimulation and lacrimal secretion.

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Situ, Ping; Simpson, Trefford L

2010-11-01

To investigate the interaction between corneal stimuli at different positions and tear secretion and to establish relationships between nociceptive stimuli detection thresholds and stimulated tearing. Using a computerized Belmonte-esthesiometer, mechanical and chemical stimuli, from 0% to 200% of the threshold in 50% steps, were delivered (in random order) to the central and peripheral (approximately 2-mm inside the limbus) cornea during four separate sessions to 15 subjects. Immediately after each stimulus, tear meniscus height (TMH) was measured using optical coherence tomography to quantify the amount of lacrimal secretion, and subjects reported whether they felt tears starting to accumulate in their eyes. Thresholds (50% detection) for detection of tearing were estimated. TMH increased with increasing stimulus intensity (P lacrimation reflex. Central mechanical corneal stimulation is the most effective stimulus-position pairing and appears to be the major sensory driving force for reflex tear secretion by the lacrimal functional unit.

Neuro chemical characteristic of structures of nociceptive system athyperthyroid function of the thyroid gland

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O. M. Demchenko

2015-06-01

Full Text Available The papercomprises the study of the conditionofpro-antioxidantprocesses in the formationso fnociceptivesystem (cerebral cortex, hippocampus, stem and thalamus in the presence of the experiment al induced hyperthyroidism. It was found that nociceptive irritation (laparotomy on the background of hyper thyroidism had not pronounced effect on the content of diene conjugates (DC and malondialdehyde. The level of enzymes of antioxidant system of superoxidedismutase (SOD and glutathioneperoxidase (GPO decreased.

Regulation of Lipolysis and Adipose Tissue Signaling during Acute Endotoxin-Induced Inflammation

DEFF Research Database (Denmark)

Rittig, Nikolaj; Bach, Ermina; Thomsen, Henrik Holm

2016-01-01

BACKGROUND: Lipolysis is accelerated during the acute phase of inflammation, a process being regulated by pro-inflammatory cytokines (e.g. TNF-α), stress-hormones, and insulin. The intracellular mechanisms remain elusive and we therefore measured pro- and anti-lipolytic signaling pathways...... to measure palmitate rate of appearance (Rapalmitate) and indirect calorimetry was performed to measure energy expenditures and lipid oxidation rates. A subcutaneous abdominal fat biopsy was obtained during both interventions and subjected to western blotting and qPCR quantifications. RESULTS: LPS caused...... a mean increase in serum free fatty acids (FFA) concentrations of 90% (CI-95%: 37-142, p = 0.005), a median increase in Rapalmitate of 117% (CI-95%: 77-166, penergy expenditure of 28% (CI-95%: 16-42, p...

An Epstein-Barr virus encoded inhibitor of Colony Stimulating Factor-1 signaling is an important determinant for acute and persistent EBV infection.

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Makoto Ohashi

2012-12-01

Full Text Available Acute Epstein-Barr virus (EBV infection is the most common cause of Infectious Mononucleosis. Nearly all adult humans harbor life-long, persistent EBV infection which can lead to development of cancers including Hodgkin Lymphoma, Burkitt Lymphoma, nasopharyngeal carcinoma, gastric carcinoma, and lymphomas in immunosuppressed patients. BARF1 is an EBV replication-associated, secreted protein that blocks Colony Stimulating Factor 1 (CSF-1 signaling, an innate immunity pathway not targeted by any other virus species. To evaluate effects of BARF1 in acute and persistent infection, we mutated the BARF1 homologue in the EBV-related herpesvirus, or lymphocryptovirus (LCV, naturally infecting rhesus macaques to create a recombinant rhLCV incapable of blocking CSF-1 (ΔrhBARF1. Rhesus macaques orally challenged with ΔrhBARF1 had decreased viral load indicating that CSF-1 is important for acute virus infection. Surprisingly, ΔrhBARF1 was also associated with dramatically lower virus setpoints during persistent infection. Normal acute viral load and normal viral setpoints during persistent rhLCV infection could be restored by Simian/Human Immunodeficiency Virus-induced immunosuppression prior to oral inoculation with ΔrhBARF1 or infection of immunocompetent animals with a recombinant rhLCV where the rhBARF1 was repaired. These results indicate that BARF1 blockade of CSF-1 signaling is an important immune evasion strategy for efficient acute EBV infection and a significant determinant for virus setpoint during persistent EBV infection.

Metformin induces differentiation in acute promyelocytic leukemia by activating the MEK/ERK signaling pathway

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Huai, Lei; Wang, Cuicui; Zhang, Cuiping; Li, Qihui; Chen, Yirui; Jia, Yujiao; Li, Yan; Xing, Haiyan; Tian, Zheng; Rao, Qing; Wang, Min [State Key Laboratory of Experimental Hematology, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin 300020 (China); Wang, Jianxiang, E-mail: wangjx@ihcams.ac.cn [State Key Laboratory of Experimental Hematology, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin 300020 (China)

2012-06-08

Highlights: Black-Right-Pointing-Pointer Metformin induces differentiation in NB4 and primary APL cells. Black-Right-Pointing-Pointer Metformin induces activation of the MEK/ERK signaling pathway in APL cells. Black-Right-Pointing-Pointer Metformin synergizes with ATRA to trigger maturation of NB4 and primary APL cells. Black-Right-Pointing-Pointer Metformin induces the relocalization and degradation of the PML-RAR{alpha} fusion protein. Black-Right-Pointing-Pointer The study may be applicable for new differentiation therapy in cancer treatment. -- Abstract: Recent studies have shown that metformin, a widely used antidiabetic agent, may reduce the risk of cancer development. In this study, we investigated the antitumoral effect of metformin on both acute myeloid leukemia (AML) and acute promyelocytic leukemia (APL) cells. Metformin induced apoptosis with partial differentiation in an APL cell line, NB4, but only displayed a proapoptotic effect on several non-M3 AML cell lines. Further analysis revealed that a strong synergistic effect existed between metformin and all-trans retinoic acid (ATRA) during APL cell maturation and that metformin induced the hyperphosphorylation of extracellular signal-regulated kinase (ERK) in APL cells. U0126, a specific MEK/ERK activation inhibitor, abrogated metformin-induced differentiation. Finally, we found that metformin induced the degradation of the oncoproteins PML-RAR{alpha} and c-Myc and activated caspase-3. In conclusion, these results suggest that metformin treatment may contribute to the enhancement of ATRA-induced differentiation in APL, which may deepen the understanding of APL maturation and thus provide insight for new therapy strategies.

Psychophysics of a nociceptive test in the mouse: ambient temperature as a key factor for variation.

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Ivanne Pincedé

Full Text Available The mouse is increasingly used in biomedical research, notably in behavioral neurosciences for the development of tests or models of pain. Our goal was to provide the scientific community with an outstanding tool that allows the determination of psychophysical descriptors of a nociceptive reaction, which are inaccessible with conventional methods: namely the true threshold, true latency, conduction velocity of the peripheral fibers that trigger the response and latency of the central decision-making process.Basically, the procedures involved heating of the tail with a CO(2 laser, recording of tail temperature with an infrared camera and stopping the heating when the animal reacted. The method is based mainly on the measurement of three observable variables, namely the initial temperature, the heating rate and the temperature reached at the actual moment of the reaction following random variations in noxious radiant heat. The initial temperature of the tail, which itself depends on the ambient temperature, very markedly influenced the behavioral threshold, the behavioral latency and the conduction velocity of the peripheral fibers but not the latency of the central decision-making.We have validated a psychophysical approach to nociceptive reactions for the mouse, which has already been described for rats and Humans. It enables the determination of four variables, which contribute to the overall latency of the response. The usefulness of such an approach was demonstrated by providing new fundamental findings regarding the influence of ambient temperature on nociceptive processes. We conclude by challenging the validity of using as "pain index" the reaction time of a behavioral response to an increasing heat stimulus and emphasize the need for a very careful control of the ambient temperature, as a prevailing environmental source of variation, during any behavioral testing of mice.

Evidence of altered pressure pain thresholds in persons with disorders of consciousness as measured by the Nociception Coma Scale-Italian version.

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Sattin, Davide; Schnakers, Caroline; Pagani, Marco; Arenare, Francesca; Devalle, Guya; Giunco, Fabrizio; Guizzetti, GianBattista; Lanfranchi, Maurizio; Giovannetti, Ambra M; Covelli, Venusia; Bersano, Anna; Nigri, Anna; Minati, Ludovico; Rossi Sebastiano, Davide; Parati, Eugenio; Bruzzone, MariaGrazia; Franceschetti, Silvana; Leonardi, Matilde

2017-02-28

Pain assessment in patients with disorders of consciousness (DoC) is a controversial issue for clinicians, who require tools and standardised procedures for testing nociception in non-communicative patients. The aims of the present study were, first, to analyse the psychometric properties of the Italian version of the Nociception Coma Scale and, second, to evaluate pressure pain thresholds in a group of patients with DoC. The authors conducted a multi-centre study on 40 healthy participants and 60 DoC patients enrolled from six hospitals in Italy. For each group an electronic algometer was used to apply all nociceptive pressure stimuli. Our results show that the Italian version of the NCS retains the good psychometric properties of the original version and is therefore suitable for standardised pain assessment in clinical practice. In our study, pressure pain thresholds measured in a group of patients in vegetative and minimally conscious state were relatively lower than pain threshold values found in a group of healthy participants. Such findings motivate additional investigation on possible pain sensitisation in patients with severe brain injury and multiple co-morbidities, and on application of tailored therapeutic approaches useful for pain management in patients unable verbally to communicate their feelings.

The selective effect of N-feruloylserotonins isolated from Leuzea carthamoides on nociception and anxiety in rats

Czech Academy of Sciences Publication Activity Database

Yamamotová, A.; Pometlová, M.; Harmatha, Juraj; Rašková, H.; Rokyta, R.

2007-01-01

Roč. 112, č. 2 (2007), s. 368-374 ISSN 0378-8741 R&D Projects: GA MŠk(CZ) 1M0517; GA ČR(CZ) GA203/07/1227 Institutional research plan: CEZ:AV0Z40550506 Keywords : nociception * anxiety * N-feruloylserotonin * Leuzea carthamoides Subject RIV: CC - Organic Chemistry Impact factor: 2.049, year: 2007

Corticotrigeminal Projections from the Insular Cortex to the Trigeminal Caudal Subnucleus Regulate Orofacial Pain after Nerve Injury via Extracellular Signal-Regulated Kinase Activation in Insular Cortex Neurons.

Science.gov (United States)

Wang, Jian; Li, Zhi-Hua; Feng, Ban; Zhang, Ting; Zhang, Han; Li, Hui; Chen, Tao; Cui, Jing; Zang, Wei-Dong; Li, Yun-Qing

2015-01-01

Cortical neuroplasticity alterations are implicated in the pathophysiology of chronic orofacial pain. However, the relationship between critical cortex excitability and orofacial pain maintenance has not been fully elucidated. We recently demonstrated a top-down corticospinal descending pain modulation pathway from the anterior cingulate cortex (ACC) to the spinal dorsal horn that could directly regulate nociceptive transmission. Thus, we aimed to investigate possible corticotrigeminal connections that directly influence orofacial nociception in rats. Infraorbital nerve chronic constriction injury (IoN-CCI) induced significant orofacial nociceptive behaviors as well as pain-related negative emotions such as anxiety/depression in rats. By combining retrograde and anterograde tract tracing, we found powerful evidence that the trigeminal caudal subnucleus (Vc), especially the superficial laminae (I/II), received direct descending projections from granular and dysgranular parts of the insular cortex (IC). Extracellular signal-regulated kinase (ERK), an important signaling molecule involved in neuroplasticity, was significantly activated in the IC following IoN-CCI. Moreover, in IC slices from IoN-CCI rats, U0126, an inhibitor of ERK activation, decreased both the amplitude and the frequency of spontaneous excitatory postsynaptic currents (sEPSCs) and reduced the paired-pulse ratio (PPR) of Vc-projecting neurons. Additionally, U0126 also reduced the number of action potentials in the Vc-projecting neurons. Finally, intra-IC infusion of U0126 obviously decreased Fos expression in the Vc, accompanied by the alleviation of both nociceptive behavior and negative emotions. Thus, the corticotrigeminal descending pathway from the IC to the Vc could directly regulate orofacial pain, and ERK deactivation in the IC could effectively alleviate neuropathic pain as well as pain-related negative emotions in IoN-CCI rats, probably through this top-down pathway. These findings may help

The Purinergic System and Glial Cells: Emerging Costars in Nociception

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Giulia Magni

2014-01-01

Full Text Available It is now well established that glial cells not only provide mechanical and trophic support to neurons but can directly contribute to neurotransmission, for example, by release and uptake of neurotransmitters and by secreting pro- and anti-inflammatory mediators. This has greatly changed our attitude towards acute and chronic disorders, paving the way for new therapeutic approaches targeting activated glial cells to indirectly modulate and/or restore neuronal functions. A deeper understanding of the molecular mechanisms and signaling pathways involved in neuron-to-glia and glia-to-glia communication that can be pharmacologically targeted is therefore a mandatory step toward the success of this new healing strategy. This holds true also in the field of pain transmission, where the key involvement of astrocytes and microglia in the central nervous system and satellite glial cells in peripheral ganglia has been clearly demonstrated, and literally hundreds of signaling molecules have been identified. Here, we shall focus on one emerging signaling system involved in the cross talk between neurons and glial cells, the purinergic system, consisting of extracellular nucleotides and nucleosides and their membrane receptors. Specifically, we shall summarize existing evidence of novel “druggable” glial purinergic targets, which could help in the development of innovative analgesic approaches to chronic pain states.

Resveratrol Downregulates Interleukin-6-Stimulated Sonic Hedgehog Signaling in Human Acute Myeloid Leukemia

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Su, Yu-Chieh; Li, Szu-Chin; Wu, Yin-Chi; Wang, Li-Min; Chao, K. S. Clifford; Liao, Hui-Fen

2013-01-01

IL-6 and sonic hedgehog (Shh) signaling molecules are considered to maintain the growth of cancer stem cells (CSCs). Resveratrol, an important integrant in traditional Chinese medicine, possesses certain antitumor effects. However, the mechanisms on regulating acute myeloid leukemia (AML) are unclear. This study first used human subjects to demonstrate that the plasma levels of IL-6 and IL-1β in AML patients were higher and lower, respectively, than healthy donors. The expression of Shh preproproteins, and C- and N-terminal Shh peptides increased in bone marrow and peripheral blood mononuclear cells isolated from AML patients, and the plasma N-Shh secretion was greater. To further clarify the effect of IL-6 and resveratrol in Shh signaling, human AML HL-60 cells were tested. IL-6 upregulated Shh and Gli-1 expression and was accompanied by an increase of cell viability. Resveratrol significantly decreased CSC-related Shh expression, Gli-1 nuclear translocation, and cell viability in IL-6-treated HL-60 cells and had synergistic effect with Shh inhibitor cyclopamine on inhibiting cell growth. Conclusions. IL-6 stimulated the growth of AML cells through Shh signaling, and this effect might be blocked by resveratrol. Further investigations of Shh as a prognostic marker and resveratrol as a therapeutic drug target to CSCs in AML are surely warranted. PMID:23533494

The effect of social isolation, gender and familiarity with the experimental procedure on tests of porcine nociceptive thresholds

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di Giminiani, Pierpaolo; Stausholm, Julie S.; Viitasaari, Eliina

2015-01-01

Objective To investigate the effects of habituation and isolation on mechanical nociceptive thresholds in pigs at the pelvic limbs and at the tail. Study design Prospective randomized multifactorial study. Animals Thirty-two healthy castrated male (experiment 1), and 12 castrated male and 12 female...

Effects of acute versus repeated cocaine exposure on the expression of endocannabinoid signaling-related proteins in the mouse cerebellum

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Ana ePalomino

2014-03-01

Full Text Available Growing awareness of cerebellar involvement in addiction is based on the cerebellum’s intermediary position between motor and reward, potentially acting as an interface between motivational and cognitive functions. Here, we examined the impact of acute and repeated cocaine exposure on the two main signaling systems in the mouse cerebellum: the endocannabinoid (eCB and glutamate systems. To this end, we investigated whether eCB signaling-related gene and protein expression (CB1 receptors and enzymes that produce (DAGLα/β and NAPE-PLD and degrade (MAGL and FAAH eCB were altered. In addition, we analyzed the gene expression of relevant components of the glutamate signaling system (glutamate synthesizing enzymes LGA and KGA, mGluR3/5 metabotropic receptors, and NR1/2A/2B/2C-NMDA and GluR1/2/3/4-AMPA ionotropic receptor subunits and the gene expression of tyrosine hydroxylase (TH, the rate-limiting enzyme in catecholamine biosynthesis, because noradrenergic terminals innervate the cerebellar cortex. Results indicated that acute cocaine exposure decreased DAGLα expression, suggesting a down-regulation of 2-AG production, as well as gene expression of TH, KGA, mGluR3 and all ionotropic receptor subunits analyzed in the cerebellum. The acquisition of conditioned locomotion and sensitization after repeated cocaine exposure were associated with an increased NAPE-PLD/FAAH ratio, suggesting enhanced anandamide production, and a decreased DAGLβ/MAGL ratio, suggesting decreased 2-AG generation. Repeated cocaine also increased LGA gene expression but had no effect on glutamate receptors. These findings indicate that acute cocaine modulates the expression of the eCB and glutamate systems. Repeated cocaine results in normalization of glutamate receptor expression, although sustained changes in eCB is observed. We suggest that cocaine-induced alterations to cerebellar eCB should be considered when analyzing the adaptations imposed by psychostimulants that

Classical Conditioning Fails to Elicit Allodynia in an Experimental Study with Healthy Humans

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Madden, Victoria J; Russek, Leslie N; Harvie, Daniel S; Vlaeyen, Johan W S; Moseley, G Lorimer

2016-01-01

OBJECTIVE : Associative learning has been proposed as a mechanism behind the persistence of pain after tissue healing. The simultaneous occurrence of nociceptive and non-nociceptive input during acute injury mimics the pairings thought to drive classical conditioning effects. However, empirical

Divergent functions of the left and right central amygdala in visceral nociception.

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Sadler, Katelyn E; McQuaid, Neal A; Cox, Abigail C; Behun, Marissa N; Trouten, Allison M; Kolber, Benedict J

2017-04-01

The left and right central amygdalae (CeA) are limbic regions involved in somatic and visceral pain processing. These 2 nuclei are asymmetrically involved in somatic pain modulation; pain-like responses on both sides of the body are preferentially driven by the right CeA, and in a reciprocal fashion, nociceptive somatic stimuli on both sides of the body predominantly alter molecular and physiological activities in the right CeA. Unknown, however, is whether this lateralization also exists in visceral pain processing and furthermore what function the left CeA has in modulating nociceptive information. Using urinary bladder distension (UBD) and excitatory optogenetics, a pronociceptive function of the right CeA was demonstrated in mice. Channelrhodopsin-2-mediated activation of the right CeA increased visceromotor responses (VMRs), while activation of the left CeA had no effect. Similarly, UBD-evoked VMRs increased after unilateral infusion of pituitary adenylate cyclase-activating polypeptide in the right CeA. To determine intrinsic left CeA involvement in bladder pain modulation, this region was optogenetically silenced during noxious UBD. Halorhodopsin (NpHR)-mediated inhibition of the left CeA increased VMRs, suggesting an ongoing antinociceptive function for this region. Finally, divergent left and right CeA functions were evaluated during abdominal mechanosensory testing. In naive animals, channelrhodopsin-2-mediated activation of the right CeA induced mechanical allodynia, and after cyclophosphamide-induced bladder sensitization, activation of the left CeA reversed referred bladder pain-like behaviors. Overall, these data provide evidence for functional brain lateralization in the absence of peripheral anatomical asymmetries.

Preferential activation of HIF-2α adaptive signalling in neuronal-like cells in response to acute hypoxia.

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Miguel A S Martín-Aragón Baudel

Full Text Available Stroke causes severe neuronal damage as disrupted cerebral blood flow starves neurons of oxygen and glucose. The hypoxia inducible factors (HIF-1α and HIF-2α orchestrate oxygen homeostasis and regulate specific aspects of hypoxic adaptation. Here we show the importance of HIF-2α dependant signalling in neuronal adaptation to hypoxic insult. PC12 and NT2 cells were differentiated into neuronal-like cells using NGF and retinoic acid, and exposed to acute hypoxia (1% O2. Gene and protein expression was analysed by qPCR and immunoblotting and the neuronal-like phenotype was examined. PC12 and NT2 differentiation promoted neurite extension and expression of neuronal markers, NSE and KCC2. Induction of HIF-1α mRNA or protein was not detected in hypoxic neuronal-like cells, however marked induction of HIF-2α mRNA and protein expression was observed. Induction of HIF-1α target genes was also not detected in response to acute hypoxia, however significant induction of HIF-2α transcriptional targets was clearly evident. Furthermore, hypoxic insult dramatically reduced both neurite number and length, and attenuated expression of neuronal markers, NSE and KCC2. This correlated with an increase in expression of the neural progenitor and stem cell-like markers, CD44 and vimentin, suggesting HIF-2α molecular mechanisms could potentially promote regression of neuronal-like cells to a stem-like state and trigger neuronal recovery following ischaemic insult. Our findings suggest the HIF-2α pathway predominates over HIF-1α signalling in neuronal-like cells following acute hypoxia.

Modulation of melanocortin- induced changes in spinal nociception by µ-opioid receptor agonist and antagonist in neuropathic rats

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Gispen, W.H.; Starowitcz, K.; Przewlocki, R.; Przewlocka, B.

2002-01-01

Co-localization of opioid and melanocortin receptor expression, especially at the spinal cord level in the dorsal horn and in the gray matter surrounding the central canal led to the suggestion that melanocortins might play a role in nociceptive processes. In the present studies, we aimed to

Acute Podocyte Vascular Endothelial Growth Factor (VEGF-A) Knockdown Disrupts alphaVbeta3 Integrin Signaling in the Glomerulus

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Veron, Delma; Villegas, Guillermo; Aggarwal, Pardeep Kumar; Bertuccio, Claudia; Jimenez, Juan; Velazquez, Heino; Reidy, Kimberly; Abrahamson, Dale R.; Moeckel, Gilbert; Kashgarian, Michael; Tufro, Alda

2012-01-01

Podocyte or endothelial cell VEGF-A knockout causes thrombotic microangiopathy in adult mice. To study the mechanism involved in acute and local injury caused by low podocyte VEGF-A we developed an inducible, podocyte-specific VEGF-A knockdown mouse, and we generated an immortalized podocyte cell line (VEGFKD) that downregulates VEGF-A upon doxycycline exposure. Tet-O-siVEGF:podocin-rtTA mice express VEGF shRNA in podocytes in a doxycycline-regulated manner, decreasing VEGF-A mRNA and VEGF-A protein levels in isolated glomeruli to ∼20% of non-induced controls and urine VEGF-A to ∼30% of control values a week after doxycycline induction. Induced tet-O-siVEGF:podocin-rtTA mice developed acute renal failure and proteinuria, associated with mesangiolysis and microaneurisms. Glomerular ultrastructure revealed endothelial cell swelling, GBM lamination and podocyte effacement. VEGF knockdown decreased podocyte fibronectin and glomerular endothelial alphaVbeta3 integrin in vivo. VEGF receptor-2 (VEGFR2) interacts with beta3 integrin and neuropilin-1 in the kidney in vivo and in VEGFKD podocytes. Podocyte VEGF knockdown disrupts alphaVbeta3 integrin activation in glomeruli, detected by WOW1-Fab. VEGF silencing in cultured VEGFKD podocytes downregulates fibronectin and disrupts alphaVbeta3 integrin activation cell-autonomously. Collectively, these studies indicate that podocyte VEGF-A regulates alphaVbeta3 integrin signaling in the glomerulus, and that podocyte VEGF knockdown disrupts alphaVbeta3 integrin activity via decreased VEGFR2 signaling, thereby damaging the three layers of the glomerular filtration barrier, causing proteinuria and acute renal failure. PMID:22808199

Antinociceptive Effects of Transcytosed Botulinum Neurotoxin Type A on Trigeminal Nociception in Rats

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Kim, Hye-Jin; Lee, Geun-Woo; Kim, Min-Ji; Yang, Kui-Ye; Kim, Seong-Taek; Bae, Yong-Cheol

2015-01-01

We examined the effects of peripherally or centrally administered botulinum neurotoxin type A (BoNT-A) on orofacial inflammatory pain to evaluate the antinociceptive effect of BoNT-A and its underlying mechanisms. The experiments were carried out on male Sprague-Dawley rats. Subcutaneous (3 U/kg) or intracisternal (0.3 or 1 U/kg) administration of BoNT-A significantly inhibited the formalin-induced nociceptive response in the second phase. Both subcutaneous (1 or 3 U/kg) and intracisternal (0.3 or 1 U/kg) injection of BoNT-A increased the latency of head withdrawal response in the complete Freund's adjuvant (CFA)-treated rats. Intracisternal administration of N-methyl-D-aspartate (NMDA) evoked nociceptive behavior via the activation of trigeminal neurons, which was attenuated by the subcutaneous or intracisternal injection of BoNT-A. Intracisternal injection of NMDA up-regulated c-Fos expression in the trigeminal neurons of the medullary dorsal horn. Subcutaneous (3 U/kg) or intracisternal (1 U/kg) administration of BoNT-A significantly reduced the number of c-Fos immunoreactive neurons in the NMDA-treated rats. These results suggest that the central antinociceptive effects the peripherally or centrally administered BoNT-A are mediated by transcytosed BoNT-A or direct inhibition of trigeminal neurons. Our data suggest that central targets of BoNT-A might provide a new therapeutic tool for the treatment of orofacial chronic pain conditions. PMID:26170739

Polysaccharide rich fractions from barks of Ximenia americana inhibit peripheral inflammatory nociception in mice Antinociceptive effect of Ximenia americana polysaccharide rich fractions

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Kaira E.S. da Silva-Leite

Full Text Available Abstract Ximenia americana L., Olacaceae, barks are utilized in folk medicine as analgesic and anti-inflammatory. The objective was to evaluate the toxicity and antinociceptive effect of polysaccharides rich fractions from X. americana barks. The fractions were obtained by extraction with NaOH, followed by precipitation with ethanol and fractionation by ion exchange chromatography. They were administered i.v. or p.o. before nociception tests (writhing, formalin, carragenan-induced hypernociception, hot plate, or during 14 days for toxicity assay. The total polysaccharides fraction (TPL-Xa: 8.1% yield presented 43% carbohydrate (21% uronic acid and resulted in two main fractions after chromatography (FI: 12%, FII: 22% yield. FII showed better homogeneity/purity, content of 44% carbohydrate, including 39% uronic acid, arabinose and galactose as major monosaccharides, and infrared spectra with peaks in carbohydrate range for COO- groups of uronic acid. TPL-Xa (10 mg/kg and FII (0.1 and 1 mg/kg presented inhibitory effect in behavior tests that evaluate nociception induced by chemical and mechanical, but not thermal stimuli. TPL-Xa did not alter parameters of systemic toxicity. In conclusion, polysaccharides rich fractions of X. americana barks inhibit peripheral inflammatory nociception, being well tolerated by animals.

Anti-nociceptive effect of patchouli alcohol: Involving attenuation of cyclooxygenase 2 and modulation of mu-opioid receptor.

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Yu, Xuan; Wang, Xin-Pei; Yan, Xiao-Jin; Jiang, Jing-Fei; Lei, Fan; Xing, Dong-Ming; Guo, Yue-Ying; Du, Li-Jun

2017-08-09

To explore the anti-nociceptive effect of patchouli alcohol (PA), the essential oil isolated from Pogostemon cablin (Blanco) Bent, and determine the mechanism in molecular levels. The acetic acid-induced writhing test and formalin-induced plantar injection test in mice were employed to confifirm the effect in vivo. Intracellular calcium ion was imaged to verify PA on mu-opioid receptor (MOR). Cyclooxygenase 2 (COX2) and MOR of mouse brain were expressed for determination of PA's target. Cellular experiments were carried out to find out COX2 and MOR expression induced by PA. PA significantly reduced latency period of visceral pain and writhing induced by acetic acid saline solution (Peffect of PA. A decrease in the intracellular calcium level (Peffect. PA showed the characters of enhancing the MOR expression and reducing the intracellular calcium ion similar to opioid effect. Both COX2 and MOR are involved in the mechanism of PA's anti-nociceptive effect, and the up-regulation of the receptor expression and the inhibition of intracellular calcium are a new perspective to PA's effect on MOR.

Ethanolic extract of Aconiti Brachypodi Radix attenuates nociceptive pain probably via inhibition of voltage-dependent Na⁺ channel.

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Ren, Wei; Yuan, Lin; Li, Jun; Huang, Xian-Ju; Chen, Su; Zou, Da-Jiang; Liu, Xiangming; Yang, Xin-Zhou

2012-01-01

Aconiti Brachypodi Radix, belonging to the genus of Aconitum (Family Ranunculaceae), are used clinically as anti-rheumatic, anti-inflammatory and anti-nociceptive in traditional medicine of China. However, its mechanism and influence on nociceptive threshold are unknown and need further investigation. The analgesic effects of ethanolic extract of Aconiti Brachypodi Radix (EABR) were thus studied in vivo and in vitro. Three pain models in mice were used to assess the effect of EABR on nociceptive threshold. In vitro study was conducted to clarify the modulation of the extract on the tetrodotoxin-sensitive (TTX-S) sodium currents in rat's dorsal root ganglion (DRG) neurons using whole-cell patch clamp technique. The results showed that EABR (5-20 mg/kg, i.g.) could produce dose-dependent analgesic effect on hot-plate tests as well as writhing response induced by acetic acid. In addition, administration of 2.5-10 mg/kg EABR (i.g.) caused significant decrease in pain responses in the first and second phases of formalin test without altering the PGE₂ production in the hind paw of the mice. Moreover, EABR (10 µg/ml -1 mg/ml) could suppress TTX-S voltage-gated sodium currents in a dose-dependent way, indicating the underlying electrophysiological mechanism of the analgesic effect of the folk plant medicine. Collectively, our results indicated that EABR has analgesic property in three pain models and useful influence on TTX-S sodium currents in DRG neurons, suggesting that the interference with pain messages caused by the modulation of EABR on TTX-S sodium currents in DRG neurones may explain some of its analgesic effect.

Superficial dorsal horn neurons with double spike activity in the rat.

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Rojas-Piloni, Gerardo; Dickenson, Anthony H; Condés-Lara, Miguel

2007-05-29

Superficial dorsal horn neurons promote the transfer of nociceptive information from the periphery to supraspinal structures. The membrane and discharge properties of spinal cord neurons can alter the reliability of peripheral signals. In this paper, we analyze the location and response properties of a particular class of dorsal horn neurons that exhibits double spike discharge with a very short interspike interval (2.01+/-0.11 ms). These neurons receive nociceptive C-fiber input and are located in laminae I-II. Double spikes are generated spontaneously or by depolarizing current injection (interval of 2.37+/-0.22). Cells presenting double spike (interval 2.28+/-0.11) increased the firing rate by electrical noxious stimulation, as well as, in the first minutes after carrageenan injection into their receptive field. Carrageenan is a polysaccharide soluble in water and it is used for producing an experimental model of semi-chronic pain. In the present study carrageenan also produces an increase in the interval between double spikes and then, reduced their occurrence after 5-10 min. The results suggest that double spikes are due to intrinsic membrane properties and that their frequency is related to C-fiber nociceptive activity. The present work shows evidence that double spikes in superficial spinal cord neurones are related to the nociceptive stimulation, and they are possibly part of an acute pain-control mechanism.

Nociceptive responses to thermal and mechanical stimulations in awake pigs

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di Giminiani, Pierpaolo; Petersen, Lars Jelstrup; Herskin, Mette S.

2013-01-01

body sizes (30 and 60 kg) were exposed to thermal (CO(2) laser) and mechanical (pressure application measurement device) stimulations to the flank and the hind legs in a balanced order. The median response latency and the type of behavioural response were recorded. RESULTS: Small pigs exhibited...... animal studies in a large species require further examination. This manuscript describes the initial development of a porcine model of cutaneous nociception and focuses on interactions between the sensory modality, body size and the anatomical location of the stimulation site. METHODS: Pigs of different...... significantly lower pain thresholds (shorter latency to response) than large pigs to thermal and mechanical stimulations. Stimulations at the two anatomical locations elicited very distinct sets of behavioural responses, with different levels of sensitivity between the flank and the hind legs. Furthermore...

Unusual Voltage-Gated Sodium Currents as Targets for Pain.

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Barbosa, C; Cummins, T R

2016-01-01

Pain is a serious health problem that impacts the lives of many individuals. Hyperexcitability of peripheral sensory neurons contributes to both acute and chronic pain syndromes. Because voltage-gated sodium currents are crucial to the transmission of electrical signals in peripheral sensory neurons, the channels that underlie these currents are attractive targets for pain therapeutics. Sodium currents and channels in peripheral sensory neurons are complex. Multiple-channel isoforms contribute to the macroscopic currents in nociceptive sensory neurons. These different isoforms exhibit substantial variations in their kinetics and pharmacology. Furthermore, sodium current complexity is enhanced by an array of interacting proteins that can substantially modify the properties of voltage-gated sodium channels. Resurgent sodium currents, atypical currents that can enhance recovery from inactivation and neuronal firing, are increasingly being recognized as playing potentially important roles in sensory neuron hyperexcitability and pain sensations. Here we discuss unusual sodium channels and currents that have been identified in nociceptive sensory neurons, describe what is known about the molecular determinants of the complex sodium currents in these neurons. Finally, we provide an overview of therapeutic strategies to target voltage-gated sodium currents in nociceptive neurons. Copyright © 2016 Elsevier Inc. All rights reserved.

Effects of an acute therapeutic or rewarding dose of amphetamine on acquisition of Pavlovian autoshaping and ventral striatal dopamine signaling.

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Schuweiler, D R; Athens, J M; Thompson, J M; Vazhayil, S T; Garris, P A

2018-01-15

Rewarding doses of amphetamine increase the amplitude, duration, and frequency of dopamine transients in the ventral striatum. Debate continues at the behavioral level about which component of reward, learning or incentive salience, is signaled by these dopamine transients and thus altered in addiction. The learning hypothesis proposes that rewarding drugs result in pathological overlearning of drug-predictive cues, while the incentive sensitization hypothesis suggests that rewarding drugs result in sensitized attribution of incentive salience to drug-predictive cues. Therapeutic doses of amphetamine, such as those used to treat attention-deficit hyperactivity disorder, are hypothesized to enhance the ventral striatal dopamine transients that are critical for reward-related learning and to enhance Pavlovian learning. However, the effects of therapeutic doses of amphetamine on Pavlovian learning are poorly understood, and the effects on dopamine transients are completely unknown. We determined the effects of an acute pre-training therapeutic or rewarding amphetamine injection on the acquisition of Pavlovian autoshaping in the intact rat. We also determined the effects of these doses on electrically evoked transient-like dopamine signals using fast-scan cyclic voltammetry in the anesthetized rat. The rewarding dose enhanced the amplitude and duration of DA signals, caused acute task disengagement, impaired learning for several days, and triggered incentive sensitization. The therapeutic dose produced smaller enhancements in DA signals but did not have similar behavioral effects. These results underscore the necessity of more studies using therapeutic doses, and suggest a hybrid learning/incentive sensitization model may be required to explain the development of addiction. Copyright © 2017 Elsevier B.V. All rights reserved.

Factors affecting mechanical nociceptive thresholds in healthy sows.

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Nalon, Elena; Maes, Dominiek; Piepers, Sofie; Taylor, Polly; van Riet, Miriam M J; Janssens, Geert P J; Millet, Sam; Tuyttens, Frank A M

2016-05-01

To describe anatomical and methodological factors influencing mechanical nociceptive thresholds (MNTs) and intra-site variability in healthy sows. Prospective, randomized validation. Eight pregnant, healthy, mixed-parity sows (176-269 kg). Repeated MNT measurements were taken: 1) with a hand-held probe and a limb-mounted actuator connected to a digital algometer; 2) at nine landmarks on the limbs and tail; and 3) at 1 and 3 minute intervals. Data were analysed using linear mixed regression models. The MNTs (±SEM) of the limbs were lower with the probe (14.7 ± 1.2 N) than with the actuator (21.3 ± 1.2 N; p testing compared with day 1 (p < 0.001). The mean CV (±SE) was 38.9% (±1.1%). MNTs and intra-site variability in healthy sows were affected by several factors, indicating that this methodology requires considerable attention to detail. © 2015 Association of Veterinary Anaesthetists and the American College of Veterinary Anesthesia and Analgesia.

Molecular Analysis of Sensory Axon Branching Unraveled a cGMP-Dependent Signaling Cascade.

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Dumoulin, Alexandre; Ter-Avetisyan, Gohar; Schmidt, Hannes; Rathjen, Fritz G

2018-04-24

Axonal branching is a key process in the establishment of circuit connectivity within the nervous system. Molecular-genetic studies have shown that a specific form of axonal branching—the bifurcation of sensory neurons at the transition zone between the peripheral and the central nervous system—is regulated by a cyclic guanosine monophosphate (cGMP)-dependent signaling cascade which is composed of C-type natriuretic peptide (CNP), the receptor guanylyl cyclase Npr2, and cGMP-dependent protein kinase Iα (cGKIα). In the absence of any one of these components, neurons in dorsal root ganglia (DRG) and cranial sensory ganglia no longer bifurcate, and instead turn in either an ascending or a descending direction. In contrast, collateral axonal branch formation which represents a second type of axonal branch formation is not affected by inactivation of CNP, Npr2, or cGKI. Whereas axon bifurcation was lost in mouse mutants deficient for components of CNP-induced cGMP formation; the absence of the cGMP-degrading enzyme phosphodiesterase 2A had no effect on axon bifurcation. Adult mice that lack sensory axon bifurcation due to the conditional inactivation of Npr2-mediated cGMP signaling in DRG neurons demonstrated an altered shape of sensory axon terminal fields in the spinal cord, indicating that elaborate compensatory mechanisms reorganize neuronal circuits in the absence of bifurcation. On a functional level, these mice showed impaired heat sensation and nociception induced by chemical irritants, whereas responses to cold sensation, mechanical stimulation, and motor coordination are normal. These data point to a critical role of axon bifurcation for the processing of acute pain perception.

Molecular Analysis of Sensory Axon Branching Unraveled a cGMP-Dependent Signaling Cascade

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Alexandre Dumoulin

2018-04-01

Full Text Available Axonal branching is a key process in the establishment of circuit connectivity within the nervous system. Molecular-genetic studies have shown that a specific form of axonal branching—the bifurcation of sensory neurons at the transition zone between the peripheral and the central nervous system—is regulated by a cyclic guanosine monophosphate (cGMP-dependent signaling cascade which is composed of C-type natriuretic peptide (CNP, the receptor guanylyl cyclase Npr2, and cGMP-dependent protein kinase Iα (cGKIα. In the absence of any one of these components, neurons in dorsal root ganglia (DRG and cranial sensory ganglia no longer bifurcate, and instead turn in either an ascending or a descending direction. In contrast, collateral axonal branch formation which represents a second type of axonal branch formation is not affected by inactivation of CNP, Npr2, or cGKI. Whereas axon bifurcation was lost in mouse mutants deficient for components of CNP-induced cGMP formation; the absence of the cGMP-degrading enzyme phosphodiesterase 2A had no effect on axon bifurcation. Adult mice that lack sensory axon bifurcation due to the conditional inactivation of Npr2-mediated cGMP signaling in DRG neurons demonstrated an altered shape of sensory axon terminal fields in the spinal cord, indicating that elaborate compensatory mechanisms reorganize neuronal circuits in the absence of bifurcation. On a functional level, these mice showed impaired heat sensation and nociception induced by chemical irritants, whereas responses to cold sensation, mechanical stimulation, and motor coordination are normal. These data point to a critical role of axon bifurcation for the processing of acute pain perception.

Intrathecal administration of clonidine or yohimbine decreases the nociceptive behavior caused by formalin injection in the marsh terrapin (Pelomedusa subrufa)

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Makau, Christopher M; Towett, Philemon K; Abelson, Klas S P

2014-01-01

BACKGROUND: The role of noradrenergic system in the control of nociception is documented in some vertebrate animals. However, there are no data showing the role of this system on nociception in the marsh terrapins. METHODOLOGY: In this study, the antinociceptive action of intrathecal administration...... of the α 2-adrenoreceptor agonist clonidine and α 2-adrenoreceptor antagonist yohimbine was evaluated in the African marsh terrapin using the formalin test. The interaction of clonidine and yohimbine was also evaluated. RESULTS: Intrathecal administration of clonidine (37.5 or 65 μg/kg) caused...... a significant reduction in the mean time spent in pain-related behavior. Yohimbine, at a dose of 25 μg/kg, significantly blocked the effect of clonidine (65 μg/kg). However, administration of yohimbine (40 or 53 μg/kg) caused a significant reduction in the mean time spent in pain-related behavior. Intrathecal...

Separate transcriptionally regulated pathways specify distinct classes of sister dendrites in a nociceptive neuron.

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O'Brien, Barbara M J; Palumbos, Sierra D; Novakovic, Michaela; Shang, Xueying; Sundararajan, Lakshmi; Miller, David M

2017-12-15

The dendritic processes of nociceptive neurons transduce external signals into neurochemical cues that alert the organism to potentially damaging stimuli. The receptive field for each sensory neuron is defined by its dendritic arbor, but the mechanisms that shape dendritic architecture are incompletely understood. Using the model nociceptor, the PVD neuron in C. elegans, we determined that two types of PVD lateral branches project along the dorsal/ventral axis to generate the PVD dendritic arbor: (1) Pioneer dendrites that adhere to the epidermis, and (2) Commissural dendrites that fasciculate with circumferential motor neuron processes. Previous reports have shown that the LIM homeodomain transcription factor MEC-3 is required for all higher order PVD branching and that one of its targets, the claudin-like membrane protein HPO-30, preferentially promotes outgrowth of pioneer branches. Here, we show that another MEC-3 target, the conserved TFIIA-like zinc finger transcription factor EGL-46, adopts the alternative role of specifying commissural dendrites. The known EGL-46 binding partner, the TEAD transcription factor EGL-44, is also required for PVD commissural branch outgrowth. Double mutants of hpo-30 and egl-44 show strong enhancement of the lateral branching defect with decreased numbers of both pioneer and commissural dendrites. Thus, HPO-30/Claudin and EGL-46/EGL-44 function downstream of MEC-3 and in parallel acting pathways to direct outgrowth of two distinct classes of PVD dendritic branches. Copyright © 2017 Elsevier Inc. All rights reserved.

Ventrolateral periaqueductal gray lesion attenuates nociception but does not change anxiety-like indices or fear-induced antinociception in mice.

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Mendes-Gomes, Joyce; Amaral, Vanessa Cristiane Santana; Nunes-de-Souza, Ricardo Luiz

2011-06-01

The exposure of rodents to an open elevated plus-maze (oEPM: four open arms raised from the floor) elicits naloxone-insensitive antinociception. Midazolam infusion into the dorsal portion of the periaqueductal gray (dPAG), a structure of the descending inhibitory system of pain, failed to alter oEPM-induced antinociception. Chemical lesion of dorsomedial and dorsolateral PAG attenuated defensive behavior in the standard EPM (sEPM), an animal model of anxiety, but failed to change oEPM-induced antinociception. The present study investigated the effects of bilateral lesion, with the injection of NMDA (N-methyl-D-aspartic acid), of the ventrolateral column of PAG (vlPAG) (i) on nociceptive response induced by 2.5% formalin injected into the right hind paw (nociception test) in mice exposed to the enclosed EPM (eEPM: four enclosed arms - a non-aversive situation) or to the oEPM and (ii) on anxiety indices in mice exposed to the sEPM without prior formalin injection. Results showed that oEPM-induced antinociception was not altered by lesion of vlPAG. Nevertheless, the lesion reduced the nociceptive response in mice exposed to the eEPM and increased general locomotor activity during the eEPM and oEPM exposure. Furthermore, vlPAG lesion did not alter anxiety-like indices in mice exposed to the sEPM. The results suggest that vlPAG does not play a role in oEPM-induced antinociception or in defensive reactions assessed in the sEPM. Moreover, vlPAG inactivation induces pain inhibition in mice not exposed to an aversive situation and seems to increase general activity. Copyright © 2011 Elsevier B.V. All rights reserved.

Inhibition of vascular endothelial growth factor signaling facilitates liver repair from acute ethanol-induced injury in zebrafish

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Changwen Zhang

2016-11-01

Full Text Available Alcoholic liver disease (ALD results from alcohol overconsumption and is among the leading causes of liver-related morbidity and mortality worldwide. Elevated expression of vascular endothelial growth factor (VEGF and its receptors has been observed in ALD, but how it contributes to ALD pathophysiology is unclear. Here, we investigated the impact of VEGF signaling inhibition on an established zebrafish model of acute alcoholic liver injury. Kdrl activity was blocked by chemical inhibitor treatment or by genetic mutation. Exposing 4-day-old zebrafish larvae to 2% ethanol for 24 h induced hepatic steatosis, angiogenesis and fibrogenesis. The liver started self-repair once ethanol was removed. Although inhibiting Kdrl did not block the initial activation of hepatic stellate cells during ethanol treatment, it suppressed their proliferation, extracellular matrix protein deposition and fibrogenic gene expression after ethanol exposure, thus enhancing the liver repair. It also ameliorated hepatic steatosis and attenuated hepatic angiogenesis that accelerated after the ethanol treatment. qPCR showed that hepatic stellate cells are the first liver cell type to increase the expression of VEGF ligand and receptor genes in response to ethanol exposure. Both hepatic stellate cells and endothelial cells, but not hepatic parenchymal cells, expressed kdrl upon ethanol exposure and were likely the direct targets of Kdrl inhibition. Ethanol-induced steatosis and fibrogenesis still occurred in cloche mutants that have hepatic stellate cells but lack hepatic endothelial cells, and Kdrl inhibition suppressed both phenotypes in the mutants. These results suggest that VEGF signaling mediates interactions between activated hepatic stellate cells and hepatocytes that lead to steatosis. Our study demonstrates the involvement of VEGF signaling in regulating sustained liver injuries after acute alcohol exposure. It also provides a proof of principle of using the

Comparative effects of traditional Chinese and Western migraine medicines in an animal model of nociceptive trigeminovascular activation.

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Zhao, Yonglie; Martins-Oliveira, Margarida; Akerman, Simon; Goadsby, Peter J

2017-01-01

Background Migraine is a highly prevalent and disabling disorder of the brain with limited therapeutic options, particularly for preventive treatment. There is a need to identify novel targets and test their potential efficacy in relevant preclinical migraine models. Traditional Chinese medicines have been used for millennia and may offer avenues for exploration. Methods We evaluated two traditional Chinese medicines, gastrodin and ligustrazine, and compared them to two Western approaches with propranolol and levetiracetam, one effective and one ineffective, in an established in vivo rodent model of nociceptive durovascular trigeminal activation. Results Intravenous gastrodin (30 and 100 mg/kg) significantly inhibited nociceptive dural-evoked neuronal firing in the trigeminocervical complex. Ligustrazine (10 mg/kg) and propranolol (3 mg/kg) also significantly inhibited dural-evoked trigeminocervical complex responses, although the timing of responses of ligustrazine does not match its pharmacokinetic profile. Levetiracetam had no effects on trigeminovascular responses. Conclusion Our data suggest gastrodin has potential as an anti-migraine treatment, whereas ligustrazine seems less promising. Interestingly, in line with clinical trial data, propranolol was effective and levetiracetam not. Exploration of the mechanisms and modelling effects of Chinese traditional therapies offers novel route for drug discovery in migraine.

Xanthohumol ameliorates lipopolysaccharide (LPS-induced acute lung injury via induction of AMPK/GSK3β-Nrf2 signal axis

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Hongming Lv

2017-08-01

Full Text Available Abundant natural flavonoids can induce nuclear factor-erythroid 2 related factor 2 (Nrf2 and/or AMP-activated protein kinase (AMPK activation, which play crucial roles in the amelioration of various inflammation- and oxidative stress-induced diseases, including acute lung injury (ALI. Xanthohumol (Xn, a principal prenylflavonoid, possesses anti-inflammation and anti-oxidant activities. However, whether Xn could protect from LPS-induced ALI through inducing AMPK/Nrf2 activation and its downstream signals, are still poorly elucidated. Accordingly, we focused on exploring the protective effect of Xn in the context of ALI and the involvement of underlying molecular mechanisms. Our findings indicated that Xn effectively alleviated lung injury by reduction of lung W/D ratio and protein levels, neutrophil infiltration, MDA and MPO formation, and SOD and GSH depletion. Meanwhile, Xn significantly lessened histopathological changes, reactive oxygen species (ROS generation, several cytokines secretion, and iNOS and HMGB1 expression, and inhibited Txnip/NLRP3 inflammasome and NF-κB signaling pathway activation. Additionally, Xn evidently decreased t-BHP-stimulated cell apoptosis, ROS generation and GSH depletion but increased various anti-oxidative enzymes expression regulated by Keap1-Nrf2/ARE activation, which may be associated with AMPK and GSK3β phosphorylation. However, Xn-mediated inflammatory cytokines and ROS production, histopathological changes, Txnip/NLRP3 inflammasome and NF-κB signaling pathway in WT mice were remarkably abrogated in Nrf2-/- mice. Our experimental results firstly provided a support that Xn effectively protected LPS-induced ALI against oxidative stress and inflammation damage which are largely dependent upon upregulation of the Nrf2 pathway via activation of AMPK/GSK3β, thereby suppressing LPS-activated Txnip/NLRP3 inflammasome and NF-κB signaling pathway. Keywords: Xanthohumol, Acute lung injury, Oxidative stress

A potent and selective calcitonin gene-related peptide (CGRP) receptor antagonist, MK-8825, inhibits responses to nociceptive trigeminal activation: Role of CGRP in orofacial pain.

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Romero-Reyes, Marcela; Pardi, Vanessa; Akerman, Simon

2015-09-01

Temporomandibular disorders (TMDs) are orofacial pains within the trigeminal distribution, which involve the masticatory musculature, the temporomandibular joint or both. Their pathophysiology remains unclear, as inflammatory mediators are thought to be involved, and clinically TMD presents pain and sometimes limitation of function, but often appears without gross indications of local inflammation, such as visible edema, redness and increase in temperature. Calcitonin gene-related peptide (CGRP) has been implicated in other pain disorders with trigeminal distribution, such as migraine, of which TMD shares a significant co-morbidity. CGRP causes activation and sensitization of trigeminal primary afferent neurons, independent of any inflammatory mechanisms, and thus may also be involved in TMD. Here we used a small molecule, selective CGRP receptor antagonist, MK-8825, to dissect the role of CGRP in inducing spontaneous nociceptive facial grooming behaviors, neuronal activation in the trigeminal nucleus, and systemic release of pro-inflammatory cytokines, in a mouse model of acute orofacial masseteric muscle pain that we have developed, as a surrogate of acute TMD. We show that CFA masseteric injection causes significant spontaneous orofacial pain behaviors, neuronal activation in the trigeminal nucleus, and release of interleukin-6 (IL-6). In mice pre-treated with MK-8825 there is a significant reduction in these spontaneous orofacial pain behaviors. Also, at 2 and 24h after CFA injection the level of Fos immunoreactivity in the trigeminal nucleus, used as a marker of neuronal activation, was much lower on both ipsilateral and contralateral sides after pre-treatment with MK-8825. There was no effect of MK-8825 on the release of IL-6. These data suggest that CGRP may be involved in TMD pathophysiology, but not via inflammatory mechanisms, at least in the acute stage. Furthermore, CGRP receptor antagonists may have therapeutic efficacy in the treatment of TMD, as they

PKD signaling and pancreatitis

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Yuan, Jingzhen; Pandol, Stephen J.

2016-01-01

Background Acute pancreatitis is a serious medical disorder with no current therapies directed to the molecular pathogenesis of the disorder. Inflammation, inappropriate intracellular activation of digestive enzymes, and parenchymal acinar cell death by necrosis are the critical pathophysiologic processes of acute pancreatitis. Thus, it is necessary to elucidate the key molecular signals that mediate these pathobiologic processes and develop new therapeutic strategies to attenuate the appropriate signaling pathways in order to improve outcomes for this disease. A novel serine/threonine protein kinase D (PKD) family has emerged as key participants in signal transduction, and this family is increasingly being implicated in the regulation of multiple cellular functions and diseases. Methods This review summarizes recent findings of our group and others regarding the signaling pathway and the biological roles of the PKD family in pancreatic acinar cells. In particular, we highlight our studies of the functions of PKD in several key pathobiologic processes associated with acute pancreatitis in experimental models. Results Our findings reveal that PKD signaling is required for NF-κB activation/inflammation, intracellular zymogen activation, and acinar cell necrosis in rodent experimental pancreatitis. Novel small-molecule PKD inhibitors attenuate the severity of pancreatitis in both in vitro and in vivo experimental models. Further, this review emphasizes our latest advances in the therapeutic application of PKD inhibitors to experimental pancreatitis after the initiation of pancreatitis. Conclusions These novel findings suggest that PKD signaling is a necessary modulator in key initiating pathobiologic processes of pancreatitis, and that it constitutes a novel therapeutic target for treatments of this disorder. PMID:26879861

Early, middle, or late administration of zoledronate alleviates spontaneous nociceptive behavior and restores functional outcomes in a mouse model of CFA-induced arthritis.

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Morado-Urbina, Carlos Eduardo; Alvarado-Vázquez, Perla Abigail; Montiel-Ruiz, Rosa Mariana; Acosta-González, Rosa Issel; Castañeda-Corral, Gabriela; Jiménez-Andrade, Juan Miguel

2014-11-01

This study was performed to evaluate whether early, middle, or late treatment of zoledronate, an approved bisphosphonate that blocks bone resorption, can reduce nociceptive behaviors in a mouse arthritis model. Arthritis was produced by repeated intra-articular knee injections of complete Freund's adjuvant (CFA). A dose-response curve with zoledronate (3, 30, 100, and 300 μg/kg, i.p., day 4 to day 25, twice weekly for 3 weeks) was performed, and the most effective dose of zoledronate (100 μg/kg, i.p.) was initially administered at different times of disease progression: day 4 (early), day 15 (middle), or day 21 (late) and continued until day 25 after the first CFA injection. Flinching of the injected extremity (spontaneous nociceptive behavior), vertical rearings and horizontal activity (functional outcomes), and knee edema were assessed. Zoledronate improved both functional outcomes and reduced flinching behavior. At day 25, the effect of zoledronate on flinching behavior and vertical rearings was greater in magnitude when it was given early or middle rather than late in the treatment regimen. Chronic zoledronate did not reduce knee edema in CFA-injected mice nor functional outcomes in naïve mice by itself. These results suggest that zoledronate may have a positive effect on arthritis-induced nociception and functional disabilities. © 2014 Wiley Periodicals, Inc.

Participation of cannabinoid receptors in peripheral nociception induced by some NSAIDs

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Silva, L.C.R.; Romero, T.R.L.; Guzzo, L.S.; Duarte, I.D.G.

2012-01-01

Nonsteroidal anti-inflammatory drugs (NSAIDs) have been used extensively to control inflammatory pain. Several peripheral antinociceptive mechanisms have been described, such as opioid system and NO/cGMP/KATP pathway activation. There is evidence that the cannabinoid system can also contribute to the in vivo pharmacological effects of ibuprofen and indomethacin. However, there is no evidence of the involvement of the endocannabinoid system in the peripheral antinociception induced by NSAIDs. Thus, the aim of this study was to investigate the participation of the endocannabinoid system in the peripheral antinociceptive effect of NSAIDs. All experiments were performed on male Wistar rats (160-200 g; N = 4 per group). Hyperalgesia was induced by a subcutaneous intraplantar (ipl) injection of prostaglandin E 2 (PGE 2 , 2 µg/paw) in the rat's hindpaw and measured by the paw pressure test 3 h after injection. The weight in grams required to elicit a nociceptive response, paw flexion, was determined as the nociceptive threshold. The hyperalgesia was calculated as the difference between the measurements made before and after PGE 2 , which induced hyperalgesia (mean = 83.3 ± 4.505 g). AM-251 (80 µg/paw) and AM-630 (100 µg/paw) were used as CB 1 and CB 2 cannabinoid receptor antagonists, respectively. Ipl injection of 40 µg dipyrone (mean = 5.825 ± 2.842 g), 20 µg diclofenac (mean = 4.825 ± 3.850 g) and 40 µg indomethacin (mean = 6.650 ± 3.611 g) elicited a local peripheral antinociceptive effect. This effect was not antagonized by ipl CB 1 cannabinoid antagonist to dipyrone (mean = 5.00 ± 0.9815 g), diclofenac (mean = 2.50 ± 0.8337 g) and indomethacin (mean = 6.650 ± 4.069 g) or CB 2 cannabinoid antagonist to dipyrone (mean = 1.050 ± 6.436 g), diclofenac (mean = 6.675 ± 1.368 g) and indomethacin (mean = 2.85 ± 5.01 g). Thus, cannabinoid receptors do not seem to be involved in the peripheral antinociceptive mechanism of the NSAIDs dipyrone, diclofenac

Objective evaluation for venous leg ulcer-related nociceptive pain using thermography

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Goto T

2014-08-01

Full Text Available Taichi Goto,1 Ayumi Naito,1,2 Nao Tamai,1 Gojiro Nakagami,1 Makoto Mo,3 Hiromi Sanada1 1Department of Gerontological Nursing/Wound Care Management, Graduate School of Medicine, The University of Tokyo, Bunkyo-ku, Tokyo, Japan; 2Fujisawa City Hospital, Fujisawa, Kanagawa, Japan; 3Department of Cardiovascular Surgery, Yokohama Minami Kyosai Hospital, Yokohama, Kanagawa, Japan Purpose: We aimed to identify distinguishing characteristics in thermographic images of venous leg ulcer (VLU, for objective evaluation of VLU-related nociceptive pain. Patients and methods: Secondary analysis was performed, using existing data obtained from April to November 2010, for patients with VLU. Thermographic images of wounds and their surrounding area were classified according to the periwound temperature pattern as "normal temperature" or "high temperature". These results were compared with the self-reported pain intensity assessed by the short-form McGill Pain Questionnaire. Cohen's kappa coefficients were used to evaluate the interrater reliability for temperature assessment, and Wilcoxon rank sum test was used to compare pain intensities between the two groups. Results: Among 39 thermographic examinations in eight patients, 22 were classified into the high-temperature group and 17 into the normal-temperature group. Kappa coefficients for the temperature classification were 0.90 between the wound, ostomy, and continence nurse and a wound care specialist, and 0.90 between the wound, ostomy, and continence nurse and a graduate student. The pain rating index (Z=−2.981, P=0.003, sensory pain (Z=−3.083, P=0.002, affective pain (Z=−2.764, P=0.006, and present pain intensity (Z=−2.639, P=0.006 ratings were significantly higher in the high-temperature group than in the normal-temperature group, but the visual analog scale (Z=−0.632, P=0.527 was not significantly different between the two groups. Conclusion: Thermographic pattern may reflect VLU

Deciphering neuronal population codes for acute thermal pain

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Chen, Zhe; Zhang, Qiaosheng; Phuong Sieu Tong, Ai; Manders, Toby R.; Wang, Jing

2017-06-01

Objective. Pain is defined as an unpleasant sensory and emotional experience associated with actual or potential tissue damage, or described in terms of such damage. Current pain research mostly focuses on molecular and synaptic changes at the spinal and peripheral levels. However, a complete understanding of pain mechanisms requires the physiological study of the neocortex. Our goal is to apply a neural decoding approach to read out the onset of acute thermal pain signals, which can be used for brain-machine interface. Approach. We used micro wire arrays to record ensemble neuronal activities from the primary somatosensory cortex (S1) and anterior cingulate cortex (ACC) in freely behaving rats. We further investigated neural codes for acute thermal pain at both single-cell and population levels. To detect the onset of acute thermal pain signals, we developed a novel latent state-space framework to decipher the sorted or unsorted S1 and ACC ensemble spike activities, which reveal information about the onset of pain signals. Main results. The state space analysis allows us to uncover a latent state process that drives the observed ensemble spike activity, and to further detect the ‘neuronal threshold’ for acute thermal pain on a single-trial basis. Our method achieved good detection performance in sensitivity and specificity. In addition, our results suggested that an optimal strategy for detecting the onset of acute thermal pain signals may be based on combined evidence from S1 and ACC population codes. Significance. Our study is the first to detect the onset of acute pain signals based on neuronal ensemble spike activity. It is important from a mechanistic viewpoint as it relates to the significance of S1 and ACC activities in the regulation of the acute pain onset.

Specific cellular signal-transduction responses to in vivo combination therapy with ATRA, valproic acid and theophylline in acute myeloid leukemia

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Skavland, J; Jørgensen, K M [Hematology Section, Institute of Medicine, University of Bergen, Bergen (Norway); Hadziavdic, K [Department of Informatics, University of Bergen, Bergen (Norway); Hovland, R [Center for Medical Genetics and Molecular Medicine, Haukeland University Hospital, Bergen (Norway); Jonassen, I [Department of Informatics, University of Bergen, Bergen (Norway); Computational Biology Unit, Bergen Centre for Computational Science, University of Bergen, Bergen (Norway); Bruserud, Ø; Gjertsen, B T, E-mail: bjorn.gjertsen@med.uib.no [Hematology Section, Institute of Medicine, University of Bergen, Bergen (Norway); Hematology Section, Department of Medicine, Haukeland University Hospital, Bergen (Norway)

2011-02-01

Acute myeloid leukemia (AML) frequently comprises mutations in genes that cause perturbation in intracellular signaling pathways, thereby altering normal responses to growth factors and cytokines. Such oncogenic cellular signal transduction may be therapeutic if targeted directly or through epigenetic regulation. We treated 24 selected elderly AML patients with all-trans retinoic acid for 2 days before adding theophylline and the histone deacetylase inhibitor valproic acid (ClinicalTrials.gov NCT00175812; EudraCT no. 2004-001663-22), and sampled 11 patients for peripheral blood at day 0, 2 and 7 for single-cell analysis of basal level and signal-transduction responses to relevant myeloid growth factors (granulocyte-colony-stimulating factor, granulocyte/macrophage-colony-stimulating factor, interleukin-3, Flt3L, stem cell factor, erythropoietin, CXCL-12) on 10 signaling molecules (CREB, STAT1/3/5, p38, Erk1/2, Akt, c-Cbl, ZAP70/Syk and rpS6). Pretreatment analysis by unsupervised clustering and principal component analysis divided the patients into three distinguishable signaling clusters (non-potentiated, potentiated basal and potentiated signaling). Signal-transduction pathways were modulated during therapy and patients moved between the clusters. Patients with multiple leukemic clones demonstrated distinct stimulation responses and therapy-induced modulation. Individual signaling profiles together with clinical and hematological information may be used to early identify AML patients in whom epigenetic and signal-transduction targeted therapy is beneficial.

Regulation of body temperature and nociception induced by non-noxious stress in rat.

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Vidal, C; Suaudeau, C; Jacob, J

1984-04-09

The effects of 3 different non-noxious stressors on body temperature (Tb) were investigated in the rat: (1) loose restraint in cylinders, (2) removal of the rats from cylinders, exposure to a novel environment and replacement in cylinders, a stressor called here 'novelty', and (3) gentle holding of the rats by the nape of the neck. Loose restraint and 'novelty' produced hyperthermia. On the contrary, holding induced hypothermia. Hypophysectomy (HX) reduced basal Tb, abolished restraint hyperthermia and reduced both 'novelty' hyperthermia and holding hypothermia. Dexamethasone ( DEXA ) had no effect upon either restraint or novelty hyperthermia but reduced the hypothermia. Naloxone (Nx) produced a slight fall in basal Tb accounting for its reduction of restraint and 'novelty' hyperthermias ; it did not affect holding hypothermia. The inhibitory effects of HX suggest a participation of the pituitary in the hyperthermias ; the neurointermediate lobe would be involved as the hyperthermias were not affected by DEXA , which is known to block the stress-induced release of pituitary secretions from the anterior lobe but not from the neurointermediate lobe. In contrast, substances from the anterior lobe might participate in hypothermia due to holding since it is reduced by HX and DEXA . As to the effects of Nx, endogenous opioids would not be significantly involved in the thermic effects of the stressors used in this study; they might play, if any, only a minor role in the regulation of basal Tb. These results are compared with those previously obtained on nociception using the same non-noxious stressors. It emerges that, depending on the stressor, different types of association between thermoregulation and nociception may occur, i.e. hyperthermia with analgesia, hyperthermia with hyperalgesia and hypothermia with hyperalgesia.

New Challenges in Targeting Signaling Pathways in Acute Lymphoblastic Leukemia by NGS Approaches: An Update

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Hernández-Rivas, Jesús María

2018-01-01

The identification and study of genetic alterations involved in various signaling pathways associated with the pathogenesis of acute lymphoblastic leukemia (ALL) and the application of recent next-generation sequencing (NGS) in the identification of these lesions not only broaden our understanding of the involvement of various genetic alterations in the pathogenesis of the disease but also identify new therapeutic targets for future clinical trials. The present review describes the main deletions, amplifications, sequence mutations, epigenetic lesions, and new structural DNA rearrangements detected by NGS in B-ALL and T-ALL and their clinical importance for therapeutic procedures. We reviewed the molecular basis of pathways including transcriptional regulation, lymphoid differentiation and development, TP53 and the cell cycle, RAS signaling, JAK/STAT, NOTCH, PI3K/AKT/mTOR, Wnt/β-catenin signaling, chromatin structure modifiers, and epigenetic regulators. The implementation of NGS strategies has enabled important mutated genes in each pathway, their associations with the genetic subtypes of ALL, and their outcomes, which will be described further. We also discuss classic and new cryptic DNA rearrangements in ALL identified by mRNA-seq strategies. Novel cooperative abnormalities in ALL could be key prognostic and/or predictive biomarkers for selecting the best frontline treatment and for developing therapies after the first relapse or refractory disease. PMID:29642462

Phosphorylation of the Transient Receptor Potential Ankyrin 1 by Cyclin-dependent Kinase 5 affects Chemo-nociception

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Hall, Bradford E.; Prochazkova, Michaela; Sapio, Matthew R.; Minetos, Paul; Kurochkina, Natalya; Binukumar, B. K.; Amin, Niranjana D.; Terse, Anita; Joseph, John; Raithel, Stephen J.; Mannes, Andrew J.; Pant, Harish C.; Chung, Man-Kyo; Iadarola, Michael J.; Kulkarni, Ashok B.

2018-01-01

Cyclin-dependent kinase 5 (Cdk5) is a key neuronal kinase that is upregulated during inflammation, and can subsequently modulate sensitivity to nociceptive stimuli. We conducted an in silico screen for Cdk5 phosphorylation sites within proteins whose expression was enriched in nociceptors and identified the chemo-responsive ion channel Transient Receptor Potential Ankyrin 1 (TRPA1) as a possible Cdk5 substrate. Immunoprecipitated full length TRPA1 was shown to be phosphorylated by Cdk5 and th...

The Anti-Nociceptive Effect of Aloe. Vera Aqueous Extract in Fructose-Fed Male Rats

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Mohammad Reza Shahraki

2010-05-01

Full Text Available A B S T R A C T Introduction: Aloe Vera extract is used as an anti-inflammatory and anti-bradikinin agent in laboratory animals. The aim of this survey was to evaluate the ant-nociceptive effect of A. Vera aqueous extract in fructose-fed male rats. Methods: Forty-five Wistar-Albino male rats were equally and randomly divided into five groups including sham operated and four test groups. Sham operated group consumed tap water and the test groups consumed fructoseenriched water. Test groups 2, 3 and 4 additionally received, 0, 100, 150 and 200 mg/kg of A. Vera extract, respectively, whereas the other test group received distilled water daily. Tail flick reaction time, serum glucose and oral glucose tolerance test (OGTT were measured. The results were analyzed by SPSS software using ANOVA and Tukey tests. Results were expressed as mean ± SD. Statistical differences were considered significant at p<0.05. Results: The results showed that tail flick reaction time significantly increased in test group 3 which received 200 mg/kg A. Vera extract comparing with that of sham operated group. However, OGTT and serum glucose value were significantly increased in all fructose-fed male rats comparing with those of sham operated group. Discussion: These results indicated that A. Vera aqueous extract can affect tail flick reaction time in fructose-fed male rats. Further studies are required to show the exact mechanism of anti-nociceptive effect of A. Vera extract.

Inhibition of myostatin signaling through Notch activation following acute resistance exercise.

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Matthew G MacKenzie

Full Text Available Myostatin is a TGFβ family member and negative regulator of muscle size. Due to the complexity of the molecular pathway between myostatin mRNA/protein and changes in transcription, it has been difficult to understand whether myostatin plays a role in resistance exercise-induced skeletal muscle hypertrophy. To circumvent this problem, we determined the expression of a unique myostatin target gene, Mighty, following resistance exercise. Mighty mRNA increased by 6 h (82.9 ± 24.21% and remained high out to 48 h (56.5 ± 19.67% after resistance exercise. Further examination of the soleus, plantaris and tibialis anterior muscles showed that the change in Mighty mRNA at 6 h correlated with the increase in muscle size associated with this protocol (R(2 = 0.9996. The increase in Mighty mRNA occurred both independent of Smad2 phosphorylation and in spite of an increase in myostatin mRNA (341.8 ± 147.14% at 3 h. The myostatin inhibitor SKI remained unchanged. However, activated Notch, another potential inhibitor of TGFβ signaling, increased immediately following resistance exercise (83 ± 11.2% and stayed elevated out to 6 h (78 ± 16.6%. Electroportion of the Notch intracellular domain into the tibialis anterior resulted in an increase in Mighty mRNA (63 ± 13.4% that was equivalent to the canonical Notch target HES-1 (94.4 ± 7.32%. These data suggest that acute resistance exercise decreases myostatin signaling through the activation of the TGFβ inhibitor Notch resulting in a decrease in myostatin transcriptional activity that correlates well with muscle hypertrophy.

Differences in gene expression profiles and signaling pathways in rhabdomyolysis-induced acute kidney injury.

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Geng, Xiaodong; Wang, Yuanda; Hong, Quan; Yang, Jurong; Zheng, Wei; Zhang, Gang; Cai, Guangyan; Chen, Xiangmei; Wu, Di

2015-01-01

Rhabdomyolysis is a threatening syndrome because it causes the breakdown of skeletal muscle. Muscle destruction leads to the release of myoglobin, intracellular proteins, and electrolytes into the circulation. The aim of this study was to investigate the differences in gene expression profiles and signaling pathways upon rhabdomyolysis-induced acute kidney injury (AKI). In this study, we used glycerol-induced renal injury as a model of rhabdomyolysis-induced AKI. We analyzed data and relevant information from the Gene Expression Omnibus database (No: GSE44925). The gene expression data for three untreated mice were compared to data for five mice with rhabdomyolysis-induced AKI. The expression profiling of the three untreated mice and the five rhabdomyolysis-induced AKI mice was performed using microarray analysis. We examined the levels of Cyp3a13, Rela, Aldh7a1, Jun, CD14. And Cdkn1a using RT-PCR to determine the accuracy of the microarray results. The microarray analysis showed that there were 1050 downregulated and 659 upregulated genes in the rhabdomyolysis-induced AKI mice compared to the control group. The interactions of all differentially expressed genes in the Signal-Net were analyzed. Cyp3a13 and Rela had the most interactions with other genes. The data showed that Rela and Aldh7a1 were the key nodes and had important positions in the Signal-Net. The genes Jun, CD14, and Cdkn1a were also significantly upregulated. The pathway analysis classified the differentially expressed genes into 71 downregulated and 48 upregulated pathways including the PI3K/Akt, MAPK, and NF-κB signaling pathways. The results of this study indicate that the NF-κB, MAPK, PI3K/Akt, and apoptotic pathways are regulated in rhabdomyolysis-induced AKI.

Curcumin alleviates lumbar radiculopathy by reducing neuroinflammation, oxidative stress and nociceptive factors

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L Xiao

2017-09-01

Full Text Available Current non-surgical treatments for lumbar radiculopathy [e.g. epidural steroids and Tumour necrosis factor-α (TNF-α antagonists] are neither effective nor safe. As a non-toxic natural product, curcumin possesses an exceptional anti-inflammatory profile. We hypothesised that curcumin alleviates lumbar radiculopathy by attenuating neuroinflammation, oxidative stress and nociceptive factors. In a dorsal root ganglion (DRG culture, curcumin effectively inhibited TNF-α-induced neuroinflammation, in a dose-dependent manner, as shown by mRNA and protein expression of IL-6 and COX-2. Such effects might be mediated via protein kinase B (AKT and extracellular signal regulated kinase (ERK pathways. Also, a similar effect in combating TNF-α-induced neuroinflammation was observed in isolated primary neurons. In addition, curcumin protected neurons from TNF-α-triggered excessive reactive oxygen species (ROS production and cellular apoptosis and, accordingly, promoted mRNA expression of the anti-oxidative enzymes haem oxygenase-1, catalase and superoxide dismutase-2. Intriguingly, electronic von Frey test suggested that intraperitoneal injection of curcumin significantly abolished ipsilateral hyperalgesia secondary to disc herniation in mice, for up to 2 weeks post-surgery. Such in vivo pain alleviation could be attributed to the suppression, observed in DRG explant culture, of TNF-α-elicited neuropeptides, such as substance P and calcitonin gene-related peptide. Surprisingly, micro-computed tomography (μCT data suggested that curcumin treatment could promote disc height recovery following disc herniation. Alcian blue/picrosirius red staining confirmed that systemic curcumin administration promoted regeneration of extracellular matrix proteins, visualised by presence of abundant newly-formed collagen and proteoglycan content in herniated disc. Our study provided pre-clinical evidence for expediting this natural, non-toxic pleiotropic agent to become a

Acute pancreatitis in cats with hepatic lipidosis.

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Akol, K G; Washabau, R J; Saunders, H M; Hendrick, M J

1993-01-01

The purpose of this study was to characterize the incidence, clinical features, and prognosis of acute pancreatitis in cats with hepatic lipidosis. Of 13 cats histologically diagnosed with hepatic lipidosis between July 1988, and November 1989, 5(38%) were also histologically diagnosed with acute pancreatitis. In cats with hepatic lipidosis alone, the signalment, history, physical examination, and clinicopathologic findings were generally indistinguishable from those of cats with concurrent acute pancreatitis except that cats with acute pancreatitis were more likely to be cachectic and to have coagulation abnormalities. Hepatomegaly was seen on abdominal radiographs in both groups. Of the 5 cats with concurrent acute pancreatitis, abdominal ultrasonography detected 1 cat with a hypoechoic pancreas and 5 with peritoneal effusion; those abnormalities were not seen in cats without concurrent acute pancreatitis. Cats with concurrent acute pancreatitis had only a 20% recovery rate, compared with a 50% recovery rate in cats with hepatic lipidosis alone. We conclude that cats with hepatic lipidosis should be rigorously evaluated for concurrent acute pancreatitis because of 1) the rate of disease coincidence, 2) the inability of signalment, history, physical examination, and clinicopathologic findings to adequately distinguish between hepatic lipidosis and acute pancreatitis, 3) the worse prognosis associated with concurrent acute pancreatitis, and 4) the opposing nutritional strategies for hepatic lipidosis and acute pancreatitis.

Acute up-regulation of the rat brain somatostatin receptor-effector system by leptin is related to activation of insulin signaling and may counteract central leptin actions.

Science.gov (United States)

Perianes-Cachero, A; Burgos-Ramos, E; Puebla-Jiménez, L; Canelles, S; Frago, L M; Hervás-Aguilar, A; de Frutos, S; Toledo-Lobo, M V; Mela, V; Viveros, M P; Argente, J; Chowen, J A; Arilla-Ferreiro, E; Barrios, V

2013-11-12

Leptin and somatostatin (SRIF) have opposite effects on food seeking and ingestive behaviors, functions partially regulated by the frontoparietal cortex and hippocampus. Although it is known that the acute suppression of food intake mediated by leptin decreases with time, the counter-regulatory mechanisms remain unclear. Our aims were to analyze the effect of acute central leptin infusion on the SRIF receptor-effector system in these areas and the implication of related intracellular signaling mechanisms in this response. We studied 20 adult male Wister rats including controls and those treated intracerebroventricularly with a single dose of 5 μg of leptin and sacrificed 1 or 6h later. Density of SRIF receptors was unchanged at 1h, whereas leptin increased the density of SRIF receptors at 6h, which was correlated with an elevated capacity of SRIF to inhibit forskolin-stimulated adenylyl cyclase activity in both areas. The functional capacity of SRIF receptors was unaltered as cell membrane levels of αi1 and αi2 subunits of G inhibitory proteins were unaffected in both brain areas. The increased density of SRIF receptors was due to enhanced SRIF receptor subtype 2 (sst2) protein levels that correlated with higher mRNA levels for this receptor. These changes in sst2 mRNA levels were concomitant with increased activation of the insulin signaling, c-Jun and cyclic AMP response element-binding protein (CREB); however, activation of signal transducer and activator of transcription 3 was reduced in the cortex and unchanged in the hippocampus and suppressor of cytokine signaling 3 remained unchanged in these areas. In addition, the leptin antagonist L39A/D40A/F41A blocked the leptin-induced changes in SRIF receptors, leptin signaling and CREB activation. In conclusion, increased activation of insulin signaling after leptin infusion is related to acute up-regulation of the SRIF receptor-effector system that may antagonize short-term leptin actions in the rat brain

MRI diagnosis of acute spinal cord decompression sickness

International Nuclear Information System (INIS)

Tang Xiaofeng; Yuan Fengmei; Ma Heng; Xu Yongzhong; Gai Qingzhu; Wang Ying

2008-01-01

Objective: To describe MRI findings of acute spinal cord decompression sickness. Methods: MRI findings of 5 cases with clinical definite acute spinal cord decompression sickness were retrospectively analyzed. The main clinical informations included underwater performance history against regulations, short-term complete or incomplete spinal cord injury symptoms after fast going out of water, sensory disability and urinary and fecal incontinence, etc. Results: Spinal cord vacuole sign was found in all 5 cases. Iso-signal intensity (n=3), high signal intensity (n=1), and low signal intensity (n=1) was demonstrated on T 1 WI, and high signal intensity (n=5) was found on T 2 WI. Owl eye sign was detected in 3 cases, and lacune foci were seen in 2 cases. Conclusion: MRI findings of acute spinal cord decompression sickness had some characteristics, and it was easy to diagnose by combining diving history with clinical manifestations. (authors)

Maresin 1 Inhibits TRPV1 in Temporomandibular Joint-Related Trigeminal Nociceptive Neurons and TMJ Inflammation-Induced Synaptic Plasticity in the Trigeminal Nucleus

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Chul-Kyu Park

2015-01-01

Full Text Available In the trigeminal system, disruption of acute resolution processing may lead to uncontrolled inflammation and chronic pain associated with the temporomandibular joint (TMJ. Currently, there are no effective treatments for TMJ pain. Recently, it has been recognized that maresin 1, a newly identified macrophage-derived mediator of inflammation resolution, is a potent analgesic for somatic inflammatory pain without noticeable side effects in mice and a potent endogenous inhibitor of transient receptor potential vanilloid 1 (TRPV1 in the somatic system. However, the molecular mechanisms underlying the analgesic actions of maresin 1 on TMJ pain are unclear in the trigeminal system. Here, by performing TMJ injection of a retrograde labeling tracer DiI (a fluorescent dye, I showed that maresin 1 potently inhibits capsaicin-induced TRPV1 currents and neuronal activity via Gαi-coupled G-protein coupled receptors in DiI-labeled trigeminal nociceptive neurons. Further, maresin 1 blocked TRPV1 agonist-evoked increases in spontaneous excitatory postsynaptic current frequency and abolished TMJ inflammation-induced synaptic plasticity in the trigeminal nucleus. These results demonstrate the potent actions of maresin 1 in regulating TRPV1 in the trigeminal system. Thus, maresin 1 may serve as a novel endogenous inhibitor for treating TMJ-inflammatory pain in the orofacial region.

Acute Exercise Induced Mitochondrial H2O2 Production in Mouse Skeletal Muscle: Association with p66Shc and FOXO3a Signaling and Antioxidant Enzymes

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Ping Wang

2015-01-01

Full Text Available Exercise induced skeletal muscle phenotype change involves a complex interplay between signaling pathways and downstream regulators. This study aims to investigate the effect of acute exercise on mitochondrial H2O2 production and its association with p66Shc, FOXO3a, and antioxidant enzymes. Male ICR/CD-1 mice were subjected to an acute exercise. Muscle tissues (gastrocnemius and quadriceps femoris were taken after exercise to measure mitochondrial H2O2 content, expression of p66Shc and FOXO3a, and the activity of antioxidant enzymes. The results showed that acute exercise significantly increased mitochondrial H2O2 content and expressions of p66Shc and FOXO3a in a time-dependent manner, with a linear correlation between the increase in H2O2 content and p66Shc or FOXO3a expression. The activity of mitochondrial catalase was slightly reduced in the 90 min exercise group, but it was significantly higher in groups with 120 and 150 min exercise compared to that of 90 min exercise group. The activity of SOD was not significantly affected. The results indicate that acute exercise increases mitochondrial H2O2 production in the skeletal muscle, which is associated with the upregulation of p66Shc and FOXO3a. The association of p66Shc and FOXO3a signaling with exercise induced H2O2 generation may play a role in regulating cellular oxidative stress during acute exercise.

nociceptive activities of Elephantorrhiza elephantina

African Journals Online (AJOL)

PRECIOUS

2009-06-15

Jun 15, 2009 ... The acute toxicity test showed that the plant is relatively safe to use. Key words: Inflammation ... MATERIALS AND METHODS. Plant material ..... plants: An inventory, Natal, South Africa: University of Natal Press. pp. 266-267.

IL-1RI (Interleukin-1 Receptor Type I Signalling is Essential for Host Defence and Hemichannel Activity During Acute Central Nervous System Bacterial Infection

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Juan Xiong

2012-03-01

Full Text Available Staphylococcus aureus is a common aetiological agent of bacterial brain abscesses. We have previously established that a considerable IL-1 (interleukin-1 response is elicited immediately following S. aureus infection, where the cytokine can exert pleiotropic effects on glial activation and blood–brain barrier permeability. To assess the combined actions of IL-1α and IL-1β during CNS (central nervous system infection, host defence responses were evaluated in IL-1RI (IL-1 receptor type I KO (knockout animals. IL-1RI KO mice were exquisitely sensitive to intracerebral S. aureus infection, as demonstrated by enhanced mortality rates and bacterial burdens within the first 24 h following pathogen exposure compared with WT (wild-type animals. Loss of IL-1RI signalling also dampened the expression of select cytokines and chemokines, concomitant with significant reductions in neutrophil and macrophage infiltrates into the brain. In addition, the opening of astrocyte hemichannels during acute infection was shown to be dependent on IL-1RI activity. Collectively, these results demonstrate that IL-1RI signalling plays a pivotal role in the genesis of immune responses during the acute stage of brain abscess development through S. aureus containment, inflammatory mediator production, peripheral immune cell recruitment, and regulation of astrocyte hemichannel activity. Taken in the context of previous studies with MyD88 (myeloid differentiation primary response gene 88 and TLR2 (Toll-like receptor 2 KO animals, the current report advances our understanding of MyD88-dependent cascades and implicates IL-1RI signalling as a major antimicrobial effector pathway during acute brain-abscess formation.

Participation of cannabinoid receptors in peripheral nociception induced by some NSAIDs

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Silva, L.C.R.; Romero, T.R.L.; Guzzo, L.S.; Duarte, I.D.G. [Departamento de Farmacologia, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Belo Horizonte, MG (Brazil)

2012-09-21

Nonsteroidal anti-inflammatory drugs (NSAIDs) have been used extensively to control inflammatory pain. Several peripheral antinociceptive mechanisms have been described, such as opioid system and NO/cGMP/KATP pathway activation. There is evidence that the cannabinoid system can also contribute to the in vivo pharmacological effects of ibuprofen and indomethacin. However, there is no evidence of the involvement of the endocannabinoid system in the peripheral antinociception induced by NSAIDs. Thus, the aim of this study was to investigate the participation of the endocannabinoid system in the peripheral antinociceptive effect of NSAIDs. All experiments were performed on male Wistar rats (160-200 g; N = 4 per group). Hyperalgesia was induced by a subcutaneous intraplantar (ipl) injection of prostaglandin E{sub 2} (PGE{sub 2}, 2 µg/paw) in the rat's hindpaw and measured by the paw pressure test 3 h after injection. The weight in grams required to elicit a nociceptive response, paw flexion, was determined as the nociceptive threshold. The hyperalgesia was calculated as the difference between the measurements made before and after PGE{sub 2}, which induced hyperalgesia (mean = 83.3 ± 4.505 g). AM-251 (80 µg/paw) and AM-630 (100 µg/paw) were used as CB{sub 1} and CB{sub 2} cannabinoid receptor antagonists, respectively. Ipl injection of 40 µg dipyrone (mean = 5.825 ± 2.842 g), 20 µg diclofenac (mean = 4.825 ± 3.850 g) and 40 µg indomethacin (mean = 6.650 ± 3.611 g) elicited a local peripheral antinociceptive effect. This effect was not antagonized by ipl CB{sub 1} cannabinoid antagonist to dipyrone (mean = 5.00 ± 0.9815 g), diclofenac (mean = 2.50 ± 0.8337 g) and indomethacin (mean = 6.650 ± 4.069 g) or CB{sub 2} cannabinoid antagonist to dipyrone (mean = 1.050 ± 6.436 g), diclofenac (mean = 6.675 ± 1.368 g) and indomethacin (mean = 2.85 ± 5.01 g). Thus, cannabinoid receptors do not seem to be involved in the peripheral antinociceptive mechanism of

Participation of cannabinoid receptors in peripheral nociception induced by some NSAIDs

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L.C.R. Silva

2012-12-01

Full Text Available Nonsteroidal anti-inflammatory drugs (NSAIDs have been used extensively to control inflammatory pain. Several peripheral antinociceptive mechanisms have been described, such as opioid system and NO/cGMP/KATP pathway activation. There is evidence that the cannabinoid system can also contribute to the in vivo pharmacological effects of ibuprofen and indomethacin. However, there is no evidence of the involvement of the endocannabinoid system in the peripheral antinociception induced by NSAIDs. Thus, the aim of this study was to investigate the participation of the endocannabinoid system in the peripheral antinociceptive effect of NSAIDs. All experiments were performed on male Wistar rats (160-200 g; N = 4 per group. Hyperalgesia was induced by a subcutaneous intraplantar (ipl injection of prostaglandin E2 (PGE2, 2 μg/paw in the rat’s hindpaw and measured by the paw pressure test 3 h after injection. The weight in grams required to elicit a nociceptive response, paw flexion, was determined as the nociceptive threshold. The hyperalgesia was calculated as the difference between the measurements made before and after PGE2, which induced hyperalgesia (mean = 83.3 ± 4.505 g. AM-251 (80 μg/paw and AM-630 (100 μg/paw were used as CB1 and CB2 cannabinoid receptor antagonists, respectively. Ipl injection of 40 μg dipyrone (mean = 5.825 ± 2.842 g, 20 μg diclofenac (mean = 4.825 ± 3.850 g and 40 μg indomethacin (mean = 6.650 ± 3.611 g elicited a local peripheral antinociceptive effect. This effect was not antagonized by ipl CB1 cannabinoid antagonist to dipyrone (mean = 5.00 ± 0.9815 g, diclofenac (mean = 2.50 ± 0.8337 g and indomethacin (mean = 6.650 ± 4.069 g or CB2 cannabinoid antagonist to dipyrone (mean = 1.050 ± 6.436 g, diclofenac (mean = 6.675 ± 1.368 g and indomethacin (mean = 2.85 ± 5.01 g. Thus, cannabinoid receptors do not seem to be involved in the peripheral antinociceptive mechanism of the NSAIDs dipyrone, diclofenac and

Stimulation of the ventral tegmental area increased nociceptive thresholds and decreased spinal dorsal horn neuronal activity in rat.

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Li, Ai-Ling; Sibi, Jiny E; Yang, Xiaofei; Chiao, Jung-Chih; Peng, Yuan Bo

2016-06-01

Deep brain stimulation has been found to be effective in relieving intractable pain. The ventral tegmental area (VTA) plays a role not only in the reward process, but also in the modulation of nociception. Lesions of VTA result in increased pain thresholds and exacerbate pain in several pain models. It is hypothesized that direct activation of VTA will reduce pain experience. In this study, we investigated the effect of direct electrical stimulation of the VTA on mechanical, thermal and carrageenan-induced chemical nociceptive thresholds in Sprague-Dawley rats using our custom-designed wireless stimulator. We found that: (1) VTA stimulation itself did not show any change in mechanical or thermal threshold; and (2) the decreased mechanical and thermal thresholds induced by carrageenan injection in the hind paw contralateral to the stimulation site were significantly reversed by VTA stimulation. To further explore the underlying mechanism of VTA stimulation-induced analgesia, spinal cord dorsal horn neuronal responses to graded mechanical stimuli were recorded. VTA stimulation significantly inhibited dorsal horn neuronal activity in response to pressure and pinch from the paw, but not brush. This indicated that VTA stimulation may have exerted its analgesic effect via descending modulatory pain pathways, possibly through its connections with brain stem structures and cerebral cortex areas.

Wen-Luo-Tong Prevents Glial Activation and Nociceptive Sensitization in a Rat Model of Oxaliplatin-Induced Neuropathic Pain.

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Deng, Bo; Jia, Liqun; Pan, Lin; Song, Aiping; Wang, Yuanyuan; Tan, Huangying; Xiang, Qing; Yu, Lili; Ke, Dandan

2016-01-01

One of the main dose-limiting complications of the chemotherapeutic agent oxaliplatin (OXL) is painful neuropathy. Glial activation and nociceptive sensitization may be responsible for the mechanism of neuropathic pain. The Traditional Chinese Medicine (TCM) Wen-luo-tong (WLT) has been widely used in China to treat chemotherapy induced neuropathic pain. However, there is no study on the effects of WLT on spinal glial activation induced by OXL. In this study, a rat model of OXL-induced chronic neuropathic pain was established and WLT was administrated. Pain behavioral tests and morphometric examination of dorsal root ganglia (DRG) were conducted. Glial fibrillary acidic protein (GFAP) immunostaining was performed, glial activation was evaluated, and the excitatory neurotransmitter substance P (SP) and glial-derived proinflammatory cytokine tumor necrosis factor-α (TNF-α) were analyzed. WLT treatment alleviated OXL-induced mechanical allodynia and mechanical hyperalgesia. Changes in the somatic, nuclear, and nucleolar areas of neurons in DRG were prevented. In the spinal dorsal horn, hypertrophy and activation of GFAP-positive astrocytes were averted, and the level of GFAP mRNA decreased significantly. Additionally, TNF-α mRNA and protein levels decreased. Collectively, these results indicate that WLT reversed both glial activation in the spinal dorsal horn and nociceptive sensitization during OXL-induced chronic neuropathic pain in rats.

Automated single-trial assessment of laser-evoked potentials as an objective functional diagnostic tool for the nociceptive system.

Science.gov (United States)

Hatem, S M; Hu, L; Ragé, M; Gierasimowicz, A; Plaghki, L; Bouhassira, D; Attal, N; Iannetti, G D; Mouraux, A

2012-12-01

To assess the clinical usefulness of an automated analysis of event-related potentials (ERPs). Nociceptive laser-evoked potentials (LEPs) and non-nociceptive somatosensory electrically-evoked potentials (SEPs) were recorded in 37 patients with syringomyelia and 21 controls. LEP and SEP peak amplitudes and latencies were estimated using a single-trial automated approach based on time-frequency wavelet filtering and multiple linear regression, as well as a conventional approach based on visual inspection. The amplitudes and latencies of normal and abnormal LEP and SEP peaks were identified reliably using both approaches, with similar sensitivity and specificity. Because the automated approach provided an unbiased solution to account for average waveforms where no ERP could be identified visually, it revealed significant differences between patients and controls that were not revealed using the visual approach. The automated analysis of ERPs characterized reliably and objectively LEP and SEP waveforms in patients. The automated single-trial analysis can be used to characterize normal and abnormal ERPs with a similar sensitivity and specificity as visual inspection. While this does not justify its use in a routine clinical setting, the technique could be useful to avoid observer-dependent biases in clinical research. Copyright © 2012 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved.

In vivo anti-arthritic and anti-nociceptive effects of ethanol extract of Moringa oleifera leaves on complete Freund's adjuvant (CFA)-induced arthritis in rats.

Science.gov (United States)

Mahdi, Harith Jameel; Khan, Nurzalina Abdul Karim; Asmawi, Mohd Zaini Bin; Mahmud, Roziahanim; A/L Murugaiyah, Vikneswaran

2018-03-01

The medicinal uses of plants are in many cases based exclusively on traditional knowledge without enough scientific evidences. Different parts of Moringa oleifera were traditionally used for the treatment of wide variety of ailments including arthritis and joints pain. The present study had been designed to evaluate the anti-arthritic and anti-nociceptive activities of ethanol extract of Moringa leaves, this being the most abundant plant part suitable for commercial mass production of botanical medicinal products. Complete Freund's adjuvant (CFA)-induced arthritis in rats was used as disease model. CFA-induced inflammatory paw edema, body weight, arthritic index, X-ray radiography, hematological parameters, and walk track and locomotion analysis were all evaluated for the assessment of disease progression. In addition to that, anti-nociceptive activity was examined at different dose levels in both normal and arthritic-induced rats using Eddy's hot plate and tail flick thermal analgesia. The analysis of various arthritic assessment parameters used in this study revealed that Moringa extract has a considerable effect in preventing development or ameliorate arthritis disease severity. Moreover, the ethanol extract of Moringa leaves revealed significant anti-nociceptive activity at in both normal and CFA-induced arthritis rats in a dose-dependent manner. Ethanol extract of Moringa leaves appears to be a really promising as analgesic and arthritis medication, but a larger and more detailed preclinical and clinical studies especially in human is highly recommended.

Chemical composition and anti-inflamatory, anti-nociceptive and antipyretic activity of rhizome essential oil of Globba sessiliflora Sims. collected from Garhwal region of Uttarakhand

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Ravendra Kumar

2017-07-01

Full Text Available Background & Aim: Family Zingiberaceae is worldwide in distribution. Plants of the zingiberaceae family are used in traditional herbal folk medicine besides their uses in spices, cosmetic, ornamental, food preservatives etc. In Uttarakhand the herbs grow from sub-tropical to temperate region. Globba sessiliflora Simsrhizomes were collected at maturity stage in November from Garhwal region of Uttarakhand, India. In present communication the medicinal use of various zingiberaceous herb provoked us to study the chemical diversity and pharmacological activity determination of this important traditional herb. Experimental: The essential oil was extracted using hydrodistillation method and analyzed by GC-MS. Anti-inflamatory, anti-nociceptive and antipyretic activities of essential oil were experimently determined using mice model. Results: The major compounds identified were β-eudesmol (27.6%, (E-β-caryophyllene (24.3%, α-humulene (3.0%, (6E-nerolidol (4.1%, caryophyllene oxide (9.7%, γ-eudesmol (6.4% and τ-muurolol (8.3% besides other minor constituents. Essential oil of G. sessiliflora rhizome showed good anti-inflamatory, anti-nociceptive and antipyretic activities at the dose level of 100 mg/kg body weight. The oral administration of the essential oil exhibited no toxicity at 400, 600 and 800 mg/kg b.wt. concentration. Ibuprofen, indomthacin and paracetamol were used as standard drugs for comparison. Recommended applications/industries: G. sessiliflora essential oil can be used as herbal remedy for its nontoxicityanti-inflamatory, anti-nociceptive and antipyretic activities.

Learned control over spinal nociception: Transfer and stability of training success in a long-term study.

Science.gov (United States)

Bäumler, Maximilian; Feller, Moritz; Krafft, Stefanie; Schiffer, Manuela; Sommer, Jens; Straube, Andreas; Weinges, Fabian; Ruscheweyh, Ruth

2017-12-01

Healthy subjects can learn to use cognitive-emotional strategies to suppress their spinal nociception, quantified by the nociceptive flexor reflex (RIII reflex), when given visual RIII feedback. This likely reflects learned activation of descending pain inhibition. Here, we investigated if training success persists 4 and 8 months after the end of RIII feedback training, and if transfer (RIII suppression without feedback) is possible. 18 and 8 subjects who had successfully completed feedback training were investigated 4 and 8 months later. At 4 months, RIII suppression during feedback and transfer was similar to that achieved at the final RIII feedback training session (to 50 ± 22%, 53 ± 21% and 52 ± 21% of baseline, all differences n.s.). At 8 months, RIII suppression was somewhat (not significantly) smaller in the feedback run (to 64 ± 17%) compared to the final training session (56 ± 19%). Feedback and transfer runs were similar (to 64 ± 17% vs. 68 ± 24%, n.s.). Concomitant reductions in pain intensity ratings were stable at 4 and 8 months. RIII feedback training success was completely maintained after 4 months, and somewhat attenuated 8 months after training. Transfer was successful. These results are an important pre-requisite for application of RIII feedback training in the context of clinical pain. Copyright © 2017 International Federation of Clinical Neurophysiology. Published by Elsevier B.V. All rights reserved.

Cannabinoid-induced effects on the nociceptive system: a neurophysiological study in patients with secondary progressive multiple sclerosis.

Science.gov (United States)

Conte, Antonella; Bettolo, Chiara Marini; Onesti, Emanuela; Frasca, Vittorio; Iacovelli, Elisa; Gilio, Francesca; Giacomelli, Elena; Gabriele, Maria; Aragona, Massimiliano; Tomassini, Valentina; Pantano, Patrizia; Pozzilli, Carlo; Inghilleri, Maurizio

2009-05-01

Although clinical studies show that cannabinoids improve central pain in patients with multiple sclerosis (MS) neurophysiological studies are lacking to investigate whether they also suppress these patients' electrophysiological responses to noxious stimulation. The flexion reflex (FR) in humans is a widely used technique for assessing the pain threshold and for studying spinal and supraspinal pain pathways and the neurotransmitter system involved in pain control. In a randomized, double-blind, placebo-controlled, cross-over study we investigated cannabinoid-induced changes in RIII reflex variables (threshold, latency and area) in a group of 18 patients with secondary progressive MS. To investigate whether cannabinoids act indirectly on the nociceptive reflex by modulating lower motoneuron excitability we also evaluated the H-reflex size after tibial nerve stimulation and calculated the H wave/M wave (H/M) ratio. Of the 18 patients recruited and randomized 17 completed the study. After patients used a commercial delta-9-tetrahydrocannabinol (THC) and cannabidiol mixture as an oromucosal spray the RIII reflex threshold increased and RIII reflex area decreased. The visual analogue scale score for pain also decreased, though not significantly. Conversely, the H/M ratio measured before patients received cannabinoids remained unchanged after therapy. In conclusion, the cannabinoid-induced changes in the RIII reflex threshold and area in patients with MS provide objective neurophysiological evidence that cannabinoids modulate the nociceptive system in patients with MS.

CT and MR imaging of acute cerebellar ataxia

International Nuclear Information System (INIS)

Shoji, H.; Hirai, S.; Ishikawa, K.; Aramaki, M.; Sato, Y.; Abe, T.; Kojima, K.

1991-01-01

An adult female showed mild cerebellar ataxia and CSF pleocytosis following an acute infection of the upper respiratory tract, and was diagnosed as having acute cerebellar ataxia (ACA). CT and MR appearances in the acute stage revealed moderate swelling of the cerebellum and bilaterally increased signal intensity in the cerebellar cortex. (orig.)

Brain potentials evoked by intraepidermal electrical stimuli reflect the central sensitization of nociceptive pathways.

Science.gov (United States)

Liang, M; Lee, M C; O'Neill, J; Dickenson, A H; Iannetti, G D

2016-08-01

Central sensitization (CS), the increased sensitivity of the central nervous system to somatosensory inputs, accounts for secondary hyperalgesia, a typical sign of several painful clinical conditions. Brain potentials elicited by mechanical punctate stimulation using flat-tip probes can provide neural correlates of CS, but their signal-to-noise ratio is limited by poor synchronization of the afferent nociceptive input. Additionally, mechanical punctate stimulation does not activate nociceptors exclusively. In contrast, low-intensity intraepidermal electrical stimulation (IES) allows selective activation of type II Aδ-mechano-heat nociceptors (II-AMHs) and elicits reproducible brain potentials. However, it is unclear whether hyperalgesia from IES occurs and coexists with secondary mechanical punctate hyperalgesia, and whether the magnitude of the electroencephalographic (EEG) responses evoked by IES within the hyperalgesic area is increased. To address these questions, we explored the modulation of the psychophysical and EEG responses to IES by intraepidermal injection of capsaicin in healthy human subjects. We obtained three main results. First, the intensity of the sensation elicited by IES was significantly increased in participants who developed robust mechanical punctate hyperalgesia after capsaicin injection (i.e., responders), indicating that hyperalgesia from IES coexists with punctate mechanical hyperalgesia. Second, the N2 peak magnitude of the EEG responses elicited by IES was significantly increased after the intraepidermal injection of capsaicin in responders only. Third, a receiver-operator characteristics analysis showed that the N2 peak amplitude is clearly predictive of the presence of CS. These findings suggest that the EEG responses elicited by IES reflect secondary hyperalgesia and therefore represent an objective correlate of CS. Copyright © 2016 the American Physiological Society.

Anti-nociceptive and anti-inflammatory activities of ethanolic flower extract of Newbouldia laevis in mice and rats

OpenAIRE

Y Tanko; B Kamba; MI Saleh; K Y Musa; A Mohammed

2008-01-01

Summary: The ethanolic flower extract of Newbouldia laevis was investigated for possible anti-nociceptive and anti-inflammatory effects in rodents. Acetic acid induced writhing (in mice) and formalin tests (in rats) were used to study. The extract caused a significant decrease (P< 0.05), which was not dose a dependent inhibition on acetic acid-induced writhing and the neurogenic pain induced by formalin. The extract at the doses (25, 50 and 100mg/kg) tested showed 59, 71 and 47% inhibition...

Upregulation of Ih expressed in IB4-negative Aδ nociceptive DRG neurons contributes to mechanical hypersensitivity associated with cervical radiculopathic pain

Science.gov (United States)

Liu, Da-Lu; Lu, Na; Han, Wen-Juan; Chen, Rong-Gui; Cong, Rui; Xie, Rou-Gang; Zhang, Yu-Fei; Kong, Wei-Wei; Hu, San-Jue; Luo, Ceng

2015-01-01

Cervical radiculopathy represents aberrant mechanical hypersensitivity. Primary sensory neuron’s ability to sense mechanical force forms mechanotransduction. However, whether this property undergoes activity-dependent plastic changes and underlies mechanical hypersensitivity associated with cervical radiculopathic pain (CRP) is not clear. Here we show a new CRP model producing stable mechanical compression of dorsal root ganglion (DRG), which induces dramatic behavioral mechanical hypersensitivity. Amongst nociceptive DRG neurons, a mechanically sensitive neuron, isolectin B4 negative Aδ-type (IB4− Aδ) DRG neuron displays spontaneous activity with hyperexcitability after chronic compression of cervical DRGs. Focal mechanical stimulation on somata of IB4- Aδ neuron induces abnormal hypersensitivity. Upregulated HCN1 and HCN3 channels and increased Ih current on this subset of primary nociceptors underlies the spontaneous activity together with neuronal mechanical hypersensitivity, which further contributes to the behavioral mechanical hypersensitivity associated with CRP. This study sheds new light on the functional plasticity of a specific subset of nociceptive DRG neurons to mechanical stimulation and reveals a novel mechanism that could underlie the mechanical hypersensitivity associated with cervical radiculopathy. PMID:26577374

Analgesic effect of paeoniflorin in rats with neonatal maternal separation-induced visceral hyperalgesia is mediated through adenosine A(1) receptor by inhibiting the extracellular signal-regulated protein kinase (ERK) pathway.

Science.gov (United States)

Zhang, Xiao-Jun; Chen, Hong-Li; Li, Zhi; Zhang, Hong-Qi; Xu, Hong-Xi; Sung, Joseph J Y; Bian, Zhao-Xiang

2009-11-01

Paeoniflorin (PF), a chief active ingredient in the root of Paeonia lactiflora Pall (family Ranunculaceae), is effective in relieving colorectal distention (CRD)-induced visceral pain in rats with visceral hyperalgesia induced by neonatal maternal separation (NMS). This study aimed at exploring the underlying mechanisms of PF's analgesic effect on CRD-evoked nociceptive signaling in the central nervous system (CNS) and investigating whether the adenosine A(1) receptor is involved in PF's anti-nociception. CRD-induced visceral pain as well as phosphorylated-extracellular signal-regulated protein kinase (p-ERK) and phospho-cAMP response element-binding protein (p-CREB) expression in the CNS structures of NMS rats were suppressed by NMDA receptor antagonist dizocilpine (MK-801) and ERK phosphorylation inhibitor U0126. PF could similarly inhibit CRD-evoked p-ERK and c-Fos expression in laminae I-II of the lumbosacral dorsal horn and anterior cingulate cortex (ACC). PF could also reverse the CRD-evoked increased glutamate concentration by CRD as shown by dynamic microdialysis monitoring in ACC, whereas, DPCPX, an antagonist of adenosine A(1) receptor, significantly blocked the analgesic effect of PF and PF's inhibition on CRD-induced p-ERK and p-CREB expression. These results suggest that PF's analgesic effect is possibly mediated by adenosine A(1) receptor by inhibiting CRD-evoked glutamate release and the NMDA receptor dependent ERK signaling.

The nociceptive withdrawal reflex does not adapt to joint position change and short-term motor practice [v2; ref status: indexed, http://f1000r.es/2lr

Directory of Open Access Journals (Sweden)

Nathan Eckert

2013-12-01

Full Text Available The nociceptive withdrawal reflex is a protective mechanism to mediate interactions within a potentially dangerous environment. The reflex is formed by action-based sensory encoding during the early post-natal developmental period, and it is unknown if the protective motor function of the nociceptive withdrawal reflex in the human upper-limb is adaptable based on the configuration of the arm or if it can be modified by short-term practice of a similar or opposing motor action. In the present study, nociceptive withdrawal reflexes were evoked by a brief train of electrical stimuli applied to digit II, 1 in five different static arm positions and, 2 before and after motor practice that was opposite (EXT or similar (FLEX to the stereotyped withdrawal response, in 10 individuals. Withdrawal responses were quantified by the electromyography (EMG reflex response in several upper limb muscles, and by the forces and moments recorded at the wrist. EMG onset latencies and response amplitudes were not significantly different across the arm positions or between the EXT and FLEX practice conditions, and the general direction of the withdrawal response was similar across arm positions. In addition, the force vectors were not different after practice in either the practice condition or between EXT and FLEX conditions. We conclude the withdrawal response is insensitive to changes in elbow or shoulder joint angles as well as remaining resistant to short-term adaptations from the practice of motor actions, resulting in a generalized limb withdrawal in each case. It is further hypothesized that the multisensory feedback is weighted differently in each arm position, but integrated to achieve a similar withdrawal response to safeguard against erroneous motor responses that could cause further harm. The results remain consistent with the concept that nociceptive withdrawal reflexes are shaped through long-term and not short-term action based sensory encoding.

In adenosine A2B knockouts acute treatment with inorganic nitrate improves glucose disposal, oxidative stress and AMPK signaling in the liver

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Maria ePeleli

2015-08-01

Full Text Available Rationale: Accumulating studies suggest that nitric oxide (NO deficiency and oxidative stress are central pathological mechanisms in type 2 diabetes. Recent findings demonstrate therapeutic effects by boosting a nitrate-nitrite-NO pathway, an alternative pathway for NO formation. This study aimed at investigating the acute effects of inorganic nitrate on glucose and insulin signaling in adenosine A2B receptor knockout mice (A2B-/-, a genetic model of impaired metabolic regulation.Methods: Acute effects of nitrate treatment were investigated in aged wild-type (WT and A2B-/- mice. One hour after injection with nitrate or placebo, metabolic regulation was evaluated by glucose and insulin tolerance tests. NADPH oxidase-mediated superoxide production and AMPK phosphorylation were measured in livers obtained from non-treated or glucose-treated mice, with or without prior nitrate injection. Plasma was used to determine insulin resistance (HOMA-IR and NO signaling.Results: A2B-/- displayed increased body weight, reduced glucose clearance and attenuated overall insulin responses compared with age-matched WT. Nitrate treatment increased circulating levels of nitrate, nitrite and cGMP in A2B-/-, and improved glucose clearance. In WT mice, however, nitrate treatment did not influence glucose clearance. HOMA-IR increased following glucose injection in A2B-/-, but remained at basal levels in mice pretreated with nitrate. NADPH oxidase activity in livers from A2B-/-, but not WT mice, was reduced by nitrate. Livers from A2B-/- displayed reduced AMPK phosphorylation compared with WT mice, and this was increased by nitrate treatment. Injection with the anti-diabetic agent metformin induced similar therapeutic effects in the A2B-/- as observed with nitrate. Conclusion: The A2B-/- mouse is a genetic model of metabolic syndrome. Acute treatment with nitrate improved the metabolic profile, at least partly via reduction in oxidative stress and improved AMPK signaling

Insulin signaling in various equine tissues under basal conditions and acute stimulation by intravenously injected insulin.

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Warnken, Tobias; Brehm, Ralph; Feige, Karsten; Huber, Korinna

2017-10-01

The aim of the study was to analyze key proteins of the equine insulin signaling cascade and their extent of phosphorylation in biopsies from muscle tissue (MT), liver tissue (LT), and nuchal AT, subcutaneous AT, and retroperitoneal adipose tissues. This was investigated under unstimulated (B1) and intravenously insulin stimulated (B2) conditions, which were achieved by injection of insulin (0.1 IU/kg bodyweight) and glucose (150 mg/kg bodyweight). Twelve warmblood horses aged 15 ± 6.8 yr (yr), weighing 559 ± 79 kg, and with a mean body condition score of 4.7 ± 1.5 were included in the study. Key proteins of the insulin signaling cascade were semiquantitatively determined using Western blotting. Furthermore, modulation of the cascade was assessed. The basal expression of the proteins was only slightly influenced during the experimental period. Insulin induced a high extent of phosphorylation of insulin receptor in LT (P < 0.01) but not in MT. Protein kinase B and mechanistic target of rapamycin expressed a higher extent of phosphorylation in all tissues in B2 biopsies. Adenosine monophosphate protein kinase, as a component related to insulin signaling, expressed enhanced phosphorylation in MT (P < 0.05) and adipose tissues (nuchal AT P < 0.05; SCAT P < 0.01; retroperitoneal adipose tissue P < 0.05), but not in LT at B2. Tissue-specific variations in the acute response of insulin signaling to intravenously injected insulin were observed. In conclusion, insulin sensitivity in healthy horses is based on a complex concerted action of different tissues by their variations in the molecular response to insulin. Copyright © 2017 Elsevier Inc. All rights reserved.

Tachycardia in response to remote capsaicin injection as a model for nociception in the ball python (Python regius).

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Williams, Catherine J A; James, Lauren E; Bertelsen, Mads F; Wang, Tobias

2016-07-01

To quantify the effect of subcutaneous (SC) capsaicin injection on heart rate (HR) in ball pythons (Python regius) and to assess the efficacy of two opioids (morphine and butorphanol) in modifying this response. Prospective, randomized, unmatched study. Eleven mixed-sex, captive-bred ball pythons. Snakes were randomly assigned to three groups (n = 6) by intramuscular premedication: 1) control: saline (0.9 mL); 2) morphine (10 mg kg(-1) ); and 3) butorphanol (10 mg kg(-1) ). Three snakes were tested twice and another two were tested three times in different treatments administered 1 month apart. Under isoflurane anaesthesia, snakes were instrumented with SC electrocardiogram (ECG) electrodes and an SC catheter for remote stimulus delivery. After recovery from anaesthesia, all snakes, in visual and audial isolation from the experimenter, received a sham stimulus of saline (0.4 mL) via the SC catheter. A nociceptive stimulus of SC capsaicin (3 mg in 0.2 mL saline with 7% Tween 80) was then applied by catheter at 7 hours after premedication. In a subset (n = 3), two sham injections (saline 0.2 mL) preceded the capsaicin treatment. HR was recorded via ECG, and changes in HR (ΔHR) from baseline were calculated for all stimulations. Capsaicin injection was associated with a significant increase in HR [peak ΔHR: saline group: 8.8 ± 7.1 beats minute(-1) ; capsaicin group: 21.1 ± 5.8 beats minute(-1) (p = 0.0055)] and integrated ΔHR as a function of time. The administration of morphine or butorphanol 7 hours prior to nociception failed to significantly reduce the peak and integrated ΔHR. Butorphanol caused marked, long-lasting sedation as assessed by muscle tone. The HR response to an SC capsaicin injection can serve as a nociceptive model in P. regius. Morphine and butorphanol administration did not reduce HR response to capsaicin stimulation but produced significantly different effects on pre-stimulation HR and sedation. © 2015 Association

Differences in neurotransmitter systems of ventrolateral periaqueductal gray between the micturition reflex and nociceptive regulation: An in vivo microdialysis study.

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Kitta, Takeya; Mitsui, Takahiko; Kanno, Yukiko; Chiba, Hiroki; Moriya, Kimihiko; Yoshioka, Mitsuhiro; Shinohara, Nobuo

2016-07-01

To elucidate the possible involvement of glutamate and serotonin (5-hydroxytryptamine) neurons in the ventrolateral midbrain periaqueductal gray during noxious stimulation. The study was carried out by evoking a noxious stimulation by acetic acid in an animal model of cystitis. Changes in glutamate and 5-hydroxytryptamine in the periaqueductal gray during the micturition reflex and acetic acid-induced cystitis were determined using in vivo microdialysis combined with cystometry in rats. Extracellular glutamate levels slightly, but significantly, increased during the micturition reflex induced by saline infusion into the bladder. Intravesical infusion of acetic acid facilitated the micturition reflex characterized by increases in voiding pressure and decreases in the intercontraction interval. Glutamate levels were markedly increased by acetic acid, and this enhancement was sustained for at least 3 h. 5-Hydroxytryptamine levels, which were not altered during the micturition reflex, were increased after intravesical infusion of acetic acid. The results suggest that periaqueductal gray glutamate and 5-hydroxytryptamine neurons differentially participate in the modulation of both nociception and the micturition reflex. Furthermore, periaqueductal gray 5-hydroxytryptamine levels appear to reflect the nociceptive stimuli. © 2016 The Japanese Urological Association.

The Nociceptive and Anti-Inflammatory Effects of Artemisia dracunculus L. Aqueous Extract on Fructose Fed Male Rats

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Shahraki Mohammad Reza

2015-01-01

Full Text Available Aim & Objective. Artemisia dracunculus L. (Tarragon species have been used as a traditional medicine. The present study was designed to evaluate the nociceptive and anti-inflammatory effects of A. dracunculus L. leaf aqueous extract on fructose drinking water (FDW in male rats. Materials & Methods. Forty-eight Wistar-albino male rats weighing 200–250 g were divided into control (C, control extract (CE, FDW, and FDWE groups (n=12. Group C did not receive any agents; Group CE did 100 mg/kg A. dracunculus L. aqueous extract on a daily basis for duration of four weeks. FDW Group received fructose drinking water (10%, weight/volume but did not receive any agents during trial period. FDWE group received 100 mg/kg A. dracunculus L. aqueous extract during trial period. At the end of experiment, a biphasic pain response was induced following interplanetary injection of formalin (50 µL, 1%. Obtained data were analyzed using SPSS software version 17 and using ANOVA and Tukey post hoc tests. Results were expressed as mean ± SE. Statistical differences were considered significant at P<0.05. Results. Our findings revealed that acute and chronic pain scores in FDW group are significantly higher than other ones and A. dracunculus L. aqueous extract causes significant decreasing of this parameter in FDWE group (P<0.001. Moreover, IL6 and TNF values in this group were significantly decreased compared to FDW group (P<0.05. Conclusion. Results in the present study show that FDW causes the pain response score to increase and cause proinflammatory cytokines in rat model but A. dracunculus L. leaf aqueous extract improves values of these parameters.

Characterization of nociceptive behavioural responses in the awake pig following UV–B-induced inflammation

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di Giminiani, Pierpaolo; Petersen, Lars J.; Herskin, Mette S

2014-01-01

due to its great homology with humans. Methods The skin in the flank of awake pigs was irradiated by a UV-B light source (1 J/cm2) and changes in thermal and mechanical sensitivity 24 and 48 h following irradiation were measured via assessment of nociceptive behaviours. Results Thermal sensitivity...... skin site than at the control site 24 and 48 h following irradiation (P UV-B irradiation (P = 0.092). Following the inflammatory challenge, the mechanical sensitivity was higher at the site...... of irradiation compared with the control skin at both 24 and 48 h (P UV-B inflammation in porcine skin, but they were not capable of providing a clear indication...

Discriminative ability of reflex receptive fields to distinguish patients with acute and chronic low back pain.

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Müller, Monika; Biurrun Manresa, José A; Treichel, Fabienne; Agten, Christoph A; Heini, Paul; Andersen, Ole K; Curatolo, Michele; Jüni, Peter

2016-12-01

Low back pain has a life time prevalence of 70% to 85%. Approximately 10% to 20% of all patients experience recurrent episodes or develop chronic low back pain. Sociodemographic, clinical, and psychological characteristics explain the transition from acute to chronic low back pain only to a limited extent. Altered central pain processing may be a contributing mechanism. The measurement of reflex receptive fields (RRF) is a novel method to assess altered central pain processing. The RRF area denotes the area of the foot sole from which spinal nociceptive reflexes can be elicited. It was shown to be enlarged in patients with acute and chronic low back pain compared with pain-free individuals. The aim of the study was to explore the discriminative ability of the RRF to distinguish patients with acute and chronic low back pain with the hypothesis that enlarged RRF are associated with chronic low back pain. We included 214 patients with either acute or chronic low back pain and compared RRF between groups in both univariable and multivariable analyses adjusted for different sociodemographic and clinical characteristics possibly associated with the transition to chronic pain. We found a mean difference between patients with acute and chronic low back pain of -0.01 (95% confidence interval [CI], -0.06 to 0.04) in the crude, -0.02 (95% CI, -0.08 to 0.04) in the age and sex adjusted, and -0.02 (95% CI, -0.09 to 0.05) in the fully adjusted model. Our results suggest that the enlargement of RRF area may not be associated with the transition from acute to chronic low back pain.

Effects of acute and chronic exposure to both 900 MHz and 2100 MHz electromagnetic radiation on glutamate receptor signaling pathway.

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Gökçek-Saraç, Çiğdem; Er, Hakan; Kencebay Manas, Ceren; Kantar Gok, Deniz; Özen, Şükrü; Derin, Narin

2017-09-01

To demonstrate the molecular effects of acute and chronic exposure to both 900 and 2100 MHz radiofrequency electromagnetic radiation (RF-EMR) on the hippocampal level/activity of some of the enzymes - including PKA, CaMKIIα, CREB, and p44/42 MAPK - from N-methyl-D-aspartate receptor (NMDAR)-related signaling pathways. Rats were divided into the following groups: sham rats, and rats exposed to 900 and 2100 MHz RF-EMR for 2 h/day for acute (1 week) or chronic (10 weeks), respectively. Western blotting and activity measurement assays were used to assess the level/activity of the selected enzymes. The obtained results revealed that the hippocampal level/activity of selected enzymes was significantly higher in the chronic groups as compared to the acute groups at both 900 and 2100 MHz RF-EMR exposure. In addition, hippocampal level/activity of selected enzymes was significantly higher at 2100 MHz RF-EMR than 900 MHz RF-EMR in both acute and chronic groups. The present study provides experimental evidence that both exposure duration (1 week versus 10 weeks) and different carrier frequencies (900 vs. 2100 MHz) had different effects on the protein expression of hippocampus in Wistar rats, which might encourage further research on protection against RF-EMR exposure.

Intrahippocampal Administration of Amyloid-β1–42 Oligomers Acutely Impairs Spatial Working Memory, Insulin Signaling, and Hippocampal Metabolism

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Pearson-Leary, Jiah; McNay, Ewan C.

2017-01-01

Increasing evidence suggests that abnormal brain accumulation of amyloid-β1–42 (Aβ1–42) oligomers plays a causal role in Alzheimer’s disease (AD), and in particular may cause the cognitive deficits that are the hallmark of AD. In vitro, Aβ1–42 oligomers impair insulin signaling and suppress neural functioning. We previously showed that endogenous insulin signaling is an obligatory component of normal hippocampal function, and that disrupting this signaling led to a rapid impairment of spatial working memory, while delivery of exogenous insulin to the hippocampus enhanced both memory and metabolism; diet-induced insulin resistance both impaired spatial memory and prevented insulin from increasing metabolism or cognitive function. Hence, we tested the hypothesis that Aβ1–42 oligomers could acutely impair hippocampal metabolic and cognitive processes in vivo in the rat. Our findings support this hypothesis: Aβ1–42 oligomers impaired spontaneous alternation behavior while preventing the task-associated dip in hippocampal ECF glucose observed in control animals. In addition, Aβ1–42 oligomers decreased plasma membrane translocation of the insulin-sensitive glucose transporter 4 (GluT4), and impaired insulin signaling as measured by phosphorylation of Akt. These data show in vivo that Aβ1–42 oligomers can rapidly impair hippocampal cognitive and metabolic processes, and provide support for the hypothesis that elevated Aβ1–42 leads to cognitive impairment via interference with hippocampal insulin signaling. PMID:22430529

Abnormal nociception and opiate sensitivity of STOP null mice exhibiting elevated levels of the endogenous alkaloid morphine

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Aunis Dominique

2010-12-01

Full Text Available Abstract Background- Mice deficient for the stable tubule only peptide (STOP display altered dopaminergic neurotransmission associated with severe behavioural defects including disorganized locomotor activity. Endogenous morphine, which is present in nervous tissues and synthesized from dopamine, may contribute to these behavioral alterations since it is thought to play a role in normal and pathological neurotransmission. Results- In this study, we showed that STOP null brain structures, including cortex, hippocampus, cerebellum and spinal cord, contain high endogenous morphine amounts. The presence of elevated levels of morphine was associated with the presence of a higher density of mu opioid receptor with a higher affinity for morphine in STOP null brains. Interestingly, STOP null mice exhibited significantly lower nociceptive thresholds to thermal and mechanical stimulations. They also had abnormal behavioural responses to the administration of exogenous morphine and naloxone. Low dose of morphine (1 mg/kg, i.p. produced a significant mechanical antinociception in STOP null mice whereas it has no effect on wild-type mice. High concentration of naloxone (1 mg/kg was pronociceptive for both mice strain, a lower concentration (0.1 mg/kg was found to increase the mean mechanical nociceptive threshold only in the case of STOP null mice. Conclusions- Together, our data show that STOP null mice displayed elevated levels of endogenous morphine, as well as an increase of morphine receptor affinity and density in brain. This was correlated with hypernociception and impaired pharmacological sensitivity to mu opioid receptor ligands.

Mutated CaV2.1 channels dysregulate CASK/P2X3 signaling in mouse trigeminal sensory neurons of R192Q Cacna1a knock-in mice.

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Gnanasekaran, Aswini; Bele, Tanja; Hullugundi, Swathi; Simonetti, Manuela; Ferrari, Michael D; van den Maagdenberg, Arn M J M; Nistri, Andrea; Fabbretti, Elsa

2013-12-02

ATP-gated P2X3 receptors of sensory ganglion neurons are important transducers of pain as they adapt their expression and function in response to acute and chronic nociceptive signals. The present study investigated the role of calcium/calmodulin-dependent serine protein kinase (CASK) in controlling P2X3 receptor expression and function in trigeminal ganglia from Cacna1a R192Q-mutated knock-in (KI) mice, a genetic model for familial hemiplegic migraine type-1. KI ganglion neurons showed more abundant CASK/P2X3 receptor complex at membrane level, a result that likely originated from gain-of-function effects of R192Q-mutated CaV2.1 channels and downstream enhanced CaMKII activity. The selective CaV2.1 channel blocker ω-Agatoxin IVA and the CaMKII inhibitor KN-93 were sufficient to return CASK/P2X3 co-expression to WT levels. After CASK silencing, P2X3 receptor expression was decreased in both WT and KI ganglia, supporting the role of CASK in P2X3 receptor stabilization. This process was functionally observed as reduced P2X3 receptor currents. We propose that, in trigeminal sensory neurons, the CASK/P2X3 complex has a dynamic nature depending on intracellular calcium and related signaling, that are enhanced in a transgenic mouse model of genetic hemiplegic migraine.

Plant derived aporphinic alkaloid S-(+-dicentrine induces antinociceptive effect in both acute and chronic inflammatory pain models: evidence for a role of TRPA1 channels.

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Deise Prehs Montrucchio

Full Text Available S-(+-dicentrine is an aporphinic alkaloid found in several plant species, mainly from Lauraceae family, which showed significant antinociceptive activity in an acute model of visceral pain in mice. In this work, we extended the knowledge on the antinociceptive properties of S-(+-dicentrine and showed that this alkaloid also attenuates mechanical and cold hypersensitivity associated with cutaneous inflammation induced by Complete Freund's Adjuvant in mice. Given orally, S-(+-dicentrine (100 mg/kg reversed CFA-induced mechanical hypersensitivity, evaluated as the paw withdrawal threshold to von Frey hairs, and this effect lasted up to 2 hours. S-(+-dicentrine also reversed CFA-induced cold hypersensitivity, assessed as the responses to a drop of acetone in the injured paw, but did not reverse the heat hypersensitivity, evaluated as the latency time to paw withdrawal in the hot plate (50°C. Moreover, S-(+-dicentrine (100 mg/kg, p.o. was effective in inhibit nociceptive responses to intraplantar injections of cinnamaldehyde, a TRPA1 activator, but not the responses induced by capsaicin, a TRPV1 activator. When administered either by oral or intraplantar routes, S-(+-dicentrine reduced the licking time (spontaneous nociception and increased the latency time to paw withdrawal in the cold plate (cold hypersensitivity, both induced by the intraplantar injection of cinnamaldehyde. Taken together, our data adds information about antinociceptive properties of S-(+-dicentrine in inflammatory conditions, reducing spontaneous nociception and attenuating mechanical and cold hypersensitivity, probably via a TRPA1-dependent mechanism. It also indicates that S-(+-dicentrine might be potentially interesting in the development of new clinically relevant drugs for the management of persistent pain, especially under inflammatory conditions.

Preventative effect of OMZ-SPT on lipopolysaccharide-induced acute lung injury and inflammation via nuclear factor-kappa B signaling in mice

International Nuclear Information System (INIS)

Wang, Ting; Hou, Wanru; Fu, Zhou

2017-01-01

Acute lung injury (ALI) is an early pathophysiologic change in acute respiratory distress syndrome and its management can be challenging. Omalizumab (Xolair™) is a recombinant DNA-derived, humanized antibody. OMZ-SPT is a polypeptide on the heavy chain of omalizumab monoclonal antibody. Here, we found that intramuscular administration of OMZ-SPT significantly improved survival and attenuated lung inflammation in female C57BL/6 mice suffering from lipopolysaccharide (LPS)-induced ALI. We also demonstrated that OMZ-SPT can inhibit expression of the inflammatory cytokines tumor necrosis factor-α, interleukin-1β and interleukin-6 by ELISA in mice suffering from LPS-induced ALI and a mouse macrophage line (RAW264.7 cells). In addition, we showed that OMZ-SPT inhibited LPS-induced activation of nuclear factor-kappa B (NF-κB) signaling and total expression of NF-κB by western blotting. These data suggest that OMZ-SPT could be a novel therapeutic choice for ALI. - Highlights: • OMZ-SPT is a polypeptide on the heavy chain of omalizumab monoclonal antibody. • Omalizumab (Xolair™) have anti-inflammatory effects. • OMZ-SPT can inhibit inflammatory responses and lung injury in LPS-induced ALI mice. • Protective effect of OMZ-SPT on ALI is due to inhibition of NF-κB signaling. • OMZ-SPT could be a novel therapeutic choice for ALI.

Acute and chronic rejection: compartmentalization and kinetics of counterbalancing signals in cardiac transplants.

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Kaul, A M K; Goparaju, S; Dvorina, N; Iida, S; Keslar, K S; de la Motte, C A; Valujskikh, A; Fairchild, R L; Baldwin, W M

2015-02-01

Acute and chronic rejection impact distinct compartments of cardiac allografts. Intramyocardial mononuclear cell infiltrates define acute rejection, whereas chronic rejection affects large arteries. Hearts transplanted from male to female C57BL/6 mice undergo acute rejection with interstitial infiltrates at 2 weeks that resolve by 6 weeks when large arteries develop arteriopathy. These processes are dependent on T cells because no infiltrates developed in T cell-deficient mice and transfer of CD4 T cells restored T cell as well as macrophage infiltrates and ultimately neointima formation. Markers of inflammatory macrophages were up-regulated in the interstitium acutely and decreased as markers of wound healing macrophages increased chronically. Programmed cell death protein, a negative costimulator, and its ligand PDL1 were up-regulated in the interstitium during resolution of acute rejection. Blocking PDL1:PD1 interactions in the acute phase increased interstitial T cell infiltrates. Toll-like receptor (TLR) 4 and its endogenous ligand hyaluronan were increased in arteries with neointimal expansion. Injection of hyaluronan fragments increased intragraft production of chemokines. Our data indicate that negative costimulatory pathways are critical for the resolution of acute interstitial infiltrates. In the arterial compartment recognition of endogenous ligands including hyaluronan by the innate TLRs may support the progression of arteriopathy. © Copyright 2015 The American Society of Transplantation and the American Society of Transplant Surgeons.

Losing the Warning Signal: Drought Compromises the Cross-Talk of Signaling Molecules in Quercus ilex Exposed to Ozone

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Lorenzo Cotrozzi

2017-06-01

Full Text Available Understanding the interactions between drought and acute ozone (O3 stress in terms of signaling molecules and cell death would improve the predictions of plant responses to climate change. The aim was to investigate whether drought stress influences the responses of plants to acute episodes of O3 exposure. In this study, the behavior of 84 Mediterranean evergreen Quercus ilex plants was evaluated in terms of cross-talk responses among signaling molecules. Half of the sample was subjected to drought (20% of the effective daily evapotranspiration, for 15 days and was later exposed to an acute O3 exposure (200 nL L-1 for 5 h. First, our results indicate that in well-water conditions, O3 induced a signaling pathway specific to O3-sensitive behavior. Second, different trends and consequently different roles of phytohormones and signaling molecules (ethylene, ET; abscisic acid, ABA; salycilic acid, SA and jasmonic acid, JA were observed in relation to water stress and O3. A spatial and functional correlation between these signaling molecules was observed in modulating O3-induced responses in well-watered plants. In contrast, in drought-stressed plants, these compounds were not involved either in O3-induced signaling mechanisms or in leaf senescence (a response observed in water-stressed plants before the O3-exposure. Third, these differences were ascribable to the fact that in drought conditions, most defense processes induced by O3 were compromised and/or altered. Our results highlight how Q. ilex plants suffering from water deprivation respond differently to an acute O3 episode compared to well-watered plants, and suggest new effect to be considered in plant responses to environmental changes. This poses the serious question as to whether or not multiple high-magnitude O3 events (as predicted can change these cross-talk responses, thus opening it up possible further investigations.

Participation of endogenous opioids in the antinociception induced by resistance exercise in rats

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G.S. Galdino

2010-09-01

Full Text Available Exercise is a low-cost intervention that promotes health and contributes to the maintenance of the quality of life. The present study was designed to investigate the influence of different resistance exercise protocols on the nociceptive threshold of rats. Female Wistar rats were used to perform exercises in a weight-lifting exercise model. The following groups were examined (N = 6 per group: untrained rats (control group; an acute protocol group consisting of rats submitted to 15 sets of 15 repetitions of resistance exercise (acute group; rats exercised with 3 sets of 10 repetitions, three times per week for 12 weeks (trained group, and a group consisting of trained rats that were further submitted to the acute protocol (trained-acute group. The nociceptive threshold was measured by the paw-withdrawal test, in which the withdrawal threshold (escape reaction was measured by an apparatus applying force to the plantar surface of the animal paw. The opioid antagonist naloxone (2 mg/kg was administered subcutaneously 10 min before the exercise protocols. The trained group demonstrated antinociception only up to day 45 of the 12-week training period. A significant increase (37%, P < 0.05 in the nociceptive threshold was produced immediately after exercise, decreasing to 15% after 15 min, when the acute exercise protocol was used. Naloxone reversed this effect. These data show that the acute resistance exercise protocol was effective in producing antinociception for 15 min. This antinociceptive effect is mediated by the activation of opioid receptors.

Potential Nociceptive Regulatory Effect of Probiotic Lactobacillus rhamnosus PB01 (DSM 14870 on Mechanical Sensitivity in Diet-Induced Obesity Model

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Fereshteh Dardmeh

2016-01-01

Full Text Available Treatments for obesity have been shown to reduce pain secondary to weight loss. Intestinal microbiota, as an endogenous factor, influences obesity and pain sensitivity but the effect of oral probiotic supplementation on musculoskeletal pain perception has not been studied systematically. The present study examined the effect of a single daily oral dose (1 × 109 CFU of probiotics (Lactobacillus rhamnosus PB01, DSM14870 supplement on mechanical pain thresholds in behaving diet-induced obese (DIO mice and their normal weight (NW controls. The mice (N=24, 6-week-old male were randomly divided into four groups on either standard or high fat diet with and without probiotic supplementation. Both DIO and NW groups with probiotic supplementation maintained an insignificant weight gain while the control groups gained significant weight (P<0.05. Similarly, both DIO and NW probiotics supplemented groups demonstrated a significantly (P<0.05 lower sensitivity to mechanical stimulation compared to their corresponding control. The results of this study suggest a protective effect of probiotics on nociception circuits, which propose a direct result of the weight reduction or an indirect result of anti-inflammatory properties of the probiotics. Deciphering the exact underlying mechanism of the weight loss and lowering nociception effect of the probiotic applied in this study require further investigation.

Calcium signalling in the acinar environment of the exocrine pancreas: physiology and pathophysiology

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Gryshchenko, Oleksiy; Gerasimenko, Julia V.; Peng, Shuang; Gerasimenko, Oleg V.; Petersen, Ole Holger

2018-01-01

Physiological Ca2+ signals in pancreatic acinar cells control fluid and\\ud enzyme secretion, whereas excessive Ca2+ signals induced by pathological agents\\ud induce destructive processes leading to acute pancreatitis. Ca2+ signals in the periacinar\\ud stellate cells may also play a role in the development of acute pancreatitis. In\\ud this study, we have explored Ca2+ signalling in the different cell types to be found in\\ud the acinar environment of the pancreatic tissue. We have, for the firs...

Pain in rheumatic diseases: how relevant is it?

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Sarzi-Puttini, P; Atzeni, F; Salaffi, F

2014-06-06

Pain, a complex phenomenon influenced by a series of genetic, biological, psychological and social factors, is a major component of many rheumatological conditions and the result of physiological interactions between central and peripheral nervous system signalling. It may be acute or chronic (generally defined as lasting ≥ three months): acute pain is often primarily attributable to inflammation and/or damage to peripheral structures (i.e. nociceptive input), whereas chronic pain is more likely to be due to input from the central nervous system (CNS). The many different aspects of pain mean that rheumatologists and other clinicians need to have enough expertise to diagnose the type of pain correctly and treat it appropriately. However, most rheumatologists receive little formal training concerning contemporary theories of pain processing or management, and this may affect the clinical results of any specific target therapy.

Pain in rheumatic diseases: how relevant is it?

Directory of Open Access Journals (Sweden)

P. Sarzi-Puttini

2014-06-01

Full Text Available Pain, a complex phenomenon influenced by a series of genetic, biological, psychological and social factors, is a major component of many rheumatological conditions and the result of physiological interactions between central and peripheral nervous system signalling. It may be acute or chronic (generally defined as lasting ≥ three months: acute pain is often primarily attributable to inflammation and/or damage to peripheral structures (i.e. nociceptive input, whereas chronic pain is more likely to be due to input from the central nervous system (CNS. The many different aspects of pain mean that rheumatologists and other clinicians need to have enough expertise to diagnose the type of pain correctly and treat it appropriately. However, most rheumatologists receive little formal training concerning contemporary theories of pain processing or management, and this may affect the clinical results of any specific target therapy.

Coregulation of endoplasmic reticulum stress and oxidative stress in neuropathic pain and disinhibition of the spinal nociceptive circuitry.

Science.gov (United States)

Ge, Yanhu; Jiao, Yingfu; Li, Peiying; Xiang, Zhenghua; Li, Zhi; Wang, Long; Li, Wenqian; Gao, Hao; Shao, Jiayun; Wen, Daxiang; Yu, Weifeng

2018-05-01

The accumulation of unfolded or misfolded proteins in the endoplasmic reticulum (ER) lumen leads to ER stress, which is related to cellular reactive oxygen species production. Neuropathic pain may result from spinal dorsal horn (SDH) ER stress. In this study, we examined the cause-effect relationship between ER stress and neuropathic pain using the spinal nerve ligation (SNL) rat model. We showed that ER stress was mutually promotive with oxidative stress during the process. We also tested the hypothesis that spinal sensitization arose from reduced activities of GABA-ergic interneurons and that spinal sensitization was mediated by SDH ER stress. Other important findings in this study including the following: (1) nociceptive behavior was alleviated in SNL rat as long as tauroursodeoxycholic acid injections were repeated to inhibit ER stress; (2) inducing SDH ER stress in healthy rat resulted in mechanical hyperalgesia; (3) blocking protein disulfide isomerase pharmacologically reduced ER stress and nociceptive behavior in SNL rat; (4) cells in the dorsal horn with elevated ER stress were mainly neurons; and (5) whole-cell recordings made in slide preparations revealed significant inhibition of GABA-ergic interneuron activity in the dorsal horn with ER stress vs in the healthy dorsal horn. Taken together, results of the current study demonstrate that coregulation of ER stress and oxidative stress played an important role in neuropathic pain process. Inhibiting SDH ER stress could be a potential novel strategy to manage neuropathic pain.

Jumping in aquatic environment after sciatic nerve compression: nociceptive evaluation and morphological characteristics of the soleus muscle of Wistar rats.

Science.gov (United States)

Malanotte, Jéssica Aline; Kakihata, Camila Mayumi Martin; Karvat, Jhenifer; Brancalhão, Rose Meire Costa; Ribeiro, Lucinéia de Fátima Chasko; Bertolini, Gladson Ricardo Flor

2017-01-01

To evaluate the effect of jumping in aquatic environment on nociception and in the soleus muscle of trained and not trained Wistar rats, in the treatment of compressive neuropathy of the sciatic nerve. Twenty-five Wistar rats were distributed into five groups: Control, Lesion, Trained + Lesion, Lesion + Exercise, and Trained + Lesion + Exercise. The training was jumping exercise in water environment for 20 days prior to injury, and treatment after the injury. Nociception was evaluated in two occasions, before injury and seven after injury. On the last day of the experiment, the right soleus muscles were collected, processed and analyzed as to morphology and morphometry. In the assessment of nociception in the injury site, the Control Group had higher average than the rest, and the Lesion Group was larger than the Trained + Lesion and Lesion + Exercise Groups. The Control Group showed higher nociceptive threshold in paw, compared to the others. In the morphometric analysis, in relation to Control Group, all the injured groups showed decreased muscle fiber area, and in the Lesion Group was lower than in the Lesion + Exercise Group and Trained + Lesion Group. Considering the diameter of the muscle fiber, the Control Group had a higher average than the Trained + Lesion Group and the Trained + Lesion + Exercise Group; and the Lesion Group showed an average lower than the Trained + Lesion and Lesion + Exercise Groups. Resistance exercise produced increased nociception. When performed prior or after nerve damage, it proved effective in avoiding hypotrophy. The combination of the two protocols led to decrease in diameter and area of the muscle fiber. Avaliar os efeitos do salto em meio aquático, na nocicepção e no músculo sóleo, em ratos Wistar treinados e não treinados, no tratamento de neuropatia compressiva do nervo isquiático. Foram distribuídos em cinco grupos 25 ratos Wistar: Controle, Lesão, Treinado + Lesão, Lesão + Exercício e Treinado + Lesão + Exerc

Acute hepatic encephalopathy with diffuse cortical lesions

Energy Technology Data Exchange (ETDEWEB)

Arnold, S.M.; Spreer, J.; Schumacher, M. [Section of Neuroradiology, Univ. of Freiburg (Germany); Els, T. [Dept. of Neurology, University of Freiburg (Germany)

2001-07-01

Acute hepatic encephalopathy is a poorly defined syndrome of heterogeneous aetiology. We report a 49-year-old woman with alcoholic cirrhosis and hereditary haemorrhagic telangiectasia who developed acute hepatic coma induced by severe gastrointestinal bleeding. Laboratory analysis revealed excessively elevated blood ammonia. MRI showed lesions compatible with chronic hepatic encephalopathy and widespread cortical signal change sparing the perirolandic and occipital cortex. The cortical lesions resembled those of hypoxic brain damage and were interpreted as acute toxic cortical laminar necrosis. (orig.)

Acute hepatic encephalopathy with diffuse cortical lesions

International Nuclear Information System (INIS)

Arnold, S.M.; Spreer, J.; Schumacher, M.; Els, T.

2001-01-01

Acute hepatic encephalopathy is a poorly defined syndrome of heterogeneous aetiology. We report a 49-year-old woman with alcoholic cirrhosis and hereditary haemorrhagic telangiectasia who developed acute hepatic coma induced by severe gastrointestinal bleeding. Laboratory analysis revealed excessively elevated blood ammonia. MRI showed lesions compatible with chronic hepatic encephalopathy and widespread cortical signal change sparing the perirolandic and occipital cortex. The cortical lesions resembled those of hypoxic brain damage and were interpreted as acute toxic cortical laminar necrosis. (orig.)

Tramadol effects on clinical variables and the mechanical nociceptive threshold in horses

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Leandro Guimarães Franco

2014-03-01

Full Text Available This study assessed the clinical effects and the mechanical antinociceptive potential of intravenous (IV tramadol in horses.A blinded and randomized study was designed with 7 horses treated with 1 (Tr1, 2 (Tr2 or 3 (Tr3 mg kg-1 of tramadol IV. The heart rate, respiratory rate (fR, arterial pressure, degree of sedation, gastrointestinal motility (GI, behavior changes and the mechanical nociceptive threshold (MNT were evaluated. The MNT was determined with von Frey device method.Tr3 had a significant increase in their fR and more pronounced behavioral changes than other treatments.The Tr1 showed a significant increase in arterial pressure. The GI reduced significantly, mainly in Tr2. The tramadol did not change the MNT of the horses.The clinical alterations observed with the different treatments were considered mild and transitory, being most evident in Tr2. However the tramadol did not have any analgesic effect with any of the doses evaluated.

Quantitative automated microscopy (QuAM elucidates growth factor specific signalling in pain sensitization

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Levine Jon D

2010-12-01

Full Text Available Abstract Background Dorsal root ganglia (DRG-neurons are commonly characterized immunocytochemically. Cells are mostly grouped by the experimenter's eye as "marker-positive" and "marker-negative" according to their immunofluorescence intensity. Classification criteria remain largely undefined. Overcoming this shortfall, we established a quantitative automated microscopy (QuAM for a defined and multiparametric analysis of adherent heterogeneous primary neurons on a single cell base. The growth factors NGF, GDNF and EGF activate the MAP-kinase Erk1/2 via receptor tyrosine kinase signalling. NGF and GDNF are established factors in regeneration and sensitization of nociceptive neurons. If also the tissue regenerating growth factor, EGF, influences nociceptors is so far unknown. We asked, if EGF can act on nociceptors, and if QuAM can elucidate differences between NGF, GDNF and EGF induced Erk1/2 activation kinetics. Finally, we evaluated, if the investigation of one signalling component allows prediction of the behavioral response to a reagent not tested on nociceptors such as EGF. Results We established a software-based neuron identification, described quantitatively DRG-neuron heterogeneity and correlated measured sample sizes and corresponding assay sensitivity. Analysing more than 70,000 individual neurons we defined neuronal subgroups based on differential Erk1/2 activation status in sensory neurons. Baseline activity levels varied strongly already in untreated neurons. NGF and GDNF subgroup responsiveness correlated with their subgroup specificity on IB4(+- and IB4(--neurons, respectively. We confirmed expression of EGF-receptors in all sensory neurons. EGF treatment induced STAT3 translocation into the nucleus. Nevertheless, we could not detect any EGF induced Erk1/2 phosphorylation. Accordingly, intradermal injection of EGF resulted in a fundamentally different outcome than NGF/GDNF. EGF did not induce mechanical hyperalgesia, but blocked

Acute reperfusion without recanalization

DEFF Research Database (Denmark)

Makris, Nikolaos; Chamard, Leila; Mikkelsen, Irene K

2017-01-01

Acute reperfusion despite persistent arterial occlusion may occur in up to 30% of ischemic stroke patients. Recruitment of leptomeningeal collaterals may explain this phenomenon. Using dynamic susceptibility-contrast perfusion imaging (DSC-PI), we assessed acute changes in collateral flow among...... patients without recanalization. From a multicenter prospective database (I-KNOW), 46 patients with magnetic resonance angiography visible occlusion in whom both reperfusion and recanalization were assessed within 6 h of onset were identified. Maps of collateral flow at arterial, capillary and late venous...... phases were generated from DSC-PI through inter-frame registration, baseline signal subtraction and temporal summation, and graded blind to all other relevant clinical and radiological data using the Higashida scale. Flow direction and the acute evolution of collaterals were evaluated against...

Activation of the protein tyrosine phosphatase SHP2 via the interleukin-6 signal transducing receptor protein gp130 requires tyrosine kinase Jak1 and limits acute-phase protein expression.

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Schaper, F; Gendo, C; Eck, M; Schmitz, J; Grimm, C; Anhuf, D; Kerr, I M; Heinrich, P C

1998-11-01

Stimulation of the interleukin-6 (IL-6) signalling pathway occurs via the IL-6 receptor-glycoprotein 130 (IL-6R-gp130) receptor complex and results in the regulation of acute-phase protein genes in liver cells. Ligand binding to the receptor complex leads to tyrosine phosphorylation and activation of Janus kinases (Jak), phosphorylation of the signal transducing subunit gp130, followed by recruitment and phosphorylation of the signal transducer and activator of transcription factors STAT3 and STAT1 and the src homology domain (SH2)-containing protein tyrosine phosphatase (SHP2). The tyrosine phosphorylated STAT factors dissociate from the receptor, dimerize and translocate to the nucleus where they bind to enhancer sequences of IL-6 target genes. Phosphorylated SHP2 is able to bind growth factor receptor bound protein (grb2) and thus might link the Jak/STAT pathway to the ras/raf/mitogen-activated protein kinase pathway. Here we present data on the dose-dependence, kinetics and kinase requirements for SHP2 phosphorylation after the activation of the signal transducer, gp130, of the IL-6-type family receptor complex. When human fibrosarcoma cell lines deficient in Jak1, Jak2 or tyrosine kinase 2 (Tyk2) were stimulated with IL-6-soluble IL-6R complexes it was found that only in Jak1-, but not in Jak 2- or Tyk2-deficient cells, SHP2 activation was greatly impaired. It is concluded that Jak1 is required for the tyrosine phosphorylation of SHP2. This phosphorylation depends on Tyr-759 in the cytoplasmatic domain of gp130, since a Tyr-759-->Phe exchange abrogates SHP2 activation and in turn leads to elevated and prolonged STAT3 and STAT1 activation as well as enhanced acute-phase protein gene induction. Therefore, SHP2 plays an important role in acute-phase gene regulation.

Corticotropin-Releasing Factor Mediates Pain-Induced Anxiety through the ERK1/2 Signaling Cascade in Locus Coeruleus Neurons

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Borges, Gisela Patrícia; Micó, Juan Antonio; Neto, Fani Lourença

2015-01-01

Background: The corticotropin-releasing factor is a stress-related neuropeptide that modulates locus coeruleus activity. As locus coeruleus has been involved in pain and stress-related patologies, we tested whether the pain-induced anxiety is a result of the corticotropin-releasing factor released in the locus coeruleus. Methods: Complete Freund’s adjuvant-induced monoarthritis was used as inflammatory chronic pain model. α-Helical corticotropin-releasing factor receptor antagonist was microinjected into the contralateral locus coeruleus of 4-week-old monoarthritic animals. The nociceptive and anxiety-like behaviors, as well as phosphorylated extracellular signal-regulated kinases 1/2 and corticotropin-releasing factor receptors expression, were quantified in the paraventricular nucleus and locus coeruleus. Results: Monoarthritic rats manifested anxiety and increased phosphorylated extracellular signal-regulated kinases 1/2 levels in the locus coeruleus and paraventricular nucleus, although the expression of corticotropin-releasing factor receptors was unaltered. α-Helical corticotropin-releasing factor antagonist administration reversed both the anxiogenic-like behavior and the phosphorylated extracellular signal-regulated kinases 1/2 levels in the locus coeruleus. Conclusions: Pain-induced anxiety is mediated by corticotropin-releasing factor neurotransmission in the locus coeruleus through extracellular signal-regulated kinases 1/2 signaling cascade. PMID:25716783

Magnetic resonance imaging in acute ischemic stroke

Energy Technology Data Exchange (ETDEWEB)

Ohta, Kouichi [Mito Red Cross Hospital (Japan)

2000-01-01

This paper summarizes current MRI technology used in the diagnosis of acute cerebral infarction and discusses tasks for further improvement of MRI technology. First, the principles and methods of MRI imaging are described in terms of 1) diffusion-weighted imaging (DWI) and ADC maps, 2) perfusion imaging, 3) the fluid-attenuated inversion recovery (FLAIR) method, and 4) MR angiography (MRA). Then, the actual use of MRI in the early phase of ischemic cerebrovascular disorders is discussed focusing on general MRI procedures, cases in which an ischemic lesion dose not yield a high signal with DWI in the acute phase, and chronological changes in DWI signal strength and ADC. Third, chronological changes in acute cerebrovascular disorder in an animal model of local cerebral ischemia are summarized in terms of expansion of reduced ADC areas and ischemic penumbras in the acute phase of cerebral ischemia. Finally, chronological changes in acute ischemic disorders in patients with cerebrovascular disorders are assessed by reviewing the development of reduced ADC and expansion of DWI lesions. Whether MRI can identify cerebral tissues that can be rescued by the reperfusion method by examining the mismatchs between perfusion images and DWI, relative CBV, and ADC is also discussed. (K.H.)

Calcium signalling in the acinar environment of the exocrine pancreas: physiology and pathophysiology.

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Gryshchenko, Oleksiy; Gerasimenko, Julia V; Peng, Shuang; Gerasimenko, Oleg V; Petersen, Ole H

2018-02-09

Ca 2+ signalling in different cell types in exocrine pancreatic lobules was monitored simultaneously and signalling responses to various stimuli were directly compared. Ca 2+ signals evoked by K + -induced depolarization were recorded from pancreatic nerve cells. Nerve cell stimulation evoked Ca 2+ signals in acinar but not in stellate cells. Stellate cells are not electrically excitable as they, like acinar cells, did not generate Ca 2+ signals in response to membrane depolarization. The responsiveness of the stellate cells to bradykinin was markedly reduced in experimental alcohol-related acute pancreatitis, but they became sensitive to stimulation with trypsin. Our results provide fresh evidence for an important role of stellate cells in acute pancreatitis. They seem to be a critical element in a vicious circle promoting necrotic acinar cell death. Initial trypsin release from a few dying acinar cells generates Ca 2+ signals in the stellate cells, which then in turn damage more acinar cells causing further trypsin liberation. Physiological Ca 2+ signals in pancreatic acinar cells control fluid and enzyme secretion, whereas excessive Ca 2+ signals induced by pathological agents induce destructive processes leading to acute pancreatitis. Ca 2+ signals in the peri-acinar stellate cells may also play a role in the development of acute pancreatitis. In this study, we explored Ca 2+ signalling in the different cell types in the acinar environment of the pancreatic tissue. We have, for the first time, recorded depolarization-evoked Ca 2+ signals in pancreatic nerves and shown that whereas acinar cells receive a functional cholinergic innervation, there is no evidence for functional innervation of the stellate cells. The stellate, like the acinar, cells are not electrically excitable as they do not generate Ca 2+ signals in response to membrane depolarization. The principal agent evoking Ca 2+ signals in the stellate cells is bradykinin, but in experimental alcohol

The Absence of Sensory Axon Bifurcation Affects Nociception and Termination Fields of Afferents in the Spinal Cord

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Philip Tröster

2018-02-01

Full Text Available A cGMP signaling cascade composed of C-type natriuretic peptide, the guanylyl cyclase receptor Npr2 and cGMP-dependent protein kinase I (cGKI controls the bifurcation of sensory axons upon entering the spinal cord during embryonic development. However, the impact of axon bifurcation on sensory processing in adulthood remains poorly understood. To investigate the functional consequences of impaired axon bifurcation during adult stages we generated conditional mouse mutants of Npr2 and cGKI (Npr2fl/fl;Wnt1Cre and cGKIKO/fl;Wnt1Cre that lack sensory axon bifurcation in the absence of additional phenotypes observed in the global knockout mice. Cholera toxin labeling in digits of the hind paw demonstrated an altered shape of sensory neuron termination fields in the spinal cord of conditional Npr2 mouse mutants. Behavioral testing of both sexes indicated that noxious heat sensation and nociception induced by chemical irritants are impaired in the mutants, whereas responses to cold sensation, mechanical stimulation, and motor coordination are not affected. Recordings from C-fiber nociceptors in the hind limb skin showed that Npr2 function was not required to maintain normal heat sensitivity of peripheral nociceptors. Thus, the altered behavioral responses to noxious heat found in Npr2fl/fl;Wnt1Cre mice is not due to an impaired C-fiber function. Overall, these data point to a critical role of axonal bifurcation for the processing of pain induced by heat or chemical stimuli.

Acute High-intensity Interval Exercise-induced Redox Signaling is Associated with Enhanced Insulin Sensitivity in Obese Middle-aged Men.

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Lewan Parker

2016-09-01

Full Text Available Background. Obesity and ageing are associated with increased oxidative stress, activation of stress and mitogen activated protein kinases (SAPK, and the development of insulin resistance and metabolic disease. In contrast, acute exercise also increases oxidative stress and SAPK signaling, yet is reported to enhance insulin sensitivity and reduce the risk of metabolic disease. This study explored this paradox by investigating the effect of a single session of high-intensity interval-exercise (HIIE on redox status, muscle SAPK and insulin protein signaling in eleven middle-aged obese men. Methods. Participants completed a 2 hour hyperinsulinaemic-euglycaemic clamp at rest, and 60 minutes after HIIE (4x4 mins at 95% HRpeak; 2 min recovery periods, separated by 1-3 weeks. Results. Irrespective of exercise-induced changes to redox status, insulin stimulation both at rest and after HIIE similarly increased plasma superoxide dismutase activity, plasma catalase activity, and skeletal muscle 4-HNE; and significantly decreased plasma TBARS and hydrogen peroxide. The SAPK signaling pathways of p38 MAPK, NF-κB p65, and JNK, and the distal insulin signaling protein AS160Ser588, were activated with insulin stimulation at rest and to a greater extent with insulin stimulation after a prior bout of HIIE. Higher insulin sensitivity after HIIE was associated with higher insulin-stimulated SAPK phosphorylation (JNK, p38 MAPK and NF-κB and SOD activity (p<0.05. Conclusion. These findings support a role for redox homeostasis and SAPK signaling in insulin-stimulated glucose uptake which may contribute to the enhancement of insulin sensitivity in obese men 3 hours after HIIE.

High frequency migraine is associated with lower acute pain sensitivity and abnormal insula activity related to migraine pain intensity, attack frequency, and pain catastrophizing

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Vani A Mathur

2016-09-01

Full Text Available Migraine is a pain disorder associated with abnormal brain structure and function, yet the effect of migraine on acute pain processing remains unclear. It also remains unclear whether altered pain-related brain responses and related structural changes are associated with clinical migraine characteristics. Using fMRI and three levels of thermal stimuli (non-painful, mildly painful, and moderately painful, we compared whole-brain activity between 14 migraine patients and 14 matched controls. Although, there were no significant differences in pain thresholds and pre-scan pain ratings to mildly painful thermal stimuli, patients had aberrant suprathreshold nociceptive processing. Compared to controls, patients had reduced activity in pain modulatory regions including left dorsolateral prefrontal, posterior parietal, and middle temporal cortices and, at a lower-threshold, greater activation in the right mid-insula to moderate pain versus mild pain. We also found that pain-related activity in the insula was associated with clinical variables in patients, including associations between: bilateral anterior insula and pain catastrophizing (PCS; bilateral anterior insula and contralateral posterior insula and migraine pain intensity; and bilateral posterior insula and migraine frequency at a lower-threshold. PCS and migraine pain intensity were also negatively associated with activity in midline regions including posterior cingulate and medial prefrontal cortices. Diffusion tensor imaging revealed a negative correlation between fractional anisotropy (a measure of white matter integrity; FA and migraine duration in the right mid-insula and a positive correlation between left mid-insula FA and PCS. In sum, while patients showed lower sensitivity to acute noxious stimuli, the neuroimaging findings suggest enhanced nociceptive processing and significantly disrupted modulatory networks, particularly involving the insula cortex, associated with indices of

Negative Energy Balance Blocks Neural and Behavioral Responses to Acute Stress by "Silencing" Central Glucagon-Like Peptide 1 Signaling in Rats.

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Maniscalco, James W; Zheng, Huiyuan; Gordon, Patrick J; Rinaman, Linda

2015-07-29

acute stress to activate hindbrain neurons that are immunoreactive for either prolactin-releasing peptide or glucagon-like peptide 1, and attenuates the activation of their stress-sensitive projection targets in the limbic forebrain. In nonfasted rats, central antagonism of glucagon-like peptide 1 receptors partially mimics the effect of an overnight fast by blocking the ability of acute stress to inhibit food intake, and by attenuating stress-induced activation of hindbrain and limbic forebrain neurons. We propose that caloric restriction attenuates behavioral and physiological responses to acute stress by "silencing" central glucagon-like peptide 1 signaling pathways. Copyright © 2015 the authors 0270-6474/15/3510701-14$15.00/0.

Role of Notch signalling pathway in cancer and its association with ...

Indian Academy of Sciences (India)

The Notch signalling pathway is an evolutionarily conserved cell signalling pathway involved in the development of organ- ... Abnormal Notch signalling is seen in many cancers like T-cell acute ...... Morgan T. H. 1917 The theory of the gene.

Antinociceptive and anti-exudative synergism between dexketoprofen and tramadol in a model of inflammatory pain in mice.

Science.gov (United States)

Miranda, Hugo F; Romero, Maria Asunción; Puig, Margarita M

2012-06-01

Preclinical studies have demonstrated antinociceptive synergism between dexketoprofen (DEX) and tramadol (TRM) in acute animal models of nociception. The aim of the present study was to investigate the type of interaction between DEX and TRM in a chronic musculoskeletal pain model in mice, which fairly replicates the characteristics of chronic osteoarticular pain in humans. Inflammation was induced by a subplantar injection of complete Freund's adjuvant (CFA) in male CF1 mice. Nociceptive thresholds were evaluated using the hot plate, the nocifensive spontaneous behavior and the acetone tests, while plasma extravasation (PE) was assessed with Evan's blue. We used the following experimental groups: control (no inflammation), acute (1 day after CFA injection), and chronic inflammation (7 days after CFA). Dose-response curves for DEX and TRM, individually and combined in a 1 : 1 proportion based on their potency were obtained, and the doses that produced a 50% inhibition calculated. The isobolographic analysis revealed that in all groups of study (no inflammation, acute, and chronic inflammation), the combination of DEX : TRM was synergistic, for both the inhibition of nociception and the PE. The results suggest that the DEX : TRM (1 : 1) combination could be useful in the management of acute and chronic inflammatory musculoskeletal pains in humans; in addition, the synergistic interaction between the drugs observed both during acute and chronic inflammation suggests that less doses would be required of each drug to obtain effective analgesia. © 2011 The Authors Fundamental and Clinical Pharmacology © 2011 Société Française de Pharmacologie et de Thérapeutique.

Role of Nonneuronal TRPV4 Signaling in Inflammatory Processes.

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Rajasekhar, Pradeep; Poole, Daniel P; Veldhuis, Nicholas A

2017-01-01

Transient receptor potential (TRP) ion channels are important signaling components in nociceptive and inflammatory pathways. This is attributed to their ability to function as polymodal sensors of environmental stimuli (chemical and mechanical) and as effector molecules in receptor signaling pathways. TRP vanilloid 4 (TRPV4) is a nonselective cation channel that is activated by multiple endogenous stimuli including shear stress, membrane stretch, and arachidonic acid metabolites. TRPV4 contributes to many important physiological processes and dysregulation of its activity is associated with chronic conditions of metabolism, inflammation, peripheral neuropathies, musculoskeletal development, and cardiovascular regulation. Mechanosensory and receptor- or lipid-mediated signaling functions of TRPV4 have historically been attributed to central and peripheral neurons. However, with the development of potent and selective pharmacological tools, transgenic mice and improved molecular and imaging techniques, many new roles for TRPV4 have been revealed in nonneuronal cells. In this chapter, we discuss these recent findings and highlight the need for greater characterization of TRPV4-mediated signaling in nonneuronal cell types that are either directly associated with neurons or indirectly control their excitability through release of sensitizing cellular factors. We address the integral role of these cells in sensory and inflammatory processes as well as their importance when considering undesirable on-target effects that may be caused by systemic delivery of TRPV4-selective pharmaceutical agents for treatment of chronic diseases. In future, this will drive a need for targeted drug delivery strategies to regulate such a diverse and promiscuous protein. © 2017 Elsevier Inc. All rights reserved.

Fisetin Alleviates Lipopolysaccharide-Induced Acute Lung Injury via TLR4-Mediated NF-κB Signaling Pathway in Rats.

Science.gov (United States)

Feng, Guang; Jiang, Ze-Yu; Sun, Bo; Fu, Jie; Li, Tian-Zuo

2016-02-01

Acute lung injury (ALI), a common component of systemic inflammatory disease, is a life-threatening condition without many effective treatments. Fisetin, a natural flavonoid from fruits and vegetables, was reported to have wide pharmacological properties such as anti-inflammatory, antioxidant, and anticancer activities. The aim of this study was to detect the effects of fisetin on lipopolysaccharide (LPS)-induced acute lung injury and investigate the potential mechanism. Fisetin was injected (1, 2, and 4 mg/kg, i.v.) 30 min before LPS administration (5 mg/kg, i.v.). Our results showed that fisetin effectively reduced the inflammatory cytokine release and total protein in bronchoalveolar lavage fluids (BALF), decreased the lung wet/dry ratios, and obviously improved the pulmonary histology in LPS-induced ALI. Furthermore, fisetin inhibited LPS-induced increases of neutrophils and macrophage infiltration and attenuated MPO activity in lung tissues. Additionally, fisetin could significantly inhibit the Toll-like receptor 4 (TLR4) expression and the activation of NF-κB in lung tissues. Our data indicates that fisetin has a protective effect against LPS-induced ALI via suppression of TLR4-mediated NF-κB signaling pathways, and fisetin may be a promising candidate for LPS-induced ALI treatment.

Nociceptive thermal threshold testing in horses – effect of neuroleptic sedation and neuroleptanalgesia at different stimulation sites

Science.gov (United States)

2013-01-01

Background Aim of the study was to compare the effect of neuroleptic sedation with acepromazine and neuroleptanalgesia with acepromazine and buprenorphine on thermal thresholds (TT) obtained at the nostrils and at the withers. The study was carried out as a randomized, blinded, controlled trial with cross-over design. Thermal thresholds were determined by incremental contact heat applied to the skin above the nostril (N) or the withers (W). Eleven horses were treated with saline (S), acepromazine (0.05 mg/kg) (ACE) or acepromazine and buprenorphine (0.0075 mg/kg) (AB) intravenously (IV). Single stimulations were performed 15 minutes prior and 15, 45, 75, 105, 165, 225, 285, 405 and 525 minutes after treatment. Sedation score, gastrointestinal auscultation score and occurrence of skin lesions were recorded. Data were analysed with analysis of variance for repeated measurements. Results There were no significant differences in TT between N and W with all treatments. The TT remained constant after S and there was no difference in TT between S and ACE. After AB there was a significant increase above baseline in TT until 405 minutes after treatment. Restlessness occurred 30–90 minutes after AB in 7 horses. All horses had reduced to absent borborygmi after AB administration for 165 to 495 minutes. Conclusion Thermal stimulation at both described body areas gives comparable results in the assessment of cutaneous anti-nociception in horses. There is no differential influence of neuroleptic sedation or neuroleptanalgesia on TTs obtained at N or W. Buprenorphine combined with acepromazine has a long lasting anti-nociceptive effect associated with the typical opioid induced side effects in horses. PMID:23837730

Hyperin protects against LPS-induced acute kidney injury by inhibiting TLR4 and NLRP3 signaling pathways

Science.gov (United States)

Chunzhi, Gong; Zunfeng, Li; Chengwei, Qin; Xiangmei, Bu; Jingui, Yu

2016-01-01

Hyperin is a flavonoid compound derived from Ericaceae, Guttifera, and Celastraceae that has been shown to have various biological effects, such as anti-inflammatory and anti-oxidant effects. However, there is no evidence to show the protective effects of hyperin on lipopolysaccharide (LPS)-induced acute kidney injury (AKI). Therefore, we investigated the protective effects and mechanism of hyperin on LPS-induced AKI in mice. The levels of TNF-α, IL-6, and IL-1β were tested by ELISA. The effects of hyperin on blood urea nitrogen (BUN) and serum creatinine were also detected. In addition, the expression of TLR4, NF-κB, and NLRP3 were detected by western blot analysis. The results showed that hyperin significantly inhibited LPS-induced TNF-α, IL-6, and IL-1β production. The levels of BUN and creatinine were also suppressed by hyperin. Furthermore, LPS-induced TLR4 expression and NF-κB activation were also inhibited by hyperin. In addition, treatment of hyperin dose-dependently inhibited LPS-induced NLRP3 signaling pathway. In conclusion, the results showed that hyperin inhibited LPS-induced inflammatory response by inhibiting TLR4 and NLRP3 signaling pathways. Hyperin has potential application prospects in the treatment of sepsis-induced AKI. PMID:27813491

Proton MR spectroscopy and MR imaging in acute and chronic multiple sclerosis - ringlike appearances in acute plaques

Energy Technology Data Exchange (ETDEWEB)

Landtblom, A M [Dept. of Clinical Neuroscience, Linkoeping Univ. Hospital (Sweden); Sjoeqvist, L [Dept. of Radiation Physics, Linkoeping Univ. Hospital (Sweden); Soederfeldt, B [Dept. of Clinical Neuroscience, Linkoeping Univ. Hospital (Sweden); Nyland, H [Dept. of Neurology, Haukeland Hospital, Bergen (Norway); Thuomas, K Aa [Dept. of Radiology, Linkoeping Univ. Hospital (Sweden)

1995-05-01

We wanted to compare the metabolite status of brain lesions in different clinical subtypes of multiple sclerosis (MS). Two acute MS lesions with ringlike appearances were also investigated. Twenty-three clinically stable MS patients, 2 patients with acute relapses, and 15 healthy individuals were examined by MR imaging and localized proton MRS. No metabolite differences were seen in plaques of different subtypes. Decreased NAA/Cr and NAA/choline ratios as well as increased inositol/CR ratios were observed in the plaques of the clinically stable or chronic active MS patients as compared with controls. The ring plaques had hyperintense cores with surrounding halos, separated from the cores by rings with low signal intensity in T2-weighted images. The core exhibited a prolonged T2 relaxation time. Proton spectra initially contained lactate. No differences between the metabolite status of nonacute plaques in different clinical subtypes could be detected. The ring plaques contained lactate signals indicating oedema, inflammation, and macrophage invasion, and may be transition forms between acute oedematous lesions and chronic demyelinated plaques. (orig.).

Therapeutic potential of agmatine for CNS disorders.

Science.gov (United States)

Neis, Vivian B; Rosa, Priscila B; Olescowicz, Gislaine; Rodrigues, Ana Lúcia S

2017-09-01

Agmatine is a neuromodulator that regulates multiple neurotransmitters and signaling pathways. Several studies have focused on elucidating the mechanisms underlying the neuroprotective effects of this molecule, which seems to be mediated by a reduction in oxidative damage, neuroinflammation, and proapoptotic signaling. Since these events are implicated in acute and chronic excitotoxicity-related disorders (ischemia, epilepsy, traumatic brain injury, spinal cord injury, neurodegenerative, and psychiatric disorders) as well as in nociception, agmatine has been proposed as a therapeutic strategy for the treatment of central nervous system (CNS) disorders. Agmatine also stimulates the expression of trophic factors and adult neurogenesis, contributing to its ability to induce endogenous repair mechanisms. Therefore, considering its wide range of biological effects, this review summarizes the current knowledge about its protective and regenerative properties in the CNS. Copyright © 2017 Elsevier Ltd. All rights reserved.

Effects of Acute Exercise and Chronic Exercise on the Liver Leptin-AMPK-ACC Signaling Pathway in Rats with Type 2 Diabetes

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Xuejie Yi

2013-01-01

Full Text Available Aim. To investigate the effects of acute and chronic exercise on glucose and lipid metabolism in liver of rats with type 2 diabetes caused by a high fat diet and low dose streptozotocin (STZ. Methods. Animals were classified into control (CON, diabetes (DC, diabetic chronic exercise (DCE, and diabetic acute exercise (DAE groups. Results. Compared to CON, the leptin levels in serum and liver and ACC phosphorylation were significantly higher in DC, but the levels of liver leptin receptor, AMPKα1/2, AMPKα1, and ACC proteins expression and phosphorylation were significantly lower in DC. In addition, the levels of liver glycogen reduced significantly, and the levels of TG and FFA increased significantly in DC compared to CON. Compared to DC, the levels of liver AMPKα1/2, AMPKα2, AMPKα1, and ACC phosphorylation significantly increased in DCE and DAE. However, significant increase of the level of liver leptin receptor and glycogen as well as significant decrease of the level of TG and FFA were observed only in DEC. Conclusion. Our study demonstrated that both acute and chronic exercise indirectly activated the leptin-AMPK-ACC signaling pathway and increased insulin sensitivity in the liver of type 2 diabetic rats. However, only chronic and long-term exercise improved glucose and lipid metabolism of the liver.

Reactive oxygen species activate differentiation gene transcription of acute myeloid leukemia cells via the JNK/c-JUN signaling pathway.

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Lam, Chung Fan; Yeung, Hoi Ting; Lam, Yuk Man; Ng, Ray Kit

2018-05-01

Reactive oxygen species (ROS) and altered cellular redox status are associated with many malignancies. Acute myeloid leukemia (AML) cells are maintained at immature state by differentiation blockade, which involves deregulation of transcription factors in myeloid differentiation. AML cells can be induced to differentiate by phorbol-12-myristate-13-acetate (PMA), which possesses pro-oxidative activity. However, the signaling events mediated by ROS in the activation of transcriptional program during AML differentiation has not been fully elucidated. Here, we investigated AML cell differentiation by treatment with PMA and ROS scavenger N-acetyl-l-cysteine (NAC). We observed elevation of intracellular ROS level in the PMA-treated AML cells, which correlated with differentiated cell morphology and increased CD11b + mature cell population. The effect of PMA can be abolished by NAC co-treatment, supporting the involvement of ROS in the process. Moreover, we demonstrated that short ROS elevation mediated cell cycle arrest, but failed to activate myeloid gene transcription; whereas prolonged ROS elevation activated JNK/c-JUN signaling pathway. Inhibition of JNK suppressed the expression of key myeloid transcriptional regulators c-JUN, SPI-1 and MAFB, and prevented AML cells from undergoing terminal differentiation. These findings provide new insights into the crucial role of JNK/c-Jun signaling pathway in the activation of transcriptional program during ROS-mediated AML differentiation. Copyright © 2018 Elsevier Ltd. All rights reserved.

Biomechanical aspects of nonspecific back pain

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Ridwan Harrianto

2010-12-01

Full Text Available Low back pain (LBP is a common problem in adult life, since despite its benign nature it is commonly associated with incapacity, productivity loss due to sick leave, and correspondingly high costs to the individual worker. Psychosocial and lifestyle factors and work-place exposures have been implicated in the onset of symptoms. Heavy physical work, static work postures, frequent bending and twisting, lifting and postural movements, repetitive work, and whole body vibrations are occupational factors associated with LBP. The usual classification of LBP is related to the duration of the complaints (acute, subacute, and chronic. However, these terms fail to take into account several clinically important aspects of the course of LBP, which is frequently recurrent and thus neither acute nor chronic. More realistically, LBP should be classified as specific and nonspecific. Approximately 90% of LBP cases have no identifiable cause and is designated nonspecific LBP. However, despite its high prevalence, the etiology and nature of nonspecific LBP are not yet well understood. Its pathophysiology remains complex and multifaceted. Multiple anatomic structures and elements of the lumbar spine (e.g. bones, ligaments, tendons, discs, and muscles are all suspected of playing a role. Many of these components of the lumbar spine have sensory innervations that can generate nociceptive signals in response to tissue-damaging stimuli. Other causes could be neuropathic (e.g. sciatica. Some cases of LBP most likely involve mixed nociceptive and neuropathic etiologies.

Acute Treatment with T-Type Calcium Channel Enhancer SAK3 Reduces Cognitive Impairments Caused by Methimazole-Induced Hypothyroidism Via Activation of Cholinergic Signaling.

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Husain, Noreen; Yabuki, Yasushi; Shinoda, Yasuharu; Fukunaga, Kohji

2018-01-01

Hypothyroidism is a common disorder that is associated with psychological disturbances such as dementia, depression, and psychomotor disorders. We recently found that chronic treatment with the T-type calcium channel enhancer SAK3 prevents the cholinergic neurodegeneration induced by a single intraperitoneal (i.p.) injection of methimazole (MMI; 75 mg/kg), thereby improving cognition. Here, we evaluated the acute effect of SAK3 on cognitive impairments and its mechanism of action following the induction of hypothyroidism. Hypothyroidism was induced by 2 injections of MMI (75 mg/kg, i.p.) administered once per week. Four weeks after the final MMI treatment, MMI-treated mice showed reduced serum thyroxine (T4) levels and cognitive impairments without depression-like behaviors. Although acute SAK3 (1.0 mg/kg, p.o.) administration failed to ameliorate the decreased T4 levels and histochemical destruction of the glomerular structure, acute SAK3 (1.0 mg/kg, p.o.) administration significantly reduced cognitive impairments in MMI-treated mice. Importantly, the α7 nicotinic acetylcholine receptor (nAChR)-selective inhibitor methyllycaconitine (MLA; 12 mg/kg, i.p.) and T-type calcium channel-specific blocker NNC 55-0396 (25 mg/kg, i.p.) antagonized the acute effect of SAK3 on memory deficits in MMI-treated mice. We also confirmed that acute SAK3 administration does not rescue reduced olfactory marker protein or choline acetyltransferase immunoreactivity levels in the olfactory bulb or medial septum. Taken together, these results suggest that SAK3 has the ability to improve the cognitive decline caused by hypothyroidism directly through activation of nAChR signaling and T-type calcium channels. © 2018 S. Karger AG, Basel.

Power Doppler Imaging in Acute Renal Vein Occlusion and Recanalization: a Canine Model

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Yoo, So-Young; Kim, In-One; Kim, Young-Il; Lee, Kyoung Ho; Lee, Min Woo; Youn, Byung Jae; Kim, Woo Sun; Yeon, Kyung Mo [Seoul National University College of Medicine, Seoul (Korea, Republic of)

2008-04-15

Objective : To evaluate the dynamic changes of the power Doppler (PD) in acute renal vein occlusion and recanalization in a canine model. Materials and Methods : We performed a PD of the kidney during graded renal vein occlusion and recanalization induced by balloon inflation and deflation in nine dogs. The PD images were transferred to a personal computer, and the PD signals were quantified. Result : We observed the temporal change of the PD signal during renal vein occlusion and recanalization, with a decrease in the PD signal during occlusion and an increase during recanalization. The mean PD signal decreased gradually as the renal vein was occluded, and conversely increased gradually with sequential relief of occlusion. The sequential change of the mean value of the PD signal was statistically significant. Conclusion : The PD can detect a change in renal blood flow during acute renal vein occlusion and recanalization in a canine model. The PD may be used as a helpful tool for the early detection of acute renal vein thrombosis and the monitoring of renal perfusion.

Power Doppler Imaging in Acute Renal Vein Occlusion and Recanalization: a Canine Model

International Nuclear Information System (INIS)

Yoo, So-Young; Kim, In-One; Kim, Young-Il; Lee, Kyoung Ho; Lee, Min Woo; Youn, Byung Jae; Kim, Woo Sun; Yeon, Kyung Mo

2008-01-01

Objective : To evaluate the dynamic changes of the power Doppler (PD) in acute renal vein occlusion and recanalization in a canine model. Materials and Methods : We performed a PD of the kidney during graded renal vein occlusion and recanalization induced by balloon inflation and deflation in nine dogs. The PD images were transferred to a personal computer, and the PD signals were quantified. Result : We observed the temporal change of the PD signal during renal vein occlusion and recanalization, with a decrease in the PD signal during occlusion and an increase during recanalization. The mean PD signal decreased gradually as the renal vein was occluded, and conversely increased gradually with sequential relief of occlusion. The sequential change of the mean value of the PD signal was statistically significant. Conclusion : The PD can detect a change in renal blood flow during acute renal vein occlusion and recanalization in a canine model. The PD may be used as a helpful tool for the early detection of acute renal vein thrombosis and the monitoring of renal perfusion

Neuroendocrine signaling modulates specific neural networks relevant to migraine.

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Martins-Oliveira, Margarida; Akerman, Simon; Holland, Philip R; Hoffmann, Jan R; Tavares, Isaura; Goadsby, Peter J

2017-05-01

Migraine is a disabling brain disorder involving abnormal trigeminovascular activation and sensitization. Fasting or skipping meals is considered a migraine trigger and altered fasting glucose and insulin levels have been observed in migraineurs. Therefore peptides involved in appetite and glucose regulation including insulin, glucagon and leptin could potentially influence migraine neurobiology. We aimed to determine the effect of insulin (10U·kg -1 ), glucagon (100μg·200μl -1 ) and leptin (0.3, 1 and 3mg·kg -1 ) signaling on trigeminovascular nociceptive processing at the level of the trigeminocervical-complex and hypothalamus. Male rats were anesthetized and prepared for craniovascular stimulation. In vivo electrophysiology was used to determine changes in trigeminocervical neuronal responses to dural electrical stimulation, and phosphorylated extracellular signal-regulated kinases 1 and 2 (pERK1/2) immunohistochemistry to determine trigeminocervical and hypothalamic neural activity; both in response to intravenous administration of insulin, glucagon, leptin or vehicle control in combination with blood glucose analysis. Blood glucose levels were significantly decreased by insulin (pneuronal firing in the trigeminocervical-complex was significantly inhibited by insulin (pmetabolic homeostasis may occur through disturbed glucose regulation and a transient hypothalamic dysfunction. Copyright © 2017 The Author(s). Published by Elsevier Inc. All rights reserved.

TRPV1 and Endocannabinoids: Emerging Molecular Signals that Modulate Mammalian Vision

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Daniel A. Ryskamp

2014-09-01

Full Text Available Transient Receptor Potential Vanilloid 1 (TRPV1 subunits form a polymodal cation channel responsive to capsaicin, heat, acidity and endogenous metabolites of polyunsaturated fatty acids. While originally reported to serve as a pain and heat detector in the peripheral nervous system, TRPV1 has been implicated in the modulation of blood flow and osmoregulation but also neurotransmission, postsynaptic neuronal excitability and synaptic plasticity within the central nervous system. In addition to its central role in nociception, evidence is accumulating that TRPV1 contributes to stimulus transduction and/or processing in other sensory modalities, including thermosensation, mechanotransduction and vision. For example, TRPV1, in conjunction with intrinsic cannabinoid signaling, might contribute to retinal ganglion cell (RGC axonal transport and excitability, cytokine release from microglial cells and regulation of retinal vasculature. While excessive TRPV1 activity was proposed to induce RGC excitotoxicity, physiological TRPV1 activity might serve a neuroprotective function within the complex context of retinal endocannabinoid signaling. In this review we evaluate the current evidence for localization and function of TRPV1 channels within the mammalian retina and explore the potential interaction of this intriguing nociceptor with endogenous agonists and modulators.

Microbubble signal and trial of org in acute stroke treatment (TOAST) classification in ischemic stroke.

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Lee, Chan-Hyuk; Kang, Hyun Goo; Lee, Ji Sung; Ryu, Han Uk; Jeong, Seul-Ki

2018-07-15

Right-to-left shunt (RLS) through a patent foramen ovale (PFO) is likely associated with ischemic stroke. Many studies have attempted to demonstrate the association between RLS and ischemic stroke. However, information on the association between the degree of RLS and the subtypes of ischemic stroke categorized by the Trial of ORG 10172 in Acute Stroke Treatment (TOAST) classification is lacking. This was a retrospective study involving 508 patients with ischemic stroke who underwent a transcranial Doppler (TCD) microbubble test between 2013 and 2015. The degree of RLS was divided into 4 grades according to the microbubble signal (MBS) as follows: no MBS, grade 1; MBS  20, grade 3; curtain sign, grade 4. The degree of RLS and the type of ischemic stroke as classified by TOAST were analyzed and compared with other clinical information and laboratory findings. The higher RLS grade was associated with the cardioembolism (CE) and stroke of undetermined etiology (SUE), and the microbubble signals were inversely related with small vessel disease (SVD). An MBS higher than grade 3 showed a 2.95-fold higher association with SUE than large artery atherosclerosis (LAA), while grade 4 MBS revealed an approximately 8-fold higher association with SUE than LAA. RLS identified by the TCD microbubble test was significantly and independently associated with cryptogenic ischemic stroke (negative evaluation). Subsequent studies are needed to determine the biologic relationship between RLS and ischemic stroke, particularly the cryptogenic subtype of ischemic stroke. Copyright © 2018 Elsevier B.V. All rights reserved.

The differential effects of acute right- vs. left-sided vestibular failure on brain metabolism.

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Becker-Bense, Sandra; Dieterich, Marianne; Buchholz, Hans-Georg; Bartenstein, Peter; Schreckenberger, Mathias; Brandt, Thomas

2014-07-01

The human vestibular system is represented in the brain bilaterally, but it has functional asymmetries, i.e., a dominance of ipsilateral pathways and of the right hemisphere in right-handers. To determine if acute right- or left-sided unilateral vestibular neuritis (VN) is associated with differential patterns of brain metabolism in areas representing the vestibular network and the visual-vestibular interaction, patients with acute VN (right n = 9; left n = 13) underwent resting state (18)F-FDG PET once in the acute phase and once 3 months later after central vestibular compensation. The contrast acute vs. chronic phase showed signal differences in contralateral vestibular areas and the inverse contrast in visual cortex areas, both more pronounced in VN right. In VN left additional regions were found in the cerebellar hemispheres and vermis bilaterally, accentuated in severe cases. In general, signal changes appeared more pronounced in patients with more severe vestibular deficits. Acute phase PET data of patients compared to that of age-matched healthy controls disclosed similarities to these patterns, thus permitting the interpretation that the signal changes in vestibular temporo-parietal areas reflect signal increases, and in visual areas, signal decreases. These data imply that brain activity in the acute phase of right- and left-sided VN exhibits different compensatory patterns, i.e., the dominant ascending input is shifted from the ipsilateral to the contralateral pathways, presumably due to the missing ipsilateral vestibular input. The visual-vestibular interaction patterns were preserved, but were of different prominence in each hemisphere and more pronounced in patients with right-sided failure and more severe vestibular deficits.

Magnetic resonance imaging of acute spinal-cord injury

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Yamamoto, Hideki; Nakagawa, Hiroshi; Yamada, Takahisa; Iwata, Kinjiro; Okumura, Terufumi; Hoshino, Daisaku.

1992-01-01

Magnetic resonance imaging (MRI) provides a noninvasive and very important method of investigating spinal-cord injuries. By means of MRI we examined 36 patients with spinal injuries, 34 of them in the acute stage. 19 cases had complete spinal-cord injury with paraplegia, while 17 cases had incomplete spinal-cord injury. MRI showed the injured spinal-cord in the acute stage to be partially swollen, with a high signal intensity in the T 2 -weighted images. In the chronic stage, the injured cord may show atrophic changes with a post-traumatic cavity or myelomalacia, which appears as a high-signal-intensity lesion in the T 2 -weighted images and as a low-signal intensity in the T 1 -weighted images. The cases with complete spinal injuries showed a high signal intensity at the wide level, and these prognoses were poor. The cases with incomplete injuries showed normal findings or a high-signal-intensity spot. In the Gd-DTPA enhanced images, the injured cords were enhanced very well in the subchronic stage. MRI is thus found to be useful in the diagnosis of spinal injuries; it also demonstrates a potential for predicting the neurological prognosis. (author)

Organization of sensory input to the nociceptive-specific cutaneous trunk muscle reflex in rat, an effective experimental system for examining nociception and plasticity

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Petruska, Jeffrey C.; Barker, Darrell F.; Garraway, Sandra M.; Trainer, Robert; Fransen, James W.; Seidman, Peggy A.; Soto, Roy G.; Mendell, Lorne M.; Johnson, Richard D.

2013-01-01

Detailed characterization of neural circuitries furthers our understanding of how nervous systems perform specific functions and enables the use of those systems to test hypotheses. We have characterized the sensory input to the cutaneous trunk muscle (CTM; also cutaneus trunci (rat) or cutaneus maximus (mouse)) reflex (CTMR), which manifests as a puckering of the dorsal thoracolumbar skin and is selectively driven by noxious stimuli. CTM electromyography (EMG) and neurogram recordings in naïve rats revealed that CTMR responses were elicited by natural stimuli and electrical stimulation of all segments from C4 to L6, a much greater extent of segmental drive to the CTMR than previously described. Stimulation of some subcutaneous paraspinal tissue can also elicit this reflex. Using a selective neurotoxin, we also demonstrate differential drive of the CTMR by trkA-expressing and non-expressing small diameter afferents. These observations highlight aspects of the organization of the CTMR system which make it attractive for studies of nociception and anesthesiology and plasticity of primary afferents, motoneurons, and the propriospinal system. We use the CTMR system to qualitatively and quantitatively demonstrate that experimental pharmacological treatments can be compared to controls applied either to the contralateral side or to another segment, with the remaining segments providing controls for systemic or other treatment effects. These data indicate the potential for using the CTMR system as both an invasive and non-invasive quantitative assessment tool providing improved statistical power and reduced animal use. PMID:23983104

Optogenetic analysis of a nociceptor neuron and network reveals ion channels acting downstream of primary sensors

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Husson, Steven J.; Costa, Wagner Steuer; Wabnig, Sebastian; Stirman, Jeffrey N.; Watson, Joseph D.; Spencer, W. Clay; Akerboom, Jasper; Looger, Loren L.; Treinin, Millet; Miller, David M.; Lu, Hang; Gottschalk, Alexander

2012-01-01

Summary Background Nociception generally evokes rapid withdrawal behavior in order to protect the tissue from harmful insults. Most nociceptive neurons responding to mechanical insults display highly branched dendrites, an anatomy shared by Caenorhabditis elegans FLP and PVD neurons, which mediate harsh touch responses. Although several primary molecular nociceptive sensors have been characterized, less is known about modulation and amplification of noxious signals within nociceptor neurons. First, we analyzed the FLP/PVD network by optogenetics and studied integration of signals from these cells in downstream interneurons. Second, we investigated which genes modulate PVD function, based on prior single neuron mRNA profiling of PVD. Results Selectively photoactivating PVD, FLP and downstream interneurons using Channelrhodopsin-2 (ChR2) enabled functionally dissecting this nociceptive network, without interfering signals by other mechanoreceptors. Forward or reverse escape behaviors were determined by PVD and FLP, via integration by command interneurons. To identify mediators of PVD function, acting downstream of primary nocisensor molecules, we knocked down PVD-specific transcripts by RNAi and quantified light-evoked PVD-dependent behavior. Cell-specific disruption of synaptobrevin or voltage-gated Ca2+-channels (VGCCs) showed that PVD signals chemically to command interneurons. Knocking down the DEG/ENaC channel ASIC-1 and the TRPM channel GTL-1 indicated that ASIC-1 may extend PVD’s dynamic range and that GTL-1 may amplify its signals. These channels act cell-autonomously in PVD, downstream of primary mechanosensory molecules. Conclusions Our work implicates TRPM channels in modifying excitability of, and DEG/ENaCs in potentiating signal output from a mechano-nociceptor neuron. ASIC-1 and GTL-1 homologues, if functionally conserved, may denote valid targets for novel analgesics. PMID:22483941

ROS-activated calcium signaling mechanisms regulating endothelial barrier function.

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Di, Anke; Mehta, Dolly; Malik, Asrar B

2016-09-01

Increased vascular permeability is a common pathogenic feature in many inflammatory diseases. For example in acute lung injury (ALI) and its most severe form, the acute respiratory distress syndrome (ARDS), lung microvessel endothelia lose their junctional integrity resulting in leakiness of the endothelial barrier and accumulation of protein rich edema. Increased reactive oxygen species (ROS) generated by neutrophils (PMNs) and other inflammatory cells play an important role in increasing endothelial permeability. In essence, multiple inflammatory syndromes are caused by dysfunction and compromise of the barrier properties of the endothelium as a consequence of unregulated acute inflammatory response. This review focuses on the role of ROS signaling in controlling endothelial permeability with particular focus on ALI. We summarize below recent progress in defining signaling events leading to increased endothelial permeability and ALI. Copyright © 2016 Elsevier Ltd. All rights reserved.

cAMP signaling in skeletal muscle adaptation: hypertrophy, metabolism, and regeneration

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Stewart, Randi

2012-01-01

Among organ systems, skeletal muscle is perhaps the most structurally specialized. The remarkable subcellular architecture of this tissue allows it to empower movement with instructions from motor neurons. Despite this high degree of specialization, skeletal muscle also has intrinsic signaling mechanisms that allow adaptation to long-term changes in demand and regeneration after acute damage. The second messenger adenosine 3′,5′-monophosphate (cAMP) not only elicits acute changes within myofibers during exercise but also contributes to myofiber size and metabolic phenotype in the long term. Strikingly, sustained activation of cAMP signaling leads to pronounced hypertrophic responses in skeletal myofibers through largely elusive molecular mechanisms. These pathways can promote hypertrophy and combat atrophy in animal models of disorders including muscular dystrophy, age-related atrophy, denervation injury, disuse atrophy, cancer cachexia, and sepsis. cAMP also participates in muscle development and regeneration mediated by muscle precursor cells; thus, downstream signaling pathways may potentially be harnessed to promote muscle regeneration in patients with acute damage or muscular dystrophy. In this review, we summarize studies implicating cAMP signaling in skeletal muscle adaptation. We also highlight ligands that induce cAMP signaling and downstream effectors that are promising pharmacological targets. PMID:22354781

Modulation of Cervical Facet Joint Nociception and Pain Attenuates Physical and Psychological Features of Chronic Whiplash: A Prospective Study.

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Smith, Ashley Dean; Jull, Gwendolen; Schneider, Geoff M; Frizzell, Bevan; Hooper, Robert A; Sterling, Michele

2015-09-01

To investigate changes in clinical (physical and psychological) features of individuals with chronic whiplash-associated disorder who had previously undergone cervical radiofrequency neurotomy at the time point when the effects of radiofrequency neurotomy had dissipated and pain returned. Prospective cohort observational trial of consecutive patients. Tertiary spinal intervention centre in Calgary, Alberta, Canada. A total of 53 consecutive individuals with chronic whiplash-associated disorder. Individuals underwent radiofrequency neurotomy and were assessed before radiofrequency neurotomy, at 1 and 3 months postprocedure, and then after the return of pain (approximately 10 months postprocedure). Quantitative sensory tests (pressure; thermal pain thresholds; brachial plexus provocation test), nociceptive flexion reflex, and motor function (cervical range of movement; craniocervical flexion test) were measured. Self-reported disability, psychological distress, pain catastrophization, and posttraumatic stress disorder symptoms also were measured. Upon the return of pain after radiofrequency neurotomy, levels of disability increased (P .22). There were no significant changes in pressure hyperalgesia (P > .054) or craniocervical flexion test performance (P > .07) after the return of pain. Psychological distress and pain catastrophizing increased significantly after the return of pain (P .13). However, there was no difference in number or severity of posttraumatic stress symptoms after the return of pain (P > .30). Physical and psychological features of chronic whiplash-associated disorder are modulated dynamically with cervical radiofrequency neurotomy. These findings indicate that peripheral nociception is involved in the manifestations of chronic whiplash-associated disorder in this cohort of individuals. Copyright © 2015 American Academy of Physical Medicine and Rehabilitation. Published by Elsevier Inc. All rights reserved.

Antihyperalgesic Properties of Honokiol in Inflammatory Pain Models by Targeting of NF-κB and Nrf2 Signaling

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Sidra Khalid

2018-03-01

Full Text Available The present study investigates the possible anti-nociceptive effect of intraperitoneal (i.p. honokiol: a phenolic compound originally isolated from Magnolia officinalis, in acute and chronic inflammatory pain models. Doses of 0.1, 5, and 10 mg/kg honokiol were administered in carrageenan induced pain and the dose (honokiol 10 mg/kg i.p. with most significant response among behavioral tests was selected for further experiments. The i.p. administration of honokiol inhibits mechanical hyperalgesia, mechanical allodynia, and thermal hyperalgesia, without causing any apparent toxicity. To elucidate the effect of honokiol on various cytokines and antioxidant enzymes, quantitative real-time-PCR was performed to determine the expression levels of pro-inflammatory cytokines and antioxidant enzymes. It is demonstrated that honokiol significantly reduced the expression levels of tumor necrosis factor (TNF-α, interleukin-1β (IL-1β, interleukin-6 (IL-6, and vascular endothelial growth factor (VEGF. Similarly, honokiol was also found to potentiate the expression of nuclear factor erythroid 2–related factor 2 (Nrf2, superoxide dismutase 2 (SOD2, and heme oxygenase-1 (HO-1 levels. Additionally, honokiol significantly reduced plasma nitrite levels as compared to complete Freund’s adjuvant (CFA induced group. X-ray analysis and hematoxylin and eosin (H&E staining of inflamed and treated paws showed that honokiol reduced the inflammation with significantly less leukocyte infiltration and soft tissue inflammation. In order to explore the possible mechanism of action of honokiol, agonists [piroxicam (5 mg/kg, tramadol (50 mg/kg, and gabapentin (5 mg/kg i.p.] as well as antagonists [naloxone (4 mg/kg, olanzapine (10 mg/kg, and flumazenil (0.2 mg/kg i.p.] were used to study involvement of various receptors on the anti-nociceptive effect of honokiol. The potential side effects of honokiol on muscle activity were assessed. An adverse effect testing of honokiol by

Regulation of Lipolysis and Adipose Tissue Signaling during Acute Endotoxin-Induced Inflammation: A Human Randomized Crossover Trial.

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Nikolaj Rittig

Full Text Available Lipolysis is accelerated during the acute phase of inflammation, a process being regulated by pro-inflammatory cytokines (e.g. TNF-α, stress-hormones, and insulin. The intracellular mechanisms remain elusive and we therefore measured pro- and anti-lipolytic signaling pathways in adipocytes after in vivo endotoxin exposure.Eight healthy, lean, male subjects were investigated using a randomized cross over trial with two interventions: i bolus injection of saline (Placebo and ii bolus injection of lipopolysaccharide endotoxin (LPS. A 3H-palmitate tracer was used to measure palmitate rate of appearance (Rapalmitate and indirect calorimetry was performed to measure energy expenditures and lipid oxidation rates. A subcutaneous abdominal fat biopsy was obtained during both interventions and subjected to western blotting and qPCR quantifications.LPS caused a mean increase in serum free fatty acids (FFA concentrations of 90% (CI-95%: 37-142, p = 0.005, a median increase in Rapalmitate of 117% (CI-95%: 77-166, p<0.001, a mean increase in lipid oxidation of 49% (CI-95%: 1-96, p = 0.047, and a median increase in energy expenditure of 28% (CI-95%: 16-42, p = 0.001 compared with Placebo. These effects were associated with increased phosphorylation of hormone sensitive lipase (pHSL at ser650 in adipose tissue (p = 0.03, a trend towards elevated pHSL at ser552 (p = 0.09 and cAMP-dependent protein kinase A (PKA phosphorylation of perilipin 1 (PLIN1 (p = 0.09. Phosphatase and tensin homolog (PTEN also tended to increase (p = 0.08 while phosphorylation of Akt at Thr308 tended to decrease (p = 0.09 during LPS compared with Placebo. There was no difference between protein or mRNA expression of ATGL, G0S2, and CGI-58.LPS stimulated lipolysis in adipose tissue and is associated with increased pHSL and signs of increased PLIN1 phosphorylation combined with a trend toward decreased insulin signaling. The combination of these mechanisms appear to be the driving forces

Thrombopoietin/MPL participates in initiating and maintaining RUNX1-ETO acute myeloid leukemia via PI3K/AKT signaling.

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Pulikkan, John Anto; Madera, Dmitri; Xue, Liting; Bradley, Paul; Landrette, Sean Francis; Kuo, Ya-Huei; Abbas, Saman; Zhu, Lihua Julie; Valk, Peter; Castilla, Lucio Hernán

2012-07-26

Oncogenic mutations in components of cytokine signaling pathways elicit ligand-independent activation of downstream signaling, enhancing proliferation and survival in acute myeloid leukemia (AML). The myeloproliferative leukemia virus oncogene, MPL, a homodimeric receptor activated by thrombopoietin (THPO), is mutated in myeloproliferative disorders but rarely in AML. Here we show that wild-type MPL expression is increased in a fraction of human AML samples expressing RUNX1-ETO, a fusion protein created by chromosome translocation t(8;21), and that up-regulation of Mpl expression in mice induces AML when coexpressed with RUNX1-ETO. The leukemic cells are sensitive to THPO, activating survival and proliferative responses. Mpl expression is not regulated by RUNX1-ETO in mouse hematopoietic progenitors or leukemic cells. Moreover, we find that activation of PI3K/AKT but not ERK/MEK pathway is a critical mediator of the MPL-directed antiapoptotic function in leukemic cells. Hence, this study provides evidence that up-regulation of wild-type MPL levels promotes leukemia development and maintenance through activation of the PI3K/AKT axis, and suggests that inhibitors of this axis could be effective for treatment of MPL-positive AML.

MR of acute subarachnoid hemorrhage

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Spickler, E.; Lufkin, R.; Frazee, J.; Lylyk, P.; Vinuela, F.; Bentson, J.; Dion, J.

1987-01-01

Subarachnoid hemorrhage was produced in four Macaca nemestrina monkeys using the technique of Frazee. CT and MR imaging was performed immediately after the procedure and at frequent intervals up to 2 weeks after hemorrhage. The imaging studies were compared with clinical evaluations and pathologic specimens of all animals. Additional human clinical CT/MR studies of subarachnoid hemorrhage were also studied. Acute hemorrhage was recognized on MR images as an increase in signal in the region of clot compared with surrounding cerebrospinal fluid. This most likely reflects T1 shortening due to proton binding rather than a pure paramagnetic effect. While CT is sensitive to the hemoglobin protein in acute hemorrhage, the superior resolution of MR of the basal cisterns results in equal or better definition of acute subarachnoid hemorrhage on MR studies in many cases

Fisetin administration improves LPS-induced acute otitis media in mouse in vivo

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Li, Peng; Chen, Dan; Huang, Yang

2018-01-01

Acute otitis media is one of the most common infectious diseases worldwide in spite of the widespread vaccination. The present study was conducted to explore the effects of fisetin on mouse acute otitis media models. The animal models were established by lipopolysaccharide (LPS) injection into the middle ear of mice via the tympanic membrane. Fisetin was administered to mice for ten days through intragastric administration immediate after LPS application. Hematoxylin and eosin (H&E) staining was performed and the pro-inflammatory cytokines, including interleukin-1β (IL-1β), tumor necrosis factor-α (TNF-α), IL-6 and VEGF, were measured through enzyme-linked immunosorbent assay (ELISA) method and RT-qPCR analysis. Toll-like receptor 4 (TLR4)/nuclear factor-κB (NF-κB) signaling pathway was detected by immunoblotting assays. Reactive oxygen species (ROS) generated levels were determined through assessment of anti-oxidants, and TXNIP/MAPKs signaling pathways were explored to reveal the possible molecular mechanism for acute otitis media progression and the function of fisetin. Fisetin reduced mucosal thickness caused by LPS. In fisetin-treated animals, pro-inflammatory cytokine release was downregulated accompanied with TLR4/NF-κB inactivation. ROS production was significantly decreased in comparison to the LPS-treated group. The TXNIP/MAPKs signaling pathway was inactivated for fisetin treatment in LPS-induced mice with acute otitis media. The above results indicated that fisetin improved acute otitis media through inflammation and ROS suppression via inactivating TLR4/NF-κB and TXNIP/MAPKs signaling pathways. PMID:29568876

Fisetin administration improves LPS-induced acute otitis media in mouse in vivo.

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Li, Peng; Chen, Dan; Huang, Yang

2018-07-01

Acute otitis media is one of the most common infectious diseases worldwide in spite of the widespread vaccination. The present study was conducted to explore the effects of fisetin on mouse acute otitis media models. The animal models were established by lipopolysaccharide (LPS) injection into the middle ear of mice via the tympanic membrane. Fisetin was administered to mice for ten days through intragastric administration immediate after LPS application. Hematoxylin and eosin (H&E) staining was performed and the pro-inflammatory cytokines, including interleukin-1β (IL-1β), tumor necrosis factor-α (TNF-α), IL-6 and VEGF, were measured through enzyme-linked immunosorbent assay (ELISA) method and RT-qPCR analysis. Toll-like receptor 4 (TLR4)/nuclear factor-κB (NF-κB) signaling pathway was detected by immunoblotting assays. Reactive oxygen species (ROS) generated levels were determined through assessment of anti-oxidants, and TXNIP/MAPKs signaling pathways were explored to reveal the possible molecular mechanism for acute otitis media progression and the function of fisetin. Fisetin reduced mucosal thickness caused by LPS. In fisetin-treated animals, pro-inflammatory cytokine release was downregulated accompanied with TLR4/NF-κB inactivation. ROS production was significantly decreased in comparison to the LPS-treated group. The TXNIP/MAPKs signaling pathway was inactivated for fisetin treatment in LPS-induced mice with acute otitis media. The above results indicated that fisetin improved acute otitis media through inflammation and ROS suppression via inactivating TLR4/NF-κB and TXNIP/MAPKs signaling pathways.

New vessel formation and aberrant VEGF/VEGFR signaling in acute leukemia : Does it matter?

NARCIS (Netherlands)

De Bont, ESJM; Neefjes, VME; Rosati, S; Vellenga, E; Kamps, WA

2002-01-01

Although many patients with acute leukemia achieve a hematological complete remission with aggressive intensive therapy protocols, a large proportion shows reoccurrence of disease. Novel strategies are warranted. In acute leukemia new vessel formation is observed. New vessel formation is the result

Oral treatment with essential oil of Hyptis spicigera Lam. (Lamiaceae) reduces acute pain and inflammation in mice: Potential interactions with transient receptor potential (TRP) ion channels.

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Simões, Róli Rodrigues; Coelho, Igor Dos Santos; Junqueira, Stella Célio; Pigatto, Glauce Regina; Salvador, Marcos José; Santos, Adair Roberto Soares; de Faria, Felipe Meira

2017-03-22

The genus Hyptis comprehends almost 400 species widespread in tropical and temperate regions of America. The use of Hyptis spicigera Lam. (Lamiaceae) is reported in traditional medicine due to its gastroprotective, anti-inflammatory and analgesic properties. The rationale of this study was to investigate the potential use of the essential oil of H. spicigera (EOHs) as analgesic. The antinociceptive effect of EOHs was verified analyzing acute nocifensive behavior of mice induced by chemical noxious stimuli [i.e., formalin and transient receptor potential (TRP) channels agonists]. We also verified the effects of EOHs on locomotor activity and motor performance in mice. Finally, we investigate the involvement of central afferent C-fibers with EOHs analgesic effect. EOHs presented antinociceptive effect at 300 and 1000mg/kg on formalin-induced pain behavior model, presenting 50% and 72% of inhibition during the first phase (ED 50 =292mg/kg), and 85% and 100% during de second phase (ED 50 =205mg/kg), respectively. Temperature of the hind paw was reduced by EOHs treatment in a dose-dependent manner; oedema was diminished only by EOHs 1000mg/kg. EOHs does not impaired locomotor activity or motor performance. For mice injected with capsaicin, a TRPV1 activator, EOHs (1000mg/kg, ED 50 =660mg/kg) showed decreased (63%) nociceptive behavior. When injected with cinnamaldehyde (TRPA1 activator), mice treated with EOHs showed 23%, 43% and 66% inhibition on nociceptive behavior (100, 300 and 1000mg/kg, respectively; ED 50 402mg/kg). When mice were injected with menthol (TRPM8 activator), EOHs showed 29%, 59% and 98% inhibition of nociceptive behavior (100, 300 and 1000mg/kg, respectively; with ED 50 =198mg/kg. Finally, when desensitized mice were injected with menthol, EOHs (300mg/kg) does not show antinociceptive effect. This study demonstrated the efficacy of EOHs on experimental models of nociception. We have found the involvement of TRP channels V1, A1 and M8 with EOHs

TRPV3 and TRPV4 ion channels are not major contributors to mouse heat sensation

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Wang Juan

2011-05-01

Full Text Available Abstract Background The discovery of heat-sensitive Transient Receptor Potential Vanilloid (TRPV ion channels provided a potential molecular explanation for the perception of innocuous and noxious heat stimuli. TRPV1 has a significant role in acute heat nociception and inflammatory heat hyperalgesia. Yet, substantial innocuous and noxious heat sensitivity remains in TRPV1 knockout animals. Here we investigated the role of two related channels, TRPV3 and TRPV4, in these capacities. We studied TRPV3 knockout animals on both C57BL6 and 129S6 backgrounds, as well as animals deficient in both TRPV3 and TRPV4 on a C57BL6 background. Additionally, we assessed the contributions of TRPV3 and TRPV4 to acute heat nociception and inflammatory heat hyperalgesia during inhibition of TRPV1. Results TRPV3 knockout mice on the C57BL6 background exhibited no obvious alterations in thermal preference behavior. On the 129S6 background, absence of TRPV3 resulted in a more restrictive range of occupancy centered around cooler floor temperatures. TRPV3 knockout mice showed no deficits in acute heat nociception on either background. Mice deficient in both TRPV3 and TRPV4 on a C57BL6 background showed thermal preference behavior similar to wild-type controls on the thermal gradient, and little or no change in acute heat nociception or inflammatory heat hyperalgesia. Masking of TRPV1 by the TRPV1 antagonist JNJ-17203212 did not reveal differences between C57BL6 animals deficient in TRPV3 and TRPV4, compared to their wild-type counterparts. Conclusions Our results support the notion that TRPV3 and TRPV4 likely make limited and strain-dependent contributions to innocuous warm temperature perception or noxious heat sensation, even when TRPV1 is masked. These findings imply the existence of other significant mechanisms for heat perception.

Vestibular perception following acute unilateral vestibular lesions.

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Sian Cousins

Full Text Available Little is known about the vestibulo-perceptual (VP system, particularly after a unilateral vestibular lesion. We investigated vestibulo-ocular (VO and VP function in 25 patients with vestibular neuritis (VN acutely (2 days after onset and after compensation (recovery phase, 10 weeks. Since the effect of VN on reflex and perceptual function may differ at threshold and supra-threshold acceleration levels, we used two stimulus intensities, acceleration steps of 0.5°/s(2 and velocity steps of 90°/s (acceleration 180°/s(2. We hypothesised that the vestibular lesion or the compensatory processes could dissociate VO and VP function, particularly if the acute vertiginous sensation interferes with the perceptual tasks. Both in acute and recovery phases, VO and VP thresholds increased, particularly during ipsilesional rotations. In signal detection theory this indicates that signals from the healthy and affected side are still fused, but result in asymmetric thresholds due to a lesion-induced bias. The normal pattern whereby VP thresholds are higher than VO thresholds was preserved, indicating that any 'perceptual noise' added by the vertigo does not disrupt the cognitive decision-making processes inherent to the perceptual task. Overall, the parallel findings in VO and VP thresholds imply little or no additional cortical processing and suggest that vestibular thresholds essentially reflect the sensitivity of the fused peripheral receptors. In contrast, a significant VO-VP dissociation for supra-threshold stimuli was found. Acutely, time constants and duration of the VO and VP responses were reduced - asymmetrically for VO, as expected, but surprisingly symmetrical for perception. At recovery, VP responses normalised but VO responses remained shortened and asymmetric. Thus, unlike threshold data, supra-threshold responses show considerable VO-VP dissociation indicative of additional, higher-order processing of vestibular signals. We provide evidence of

Central nervous system mast cells in peripheral inflammatory nociception

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Ellmeier Wilfried

2011-06-01

Full Text Available Abstract Background Functional aspects of mast cell-neuronal interactions remain poorly understood. Mast cell activation and degranulation can result in the release of powerful pro-inflammatory mediators such as histamine and cytokines. Cerebral dural mast cells have been proposed to modulate meningeal nociceptor activity and be involved in migraine pathophysiology. Little is known about the functional role of spinal cord dural mast cells. In this study, we examine their potential involvement in nociception and synaptic plasticity in superficial spinal dorsal horn. Changes of lower spinal cord dura mast cells and their contribution to hyperalgesia are examined in animal models of peripheral neurogenic and non-neurogenic inflammation. Results Spinal application of supernatant from activated cultured mast cells induces significant mechanical hyperalgesia and long-term potentiation (LTP at spinal synapses of C-fibers. Lumbar, thoracic and thalamic preparations are then examined for mast cell number and degranulation status after intraplantar capsaicin and carrageenan. Intradermal capsaicin induces a significant percent increase of lumbar dural mast cells at 3 hours post-administration. Peripheral carrageenan in female rats significantly increases mast cell density in the lumbar dura, but not in thoracic dura or thalamus. Intrathecal administration of the mast cell stabilizer sodium cromoglycate or the spleen tyrosine kinase (Syk inhibitor BAY-613606 reduce the increased percent degranulation and degranulated cell density of lumbar dural mast cells after capsaicin and carrageenan respectively, without affecting hyperalgesia. Conclusion The results suggest that lumbar dural mast cells may be sufficient but are not necessary for capsaicin or carrageenan-induced hyperalgesia.

Utility of diffusion-weighted imaging in the diagnosis of acute appendicitis

Energy Technology Data Exchange (ETDEWEB)

Inci, Ercan; Hocaoglu, Elif; Aydin, Sibel; Bayramoglu, Sibel; Cimilli, Tan [Bakirkoy Dr. Sadi Konuk Training and Research Hospital, Department of Radiology, Istanbul (Turkey); Kilickesmez, Ozgur [Yeditepe University, School of Medicine, Department of Radiology, Istanbul (Turkey)

2011-04-15

To evaluate the value of diffusion-weighted MRI (DWI) in the diagnosis of acute appendicitis. 119 patients with acute appendicitis and 50 controls were enrolled in this prospective study. DWI was obtained with b factors 0, 500 and 1000 s/mm{sup 2} and were assessed with a visual scoring system by two radiologists followed by quantitative evaluation of the DW images and ADC maps. Histopathology revealed appendicitis in 79/92 patients (78%) who had undergone surgery. On visual evaluation, except for one patient with histopathologically proven appendicitis all inflamed appendixes were hyperintense on DWI (98.7%). Quantitative evaluation with DW signal intensities and ADC values revealed a significant difference with normal and inflamed appendixes (p < 0.001). The best discriminative parameter was signal intensity (b 500). With a cut-off value of 56 for the signal intensity the ratio had a sensitivity of 99% and a specificity of 97%. The cut-off ADC value at 1.66 mm{sup 2}/s had a sensitivity of 97% and a specificity of 99%. DWI is a valuable technique for the diagnosis of acute appendicitis with both qualitative and quantitative evaluation. DWI increases the conspicuity of the inflamed appendix. We recommend using DWI to diagnose acute appendicitis. (orig.)

Long-Term Effects of Neonatal Pain and Stress on Reactivity of the Nociceptive System.

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Butkevich, I P; Mikhailenko, V A

2016-10-01

The influence of inflammatory pain and/or weaning stress at different terms of neonatal development on functional activity of the nociceptive system during adulthood was studied in rats. Repeated stress in 1-2-day-old rat pups (a premature baby model) enhanced pain sensitivity to peripheral inflammation in both males and females. Repeated inflammatory pain experienced by male pups aged 1-2 or 7-8 days (models of preterm and full-term baby), even in presence of mother, enhanced pain behavior under conditions of repeated inflammatory pain in adulthood. Pain sensitivity in adult animals before (hot plate test) and after formation of the inflammatory focus (formalin test) depended on the age when the animals were subjected to the injury, type of exposure, and on animal sex. The priority data obtained by us will help to understand the mechanisms of long-term effects of early injuries and are important for pediatricians and neonatologists.

Targeting FLT3 Signaling in Childhood Acute Myeloid Leukemia

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Amy N. Sexauer

2017-11-01

Full Text Available Acute myeloid leukemia (AML is the second most common leukemia of childhood and is associated with high rates of chemotherapy resistance and relapse. Clinical outcomes for children with AML treated with maximally intensive multi-agent chemotherapy lag far behind those of children with the more common acute lymphoblastic leukemia, demonstrating continued need for new therapeutic approaches to decrease relapse risk and improve long-term survival. Mutations in the FMS-like tyrosine kinase-3 receptor gene (FLT3 occur in approximately 25% of children and adults with AML and are associated with particularly poor prognoses. Identification and development of targeted FLT3 inhibitors represents a major precision medicine paradigm shift in the treatment of patients with AML. While further development of many first-generation FLT3 inhibitors was hampered by limited potency and significant toxicity due to effects upon other kinases, the more selective second- and third-generation FLT3 inhibitors have demonstrated excellent tolerability and remarkable efficacy in the relapsed/refractory and now de novo FLT3-mutated AML settings. While these newest and most promising inhibitors have largely been studied in the adult population, pediatric investigation of FLT3 inhibitors with chemotherapy is relatively recently ongoing or planned. Successful development of FLT3 inhibitor-based therapies will be essential to improve outcomes in children with this high-risk subtype of AML.

Amphetamine activates Rho GTPase signaling to mediate dopamine transporter internalization and acute behavioral effects of amphetamine

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Wheeler, David S.; Underhill, Suzanne M.; Stolz, Donna B.; Murdoch, Geoffrey H.; Thiels, Edda; Romero, Guillermo; Amara, Susan G.

2015-01-01

Acute amphetamine (AMPH) exposure elevates extracellular dopamine through a variety of mechanisms that include inhibition of dopamine reuptake, depletion of vesicular stores, and facilitation of dopamine efflux across the plasma membrane. Recent work has shown that the DAT substrate AMPH, unlike cocaine and other nontransported blockers, can also stimulate endocytosis of the plasma membrane dopamine transporter (DAT). Here, we show that when AMPH enters the cytoplasm it rapidly stimulates DAT internalization through a dynamin-dependent, clathrin-independent process. This effect, which can be observed in transfected cells, cultured dopamine neurons, and midbrain slices, is mediated by activation of the small GTPase RhoA. Inhibition of RhoA activity with C3 exotoxin or a dominant-negative RhoA blocks AMPH-induced DAT internalization. These actions depend on AMPH entry into the cell and are blocked by the DAT inhibitor cocaine. AMPH also stimulates cAMP accumulation and PKA-dependent inactivation of RhoA, thus providing a mechanism whereby PKA- and RhoA-dependent signaling pathways can interact to regulate the timing and robustness of AMPH’s effects on DAT internalization. Consistent with this model, the activation of D1/D5 receptors that couple to PKA in dopamine neurons antagonizes RhoA activation, DAT internalization, and hyperlocomotion observed in mice after AMPH treatment. These observations support the existence of an unanticipated intracellular target that mediates the effects of AMPH on RhoA and cAMP signaling and suggest new pathways to target to disrupt AMPH action. PMID:26553986

Gastrodin Inhibits Allodynia and Hyperalgesia in Painful Diabetic Neuropathy Rats by Decreasing Excitability of Nociceptive Primary Sensory Neurons

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Ye, Xin; Han, Wen-Juan; Wang, Wen-Ting; Luo, Ceng; Hu, San-Jue

2012-01-01

Painful diabetic neuropathy (PDN) is a common complication of diabetes mellitus and adversely affects the patients’ quality of life. Evidence has accumulated that PDN is associated with hyperexcitability of peripheral nociceptive primary sensory neurons. However, the precise cellular mechanism underlying PDN remains elusive. This may result in the lacking of effective therapies for the treatment of PDN. The phenolic glucoside, gastrodin, which is a main constituent of the Chinese herbal medicine Gastrodia elata Blume, has been widely used as an anticonvulsant, sedative, and analgesic since ancient times. However, the cellular mechanisms underlying its analgesic actions are not well understood. By utilizing a combination of behavioral surveys and electrophysiological recordings, the present study investigated the role of gastrodin in an experimental rat model of STZ-induced PDN and to further explore the underlying cellular mechanisms. Intraperitoneal administration of gastrodin effectively attenuated both the mechanical allodynia and thermal hyperalgesia induced by STZ injection. Whole-cell patch clamp recordings were obtained from nociceptive, capsaicin-sensitive small diameter neurons of the intact dorsal root ganglion (DRG). Recordings from diabetic rats revealed that the abnormal hyperexcitability of neurons was greatly abolished by application of GAS. To determine which currents were involved in the antinociceptive action of gastrodin, we examined the effects of gastrodin on transient sodium currents (I NaT) and potassium currents in diabetic small DRG neurons. Diabetes caused a prominent enhancement of I NaT and a decrease of potassium currents, especially slowly inactivating potassium currents (I AS); these effects were completely reversed by GAS in a dose-dependent manner. Furthermore, changes in activation and inactivation kinetics of I NaT and total potassium current as well as I AS currents induced by STZ were normalized by GAS. This study provides a

DESENSITIZATION PROPERTIES OF P2X3 RECEPTORS SHAPING PAIN SIGNALLING

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Rashid eGiniatullin

2013-12-01

Full Text Available ATP-gated P2X3 receptors are mostly expressed by nociceptive sensory neurons and participate in transduction of pain signals. P2X3 receptors show a combination of fast desensitization onset and slow recovery. Moreover, even low nanomolar agonist concentrations unable to evoke a response, can induce desensitization via a phenomenon called ‘high affinity desensitization’. We have also observed that recovery from desensitization is agonist-specific and can range from seconds to minutes. The recovery process displays unusually high temperature dependence. Likewise, recycling of P2X3 receptors in peri-membrane regions shows unexpectedly large temperature sensitivity. By applying kinetic modeling, we have previously shown that desensitization characteristics of P2X3 receptor are best explained with a cyclic model of receptor operation involving three agonist molecules binding a single receptor and that desensitization is primarily developing from the open receptor state. Mutagenesis experiments suggested that desensitization depends on a certain conformation of the ATP binding pocket and on the structure of the transmembrane domains forming the ion pore. Further molecular determinants of desensitization have been identified by mutating the intracellular N- and C-termini of P2X3 receptor. Unlike other P2X receptors, the P2X3 subtype is facilitated by extracellular calcium that acts via specific sites in the ectodomain neighboring the ATP binding pocket. Thus, substitution of serine275 in this region (called ‘left flipper’ converts the natural facilitation induced by extracellular calcium to receptor inhibition. Given such their strategic location in nociceptive neurons and unique desensitization properties, P2X3 receptors represent an attractive target for development of new analgesic drugs via promotion of desensitization aimed at suppressing chronic pain.

Microparticles from kidney-derived mesenchymal stem cells act as carriers of proangiogenic signals and contribute to recovery from acute kidney injury.

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Hoon Young Choi

Full Text Available We recently demonstrated the use of in vitro expanded kidney-derived mesenchymal stem cells (KMSC protected peritubular capillary endothelial cells in acute renal ischemia-reperfusion injury. Herein, we isolated and characterized microparticles (MPs from KMSC. We investigated their in vitro biologic effects on human endothelial cells and in vivo renoprotective effects in acute ischemia-reperfusion renal injury. MPs were isolated from the supernatants of KMSC cultured in anoxic conditions in serum-deprived media for 24 hours. KMSC-derived MPs demonstrated the presence of several adhesion molecules normally expressed on KMSC membranes, such as CD29, CD44, CD73, α4, 5, and 6 integrins. Quantitative real time PCR confirmed the presence of 3 splicing variants of VEGF-A (120, 164, 188, bFGF and IGF-1 in isolated MPs. MPs labeled with PKH26 red fluorescence dye were incorporated by cultured human umbilical vein endothelial cells (HUVEC via surface molecules such as CD44, CD29, and α4, 5, and 6 integrins. MP dose dependently improved in vitro HUVEC proliferation and promoted endothelial tube formation on growth factor reduced Matrigel. Moreover, apoptosis of human microvascular endothelial cell was inhibited by MPs. Administration of KMSC-derived MPs into mice with acute renal ischemia was followed by selective engraftment in ischemic kidneys and significant improvement in renal function. This was achieved by improving proliferation, of peritubular capillary endothelial cell and amelioration of peritubular microvascular rarefaction. Our results support the hypothesis that KMSC-derived MPs may act as a source of proangiogenic signals and confer renoprotective effects in ischemic kidneys.

High-Frequency Neuromuscular Electrical Stimulation Increases Anabolic Signaling.

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Mettler, Joni A; Magee, Dillon M; Doucet, Barbara M

2018-03-16

Neuromuscular electrical stimulation (NMES) is commonly used in rehabilitation settings to increase muscle mass and strength. However, the effects of NMES on muscle growth are not clear and no human studies have compared anabolic signaling between low-frequency (LF-) and high-frequency (HF-) NMES. The purpose of this study was to determine the skeletal muscle anabolic signaling response to an acute bout of LF- and HF-NMES. Eleven young healthy volunteers (6 men; 5 women) received an acute bout of LF- (20 Hz) and HF- (60 Hz) NMES. Muscle biopsies were obtained from the vastus lateralis muscle prior to the first NMES treatment and 30-mins following each NMES treatment. Phosphorylation of the following key anabolic signaling proteins was measured by Western blot and proteins are expressed as a ratio of phosphorylated to total: mammalian target of rapamycin (mTOR), p70-S6 kinase 1 (S6K1), and eukaryotic initiation factor 4E binding protein 1 (4E-BP1). Compared to Pre-NMES, phosphorylation of mTOR was upregulated 40.2% for LF-NMES (P = 0.018) and 68.4% for HF-NMES (P 0.05). There were no differences between treatment conditions for 4E-BP1 phosphorylation (P > 0.05). An acute bout of LF- and HF-NMES upregulated anabolic signaling with HF-NMES producing a greater anabolic response compared to LF-NMES, suggesting that HF-stimulation may provide a stronger stimulus for processes that initiate muscle hypertrophy. Additionally, the stimulation frequency parameter should be considered by clinicians in the design of optimal NMES treatment protocols.

Involvement of AMPA receptor GluR2 and GluR3 trafficking in trigeminal spinal subnucleus caudalis and C1/C2 neurons in acute-facial inflammatory pain.

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Makiko Miyamoto

Full Text Available To evaluate the involvement of trafficking of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR GluR2 and GluR3 subunits in an acute inflammatory orofacial pain, we analyzed nocifensive behavior, phosphorylated extracellular signal-regulated kinase (pERK and Fos expression in Vi/Vc, Vc and C1/C2 in GluR2 delta7 knock-in (KI, GluR3 delta7 KI mice and wild-type mice. We also studied Vc neuronal activity to address the hypothesis that trafficking of GluR2 and GluR3 subunits plays an important role in Vi/Vc, Vc and C1/C2 neuronal activity associated with orofacial inflammation in these mice. Late nocifensive behavior was significantly depressed in GluR2 delta7 KI and GluR3 delta7 KI mice. In addition, the number of pERK-immunoreactive (IR cells was significantly decreased bilaterally in the Vi/Vc, Vc and C1/C2 in GluR2 delta7 KI and GluR3 delta7 KI mice compared to wild-type mice at 40 min after formalin injection, and was also significantly smaller in GluR3 delta7 KI compared to GluR2 delta7 KI mice. The number of Fos protein-IR cells in the ipsilateral Vi/Vc, Vc and C1/C2 was also significantly smaller in GluR2 delta7 KI and GluR3 delta7 KI mice compared to wild-type mice 40 min after formalin injection. Nociceptive neurons functionally identified as wide dynamic range neurons in the Vc, where pERK- and Fos protein-IR cell expression was prominent, showed significantly lower spontaneous activity in GluR2 delta7 KI and GluR3 delta7 KI mice than wild-type mice following formalin injection. These findings suggest that GluR2 and GluR3 trafficking is involved in the enhancement of Vi/Vc, Vc and C1/C2 nociceptive neuronal excitabilities at 16-60 min following formalin injection, resulting in orofacial inflammatory pain.

MRI of acute cervical injury: correlation with neurologic deficit

International Nuclear Information System (INIS)

Hyun, Chang Dong; Kwon, Soon Tae; Lim, Seung Chul; Shin, Myung Jin; Han, Boo Kyung; Kim, Sang Joon; Park, Man Soo; Yoon, Hyun Ki; Suh, Dae Chul

1995-01-01

To evaluate MRI findings of spinal cord according to mechanism in acute cervical spinal injury. 25 patients under went MRI within 1 month after acute cervical trauma. Axial T1Wl (TR/TE: 500/20), gradient-echo (TR/TE: 300/14), sagittal T1Wl (TR/TE: 500/20), proton (TR/TE: 2000. 20 msec), T2Wl (TR/TE: 2000/80) were performed. In 11 patients, post-enhancement T1Wl was done. Change of spinal cord signal intensity on MRI in addition to the presence of abnormal changes of vertebral body, intervertebral disc and paraspinal soft tissue were evaluated. 15 patients had flexion injury, seven had extension injury and three had injury of unknown mechanism. Twelve patients showed iso-signal intensity on T2Wl and high signal intensity on T2Wl. Three patients showed low signal intensity on T1Wl and high signal intensity on T2Wl. Spinal cord hemorrhage occured in 10 patients. We found cord swelling in nine patients and cord compression in 12 patients. In nine patients with cord swelling, extent of cord injury was more than one segment of vertebral body. Ligamentous injury, disc injury, soft tissue injury occurred in 16 (64%), 17 (68%), 15 (60%) patients respectively. Vertebral body fracture was found in 17 patients (68%). The levels of fracture were C6 (eight patients) and C5 (five patients). MRI is valuable in exaluetion of the spinal cord, intervertebral disc, and soft tissue lesions in acute cervical spinal injury. Prognosis is worse in flexion injury than in extension injury, and is well correlated with cord hemorrhage and lesion extent

Prophylactic Acetaminophen or Ibuprofen Results in Equivalent Acute Mountain Sickness Incidence at High Altitude: A Prospective Randomized Trial.

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Kanaan, Nicholas C; Peterson, Alicia L; Pun, Matiram; Holck, Peter S; Starling, Jennifer; Basyal, Bikash; Freeman, Thomas F; Gehner, Jessica R; Keyes, Linda; Levin, Dana R; O'Leary, Catherine J; Stuart, Katherine E; Thapa, Ghan B; Tiwari, Aditya; Velgersdyk, Jared L; Zafren, Ken; Basnyat, Buddha

2017-06-01

Recent trials have demonstrated the usefulness of ibuprofen in the prevention of acute mountain sickness (AMS), yet the proposed anti-inflammatory mechanism remains unconfirmed. Acetaminophen and ibuprofen were tested for AMS prevention. We hypothesized that a greater clinical effect would be seen from ibuprofen due to its anti-inflammatory effects compared with acetaminophen's mechanism of possible symptom reduction by predominantly mediating nociception in the brain. A double-blind, randomized trial was conducted testing acetaminophen vs ibuprofen for the prevention of AMS. A total of 332 non-Nepali participants were recruited at Pheriche (4371 m) and Dingboche (4410 m) on the Everest Base Camp trek. The participants were randomized to either acetaminophen 1000 mg or ibuprofen 600 mg 3 times a day until they reached Lobuche (4940 m), where they were reassessed. The primary outcome was AMS incidence measured by the Lake Louise Questionnaire score. Data from 225 participants who met inclusion criteria were analyzed. Twenty-five participants (22.1%) in the acetaminophen group and 18 (16.1%) in the ibuprofen group developed AMS (P = .235). The combined AMS incidence was 19.1% (43 participants), 14 percentage points lower than the expected AMS incidence of untreated trekkers in prior studies at this location, suggesting that both interventions reduced the incidence of AMS. We found little evidence of any difference between acetaminophen and ibuprofen groups in AMS incidence. This suggests that AMS prevention may be multifactorial, affected by anti-inflammatory inhibition of the arachidonic-acid pathway as well as other analgesic mechanisms that mediate nociception. Additional study is needed. Copyright © 2017 Wilderness Medical Society. Published by Elsevier Inc. All rights reserved.

Role of signal dose preoperative antibiotic in acute nonperforated appendicitics

International Nuclear Information System (INIS)

Malik, S.A.; Rasheed, M.; Abbasi, A.S.; Iqbal, R.A.; Mian, M.A.

2013-01-01

Objective: To determine the efficacy of a single dose of preoperative antibiotic in preventing post operative infective complications in patients undergoing appendicectomy for non perforated acute appendicitis. Study Design: Randomized controlled trials. Place and Duration of Study: Surgical unit I and II, department of General Surgery, Combined Military Hospital (CMH) Lahore from 1st June to 31st October 2010. Patients and Methods: Seventy patients with acute appendicitis scheduled for appendicectomy were included in the study and randomly divided into two groups of 35 each using random numbers table. Group A received single dose preoperative antibiotic and group B received three-dose regimens of cefuroxime. Postoperative infective complications were the primary endpoint. Results: The rate of postoperative wound infection was not statistically insignificantly different among the groups; (8.57%) group A and (5.71%) group B at 1st post operative week and (5.71%) group A and (5.71%) group B at 2nd post operative week. None of the patients from either group showed any signs of intra abdominal abscess formation. Conclusion: Single dose of preoperative antibiotics is adequate for prevention of postoperative infective complications in patients with non-perforated appendicitis undergoing open appendicectomy. (author)

MR imaging of acute subarachnoid hemorrhage

International Nuclear Information System (INIS)

Spickler, E.; Lufkin, R.B.; Frazee, J.; Lylyk, P.; Vinuela, F.; Bentson, J.R.; Dion, J.E.

1987-01-01

Subarachnoid hemorrhage was produced in four Macaca nemestrina monkeys using the technique of Frazee. CT and MR imaging were performed immediately after the procedure and at frequent intervals up to 2 weeks after hemorrhage. The imaging studies were compared with clinical evaluations and pathologic specimens of all animals. Additional human clinical CT/MR studies of subarachnoid hemorrhage were also studied. Acute hemorrhage was recognized on MR as an increase in signal in the region of clot compared with surrounding cerebrospinal fluid. This most likely reflects T1 shortening due to proton binding rather than a pure paramagnetic effect. While CT is sensitive to the hemoglobin protein in acute hemorrhage, the superior resolution of the basal cisterns on MR images results in equal or better definition of acute subarachnoid hemorrhage on MR in many cases

Role of phosphoinositide 3-kinase in the pathogenesis of acute pancreatitis.

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Lupia, Enrico; Pigozzi, Luca; Goffi, Alberto; Hirsch, Emilio; Montrucchio, Giuseppe

2014-11-07

A large body of experimental and clinical data supports the notion that inflammation in acute pancreatitis has a crucial role in the pathogenesis of local and systemic damage and is a major determinant of clinical severity. Thus, research has recently focused on molecules that can regulate the inflammatory processes, such as phosphoinositide 3-kinases (PI3Ks), a family of lipid and protein kinases involved in intracellular signal transduction. Studies using genetic ablation or pharmacologic inhibitors of different PI3K isoforms, in particular the class I PI3Kδ and PI3Kγ, have contributed to a greater understanding of the roles of these kinases in the modulation of inflammatory and immune responses. Recent data suggest that PI3Ks are also involved in the pathogenesis of acute pancreatitis. Activation of the PI3K signaling pathway, and in particular of the class IB PI3Kγ isoform, has a significant role in those events which are necessary for the initiation of acute pancreatic injury, namely calcium signaling alteration, trypsinogen activation, and nuclear factor-κB transcription. Moreover, PI3Kγ is instrumental in modulating acinar cell apoptosis, and regulating local neutrophil infiltration and systemic inflammatory responses during the course of experimental acute pancreatitis. The availability of PI3K inhibitors selective for specific isoforms may provide new valuable therapeutic strategies to improve the clinical course of this disease. This article presents a brief summary of PI3K structure and function, and highlights recent advances that implicate PI3Ks in the pathogenesis of acute pancreatitis.

Induction of synaptic long-term potentiation after opioid withdrawal.

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Drdla, Ruth; Gassner, Matthias; Gingl, Ewald; Sandkühler, Jürgen

2009-07-10

mu-Opioid receptor (MOR) agonists represent the gold standard for the treatment of severe pain but may paradoxically also enhance pain sensitivity, that is, lead to opioid-induced hyperalgesia (OIH). We show that abrupt withdrawal from MOR agonists induces long-term potentiation (LTP) at the first synapse in pain pathways. Induction of opioid withdrawal LTP requires postsynaptic activation of heterotrimeric guanine nucleotide-binding proteins and N-methyl-d-aspartate receptors and a rise of postsynaptic calcium concentrations. In contrast, the acute depression by opioids is induced presynaptically at these synapses. Withdrawal LTP can be prevented by tapered withdrawal and shares pharmacology and signal transduction pathways with OIH. These findings provide a previously unrecognized target to selectively combat pro-nociceptive effects of opioids without compromising opioid analgesia.

Involvement of transient receptor potential A1 channel in algesic and analgesic actions of the organic compound limonene.

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Kaimoto, T; Hatakeyama, Y; Takahashi, K; Imagawa, T; Tominaga, M; Ohta, T

2016-08-01

TRPA1 is a Ca-permeable nonselective cation channel expressed in sensory neurons and acts as a nocisensor. Recent reports show that some monoterpenes, a group of naturally occurring organic compounds, modulate TRP channel activity. Here, we report that limonene, being contained in citrus fruits and mushrooms, shows a unique bimodal action on TRPA1 channel. We examine the effects of limonene on sensory neurons from wild-type, TRPV1- and TRPA1-gene-deficient mice and on heterologously expressed channels in vitro. Molecular determinants were identified with using mutated channels. Cellular excitability is monitored with ratiometric Ca imaging. Nociceptive and analgesic actions of limonene are also examined in vivo. In wild-type mouse sensory neurons, limonene increased the intracellular Ca(2+) concentration ([Ca(2+) ]i ), which was inhibited by selective inhibitors of TRPA1 but not TRPV1. Limonene-responsive neurons highly corresponded to TRPA1 agonist-sensitive ones. Limonene failed to stimulate sensory neurons from the TRPA1 (-/-) mouse. Heterologously expressed mouse TRPA1 was activated by limonene. Intraplantar injection of limonene elicited acute pain, which was significantly less in TRPA1 (-/-) mice. Systemic administration of limonene reduced nociceptive behaviours evoked by H2 O2 . In both heterologously and endogenously expressed TRPA1, a low concentration of limonene significantly inhibited H2 O2 -induced TRPA1 activation. TRPA1 activation by limonene was abolished in H2 O2 -insensitive cysteine-mutated channels. Topically applied limonene stimulates TRPA1, resulting in elicitation of acute pain, but its systemic application inhibits nociception induced by oxidative stress. Because limonene is a safe compound, it may be utilized for pain control due to its inhibition of TRPA1 channels. What does this study add: Limonene, a monoterpene in essential oils of various plants, has been known for its antitumor and anti-inflammatory properties. However, molecular

Modulation of Visceral Nociception, Inflammation and Gastric Mucosal Injury by Cinnarizine

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Omar M.E. Abdel-Salam

2007-01-01

Full Text Available The effect of cinnarizine, a drug used for the treatment of vertigo was assessed in animal models of visceral nociception, inflammation and gastric mucosal injury. Cinnarizine (1.25–20 mg/kg, s.c. caused dose-dependent inhibition of the abdominal constrictions evoked by i.p. injection of acetic acid by 38.7–99.4%. This effect of cinnarizine (2.5 mg/kg was unaffected by co-administration of the centrally acting dopamine D2 receptor antagonists, sulpiride, haloperidol or metoclopramide, the peripherally acting D2 receptor antagonist domperidone, but increased by the D2 receptor agonist bromocryptine and by the non-selective dopamine receptor antagonist chlorpromazine. The antinociception caused by cinnarizine was naloxone insenstive, but enhanced by propranolol, atropine and by yohimbine. The antinociceptive effect of cinnarizine was prevented by co-treatment with the adenosine receptor blocker theophylline or by the ATP-sensitive potassium channel (KATP blocker glibenclamide. Cinnarizine at 2.5 mg/kg reversed the baclofen-induced antinociception. Cinnarizine at 2.5 mg/kg reduced immobility time in the Porsolt’s forced-swimming test by 24%. Cinnarizine inhibited the paw oedema response to carrageenan and reduced gastric mucosal lesions caused by indomethacin in rats. It is suggested that cinnarizine exerts anti-infl ammatory, antinociceptive and gastric protective properties. The mechanism by which cinnarizine modulates pain transmission is likely to involve adenosine receptors and KATP channels.

Plastic Change along the Intact Crossed Pathway in Acute Phase of Cerebral Ischemia Revealed by Optical Intrinsic Signal Imaging

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Xiaoli Guo

2016-01-01

Full Text Available The intact crossed pathway via which the contralesional hemisphere responds to the ipsilesional somatosensory input has shown to be affected by unilateral stroke. The aim of this study was to investigate the plasticity of the intact crossed pathway in response to different intensities of stimulation in a rodent photothrombotic stroke model. Using optical intrinsic signal imaging, an overall increase of the contralesional cortical response was observed in the acute phase (≤48 hours after stroke. In particular, the contralesional hyperactivation is more prominent under weak stimulations, while a strong stimulation would even elicit a depressed response. The results suggest a distinct stimulation-response pattern along the intact crossed pathway after stroke. We speculate that the contralesional hyperactivation under weak stimulations was due to the reorganization for compensatory response to the weak ipsilateral somatosensory input.

Halofuginone has anti-proliferative effects in acute promyelocytic leukemia by modulating the transforming growth factor beta signaling pathway.

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Lorena L de Figueiredo-Pontes

Full Text Available Promyelocytic leukemia-retinoic acid receptor alpha (PML-RARα expression in acute promyelocytic leukemia (APL impairs transforming growth factor beta (TGFβ signaling, leading to cell growth advantage. Halofuginone (HF, a low-molecular-weight alkaloid that modulates TGFβ signaling, was used to treat APL cell lines and non-obese diabetic/severe combined immunodeficiency (NOD/SCID mice subjected to transplantation with leukemic cells from human chorionic gonadotrophin-PML-RARα transgenic mice (TG. Cell cycle analysis using incorporated bromodeoxyuridine and 7-amino-actinomycin D showed that, in NB4 and NB4-R2 APL cell lines, HF inhibited cellular proliferation (P<0.001 and induced apoptosis (P = 0.002 after a 24-hour incubation. Addition of TGFβ revealed that NB4 cells were resistant to its growth-suppressive effects and that HF induced these effects in the presence or absence of the cytokine. Cell growth inhibition was associated with up-regulation of TGFβ target genes involved in cell cycle regulation (TGFB, TGFBRI, SMAD3, p15, and p21 and down-regulation of MYC. Additionally, TGFβ protein levels were decreased in leukemic TG animals and HF in vivo could restore TGFβ values to normal. To test the in vivo anti-leukemic activity of HF, we transplanted NOD/SCID mice with TG leukemic cells and treated them with HF for 21 days. HF induced partial hematological remission in the peripheral blood, bone marrow, and spleen. Together, these results suggest that HF has anti-proliferative and anti-leukemic effects by reversing the TGFβ blockade in APL. Since loss of the TGFβ response in leukemic cells may be an important second oncogenic hit, modulation of TGFβ signaling may be of therapeutic interest.

Survey of activated FLT3 signaling in leukemia.

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Ting-lei Gu

Full Text Available Activating mutations of FMS-like tyrosine kinase-3 (FLT3 are found in approximately 30% of patients with acute myeloid leukemia (AML. FLT3 is therefore an attractive drug target. However, the molecular mechanisms by which FLT3 mutations lead to cell transformation in AML remain unclear. To develop a better understanding of FLT3 signaling as well as its downstream effectors, we performed detailed phosphoproteomic analysis of FLT3 signaling in human leukemia cells. We identified over 1000 tyrosine phosphorylation sites from about 750 proteins in both AML (wild type and mutant FLT3 and B cell acute lymphoblastic leukemia (normal and amplification of FLT3 cell lines. Furthermore, using stable isotope labeling by amino acids in cell culture (SILAC, we were able to quantified over 400 phosphorylation sites (pTyr, pSer, and pThr that were responsive to FLT3 inhibition in FLT3 driven human leukemia cell lines. We also extended this phosphoproteomic analysis on bone marrow from primary AML patient samples, and identify over 200 tyrosine and 800 serine/threonine phosphorylation sites in vivo. This study showed that oncogenic FLT3 regulates proteins involving diverse cellular processes and affects multiple signaling pathways in human leukemia that we previously appreciated, such as Fc epsilon RI-mediated signaling, BCR, and CD40 signaling pathways. It provides a valuable resource for investigation of oncogenic FLT3 signaling in human leukemia.

Central nociceptive sensitization vs. spinal cord training: Opposing forms of plasticity that dictate function after complete spinal cord injury

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Adam R Ferguson

2012-10-01

Full Text Available The spinal cord demonstrates several forms of plasticity that resemble brain-dependent learning and memory. Among the most studied form of spinal plasticity is spinal memory for noxious (nociceptive stimulation. Numerous papers have described central pain as a spinally-stored memory that enhances future responses to cutaneous stimulation. This phenomenon, known as central sensitization, has broad relevance to a range of pathological conditions. Work from the spinal cord injury (SCI field indicates that the lumbar spinal cord demonstrates several other forms of plasticity, including formal learning and memory. After complete thoracic SCI, the lumbar spinal cord can be trained by delivering stimulation to the hindleg when the leg is extended. In the presence of this response-contingent stimulation the spinal cord rapidly learns to hold the leg in a flexed position, a centrally mediated effect that meets the formal criteria for instrumental (response-outcome learning. Instrumental flexion training produces a central change in spinal plasticity that enables future spinal learning on both the ipsilateral and contralateral leg. However, if stimulation is given in a response-independent manner, the spinal cord develops central maladaptive plasticity that undermines future spinal learning on both legs. The present paper tests for interactions between spinal cord training and central nociceptive sensitization after complete spinal cord transection. We found that spinal training alters future central sensitization by intradermal formalin (24 h post-training. Conversely intradermal formalin impaired future spinal learning (24 h post-injection. Because the NMDA receptor has been implicated in formalin-induced central sensitization, we tested whether pretreatment with NMDA affects spinal learning. We found intrathecal NMDA impaired learning in a dose-dependent fashion, and that this effect endures for at least 24h. These data provide strong evidence for an

Quercetin Inhibits Peripheral and Spinal Cord Nociceptive Mechanisms to Reduce Intense Acute Swimming-Induced Muscle Pain in Mice

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Borghi, Sergio M.; Pinho-Ribeiro, Felipe A.; Fattori, Victor; Bussmann, Allan J. C.; Vignoli, Josiane A.; Camilios-Neto, Doumit; Casagrande, Rubia; Verri, Waldiceu A.

2016-01-01

The present study aimed to evaluate the effects of the flavonoid quercetin (3,3´,4´,5,7-pentahydroxyflavone) in a mice model of intense acute swimming-induced muscle pain, which resembles delayed onset muscle soreness. Quercetin intraperitoneal (i.p.) treatment dose-dependently reduced muscle mechanical hyperalgesia. Quercetin inhibited myeloperoxidase (MPO) and N-acetyl-β-D- glucosaminidase (NAG) activities, cytokine production, oxidative stress, cyclooxygenase-2 (COX-2) and gp91phox mRNA expression and muscle injury (creatinine kinase [CK] blood levels and myoblast determination protein [MyoD] mRNA expression) as well as inhibited NFκB activation and induced Nrf2 and HO-1 mRNA expression in the soleus muscle. Beyond inhibiting those peripheral effects, quercetin also inhibited spinal cord cytokine production, oxidative stress and glial cells activation (glial fibrillary acidic protein [GFAP] and ionized calcium-binding adapter molecule 1 [Iba-1] mRNA expression). Concluding, the present data demonstrate that quercetin is a potential molecule for the treatment of muscle pain conditions related to unaccustomed exercise. PMID:27583449

Acute carbon dioxide avoidance in Caenorhabditis elegans.

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Hallem, Elissa A; Sternberg, Paul W

2008-06-10

Carbon dioxide is produced as a by-product of cellular respiration by all aerobic organisms and thus serves for many animals as an important indicator of food, mates, and predators. However, whether free-living terrestrial nematodes such as Caenorhabditis elegans respond to CO2 was unclear. We have demonstrated that adult C. elegans display an acute avoidance response upon exposure to CO2 that is characterized by the cessation of forward movement and the rapid initiation of backward movement. This response is mediated by a cGMP signaling pathway that includes the cGMP-gated heteromeric channel TAX-2/TAX-4. CO2 avoidance is modulated by multiple signaling molecules, including the neuropeptide Y receptor NPR-1 and the calcineurin subunits TAX-6 and CNB-1. Nutritional status also modulates CO2 responsiveness via the insulin and TGFbeta signaling pathways. CO2 response is mediated by a neural circuit that includes the BAG neurons, a pair of sensory neurons of previously unknown function. TAX-2/TAX-4 function in the BAG neurons to mediate acute CO2 avoidance. Our results demonstrate that C. elegans senses and responds to CO2 using multiple signaling pathways and a neural network that includes the BAG neurons and that this response is modulated by the physiological state of the worm.

Mincle Signaling Promotes Con-A Hepatitis

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Greco, Stephanie H.; Torres-Hernandez, Alejandro; Kalabin, Aleksandr; Whiteman, Clint; Rokosh, Rae; Ravirala, Sushma; Ochi, Atsuo; Gutierrez, Johana; Salyana, Muhammad Atif; Mani, Vishnu R.; Nagaraj, Savitha V.; Deutsch, Michael; Seifert, Lena; Daley, Donnele; Barilla, Rocky; Hundeyin, Mautin; Nikifrov, Yuriy; Tejada, Karla; Gelb, Bruce E.; Katz, Steven C.; Miller, George

2016-01-01

Concanavalin-A (Con-A) hepatitis is regarded as a T cell-mediated model of acute liver injury. Mincle is a C-type lectin receptor (CLR) that is critical in the immune response to mycobacteria and fungi, but does not have a well-defined role in pre-clinical models of non-pathogen mediated inflammation. Since Mincle can ligate the cell death ligand SAP130, we postulated that Mincle signaling drives intrahepatic inflammation and liver injury in Con-A hepatitis. Acute liver injury was assessed in the murine Con-A hepatitis model using C57BL/6, Mincle−/−, and Dectin-1−/− mice. The role of C/EBPβ and HIF-1α signaling was assessed using selective inhibitors. We found that Mincle was highly expressed in hepatic innate inflammatory cells and endothelial cells in both mice and humans. Furthermore, sterile Mincle ligands and Mincle signaling intermediates were increased in the murine liver in Con-A hepatitis. Most significantly, Mincle deletion or blockade protected against Con-A hepatitis whereas Mincle ligation exacerbated disease. Bone marrow chimeric and adoptive transfer experiments suggested that Mincle signaling in infiltrating myeloid cells dictates disease phenotype. Conversely, signaling via other CLRs did not alter disease course. Mechanistically, we found that Mincle blockade decreased the NF-κβ related signaling intermediates, C/EBPβ and HIF-1α, both of which are necessary in macrophage-mediated inflammatory responses. Accordingly, Mincle deletion lowered production of nitrites in Con-A hepatitis and inhibition of both C/EBPβ and HIF1-α reduced the severity of liver disease. Our work implicates a novel innate immune driver of Con-A hepatitis and, more broadly, suggests a potential role for Mincle in diseases governed by sterile inflammation. PMID:27559045

Mincle Signaling Promotes Con A Hepatitis.

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Greco, Stephanie H; Torres-Hernandez, Alejandro; Kalabin, Aleksandr; Whiteman, Clint; Rokosh, Rae; Ravirala, Sushma; Ochi, Atsuo; Gutierrez, Johana; Salyana, Muhammad Atif; Mani, Vishnu R; Nagaraj, Savitha V; Deutsch, Michael; Seifert, Lena; Daley, Donnele; Barilla, Rocky; Hundeyin, Mautin; Nikifrov, Yuriy; Tejada, Karla; Gelb, Bruce E; Katz, Steven C; Miller, George

2016-10-01

Con A hepatitis is regarded as a T cell-mediated model of acute liver injury. Mincle is a C-type lectin receptor that is critical in the immune response to mycobacteria and fungi but does not have a well-defined role in preclinical models of non-pathogen-mediated inflammation. Because Mincle can ligate the cell death ligand SAP130, we postulated that Mincle signaling drives intrahepatic inflammation and liver injury in Con A hepatitis. Acute liver injury was assessed in the murine Con A hepatitis model using C57BL/6, Mincle(-/-), and Dectin-1(-/-) mice. The role of C/EBPβ and hypoxia-inducible factor-1α (HIF-1α) signaling was assessed using selective inhibitors. We found that Mincle was highly expressed in hepatic innate inflammatory cells and endothelial cells in both mice and humans. Furthermore, sterile Mincle ligands and Mincle signaling intermediates were increased in the murine liver in Con A hepatitis. Most significantly, Mincle deletion or blockade protected against Con A hepatitis, whereas Mincle ligation exacerbated disease. Bone marrow chimeric and adoptive transfer experiments suggested that Mincle signaling in infiltrating myeloid cells dictates disease phenotype. Conversely, signaling via other C-type lectin receptors did not alter disease course. Mechanistically, we found that Mincle blockade decreased the NF-κβ-related signaling intermediates C/EBPβ and HIF-1α, both of which are necessary in macrophage-mediated inflammatory responses. Accordingly, Mincle deletion lowered production of nitrites in Con A hepatitis and inhibition of both C/EBPβ and HIF-1α reduced the severity of liver disease. Our work implicates a novel innate immune driver of Con A hepatitis and, more broadly, suggests a potential role for Mincle in diseases governed by sterile inflammation. Copyright © 2016 by The American Association of Immunologists, Inc.

Ischemic preconditioning provides both acute and delayed protection against renal ischemia and reperfusion injury in mice.

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Joo, Jin Deok; Kim, Mihwa; D'Agati, Vivette D; Lee, H Thomas

2006-11-01

Acute as well as delayed ischemic preconditioning (IPC) provides protection against cardiac and neuronal ischemia reperfusion (IR) injury. This study determined whether delayed preconditioning occurs in the kidney and further elucidated the mechanisms of renal IPC in mice. Mice were subjected to IPC (four cycles of 5 min of ischemia and reperfusion) and then to 30 min of renal ischemia either 15 min (acute IPC) or 24 h (delayed IPC) later. Both acute and delayed renal IPC provided powerful protection against renal IR injury. Inhibition of Akt but not extracellular signal-regulated kinase phosphorylation prevented the protection that was afforded by acute IPC. Neither extracellular signal-regulated kinase nor Akt inhibition prevented protection that was afforded by delayed renal IPC. Pretreatment with an antioxidant, N-(2-mercaptopropionyl)-glycine, to scavenge free radicals prevented the protection that was provided by acute but not delayed renal IPC. Inhibition of protein kinase C or pertussis toxin-sensitive G-proteins attenuated protection from both acute and delayed renal IPC. Delayed renal IPC increased inducible nitric oxide synthase (iNOS) as well as heat-shock protein 27 synthesis, and the renal protective effects of delayed preconditioning were attenuated by a selective inhibitor of iNOS (l-N(6)[1-iminoethyl]lysine). Moreover, delayed IPC was not observed in iNOS knockout mice. Both acute and delayed IPC were independent of A(1) adenosine receptors (AR) as a selective A(1)AR antagonist failed to block preconditioning and acute and delayed preconditioning occurred in mice that lacked A(1)AR. Therefore, this study demonstrated that acute or delayed IPC provides renal protection against IR injury in mice but involves distinct signaling pathways.

TSLP signaling pathway map: a platform for analysis of TSLP-mediated signaling.

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Zhong, Jun; Sharma, Jyoti; Raju, Rajesh; Palapetta, Shyam Mohan; Prasad, T S Keshava; Huang, Tai-Chung; Yoda, Akinori; Tyner, Jeffrey W; van Bodegom, Diederik; Weinstock, David M; Ziegler, Steven F; Pandey, Akhilesh

2014-01-01

Thymic stromal lymphopoietin (TSLP) is a four-helix bundle cytokine that plays a critical role in the regulation of immune responses and in the differentiation of hematopoietic cells. TSLP signals through a heterodimeric receptor complex consisting of an interleukin-7 receptor α chain and a unique TSLP receptor (TSLPR) [also known as cytokine receptor-like factor 2 (CRLF2)]. Cellular targets of TSLP include dendritic cells, B cells, mast cells, regulatory T (Treg) cells and CD4+ and CD8+ T cells. The TSLP/TSLPR axis can activate multiple signaling transduction pathways including the JAK/STAT pathway and the PI-3 kinase pathway. Aberrant TSLP/TSLPR signaling has been associated with a variety of human diseases including asthma, atopic dermatitis, nasal polyposis, inflammatory bowel disease, eosinophilic eosophagitis and, most recently, acute lymphoblastic leukemia. A centralized resource of the TSLP signaling pathway cataloging signaling events is not yet available. In this study, we present a literature-annotated resource of reactions in the TSLP signaling pathway. This pathway map is publicly available through NetPath (http://www.netpath.org/), an open access signal transduction pathway resource developed previously by our group. This map includes 236 molecules and 252 reactions that are involved in TSLP/TSLPR signaling pathway. We expect that the TSLP signaling pathway map will provide a rich resource to study the biology of this important cytokine as well as to identify novel therapeutic targets for diseases associated with dysregulated TSLP/TSLPR signaling. Database URL: http://www.netpath.org/pathways?path_id=NetPath_24.

Pressure pain threshold changes after repeated mechano-nociceptive stimulation of the trapezius muscle: possible influence of previous pain experience

DEFF Research Database (Denmark)

Sjölund, Bengt H; Persson, Ann L

2007-01-01

or an increase. Normalized data, transformed into mean unidirectional PPT differences, showed statistically highly significant changes after intervention. The relative risk of reacting with lowered PPTs on noxious stimulation was 3.7 times higher for subjects who had not given birth to children than for subjects...... over 1 trapezius muscle (skin anaesthetized) in 27 healthy women before and after the intervention. With a mean stimulation rate of 0.40 Hz and a mean nociceptive stimulation intensity of 1.78 x Threshold, subjects were found to systematically react with a change in PPT, either a decrease...... who had given birth to 1 or several children (Pstimulation of the trapezius muscle in healthy females evokes moderate and temporary...

The nociception genes painless and Piezo are required for the cellular immune response of Drosophila larvae to wasp parasitization.

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Tokusumi, Yumiko; Tokusumi, Tsuyoshi; Schulz, Robert A

2017-05-13

In vertebrates, interaction between the nervous system and immune system is important to protect a challenged host from stress inputs from external sources. In this study, we demonstrate that sensory neurons are involved in the cellular immune response elicited by wasp infestation of Drosophila larvae. Multidendritic class IV neurons sense contacts from external stimuli and induce avoidance behaviors for host defense. Our findings show that inactivation of these sensory neurons impairs the cellular response against wasp parasitization. We also demonstrate that the nociception genes encoding the mechanosensory receptors Painless and Piezo, both expressed in class IV neurons, are essential for the normal cellular immune response to parasite challenge. Copyright © 2017. Published by Elsevier Inc.

JAK/STAT-1 Signaling Is Required for Reserve Intestinal Stem Cell Activation during Intestinal Regeneration Following Acute Inflammation

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Camilla A. Richmond

2018-01-01

Full Text Available The intestinal epithelium serves as an essential barrier to the outside world and is maintained by functionally distinct populations of rapidly cycling intestinal stem cells (CBC ISCs and slowly cycling, reserve ISCs (r-ISCs. Because disruptions in the epithelial barrier can result from pathological activation of the immune system, we sought to investigate the impact of inflammation on ISC behavior during the regenerative response. In a murine model of αCD3 antibody-induced small-intestinal inflammation, r-ISCs proved highly resistant to injury, while CBC ISCs underwent apoptosis. Moreover, r-ISCs were induced to proliferate and functionally contribute to intestinal regeneration. Further analysis revealed that the inflammatory cytokines interferon gamma and tumor necrosis factor alpha led to r-ISC activation in enteroid culture, which could be blocked by the JAK/STAT inhibitor, tofacitinib. These results highlight an important role for r-ISCs in response to acute intestinal inflammation and show that JAK/STAT-1 signaling is required for the r-ISC regenerative response.

The Role of Diffusion-Weighted MRI in Differentiation of Idiopathic Acute Transverse Myelitis and Acute Spinal Cord Infarction

International Nuclear Information System (INIS)

Kim, Yeo Goon; Lee, Joon Woo; Kim, Jae Hyoung; Kang, Heung Sik; Park, Kyung Seok

2011-01-01

To compare the diffusion characteristics of idiopathic acute transverse myelitis (ATM) and acute spinal cord infarction (SCI). Diffusion-weighted images (DWI) and an apparent diffusion coefficient (ADC) map were prospectively obtained from patients diagnosed with myelopathy between February 2006 and April 2009. Inclusion criteria included 1) the presence of an intramedullary T2-high signal intensity and 2) a final diagnosis of idiopathic ATM or SCI established by one neurologist. In total, 13 patients (M : F = 8 : 5; mean age, 39.5 years; range, 29-50 years) with idiopathic ATM and seven patients (M : F = 2 : 5; mean age, 58 years; range, 48-75 years) with SCI were included in this study. Two radiologists evaluated the DWIs and ADC map in consensus. The extent of the cord signal change was also evaluated on T2-weighted sagittal images. Among the 16 patients with ATM, 14 patients showed iso-signal on an ADC map, but one case showed restricted diffusion and another showed increased diffusion on the ADC map. Among the seven patients with SCI, five patients showed restricted diffusion. Idiopathic ATM usually does not demonstrate restricted diffusion, which can be a clue to differentiate it from SCI. However, idiopathic ATM with larger segment involvement can show focal diffusion restriction.

Fentanyl Ameliorates Severe Acute Pancreatitis-Induced Myocardial Injury in Rats by Regulating NF-κB Signaling Pathway.

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Wang, Yayun; Chen, Manhua

2017-07-06

BACKGROUND Acute pancreatitis (AP) is a sudden inflammation of the pancreas. It results in multiple, severe complications, and 15-20% of patients develop severe acute pancreatitis (SAP) with mortality as high as 30%. Consequently, it is imperative to develop an effective therapy for SAP. MATERIAL AND METHODS We used 30 adult male Sprague Dawley (SD) rats. Rats were randomly divided into 3 groups - sham, SAP, and fentanyl+SAP - with 10 rats in each group. An automatic biochemical analyzer was used to analyze the concentration of creatine kinase isoenzyme (CK-MB) and lactate dehydrogenase (LDH). Terminal-deoxynucleotidyl transferase-mediated nick-end labeling (TUNEL) assay was applied to assess the cell apoptosis rate. Pathological changes in pancreas/heart were detected with hematoxylin and eosin (HE) staining. Western immunoblot assay was used to analyze protein levels of interleukin (IL)-1β, IL-6, and IκB. RESULTS Fentanyl pre-treatment inhibits SAP-induced elevation of CK-MB/LDH concentrations in serum. Compared with the sham group, SAP generates a higher brown/yellow staining rate, which is abated by fentanyl. In the pancreas, SAP generated more serious interstitial edema/hemorrhage and fat necrosis than in the sham group, which are attenuated by fentanyl. Likewise, compared to the sham group, SAP generates swelled/disordered myocardial fibers and congested blood vessels in myocardium, which are ameliorated by fentanyl. In the sham group, there was little IL-1β/IL-6, and fentanyl significantly inhibited SAP-induced up-regulation of IL-1β/IL-6 levels. Compared with the sham group, SAP significantly reduced IκB level, which was rescued by fentanyl. CONCLUSIONS Fentanyl effectively alleviates SAP-induced pancreas and heart injuries through regulating the nuclear factor-κB (NF-κB) signaling pathway.

Blocking TGF-β Signaling Pathway Preserves Mitochondrial Proteostasis and Reduces Early Activation of PDGFRβ+ Pericytes in Aristolochic Acid Induced Acute Kidney Injury in Wistar Male Rats.

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Agnieszka A Pozdzik

Full Text Available The platelet-derived growth factor receptor β (PDGFRβ+ perivascular cell activation becomes increasingly recognized as a main source of scar-associated kidney myofibroblasts and recently emerged as a new cellular therapeutic target.In this regard, we first confirmed the presence of PDGFRβ+ perivascular cells in a human case of end-stage aristolochic acid nephropathy (AAN and thereafter we focused on the early fibrosis events of transforming growth factor β (TGFβ inhibition in a rat model of AAN.Neutralizing anti-TGFβ antibody (1D11 and its control isotype (13C4 were administered (5 mg/kg, i.p. at Days -1, 0, 2 and 4; AA (15 mg/kg, sc was injected daily.At Day 5, 1D11 significantly suppressed p-Smad2/3 signaling pathway improving renal function impairment, reduced the score of acute tubular necrosis, peritubular capillaritis, interstitial inflammation and neoangiogenesis. 1D11 markedly decreased interstitial edema, disruption of tubular basement membrane loss of brush border, cytoplasmic edema and organelle ultrastructure alterations (mitochondrial disruption and endoplasmic reticulum edema in proximal tubular epithelial cells. Moreover, 1D11 significantly inhibited p-PERK activation and attenuated dysregulation of unfolded protein response (UPR pathways, endoplasmic reticulum and mitochondrial proteostasis in vivo and in vitro.The early inhibition of p-Smad2/3 signaling pathway improved acute renal function impairment, partially prevented epithelial-endothelial axis activation by maintaining PTEC proteostasis and reduced early PDGFRβ+ pericytes-derived myofibroblasts accumulation.

Effects of antagonists and heat on TRPM8 channel currents in dorsal root ganglion neuron activated by nociceptive cold stress and menthol.

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Naziroğlu, Mustafa; Ozgül, Cemil

2012-02-01

Transient receptor potential ion channel melastatin subtype 8 (TRPM8) is activated by cold temperature and cooling agents, such as menthol and icilin. Compounds containing peppermint are reported to reduce symptoms of environmental cold stress such as cold allodynia in dorsal root ganglion (DRG) neuron; however, the underlying mechanisms of action are unclear. We tested the effects of physiological heat (37°C), anthralic acid (ACA and 0.025 mM), 2-aminoethyl diphenylborinate (2-APB and 0.05) on noxious cold (10°C) and menthol (0.1 mM)-induced TRPM8 cation channel currents in the DRG neurons of rats. DRG neurons were freshly isolated from rats. In whole-cell patch clamp experiments, TRPM8 currents were consistently induced by noxious cold or menthol. TRPM8 channels current densities of the neurons were higher in cold and menthol groups than in control. When the physiological heat is introduced by chamber TRPM8 channel currents were inhibited by the heat. Noxious cold-induced Ca(2+) gates were blocked by the ACA although menthol-induced TRPM8 currents were not blocked by ACA and 2-APB. In conclusion, the results suggested that activation of TRPM8 either by menthol or nociceptive cold can activate TRPM8 channels although we observed the protective role of heat, ACA and 2-APB through a TRPM8 channel in nociceptive cold-activated DRG neurons. Since cold allodynia is a common feature of neuropathic pain and diseases of sensory neuron, our findings are relevant to the etiology of neuropathology in DRG neurons.

Handheld mechanical nociceptive threshold testing in dairy cows - intra-individual variation, inter-observer agreement and variation over time.

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Raundal, Peter M; Andersen, Pia H; Toft, Nils; Forkman, Björn; Munksgaard, Lene; Herskin, Mette S

2014-11-01

To examine the use of handheld methodology to assess mechanical nociceptive threshold (MNT) on cows kept loose-housed. Prospective randomized partial cross-over experimental study. A one-factor (test day) design was used to evaluate MNT over time. One hundred and fifteen healthy, loose-housed Danish Holstein cattle. We evaluated intra-individual variation, inter-observer agreement and variation over time of MNT using two handheld devices and two stimulation sites. Mechanical, ramped stimulations were performed with an algometer (6.5 mm diameter steel probe, 0-10.0 kgf) or an electronic von Frey device (plastic tip with diameter 0.8 mm, 0-1000 gf). Each cow received 5-6 consecutive stimulations within a 2 × 5 cm skin area on the dorsal or lateral aspect of the left third metatarsus until an avoidance reaction occurred. We investigated the difference in precision [expressed as coefficient of variation (CV)] between the combinations of devices and stimulation sites. The inter-observer agreement and the difference in MNT between test day 1, 3, 7, 10 and 24 were investigated for selected combinations. Data were analysed in mixed models and Bland-Altman as relevant. The CVs did not differ [range 0.34-0.52 (p = 0.1)]. Difference between observers (95% limits) was 0.2 kgf (2.8) and 4 gf (369) for the algometer and von Frey device, respectively. Mechanical nociceptive threshold increased from 361 on test day one to 495 gf on test day 24 (p < 0.01). All methods showed a high degree of intra-individual variation, and no combination of device and stimulation site showed superior precision. Mean difference between observers was low, and MNT was not consistent over time. Further development of the methods is required before they can be used in research to investigate possible relations between claw lesions and hyperalgesia. © 2014 The Authors Veterinary Anaesthesia and Analgesia published by John Wiley & Sons Ltd on behalf of Association of Veterinary Anaesthetists and the

Magnetic resonance direct thrombus imaging of the evolution of acute deep vein thrombosis of the leg.

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Westerbeek, R E; Van Rooden, C J; Tan, M; Van Gils, A P G; Kok, S; De Bats, M J; De Roos, A; Huisman, M V

2008-07-01

Accurate diagnosis of acute recurrent deep vein thrombosis (DVT) is relevant to avoid improper diagnosis and unnecessary life-long anticoagulant treatment. Compression ultrasound has high accuracy for a first episode of DVT, but is often unreliable in suspected recurrent disease. Magnetic resonance direct thrombus imaging (MR DTI) has been shown to accurately detect acute DVT. The purpose of this prospective study was to determine the MR signal change during 6 months follow-up in patients with acute DVT. This study was a prospective study of 43 consecutive patients with a first episode of acute DVT demonstrated by compression ultrasound. All patients underwent MR DTI. Follow-up was performed with MR-DTI and compression ultrasound at 3 and 6 months respectively. All data were coded, stored and assessed by two blinded observers. MR direct thrombus imaging identified acute DVT in 41 of 43 patients (sensitivity 95%). There was no abnormal MR-signal in controls, or in the contralateral extremity of patients with DVT (specificity 100%). In none of the 39 patients available at 6 months follow-up was the abnormal MR-signal at the initial acute DVT observed, whereas in 12 of these patients (30.8%) compression ultrasound was still abnormal. Magnetic resonance direct thrombus imaging normalizes over a period of 6 months in all patients with diagnosed DVT, while compression ultrasound remains abnormal in a third of these patients. MR-DTI may potentially allow for accurate detection in patients with acute suspected recurrent DVT, and this should be studied prospectively.

Mechanisms of alveolar fibrosis after acute lung injury.

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Marinelli, W A; Henke, C A; Harmon, K R; Hertz, M I; Bitterman, P B

1990-12-01

In patients who die after severe acute lung injury, a dramatic fibroproliferative response occurs within the alveolar air space, interstitium, and microvessels. Profound shunt physiology, dead space ventilation, and pulmonary hypertension are the physiologic consequences of this fibroproliferative response. The anatomic pattern of the response is unique within each alveolar compartment. For example, the air space is obliterated by granulation tissue, with replicating mesenchymal cells, their connective tissue products, and an expanding network of intra-alveolar capillaries. In contrast, the vascular fibroproliferative response is dominated by mesenchymal cell replication and connective tissue deposition within the walls of microvessels. Despite the unique anatomic features of these fibroproliferative processes, the regulatory signals involved are likely to be similar. Although our current understanding of the signals regulating the fibroproliferative response to acute lung injury is limited, inferences can be made from in vitro studies of mesenchymal cell behavior and several better understood fibroproliferative processes, including wound healing and chronic fibrotic lung diseases. As clinicians, our future ability to enhance effective lung repair will likely utilize therapeutic strategies specifically targeted to the signals that regulate the fibroproliferative process within the alveolar microenvironment.

Magnetic resonance imaging in the acute stage of cerebrovascular disease

International Nuclear Information System (INIS)

Tanaka, Tokutaro; Sakai, Tsuneo; Fujishima, Ichiro; Yamamoto, Takamichi; Uemura, Kenichi; Teramura, Atsushi.

1988-01-01

Thirty patients with acute cerebrovascular disease were evaluated by both computed tomography (CT) and magnetic resonance (MR) imaging. The 17 patients with cerebral infarction (CI) were evaluated within 24 hours and the 13 with intracerebral hemorrhage (ICH) within 6 hours of the onset of symptoms. All ICHs were detected in T2-weighted images and appeared as perifocal, ring-like areas of high signal intensity. T2-weighted images also demonstrated a ruptured aneurysm and an arteriovenous malformation. In T1-weighted images, all ICHs displayed high signal intensity, which paralleled the CT images and is characteristic of MR imaging with an ultra-low magnetic filed. These findings were obtained as early as 90 minutes from the onset of symptoms. In cases of CI, T2-weighted images obtained 3 - 7 hours after onset demonstrated the pathology more clearly than did CT. This study proved MR imaging useful in the evaluation of both ICH and CI in the acute stage. In addition, it was possible to differentiate ICH from CI in the acute stage by T2-weighted images alone. (author)

Hepatoprotective Effects of Antrodia cinnamomea: The Modulation of Oxidative Stress Signaling in a Mouse Model of Alcohol-Induced Acute Liver Injury

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Yange Liu

2017-01-01

Full Text Available In the present study, the components of A. cinnamomea (AC mycelia were systematically analyzed. Subsequently, its hepatoprotective effects and the underlying mechanisms were explored using a mouse model of acute alcohol-induced liver injury. AC contained 25 types of fatty acid, 16 types of amino acid, 3 types of nucleotide, and 8 types of mineral. The hepatoprotective effects were observed after 2 weeks of AC treatment at doses of 75 mg/kg, 225 mg/kg, and 675 mg/kg in the mouse model. These effects were indicated by the changes in the levels of aspartate aminotransferase, alanine aminotransferase, several oxidation-related factors, and inflammatory cytokines in serum and/or liver samples. AC reduced the incidence rate of necrosis, inflammatory infiltration, fatty droplets formation, and cell apoptosis in liver detecting via histological and TUNEL assay. In addition, AC reduced the expression of cleaved caspase-3, -8, and -9 and the levels of phosphor-protein kinase B (Akt and phosphor-nuclear factor-κB (NF-κB in the liver samples. Collectively, AC-mediated hepatoprotective effects in a mouse model of acute alcohol-induced liver injury are the result of reduction in oxidative stress. This may be associated with Akt/NF-κB signaling. These results provide valuable evidence to support the use of A. cinnamomea as a functional food and/or medicine.

Sleep Deprivation and Recovery Sleep Prior to a Noxious Inflammatory Insult Influence Characteristics and Duration of Pain.

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Vanini, Giancarlo

2016-01-01

Insufficient sleep and chronic pain are public health epidemics. Sleep loss worsens pain and predicts the development of chronic pain. Whether previous, acute sleep loss and recovery sleep determine pain levels and duration remains poorly understood. This study tested whether acute sleep deprivation and recovery sleep prior to formalin injection alter post-injection pain levels and duration. Male Sprague-Dawley rats (n = 48) underwent sleep deprivation or ad libitum sleep for 9 hours. Thereafter, rats received a subcutaneous injection of formalin or saline into a hind paw. In the recovery sleep group, rats were allowed 24 h between sleep deprivation and the injection of formalin. Mechanical and thermal nociception were assessed using the von Frey test and Hargreaves' method. Nociceptive measures were performed at 1, 3, 7, 10, 14, 17 and 21 days post-injection. Formalin caused bilateral mechanical hypersensitivity (allodynia) that persisted for up to 21 days post-injection. Sleep deprivation significantly enhanced bilateral allodynia. There was a synergistic interaction when sleep deprivation preceded a formalin injection. Rats allowed a recovery sleep period prior to formalin injection developed allodynia only in the injected limb, with higher mechanical thresholds (less allodynia) and a shorter recovery period. There were no persistent changes in thermal nociception. The data suggest that acute sleep loss preceding an inflammatory insult enhances pain and can contribute to chronic pain. The results encourage studies in a model of surgical pain to test whether enhancing sleep reduces pain levels and duration. © 2016 Associated Professional Sleep Societies, LLC.

Andrographis Paniculata shows anti-nociceptive effects in an animal model of sensory hypersensitivity associated with migraine.

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Greco, Rosaria; Siani, Francesca; Demartini, Chiara; Zanaboni, Annamaria; Nappi, Giuseppe; Davinelli, Sergio; Scapagnini, Giovanni; Tassorelli, Cristina

2016-01-01

Administration of nitroglycerin (NTG) to rats induces a hyperalgesic condition and neuronal activation of central structures involved in migraine pain. In order to identify therapeutic strategies for migraine pain, we evaluated the anti-nociceptive activity of Andrographis Paniculata (AP), a herbaceous plant, in the hyperalgesia induced by NTG administration in the formalin test. We also analyzed mRNA expression of cytokines in specific brain areas after AP treatment. Male Sprague-Dawley rats were pre-treated with AP extract 30 minutes before NTG or vehicle injection. The data show that AP extract significantly reduced NTG-induced hyperalgesia in phase II of the test, 4 hours after NTG injection. In addition, AP extract reduced IL-6 mRNA expression in the medulla and mesencephalon and also mRNA levels of TNFalpha in the mesencephalic region. These findings suggest that AP extract may be a potential therapeutic approach in the treatment of general pain, and possibly of migraine.

Diagnostic value of low-field MRI for acute poisoning brain injury

International Nuclear Information System (INIS)

Dang Lianrong; He Qinyi

2012-01-01

Objective: To investigate the value of low-field MIR in diagnosis of acute CO poisoning brain injury. Methods: The brain MIR and clinical data of 110 patients with acute CO poisoning brain injury confirmed by clinical examination were retrospectively analyzed. Results: Long T1 and T2 signal intensity was showed on MRI in cerebral hemispheres and globus pallidus symmetrically. There were three basic types of MIR manifestations, white matter of brain type, globus pallidus type and brain mixed type. Conclusions: MRI could be used for confirming the degree and range of acute CO poisoning brain injury. It has important clinical value in the diagnosis, staging and prognosis of patients with acute CO poisoning brain injury. (authors)

Anti-inflammatory and antinociceptive activities of azadirachtin in mice.

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Soares, Darly G; Godin, Adriana M; Menezes, Raquel R; Nogueira, Rafaela D; Brito, Ana Mercy S; Melo, Ivo S F; Coura, Giovanna Maria E; Souza, Danielle G; Amaral, Flávio A; Paulino, Tony P; Coelho, Márcio M; Machado, Renes R

2014-06-01

Azadirachta indica (Meliaceae) extracts have been reported to exhibit anti-inflammatory and antinociceptive properties. However, the activities of azadirachtin, a limonoid and the major bioactive compound found in the extracts, have been poorly investigated in animal models. In the present study, we investigated the effects induced by azadirachtin in experimental models of pain and inflammation in mice. Carrageenan-induced paw edema and fibrovascular tissue growth induced by subcutaneous cotton pellet implantation were used to investigate the anti-inflammatory activity of azadirachtin in mice. Zymosan-induced writhing and hot plate tests were employed to evaluate the antinociceptive activity. To explore putative mechanisms of action, the level of tumor necrosis factor-α in inflammatory tissue was measured and the effect induced by opioidergic and serotonergic antagonists was evaluated. Previous per os (p. o.) administration of azadirachtin (120 mg/kg) significantly reduced the acute paw edema induced by carrageenan. However, the concomitant increase of the paw concentration of tumor necrosis factor-α induced by this inflammatory stimulus was not reduced by azadirachtin. In addition to inhibiting the acute paw edema induced by carrageenan, azadirachtin (6, 60, and 120 mg/kg) inhibited the proliferative phase of the inflammatory response, as demonstrated by the reduced formation of fibrovascular tissue growth. Azadirachtin (120 mg/kg) also inhibited the nociceptive response in models of nociceptive (hot plate) and inflammatory (writhing induced by zymosan) pain. The activity of azadirachtin (120 mg/kg) in the model of nociceptive pain was attenuated by a nonselective opioid antagonist, naltrexone (10 mg/kg, i. p.), but not by a nonselective serotonergic antagonist, cyproheptadine. In conclusion, this study demonstrates the activity of azadirachtin in experimental models of nociceptive and inflammatory pain, and also in models of acute and chronic inflammation

Choosing the right analgesic. A guide to selection.

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Bushnell, Timothy G; Justins, Douglas M

1993-09-01

Pain is an unpleasant sensory and emotional experience, unique to each individual patient. In the dynamic processes of nociceptive stimulation, signal transmission, central decoding and interpretation there are many potential sites for pharmacological intervention, and there are many drugs which will produce analgesia. An analgesic 'ladder' has been proposed for rational pain relief in cancer and a similar concept should be used in all forms of acute and chronic pain. Continuing research and drug development undoubtedly extends our understanding, but consistent improvement in our clinical ability to relieve pain depends more on our willingness to consider the need of each patient individually, to tailor the drug, route and mode of administration to that patient's requirements, and then to monitor on the basis of the response of the patient to the treatment.

The evaluation of diffusion weighted imaging in acute cerebral infarction with permanent type MR scanner

International Nuclear Information System (INIS)

Peng Sen; Ye Wenwei; Luo Zhongrao; Yang Zenian; Zhang Zhongwei; Li Ziping

2006-01-01

Objective: To evaluate the value of diffusion weighted imaging (DWI) in acute cerebral infarction using permanent type MR scanner. Methods: DWI and conventional MRI sequences were done in 77 patients suspected with cerebral infarction. The sensitivity of DWI and conventional MRI was comparatively evaluated on lesion signal intensity and size. The characteristics and orderliness of lesions were studied. Results: (1) DWI has higher sensitivity than conventional MRI. (2) The higher b value was applied in the imaging, the higher signal intensity of acute cerebral infarction was revealed. The lesions were easier to identify on DWI images than on conventional MRI. Conclusion: DWI of permanent type MR imager is a feasible imaging modality, which is valuable in early diagnosis and management of acute cerebral infarction. (authors)

Review article: transient receptor potential channels as possible therapeutic targets in irritable bowel syndrome.

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Beckers, A B; Weerts, Z Z R M; Helyes, Z; Masclee, A A M; Keszthelyi, D

2017-11-01

Abdominal pain in irritable bowel syndrome (IBS) remains challenging to treat effectively. Researchers have attempted to elucidate visceral nociceptive processes in order to guide treatment development. Transient receptor potential (TRP) channels have been implied in the generation (TRPV1, TRPV4, TRPA1) and inhibition (TRPM8) of visceral pain signals. Pathological changes in their functioning have been demonstrated in inflammatory conditions, and appear to be present in IBS as well. To provide a comprehensive review of the current literature on TRP channels involved in visceral nociception. In particular, we emphasise the clinical implications of these nociceptors in the treatment of IBS. Evidence to support this review was obtained from an electronic database search via PubMed using the search terms "visceral nociception," "visceral hypersensitivity," "irritable bowel syndrome" and "transient receptor potential channels." After screening the abstracts the articles deemed relevant were cross-referenced for additional manuscripts. Recent studies have resulted in significant advances in our understanding of TRP channel mediated visceral nociception. The diversity of TRP channel sensitization pathways is increasingly recognised. Endogenous TRP agonists, including poly-unsaturated fatty acid metabolites and hydrogen sulphide, have been implied in augmented visceral pain generation in IBS. New potential targets for treatment development have been identified (TRPA1 and TRPV4,) and alternative means of affecting TRP channel signalling (partial antagonists, downstream targeting and RNA-based therapy) are currently being explored. The improved understanding of mechanisms involved in visceral nociception provides a solid basis for the development of new treatment strategies for abdominal pain in IBS. © 2017 John Wiley & Sons Ltd.

Intestinal Epithelial Cell Tyrosine Kinase 2 Transduces IL-22 Signals To Protect from Acute Colitis.

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Hainzl, Eva; Stockinger, Silvia; Rauch, Isabella; Heider, Susanne; Berry, David; Lassnig, Caroline; Schwab, Clarissa; Rosebrock, Felix; Milinovich, Gabriel; Schlederer, Michaela; Wagner, Michael; Schleper, Christa; Loy, Alexander; Urich, Tim; Kenner, Lukas; Han, Xiaonan; Decker, Thomas; Strobl, Birgit; Müller, Mathias

2015-11-15

In the intestinal tract, IL-22 activates STAT3 to promote intestinal epithelial cell (IEC) homeostasis and tissue healing. The mechanism has remained obscure, but we demonstrate that IL-22 acts via tyrosine kinase 2 (Tyk2), a member of the Jak family. Using a mouse model for colitis, we show that Tyk2 deficiency is associated with an altered composition of the gut microbiota and exacerbates inflammatory bowel disease. Colitic Tyk2(-/-) mice have less p-STAT3 in colon tissue and their IECs proliferate less efficiently. Tyk2-deficient primary IECs show reduced p-STAT3 in response to IL-22 stimulation, and expression of IL-22-STAT3 target genes is reduced in IECs from healthy and colitic Tyk2(-/-) mice. Experiments with conditional Tyk2(-/-) mice reveal that IEC-specific depletion of Tyk2 aggravates colitis. Disease symptoms can be alleviated by administering high doses of rIL-22-Fc, indicating that Tyk2 deficiency can be rescued via the IL-22 receptor complex. The pivotal function of Tyk2 in IL-22-dependent colitis was confirmed in Citrobacter rodentium-induced disease. Thus, Tyk2 protects against acute colitis in part by amplifying inflammation-induced epithelial IL-22 signaling to STAT3. Copyright © 2015 by The American Association of Immunologists, Inc.

Modulation of laser-evoked potentials and pain perception by transcutaneous electrical nerve stimulation (TENS): a placebo-controlled study in healthy volunteers.

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Vassal, François; Créac'h, C; Convers, Ph; Laurent, B; Garcia-Larrea, L; Peyron, R

2013-09-01

To investigate the effects of transcutaneous electrical nerve stimulation (TENS) on brain nociceptive responses (laser-evoked potentials, LEPs) and pain perception. Twenty healthy subjects were included. Nociceptive CO(2)-laser pulses were sequentially delivered to the dorsum of both feet. The amplitude of LEPs and nociceptive thresholds were collected in three consecutive conditions: T1: "sham" TENS (2 Hz/low-intensity) positioned heterotopically, over the left thigh; T2: "active" TENS (120 Hz/low-intensity) applied homotopically, over the left common peroneal nerve; and T3: "sham" TENS (replication of condition T1). Compared with "sham" TENS, "active" TENS significantly decreased the LEPs amplitude. This effect was observed exclusively when "active" TENS was applied ipsilaterally to the painful stimulus. Nociceptive thresholds increased with sessions in both limbs, but the increase observed during the "active" condition of TENS (T2) exceeded significantly that observed during the condition T3 only on the foot ipsilateral to TENS. Compared with a credible placebo TENS, high-frequency TENS induced a significant attenuation of both the acute pain and LEPs induced by noxious stimuli applied on the same dermatome. This modulation of subjective and objective concomitants of pain processing reflects a real neurophysiological TENS-related effect on nociceptive transmission. Copyright © 2013 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved.

Downregulation of miR-199b promotes the acute spinal cord injury through IKKβ-NF-κB signaling pathway activating microglial cells

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Zhou, Heng-Jun [Department of Neurosurgery, the First Affiliated Hospital, Zhejiang University, 79 Qingchun Road, Hangzhou 310003, Zhejiang (China); Wang, Li-Qing [Department of Anesthesia, the First Affiliated Hospital, Zhejiang University, Hangzhou 310003 (China); Xu, Qing-Sheng; Fan, Zuo-Xu; Zhu, Yu; Jiang, Hao; Zheng, Xiu-Jue; Ma, Yue-Hui [Department of Neurosurgery, the First Affiliated Hospital, Zhejiang University, 79 Qingchun Road, Hangzhou 310003, Zhejiang (China); Zhan, Ren-Ya, E-mail: zhanry148@163.com [Department of Neurosurgery, the First Affiliated Hospital, Zhejiang University, 79 Qingchun Road, Hangzhou 310003, Zhejiang (China)

2016-11-15

Inflammatory response played an important role in the progression of spinal cord injury (SCI). Several miRNAs were associated with the pathology of SCI. However, the molecular mechanism of miRNA involving in inflammatory response in acute SCI (ASCI) was poorly understood. Sprague-Dawley (SD) rats were divided into 2 groups: control group (n=6) and acute SCI (ASCI) group (n=6). The expression of miR-199b and IκB kinase β-nuclear factor-kappa B (IKKβ-NF-κB) signaling pathway were evaluated by quantitative reverse transcription-PCR (qRT-PCR) in rats with ASCI and in primary microglia activated by lipopolysaccharide (LPS). We found that downregulation of miR-199b and activation of IKKβ/NF-κB were observed in rats after ASCI and in activated microglia. miR-199b negatively regulated IKKβ by targeting its 3′- untranslated regions (UTR) through using luciferase reporter assay. Overexpression of miR-199b reversed the up-regulation of IKKβ, p-p65, tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β) in LPS-treated BV2 cells assessed by western blotting analysis. In addition, BMS-345541 reversed the up-regulation effects of miR-199b inhibitor on the expression of TNF-α and IL-1β. In the SCI rats, overexpression of miR-199b attenuated ASCI and decreased the expression of IKKβ-NF-κB signaling pathway and TNF-α and IL-1β. These results indicated that miR-199b attenuated ASCI at least partly through IKKβ-NF-κB signaling pathway and affecting the function of microglia. Our findings suggest that miR-199b may be employed as therapeutic for spinal cord injury. - Highlights: • Downregulation of miR-199b and activation of IKKβ/NF-κB were observed in rat after SCI. • miR-199b negatively regulated IKKβ by targeting its 3′-UTR. • miR-199b overexpression reversed the increasing IKKβ, p-p65, TNF-α and IL-1β in LPS-treated BV2. • BMS-345541 reversed the up-regulation of TNF-α and IL-1β induced by miR-199b inhibitor. • Overexpression of miR-199b

The evaluation of fat saturation fast spin-echo T2WI for patients with acute spinal trauma

International Nuclear Information System (INIS)

Kim, Sung Gyu; Lee, Chang Jun; Lee, Myung Joon; Kang, Ik Won; Yoo, Jeong Hyun

2002-01-01

To determine the usefulness of fat saturation fast spin-echo T2WI for patients with mild acute trauma of the spine. Between July 1998 and June 2002, 36 patients with acute spinal trauma underwent MRI within four months of injury. One, whose clinal symptoms indicated neurological paralysis, was excluded form our study. A superconductive 1.0-T MRI scanner was used, and conventional T1W1, T2W1, and additional fat-saturation fast spin-echo T2W1 were performed. Two radiologists compared conventional T2-weighted sagittal imaging and fat-saturation T2-weighted sagittal imaging in terms of the extension of increased high signal intensities in soft tissue and vertebral bodies, bone marrow signal change, disk herniation, and signal change of the disk. The detection rate of focal high signal intensities in soft tissue and bone marrow was significantly higher at fat-saturation fast spin-echo T2W1 is useful the evaluation of patients with mild acute spinal trauma without neurological impairment

Gadolinium-enhanced magnetic resonance imaging in acute myocardial infarction

International Nuclear Information System (INIS)

Dijkman, P.R.M. van; Wall, E.E. van der; Roos, A. de; Doornbos, J.; Laarse, A. van der; Voorthuisen, A.E. van; Bruschke, A.V.G.; Rossum, A.C. van

1990-01-01

To evaluate he usefulness of the paramagnetic contrast agent Gadolinium-DTPA (diethylenetriaminepentaacetic acid) in Magnetic Resonance. Imaging of acute myocardial infarction, we studied a total of 45 patients with a first acute myocardial infarction by ECG-gated magnetic resonance imaging before and after intravenous administration of 0.1 mmol/kg Gadolinium-DTPA. All patients received thrombolytic treatment by intravenous streptokinase. The magnetic resonance imaging studies were preformed after a meam of 88 h (range 15-241) after the acute onset of acute myocardial infarction. Five patients without evidence of cardiac disease served as controls. Spin-echo measurements (TE 30 ms) were made using a Philips Gyroscan (0.5 Tesla) or a Teslacon II (0.6 Tesla). The 45 patients were divided into four groups of patients. In Group I( patients) Gadolinium-DTPA improved the detection of myocardial infarction by Gadolinium-DTPA. In Group II (20 patients) the magnetic resonance imaging procedure was repeated every 10 min for up to 40 min following administration of Gadolinium-DTPA. Optimal contrast enhancement was obtained 20-25 min after Gadolinium-DTPA. In Group III (27 patients) signal intensities were significantly higher in the patients who underwent the magnetic resonance imaging study more than 72 h (mean 120) after the acute event, suggesting increased acculumation of Gadolinium-DTPA in a more advanced stage of the infarction process. In Group IV (45 patients) Gadolinium-DTPA was administered in an attempt to distinguish between reperfused and nonreperfused myocardial areas after thrombolytic treatment for acute myocardial infarction. The signal intensities did not differ, but reperfused areas showed a more homogeneous aspect whereas nonreperfused areas were visualized as a more heterogeneous contrast enhancement. It is concluded that magnetic resonance imaging using the contrast agent Gadolinium-DTPA significantly improves the detection of infarcted myocardial areas

Stereospecific effects of morphine on plasma opioid peptide levels and nociception in dogs

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Adams, M.L.; Morris, D.L.; Dewey, W.L.

1986-03-05

..beta..-endorphin, (met)enkephalin, and (leu)enkephalin were quantitated in canine plasma by radioimmunoassay (RIA) after extraction of the peptides on Sep Pak C18 cartridges. Plasma samples were taken one hour after a 10 mg/kg s.c. injection of (-)-morphine SO/sub 4/ or (+)-morphine HBr. Antinociception, measured by a dog tail-flick test, and morphine-induced emesis, salivation, diarrhea, and ataxia were quantitated before sampling. Control levels for each dog were taken one week earlier at the same time of day after saline injections. Antinociception, morphine signs, and opioid peptide levels in plasma were significantly increased by (-)-morphine. Antinociception increased from zero to 83.54 +/- 11.0%. The number of morphine signs increased from zero to 2.9 +/- 0.28 per dog. ..beta..-endorphin levels increased from 44.52 +/- 4.25 to 90.6 +/- 7.38 pg/ml; (met)enkephalin levels increased from 253.56 +/- 22.04 to 497.1 +/- 58.12 pg/ml; (leu)-enkephalin increased from 141.65 +/- 12.9 to 313.24 +/- 35.95 pg/ml. None of these effects were observed in the dogs that received (+)-morphine. The conclude that morphine stereospecifically inhibits nociception, induces observable signs, and increases plasma opioid peptide levels in dogs.

Stereospecific effects of morphine on plasma opioid peptide levels and nociception in dogs

International Nuclear Information System (INIS)

Adams, M.L.; Morris, D.L.; Dewey, W.L.

1986-01-01

β-endorphin, [met]enkephalin, and [leu]enkephalin were quantitated in canine plasma by radioimmunoassay (RIA) after extraction of the peptides on Sep Pak C18 cartridges. Plasma samples were taken one hour after a 10 mg/kg s.c. injection of (-)-morphine SO 4 or (+)-morphine HBr. Antinociception, measured by a dog tail-flick test, and morphine-induced emesis, salivation, diarrhea, and ataxia were quantitated before sampling. Control levels for each dog were taken one week earlier at the same time of day after saline injections. Antinociception, morphine signs, and opioid peptide levels in plasma were significantly increased by (-)-morphine. Antinociception increased from zero to 83.54 +/- 11.0%. The number of morphine signs increased from zero to 2.9 +/- 0.28 per dog. β-endorphin levels increased from 44.52 +/- 4.25 to 90.6 +/- 7.38 pg/ml; [met]enkephalin levels increased from 253.56 +/- 22.04 to 497.1 +/- 58.12 pg/ml; [leu]-enkephalin increased from 141.65 +/- 12.9 to 313.24 +/- 35.95 pg/ml. None of these effects were observed in the dogs that received (+)-morphine. The conclude that morphine stereospecifically inhibits nociception, induces observable signs, and increases plasma opioid peptide levels in dogs

Activation of IGF-1/IGFBP-3 signaling by berberine improves intestinal mucosal barrier of rats with acute endotoxemia.

Science.gov (United States)

He, Yan; Yuan, Xiaoming; Zhou, Guangrong; Feng, Aiwen

2018-01-01

Insulin-like growth factor I (IGF-I) and binding protein 3 (IGFBP-3) play a role in the maintenance of gut mucosal barrier function. Nevertheless, IGF-I/IGFBP-3 and tight junction protein (TJP) expression in small intestinal mucosa are often impaired during endotoxemia. In this model of acute endotoxemia, the regulatory effect of berberine on IGF-I/IGFBP-3 and TJP expression in ileal mucosa was evaluated. The findings revealed systemic injection of lipopolysaccharide (LPS) suppressed mRNA and protein expression of IGF-I and IGFBP-3, but berberine ameliorated their production. LPS injection inhibited occludin and claudin-1 protein generation, and this inhibitory effect of LPS was abolished by berberine. Inhibition of IGF-I/IGFBP-3 signaling by AG1024 or siRNAs reduced berberine-induced occludin and claudin-1 production. Additionally, GW9662 was found to repress berberine-induced IGF-I/IGFBP-3 expression, indicating of a cross-link between PPARγ and IGF-I/IGFBP-3 axis. Copyright © 2017 Elsevier B.V. All rights reserved.

Diffusion-weighted imaging in acute demyelinating myelopathy

International Nuclear Information System (INIS)

Zecca, Chiara; Cereda, Carlo; Tschuor, Silvia; Staedler, Claudio; Nadarajah, Navarajah; Bassetti, Claudio L.; Gobbi, Claudio; Wetzel, Stephan; Santini, Francesco

2012-01-01

Diffusion-weighted imaging (DWI) has become a reference MRI technique for the evaluation of neurological disorders. Few publications have investigated the application of DWI for inflammatory demyelinating lesions. The purpose of the study was to describe diffusion-weighted imaging characteristics of acute, spinal demyelinating lesions. Six consecutive patients (two males, four females; aged 28-64 years) with acute spinal cord demyelinating lesions were studied in a prospective case series design from June 2009 to October 2010. We performed magnetic resonance imaging studies from 2 to 14 days from symptom onset on the patients with relapsing remitting multiple sclerosis (n = 3) or clinically isolated syndrome (n = 3). Main outcome measures were diffusion-weighted imaging and apparent diffusion coefficient pattern (ADC) of acute spinal cord demyelinating lesions. All spinal lesions showed a restricted diffusion pattern (DWI+/ADC-) with a 24% median ADC signal decrease. A good correlation between clinical presentation and lesion site was observed. Acute demyelinating spinal cord lesions show a uniform restricted diffusion pattern. Clinicians and neuro-radiologists should be aware that this pattern is not necessarily confirmatory for an ischaemic aetiology. (orig.)

Diffusion-weighted imaging in acute demyelinating myelopathy

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Zecca, Chiara; Cereda, Carlo; Tschuor, Silvia; Staedler, Claudio; Nadarajah, Navarajah; Bassetti, Claudio L.; Gobbi, Claudio [Ospedale Regionale di Lugano, Servizio di Neurologia e Neuroradiologia, Neurocenter of Southern Switzerland, Lugano (Switzerland); Wetzel, Stephan [Swiss Neuro Institute (SNI), Abteilung fuer Neuroradiologie, Hirslanden Klinik Zuerich, Zuerich (Switzerland); Santini, Francesco [University of Basel Hospital, Division of Radiological Physics, Basel (Switzerland)

2012-06-15

Diffusion-weighted imaging (DWI) has become a reference MRI technique for the evaluation of neurological disorders. Few publications have investigated the application of DWI for inflammatory demyelinating lesions. The purpose of the study was to describe diffusion-weighted imaging characteristics of acute, spinal demyelinating lesions. Six consecutive patients (two males, four females; aged 28-64 years) with acute spinal cord demyelinating lesions were studied in a prospective case series design from June 2009 to October 2010. We performed magnetic resonance imaging studies from 2 to 14 days from symptom onset on the patients with relapsing remitting multiple sclerosis (n = 3) or clinically isolated syndrome (n = 3). Main outcome measures were diffusion-weighted imaging and apparent diffusion coefficient pattern (ADC) of acute spinal cord demyelinating lesions. All spinal lesions showed a restricted diffusion pattern (DWI+/ADC-) with a 24% median ADC signal decrease. A good correlation between clinical presentation and lesion site was observed. Acute demyelinating spinal cord lesions show a uniform restricted diffusion pattern. Clinicians and neuro-radiologists should be aware that this pattern is not necessarily confirmatory for an ischaemic aetiology. (orig.)

Magnetic resonance imaging findings in patients presenting with (sub)acute cerebellar ataxia

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Schneider, Tanja [University Medical Center Hamburg-Eppendorf, Department of Diagnostic and Interventional Neuroradiology, Hamburg (Germany); The Johns Hopkins Hospital School of Medicine, Russell H. Morgan Department of Radiology and Radiological Sciences, Division of Neuroradiology, Baltimore, MD (United States); Thomalla, Goetz [University Medical Center Hamburg-Eppendorf, Department of Neurology, Hamburg (Germany); Goebell, Einar [University Medical Center Hamburg-Eppendorf, Department of Diagnostic and Interventional Neuroradiology, Hamburg (Germany); Piotrowski, Anna [The Johns Hopkins University School of Medicine, Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Baltimore, MD (United States); Yousem, David Mark [The Johns Hopkins Hospital School of Medicine, Russell H. Morgan Department of Radiology and Radiological Sciences, Division of Neuroradiology, Baltimore, MD (United States)

2015-02-17

Acute or subacute cerebellar inflammation is mainly caused by postinfectious, toxic, neoplastic, vascular, or idiopathic processes and can result in cerebellar ataxia. Previous magnetic resonance (MR) studies in single patients who developed acute or subacute ataxia showed varying imaging features. Eighteen patients presenting with acute and subacute onset of ataxia were included in this study. Cases of chronic-progressive/hereditary and noncerebellar causes (ischemia, multiple sclerosis lesions, metastasis, bleedings) were excluded. MR imaging findings were then matched with the clinical history of the patient. An underlying etiology for ataxic symptoms were found in 14/18 patients (postinfectious/infectious, paraneoplastic, autoimmune, drug-induced). In two of five patients without MR imaging findings and three of eight patients with minimal imaging features (cerebellar atrophy, slight signal alterations, and small areas of restricted diffusion), adverse clinical outcomes were documented. Of the five patients with prominent MR findings (cerebellar swelling, contrast enhancement, or broad signal abnormalities), two were lost to follow-up and two showed long-term sequelae. No correlation was found between the presence of initial MRI findings in subacute or acute ataxia patients and their long-term clinical outcome. MR imaging was more flagrantly positive in cases due to encephalitis. (orig.)

Magnetic resonance imaging findings in patients presenting with (sub)acute cerebellar ataxia.

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Schneider, Tanja; Thomalla, Götz; Goebell, Einar; Piotrowski, Anna; Yousem, David Mark

2015-06-01

Acute or subacute cerebellar inflammation is mainly caused by postinfectious, toxic, neoplastic, vascular, or idiopathic processes and can result in cerebellar ataxia. Previous magnetic resonance (MR) studies in single patients who developed acute or subacute ataxia showed varying imaging features. Eighteen patients presenting with acute and subacute onset of ataxia were included in this study. Cases of chronic-progressive/hereditary and noncerebellar causes (ischemia, multiple sclerosis lesions, metastasis, bleedings) were excluded. MR imaging findings were then matched with the clinical history of the patient. An underlying etiology for ataxic symptoms were found in 14/18 patients (postinfectious/infectious, paraneoplastic, autoimmune, drug-induced). In two of five patients without MR imaging findings and three of eight patients with minimal imaging features (cerebellar atrophy, slight signal alterations, and small areas of restricted diffusion), adverse clinical outcomes were documented. Of the five patients with prominent MR findings (cerebellar swelling, contrast enhancement, or broad signal abnormalities), two were lost to follow-up and two showed long-term sequelae. No correlation was found between the presence of initial MRI findings in subacute or acute ataxia patients and their long-term clinical outcome. MR imaging was more flagrantly positive in cases due to encephalitis.

NANOG Expression as a Responsive Biomarker during Treatment with Hedgehog Signal Inhibitor in Acute Myeloid Leukemia

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Seiji Kakiuchi

2017-02-01

Full Text Available Aberrant activation of the Hedgehog (Hh signaling pathway is involved in the maintenance of leukemic stem cell (LSCs populations. PF-0444913 (PF-913 is a novel inhibitor that selectively targets Smoothened (SMO, which regulates the Hh pathway. Treatment with PF-913 has shown promising results in an early phase study of acute myeloid leukemia (AML. However, a detailed mode of action for PF-913 and relevant biomarkers remain to be elucidated. In this study, we examined bone marrow samples derived from AML patients under PF-913 monotherapy. Gene set enrichment analysis (GSEA revealed that PF-913 treatment affected the self-renewal signature and cell-cycle regulation associated with LSC-like properties. We then focused on the expression of a pluripotency factor, NANOG, because previous reports showed that a downstream effector in the Hh pathway, GLI, directly binds to the NANOG promoter and that the GLI-NANOG axis promotes stemness and growth in several cancers. In this study, we found that a change in NANOG transcripts was closely associated with GLI-target genes and NANOG transcripts can be a responsive biomarker during PF-913 therapy. Additionally, the treatment of AML with PF-913 holds promise, possibly through inducing quiescent leukemia stem cells toward cell cycling.

Acute neck pain caused by pseudogout attack of calcified cervical yellow ligament: a case report.

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Kobayashi, Takashi; Miyakoshi, Naohisa; Abe, Toshiki; Abe, Eiji; Kikuchi, Kazuma; Noguchi, Hideaki; Konno, Norikazu; Shimada, Yoichi

2016-05-30

Calcification of the yellow ligament sometimes compresses the spinal cord and can induce myelopathy. Usually, the calcification does not induce acute neck pain. We report a case of a patient with acute neck pain caused by calcium pyrophosphate dihydrate in a calcified cervical yellow ligament. A 70-year-old Japanese woman presented with acute neck pain. She had a moderately high fever (37.5 °C), and her neck pain was so severe that she could not move her neck in any direction. Computed tomography showed a high-density area between the C5 and C6 laminae suspicious for calcification of the yellow ligament. Magnetic resonance imaging showed intermediate-signal intensity on T1-weighted imaging and high-signal intensity on T2-weighted imaging surrounding a low-signal region on both T1- and T2-weighted imaging with cord compression. There was a turbid, yellow fluid collection in the yellow ligament at the time of operation. Histologically, calcium pyrophosphate dihydrate crystals were found in the fluid, and she was diagnosed as having a pseudogout attack of the yellow ligament. Pseudogout attack of the cervical yellow ligament is rare, but this clinical entity should be added to the differential diagnosis of acute neck pain, especially when calcification of the yellow ligament exists.

GSK-3β inhibitor TWS119 attenuates rtPA-induced hemorrhagic transformation and activates the Wnt/β-catenin signaling pathway after acute ischemic stroke in rats.

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Wang, Wei; Li, Mingchang; Wang, Yuefei; Li, Qian; Deng, Gang; Wan, Jieru; Yang, Qingwu; Chen, Qianxue; Wang, Jian

2016-12-01

Hemorrhagic transformation (HT) is a devastating complication for patients with acute ischemic stroke who are treated with tissue plasminogen activator (tPA). It is associated with high morbidity and mortality, but no effective treatments are currently available to reduce HT risk. Therefore, methods to prevent HT are urgently needed. In this study, we used TWS119, an inhibitor of glycogen synthase kinase 3β (GSK-3β), to evaluate the role of the Wnt/β-catenin signaling pathway in recombinant tPA (rtPA)-induced HT. Sprague-Dawley rats were subjected to a middle cerebral artery occlusion (MCAO) model of ischemic stroke and then were administered rtPA, rtPA combined with TWS119, or vehicle at 4 h. The animals were sacrificed 24 h after infarct induction. Rats treated with rtPA showed evident HT, had more severe neurologic deficit, brain edema, and blood-brain barrier breakdown, and had larger infarction volume than did the vehicle group. Rats treated with TWS119 had significantly improved outcomes compared with those of rats treated with rtPA alone. In addition, Western blot analysis showed that TWS119 increased the protein expression of β-catenin, claudin-3, and ZO-1 while suppressing the expression of GSK-3β. These results suggest that TWS119 reduces rtPA-induced HT and attenuates blood-brain barrier disruption, possibly through activation of the Wnt/β-catenin signaling pathway. This study provides a potential therapeutic strategy to prevent tPA-induced HT after acute ischemic stroke.

Tyrosine receptor kinase B receptor activation reverses the impairing effects of acute nicotine on contextual fear extinction.

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Kutlu, Munir Gunes; Cole, Robert D; Connor, David A; Natwora, Brendan; Gould, Thomas J

2018-03-01

Anxiety and stress disorders have been linked to deficits in fear extinction. Our laboratory and others have demonstrated that acute nicotine impairs contextual fear extinction, suggesting that nicotine exposure may have negative effects on anxiety and stress disorder symptomatology. However, the neurobiological mechanisms underlying the acute nicotine-induced impairment of contextual fear extinction are unknown. Therefore, based on the previous studies showing that brain-derived neurotrophic factor is central for fear extinction learning and acute nicotine dysregulates brain-derived neurotrophic factor signaling, we hypothesized that the nicotine-induced impairment of contextual fear extinction may involve changes in tyrosine receptor kinase B signaling. To test this hypothesis, we systemically, intraperitoneally, injected C57BL/6J mice sub-threshold doses (2.5 and 4.0 mg/kg) of 7,8-dihydroxyflavone, a small-molecule tyrosine receptor kinase B agonist that fully mimics the effects of brain-derived neurotrophic factor, or vehicle an hour before each contextual fear extinction session. Mice also received injections, intraperitoneally, of acute nicotine (0.18 mg/kg) or saline 2-4 min before extinction sessions. While the animals that received only 7,8-dihydroxyflavone did not show any changes in contextual fear extinction, 4.0 mg/kg of 7,8-dihydroxyflavone ameliorated the extinction deficits in mice administered acute nicotine. Overall, these results suggest that acute nicotine-induced impairment of context extinction may be related to a disrupted brain-derived neurotrophic factor signaling.

Differential expression of myocardial heat shock proteins in rats acutely exposed to fluoride.

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Panneerselvam, Lakshmikanthan; Raghunath, Azhwar; Perumal, Ekambaram

2017-09-01

Acute fluoride (F - ) toxicity is known to cause severe cardiac complications and leads to sudden heart failure. Previously, we reported that increased myocardial oxidative damage, apoptosis, altered cytoskeleton and AMPK signaling proteins associated with energy deprivation in acute F - induced cardiac dysfunction. The present study was aimed to decipher the status of myocardial heat shock proteins (Hsps-Hsp27, Hsp32, Hsp40, Hsp60, Hsp70, Hsp90) and heat shock transcription factor 1 (Hsf1) in acute F - -intoxicated rats. In order to study the expression of myocardial Hsps, male Wistar rats were treated with single oral doses of 45 and 90 mg/kg F - for 24 h. The expression levels of myocardial Hsps were determined using RT-PCR, western blotting, and immunohistochemical studies. Acute F - -intoxicated rats showed elevated levels of both the transcripts and protein expression of Hsf1, Hsp27, Hsp32, Hsp60, and Hsp70 when compared to control. In addition, the expression levels of Hsp40 and Hsp90 were significantly declined in a dose-dependent fashion in F - -treated animals. Our result suggests that differential expression of Hsps in the rat myocardium could serve as a balance between pro-survival and death signal during acute F - -induced heart failure.

Handheld mechanical nociceptive threshold testing in dairy cows – intra-individual variation, inter-observer agreement and variation over time

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Raundal, Peter M; Andersen, Pia H; Toft, Nils; Forkman, Björn; Munksgaard, Lene; Herskin, Mette S

2014-01-01

Objective To examine the use of handheld methodology to assess mechanical nociceptive threshold (MNT) on cows kept loose-housed. Study design Prospective randomized partial cross-over experimental study. A one-factor (test day) design was used to evaluate MNT over time. Animals One hundred and fifteen healthy, loose-housed Danish Holstein cattle. Methods We evaluated intra-individual variation, inter-observer agreement and variation over time of MNT using two handheld devices and two stimulation sites. Mechanical, ramped stimulations were performed with an algometer (6.5 mm diameter steel probe, 0–10.0 kgf) or an electronic von Frey device (plastic tip with diameter 0.8 mm, 0–1000 gf). Each cow received 5–6 consecutive stimulations within a 2 × 5 cm skin area on the dorsal or lateral aspect of the left third metatarsus until an avoidance reaction occurred. We investigated the difference in precision [expressed as coefficient of variation (CV)] between the combinations of devices and stimulation sites. The inter-observer agreement and the difference in MNT between test day 1, 3, 7, 10 and 24 were investigated for selected combinations. Data were analysed in mixed models and Bland-Altman as relevant. Results The CVs did not differ [range 0.34–0.52 (p = 0.1)]. Difference between observers (95% limits) was 0.2 kgf (2.8) and 4 gf (369) for the algometer and von Frey device, respectively. Mechanical nociceptive threshold increased from 361 on test day one to 495 gf on test day 24 (p < 0.01). Conclusion and clinical relevance All methods showed a high degree of intra-individual variation, and no combination of device and stimulation site showed superior precision. Mean difference between observers was low, and MNT was not consistent over time. Further development of the methods is required before they can be used in research to investigate possible relations between claw lesions and hyperalgesia. PMID:24734991

Acute bone crises in sickle cell disease: the T1 fat-saturated sequence in differentiation of acute bone infarcts from acute osteomyelitis

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Jain, R.; Sawhney, S.; Rizvi, S.G.

2008-01-01

Aim: To prove the hypothesis that acute bone infarcts in sickle cell disease are caused by sequestration of red blood cells (RBCs) in bone marrow, and to evaluate the unenhanced T1 fat-saturated (fs) sequence in the differentiation of acute bone infarction from acute osteomyelitis in patients with sickle-cell disease. Materials and methods: Two studies were undertaken: an experimental study using in-vitro packed red blood cells and normal volunteers, and a retrospective clinical study of 86 magnetic resonance imaging (MRI) studies. For the experimental study containers of packed RBCs were placed between the knees of four healthy volunteers with a saline bag under the containers as an additional control, and were scanned with the pre-contrast T1-fs sequence. Signal intensity (SI) ratios were obtained for packed RBCs:skeletal muscle and packed RBCs:saline. For the clinical study, the SIs of normal bone marrow, packed RBCs, bone and/or soft-tissue lesions, and normal skeletal muscle of 74 patients (86 MRI studies) were measured using unenhanced, T1 fat-saturated MRI. The ratios of the above SIs to normal skeletal muscle were calculated and subjected to statistical analysis. Results: Fifty-one of 86 MRI studies were included in the final analysis. The ratios of SIs for normal bone marrow, packed red cells, bone infarction, acute osteomyelitis, and soft-tissue lesions associated with bone infarct, compared with normal skeletal muscle were (mean ± SD) 0.9 ± 0.2, 2.1 ± 0.7, 1.7 ± 0.5, 1.0 ± 0.3, and 2.2 ± 0.7, respectively. The difference in the ratio of SIs of bone infarcts and osteomyelitis was significant (p = 0.003). The final diagnoses were bone infarction (n = 50), acute osteomyelitis (n = 1), and co-existent bone infarction and osteomyelitis (n = 2). Seven patients who had suspected osteomyelitis underwent image-guided aspiration. Conclusion: Acute bone infarcts in sickle cell disease are caused by sequestration of red blood cells in the bone marrow. The

Craniofacial Pain: Brainstem Mechanisms

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Barry J Sessle

1996-01-01

Full Text Available This article reviews recent research advances in animals that have identified critical neural elements in the brainstem receiving and transmitting craniofacial nociceptive inputs, as well as some of the mechanisms involved in the modulation and plasticity of nociceptive transmission. Nociceptive neurones in the trigeminal (V brainstem sensory nuclear complex can be classified as nociceptive-specific (NS or wide dynamic range (WDR. Some of these neurones respond exclusively to sensory inputs evoked by stimulation of facial skin or oral mucosa and have features suggesting that they are critical neural elements involved in the ability to localize an acute superficial pain and sense its intensity and duration. Many of the V brainstem nociceptive neurones, however, receive convergent inputs from afferents supplying deep craniofacial tissues (eg, dural vessel, muscle and skin or mucosa. These neurones are likely involved in deep pain, including headache, because few nociceptive neurones receive inputs exclusively from afferents supplying these tissues. These extensive convergent input patterns also appear to be important factors in pain spread and referral, and in central mechanisms underlying neuroplastic changes in V neuronal properties that may occur with injury and inflammation. For example, application of the small fibre excitant and inflammatory irritant mustard oil into the temporomandibular joint, masseter or tongue musculature induces a prolonged but reversible enhancement of responses to cutaneous and deep afferent inputs of most WDR and NS neurones. These effects may be accompanied by increased electromyographic activity reflexly induced in the masticatory muscles by mustard oil, and involve endogenous N-methyl-D-aspartate and opioid neurochemical mechanisms. Such peripherally induced modulation of brainstem nociceptive neuronal properties reflects the functional plasticity of the central V system, and may be involved in the development of

Inflammation of vertebral bone associated with acute calcific tendinitis of the longus colli muscle

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Mihmanli, I.; Kanberoglu, K. [Dept. of Radiology, Istanbul Univ. (Turkey); Karaarslan, E. [Intermed Medical Center, Nisantasi, Istanbul (Turkey)

2001-12-01

We present a case of acute retropharyngeal calcific tendinitis with characteristic findings on radiographic, computed tomography, and magnetic resonance imaging (MRI). To our knowledge, this is the first acute retropharyngeal calcific tendinitis report having inflammation of both the vertebra itself and the longus colli muscle diagnosed on MRI. In patients with neck pain, acute retropharyngeal calcific tendinitis should be kept in mind in the differential diagnosis, even if these patients had vertebral pathological signals on MRI. (orig.)

Inflammation of vertebral bone associated with acute calcific tendinitis of the longus colli muscle

International Nuclear Information System (INIS)

Mihmanli, I.; Kanberoglu, K.; Karaarslan, E.

2001-01-01

We present a case of acute retropharyngeal calcific tendinitis with characteristic findings on radiographic, computed tomography, and magnetic resonance imaging (MRI). To our knowledge, this is the first acute retropharyngeal calcific tendinitis report having inflammation of both the vertebra itself and the longus colli muscle diagnosed on MRI. In patients with neck pain, acute retropharyngeal calcific tendinitis should be kept in mind in the differential diagnosis, even if these patients had vertebral pathological signals on MRI. (orig.)

Involvement of glucocorticoid-mediated Zn2+ signaling in attenuation of hippocampal CA1 LTP by acute stress.

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Takeda, Atsushi; Suzuki, Miki; Tamano, Haruna; Takada, Shunsuke; Ide, Kazuki; Oku, Naoto

2012-03-01

Glucocorticoid-glutamatergic interactions have been proposed as a potential model to explain stress-mediated impairment of cognition. However, it is unknown whether glucocorticoid-zincergic interactions are involved in this impairment. Histochemically reactive zinc (Zn(2+)) is co-released with glutamate from zincergic neurons. In the present study, involvement of synaptic Zn(2+) in stress-induced attenuation of CA1 LTP was examined in hippocampal slices from young rats after exposure to tail suspension stress for 30s, which significantly increased serum corticosterone. Stress-induced attenuation of CA1 LTP was ameliorated by administration of clioquinol, a membrane permeable zinc chelator, to rats prior to exposure to stress, implying that the reduction of synaptic Zn(2+) by clioquinol participates in this amelioration. To pursue the involvement of corticosterone-mediated Zn(2+) signal in the attenuated CA1 LTP by stress, dynamics of synaptic Zn(2+) was checked in hippocampal slices exposed to corticosterone. Corticosterone increased extracellular Zn(2+) levels measured with ZnAF-2 dose-dependently, as well as the intracellular Ca(2+) levels measured with calcium orange AM, suggesting that corticosterone excites zincergic neurons in the hippocampus and increases Zn(2+) release from the neuron terminals. Intracellular Zn(2+) levels measured with ZnAF-2DA were also increased dose-dependently, but not in the coexistence of CaEDTA, a membrane-impermeable zinc chelator, suggesting that intracellular Zn(2+) levels is increased by the influx of extracellular Zn(2+). Furthermore, corticosterone-induced attenuation of CA1 LTP was abolished in the coexistence of CaEDTA. The present study suggests that corticosterone-mediated increase in postsynaptic Zn(2+) signal in the cytosolic compartment is involved in the attenuation of CA1 LTP after exposure to acute stress. Copyright © 2012 Elsevier Ltd. All rights reserved.

MR imaging of the femoral marrow in adult acute leukemia. Correlation of MRI patterns with FAB subtype and prognosis

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Tanaka, Osamu; Takagi, Shojiro; Kobayashi, Yasuyuki; Ichikawa, Tamaki; Matsuura, Katsuhiko; Nagai, Jun

1996-01-01

MR imaging of the femoral marrow was performed in 36 patients with untreated acute myeloid leukemia (AML) and 7 patients with acute lymphocytic leukemia (ALL). The MRI appearance was classified into five patterns: fatty marrow; faint signal; nodular pattern; heterogeneous infiltration; and diffuse infiltration. The MRI patterns of the femoral marrow were compared among the FAB subtypes of acute leukemia, and the MRI patterns were correlated with prognosis. All five MRI patterns were observed in the femoral marrow in adult acute leukemia, and diffuse infiltration was most commonly seen (41.9%). A completely fatty marrow was also depicted in two cases (4.7%) and faint signal in four cases (9.3%) in spite of untreated acute leukemia. The M2 subtype of AML tended to be demonstrated as a minimally abnormal MRI finding, which was significantly different from the other types of AML. The patients who showed fatty marrow or faint signal were thought to have a good prognosis, while diffuse or heterogeneous infiltration was regarded as a poor prognostic sign. However, there were some exceptions to these rules, and no significant differences were revealed in prognosis between minimally abnormal and advanced MRI patterns. We concluded that MRI of the femoral marrow could be useful in the assessment of tumor volume of adult acute leukemia, and that there were limitations to predicting prognosis on the basis of the MRI manifestations. (author)

Toxicity and antinociceptive effects of Hamelia patens

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Angel Josabad Alonso-Castro

Full Text Available Abstract Many medicinal herbs are used in folk medicine without taking into account their toxicity. Hamelia patens Jacq. (Rubiaceae, a Mexican endemic species, is used for the empirical treatment of pain. The aim of this work was to evaluate the toxicity and antinociceptive effects of ethanolic extracts of H. patens leaves. The toxicity of H. patens leaves (500–5000 mg/kg was evaluated in acute (14 days and subacute (28 days assays. In the subacute assay, a blood analysis (both hematology and chemistry was carried out. The antinociceptive effects of H. patens leaves (50–200 mg/kg were evaluated using thermal-induced nociception (hot plate and the chemical-induced nociceptive tests (acid acetic and formalin. In the acute toxicity test, the LD50 estimated for H. patens leaves was 2964 mg/kg i.p. and >5000 mg/kg p.o., whereas in the subacute test HPE did not affect hematological or biochemical parameters. In chemical-induced nociception models, H. patens (100 and 200 mg/kg p.o. showed antinociceptive effects with similar activity than 100 mg/kg naproxen. In the hot plate test, HPE at 100 mg/kg (17% and 200 mg/kg (25% showed moderate antinociceptive effects. HPE could be a good source of antinociceptive agents because of its good activity and low toxicity.

Astrocyte Sodium Signalling and Panglial Spread of Sodium Signals in Brain White Matter.

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Moshrefi-Ravasdjani, Behrouz; Hammel, Evelyn L; Kafitz, Karl W; Rose, Christine R

2017-09-01

In brain grey matter, excitatory synaptic transmission activates glutamate uptake into astrocytes, inducing sodium signals which propagate into neighboring astrocytes through gap junctions. These sodium signals have been suggested to serve an important role in neuro-metabolic coupling. So far, it is unknown if astrocytes in white matter-that is in brain regions devoid of synapses-are also able to undergo such intra- and intercellular sodium signalling. In the present study, we have addressed this question by performing quantitative sodium imaging in acute tissue slices of mouse corpus callosum. Focal application of glutamate induced sodium transients in SR101-positive astrocytes. These were largely unaltered in the presence of ionotropic glutamate receptors blockers, but strongly dampened upon pharmacological inhibition of glutamate uptake. Sodium signals induced in individual astrocytes readily spread into neighboring SR101-positive cells with peak amplitudes decaying monoexponentially with distance from the stimulated cell. In addition, spread of sodium was largely unaltered during pharmacological inhibition of purinergic and glutamate receptors, indicating gap junction-mediated, passive diffusion of sodium between astrocytes. Using cell-type-specific, transgenic reporter mice, we found that sodium signals also propagated, albeit less effectively, from astrocytes to neighboring oligodendrocytes and NG2 cells. Again, panglial spread was unaltered with purinergic and glutamate receptors blocked. Taken together, our results demonstrate that activation of sodium-dependent glutamate transporters induces sodium signals in white matter astrocytes, which spread within the astrocyte syncytium. In addition, we found a panglial passage of sodium signals from astrocytes to NG2 cells and oligodendrocytes, indicating functional coupling between these macroglial cells in white matter.

NF-κB in T-cell Acute Lymphoblastic Leukemia: Oncogenic Functions in Leukemic and in Microenvironmental Cells

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Santos, Nuno R. dos; Ghezzo, Marinella N.; Silva, Ricardo C. da; Fernandes, Mónica T.

2010-01-01

Two main NF-κB signaling pathways, canonical and noncanonical, performing distinct functions in organisms have been characterized. Identification of mutations in genes encoding components of these NF-κB signaling pathways in lymphoid malignancies confirmed their key role in leukemogenesis. T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive malignancy of thymocytes that despite significant therapeutic advances can still be fatal. Although mutations in NF-κB genes have not been reported in T-ALL, NF-κB constitutive activation in human T-ALL and in acute T-cell leukemia mouse models has been observed. Although these studies revealed activation of members of both canonical and noncanonical NF-κB pathways in acute T-cell leukemia, only inhibition of canonical NF-κB signaling was shown to impair leukemic T cell growth. Besides playing an important pro-oncogenic role in leukemic T cells, NF-κB signaling also appears to modulate T-cell leukemogenesis through its action in microenvironmental stromal cells. This article reviews recent data on the role of these transcription factors in T-ALL and pinpoints further research crucial to determine the value of NF-κB inhibition as a means to treat T-ALL

NF-κB in T-cell Acute Lymphoblastic Leukemia: Oncogenic Functions in Leukemic and in Microenvironmental Cells

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Santos, Nuno R. dos, E-mail: nrsantos@ualg.pt; Ghezzo, Marinella N.; Silva, Ricardo C. da; Fernandes, Mónica T. [IBB-Institute for Biotechnology and Bioengineering, Centre for Molecular and Structural Biomedicine (CBME), University of Algarve, Campus de Gambelas, 8005-139 Faro (Portugal)

2010-11-05

Two main NF-κB signaling pathways, canonical and noncanonical, performing distinct functions in organisms have been characterized. Identification of mutations in genes encoding components of these NF-κB signaling pathways in lymphoid malignancies confirmed their key role in leukemogenesis. T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive malignancy of thymocytes that despite significant therapeutic advances can still be fatal. Although mutations in NF-κB genes have not been reported in T-ALL, NF-κB constitutive activation in human T-ALL and in acute T-cell leukemia mouse models has been observed. Although these studies revealed activation of members of both canonical and noncanonical NF-κB pathways in acute T-cell leukemia, only inhibition of canonical NF-κB signaling was shown to impair leukemic T cell growth. Besides playing an important pro-oncogenic role in leukemic T cells, NF-κB signaling also appears to modulate T-cell leukemogenesis through its action in microenvironmental stromal cells. This article reviews recent data on the role of these transcription factors in T-ALL and pinpoints further research crucial to determine the value of NF-κB inhibition as a means to treat T-ALL.

Qi-Dong-Huo-Xue-Yin Inhibits Inflammation in Acute Lung Injury in Mice via Toll-Like Receptor 4/Caveolin-1 Signaling

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Li-Ying Xu

2018-01-01

Full Text Available Acute lung injury (ALI is a critical illness with no current effective treatment. Caveolin-1 indirectly activates inflammation-associated signaling pathways by inhibiting endothelial nitric oxide synthase (eNOS. This induces an imbalance between pro- and anti-inflammatory cytokine levels, which are involved in the pathogenesis of ALI. The compound Chinese prescription Qi-Dong-Huo-Xue-Yin (QDHXY is efficacious for ALI treatment via an anti-inflammatory effect; however, the exact underlying mechanism is unknown. Therefore, we explored the protective effect of QDHXY against lipopolysaccharide- (LPS- induced ALI in mice. Histopathological changes in mouse lung tissues were studied. Furthermore, alterations in the serum levels of pro- and anti-inflammatory cytokines were investigated. The levels of tumor necrosis factor- (TNF-α, interleukin- (IL- 6, IL-1β, and interferon-γ-induced protein 10 in bronchoalveolar lavage fluid were measured. Additionally, the expression levels of myeloid differentiation factor 88 (MyD88, caveolin-1, and eNOS were assessed. QDHXY significantly reduced lung infiltration with inflammatory cells and the production of serum pro- and anti-inflammatory cytokines and inhibited the expression of TNF-α, IL-1β, caveolin-1, and MyD88 but not eNOS. These indicate that QDHXY significantly improved the balance between pro- and anti-inflammatory cytokine levels, possibly by inhibiting the caveolin-1 signaling pathway. Therefore, QDHXY may be a potential treatment for ALI.

Effects of CD44 Ligation on Signaling and Metabolic Pathways in Acute Myeloid Leukemia

KAUST Repository

Madhoun, Nour Y.

2017-04-01

Acute myeloid leukemia (AML) is characterized by a blockage in the differentiation of myeloid cells at different stages. CD44-ligation using anti-CD44 monoclonal antibodies (mAbs) has been shown to reverse the blockage of differentiation and to inhibit the proliferation of blasts in most AML-subtypes. However, the molecular mechanisms underlying this property have not been fully elucidated. Here, we sought to I) analyze the effects of anti-CD44 mAbs on downstream signaling pathways, including the ERK1/2 (extracellular signal-regulated kinase 1 and 2) and mTOR (mammalian target of rapamycin) pathways and II) use state-of-the-art Nuclear Magnetic Resonance (NMR) technology to determine the global metabolic changes during differentiation induction of AML cells using anti-CD44 mAbs and other two previously reported differentiation agents. In the first objective (Chapter 4), our studies provide evidence that CD44-ligation with specific mAbs in AML cells induced an increase in ERK1/2 phosphorylation. The use of the MEK inhibitor (U0126) significantly inhibited the CD44-induced differentiation of HL60 cells, suggesting that ERK1/2 is critical for the CD44-triggered differentiation in AML. In addition, this was accompanied by a marked decrease in the phosphorylation of the mTORC1 and mTORC2 complexes, which are strongly correlated with the inhibition of the PI3K/Akt pathway. In the second objective (Chapter 5), 1H NMR experiments demonstrated that considerable changes in the metabolic profiles of HL60 cells were induced in response to each differentiation agent. These most notable metabolites that significantly changed upon CD44 ligation were involved in the tricarboxylic acid (TCA) cycle and glycolysis such as, succinate, fumarate and lactate. Therefore, we sought to analyze the mechanisms underlying their alterations. Our results revealed that anti-CD44 mAbs treatment induced upregulation in fumarate hydratase (FH) expression and its activity which was accompanied by a

Targeting the phosphatidylinositol 3-kinase/Akt/mechanistic target of rapamycin signaling pathway in B-lineage acute lymphoblastic leukemia: An update.

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Simioni, Carolina; Martelli, Alberto M; Zauli, Giorgio; Vitale, Marco; McCubrey, James A; Capitani, Silvano; Neri, Luca M

2018-04-18

Despite considerable progress in treatment protocols, B-lineage acute lymphoblastic leukemia (B-ALL) displays a poor prognosis in about 15-20% of pediatric cases and about 60% of adult patients. In addition, life-long irreversible late effects from chemo- and radiation therapy, including secondary malignancies, are a growing problem for leukemia survivors. Targeted therapy holds promising perspectives for cancer treatment as it may be more effective and have fewer side effects than conventional therapies. The phosphatidylinositol 3-phosphate kinase (PI3K)/Akt/mechanistic target of rapamycin (mTOR) signaling pathway is a key regulatory cascade which controls proliferation, survival and drug-resistance of cancer cells, and it is frequently upregulated in the different subtypes of B-ALL, where it plays important roles in the pathophysiology, maintenance and progression of the disease. Moreover, activation of this signaling cascade portends a poorer prognosis in both pediatric and adult B-ALL patients. Promising preclinical data on PI3K/Akt/mTOR inhibitors have documented their anticancer activity in B-ALL and some of these novel drugs have entered clinical trials as they could lead to a longer event-free survival and reduce therapy-associated toxicity for patients with B-ALL. This review highlights the current status of PI3K/Akt/mTOR inhibitors in B-ALL, with an emphasis on emerging evidence of the superior efficacy of synergistic combinations involving the use of traditional chemotherapeutics or other novel, targeted agents. © 2018 Wiley Periodicals, Inc.

Ketamine as an Adjunct to Postoperative Pain Management in Opioid Tolerant Patients After Spinal Fusions: A Prospective Randomized Trial

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Urban, Michael K.; Ya Deau, Jacques T.; Wukovits, Barbara; Lipnitsky, Jane Y.

2007-01-01

Management of acute postoperative pain is challenging, particularly in patients with preexisting narcotic dependency. Ketamine has been used at subanesthetic doses as a N-methyl d-aspartate (NMDA) receptor antagonist to block the processing of nociceptive input in chronic pain syndromes. This prospective randomized study was designed to assess the use of ketamine as an adjunct to acute pain management in narcotic tolerant patients after spinal fusions. Twenty-six patients for 1–2 level poster...

The role of c-AMP-dependent protein kinase in spinal cord and post synaptic dorsal column neurons in a rat model of visceral pain.

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Wu, Jing; Su, Guangxiao; Ma, Long; Zhang, Xuan; Lei, Yongzhong; Lin, Qing; Nauta, Haring J W; Li, Junfa; Fang, Li

2007-04-01

Visceral noxious stimulation induces central neuronal plasticity changes and suggests that the c-AMP-dependent protein kinase (PKA) signal transduction cascade contributes to long-term changes in nociceptive processing at the spinal cord level. Our previous studies reported the clinical neurosurgical interruption of post synaptic dorsal column neuron (PSDC) pathway by performing midline myelotomy effectively alleviating the intractable visceral pain in patients with severe pain. However, the intracellular cascade in PSDC neurons mediated by PKA nociceptive neurotransmission was not known. In this study, by using multiple experimental approaches, we investigated the role of PKA in nociceptive signaling in the spinal cord and PSDC neurons in a visceral pain model in rats with the intracolonic injection of mustard oil. We found that mustard oil injection elicited visceral pain that significantly changed exploratory behavior activity in rats in terms of decreased numbers of entries, traveled distance, active and rearing time, rearing activity and increased resting time when compared to that of rats receiving mineral oil injection. However, the intrathecal infusion of PKA inhibitor, H89 partially reversed the visceral pain-induced effects. Results from Western blot studies showed that mustard oil injection significantly induced the expression of PKA protein in the lumbosacral spinal cord. Immunofluorescent staining in pre-labeled PSDC neurons showed that mustard oil injection greatly induces the neuronal profile numbers. We also found that the intrathecal infusion of a PKA inhibitor, H89 significantly blocked the visceral pain-induced phosphorylation of c-AMP-responsive element binding (CREB) protein in spinal cord in rats. The results of our study suggest that the PKA signal transduction cascade may contribute to visceral nociceptive changes in spinal PSDC pathways.

Blockade of Cannabinoid CB1 Receptors in the Dorsal Periaqueductal Gray Unmasks the Antinociceptive Effect of Local Injections of Anandamide in Mice

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Diego C. Mascarenhas

2017-10-01

Full Text Available Divergent results in pain management account for the growing number of studies aiming at elucidating the pharmacology of the endocannabinoid/endovanilloid anandamide (AEA within several pain-related brain structures. For instance, the stimulation of both Transient Receptor Potential Vanilloid type 1 (TRPV1 and Cannabinoid type 1 (CB1 receptors led to paradoxical effects on nociception. Here, we attempted to propose a clear and reproducible methodology to achieve the antinociceptive effect of exogenous AEA within the dorsal periaqueductal gray (dPAG of mice exposed to the tail-flick test. Accordingly, male Swiss mice received intra-dPAG injection of AEA (CB1/TRPV1 agonist, capsaicin (TRPV1 agonist, WIN (CB1 agonist, AM251 (CB1 antagonist, and 6-iodonordihydrocapsaicin (6-IODO (TRPV1 selective antagonist and their nociceptive response was assessed with the tail-flick test. In order to assess AEA effects on nociception specifically at vanilloid or cannabinoid (CB substrates into the dPAG, mice underwent an intrinsically inactive dose of AM251 or 6-IODO followed by local AEA injections and were subjected to the same test. While intra-dPAG AEA did not change acute pain, local injections of capsaicin or WIN induced a marked TRPV1- and CB1-dependent antinociceptive effect, respectively. Regarding the role of AEA specifically at CB/vanilloid substrates, while the blockade of TRPV1 did not change the lack of effects of intra-dPAG AEA on nociception, local pre-treatment of AM251, a CB1 antagonist, led to a clear AEA-induced antinociception. It seems that the exogenous AEA-induced antinociception is unmasked when it selectively binds to vanilloid substrates, which might be useful to address acute pain in basic and perhaps clinical trials.

The evaluation of fat saturation fast spin-echo T2W1 for patients with acute spinal trauma

International Nuclear Information System (INIS)

Kim, Sung Gyu; Lee, Chang Jun; Lee, Myung Joon; Kang, Ik Won; Yoo, Jeong Hyun

2002-01-01

To determine the usefulness of fat saturation fast spin-echo T2W1 for patients with mild acute trauma of the spine. Between July 1998 and June 2002, 36 patients with acute spinal trauma underwent MRI within four months of injury. One, whose clinal symptoms indicated neurological paralysis, was excluded form our study. A superconductive 1.0-T MRI scanner was used, and conventional T1W1, T2W1, and additional fat-saturation fast spin-echo T2W1 were performed. Two radiologists compared conventional T2-weighted sagittal imaging and fat-saturation T2-weighted sagittal imaging in terms of the extension of increased high signal intensities in soft tissue and vertebral bodies, bone marrow signal change, disk herniation, and signal change of the disk. The detection rate of focal high signal intensities in soft tissue and bone marrow was significantly higher at fat-saturation fast spin-echo T2W1 than at conventional T2W1. Fat-saturation fast spin-echo T2W1 is useful for the evaluation of patients with mild acute spinal trauma without neurological impairment

Acute carbon monoxide intoxication : the relation between MR findings and clinical outcome

International Nuclear Information System (INIS)

Chang, Jin Bae; Jeong, Hae Woong; Kim, Ki Nam; Kim, Dong Wook; Kim, Chang Soo

1999-01-01

To analyse MR findings of various involving sites and the relation between such findings and clinical outcome, the authors retrospectively reviewed MR images of acute carbon monoxide intoxication. In 12 patients, MR images obtained from several hours to 12 days after acute carbon monoxide intoxication were reviewed. The images were analysed with regard to involved sites, symmetricity, signal intensity, and the presence or absence of hemorrhage, and the relationship between MR findings and clinical outcome; the presence of delayed encephalopathy was then determined. The globus pallidus(n=9), white matter(n=3), [centrum semiovale(n=2), periventricular white matter(n=1)] and gyrus(n=6) [inferior temporal gyrus(n=2), cingulate gyrus(n=1), precentral gyrus(n=1), hippocampal gyrus(n=1), parahippocampal gyrus(n=1)] were typically involved, and there was also involvenent of the corpus callosum(n=3), thalamus(n=2) and midbrain(n=2). All lesions of the globus pallidus, thalamus, midbrain and temporal lobe were bilaterally symmetric. In all these cases, subtle or prominent low signal intensity was seen on spin-echo T1WI, and high signal intensity on PDWI and T2WI. Some lesions of the globus pallidus(n=1), thalamus(n=1) and midbrain(n=1) were associated with hemorrhage, which occurred during the early subacute stage and was seen on high/low signal intensity T1/T2WI images. Acute cerebral(n=1) and cerebellar(n=1) infarctions were also seen. Cerebral white matter involvement correlated with poor clinical outcome, and in two cases, delayed encephalopathy developed. In these cases of acute carbon monoxide intoxication, the globus pallidus, white matter, cortex and hippocampus were frequently involved, and there was also involvement of various sites such as the corpus callosum, thalamus and midbrain. Lesions of the temporal lobe, thalamus and midbrain were bilaterally symmetric. The involvement of cerebral white matter and the presence of delayed encephalopathy can influence

Effect of painless diabetic neuropathy on pressure pain hypersensitivity (hyperalgesia after acute foot trauma

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Tobias Wienemann

2014-11-01

Full Text Available Introduction and objective: Acute injury transiently lowers local mechanical pain thresholds at a limb. To elucidate the impact of painless (diabetic neuropathy on this post-traumatic hyperalgesia, pressure pain perception thresholds after a skeletal foot trauma were studied in consecutive persons without and with neuropathy (i.e. history of foot ulcer or Charcot arthropathy. Design and methods: A case–control study was done on 25 unselected clinical routine patients with acute unilateral foot trauma (cases: elective bone surgery; controls: sprain, toe fracture. Cases were 12 patients (11 diabetic subjects with severe painless neuropathy and chronic foot pathology. Controls were 13 non-neuropathic persons. Over 1 week after the trauma, cutaneous pressure pain perception threshold (CPPPT and deep pressure pain perception threshold (DPPPT were measured repeatedly, adjacent to the injury and at the opposite foot (pinprick stimulators, Algometer II®. Results: In the control group, post-traumatic DPPPT (but not CPPPT at the injured foot was reduced by about 15–25%. In the case group, pre- and post-operative CPPPT and DPPPT were supranormal. Although DPPPT fell post-operatively by about 15–20%, it remained always higher than the post-traumatic DPPPT in the control group: over musculus abductor hallucis 615 kPa (kilopascal versus 422 kPa, and over metatarsophalangeal joint 518 kPa versus 375 kPa (medians; case vs. control group; CPPPT did not decrease post-operatively. Conclusion: Physiological nociception and post-traumatic hyperalgesia to pressure are diminished at the foot with severe painless (diabetic neuropathy. A degree of post-traumatic hypersensitivity required to ‘pull away’ from any one, even innocuous, mechanical impact in order to avoid additional damage is, therefore, lacking.

Effect of painless diabetic neuropathy on pressure pain hypersensitivity (hyperalgesia) after acute foot trauma

Science.gov (United States)

Wienemann, Tobias; Chantelau, Ernst A.; Koller, Armin

2014-01-01

Introduction and objective Acute injury transiently lowers local mechanical pain thresholds at a limb. To elucidate the impact of painless (diabetic) neuropathy on this post-traumatic hyperalgesia, pressure pain perception thresholds after a skeletal foot trauma were studied in consecutive persons without and with neuropathy (i.e. history of foot ulcer or Charcot arthropathy). Design and methods A case–control study was done on 25 unselected clinical routine patients with acute unilateral foot trauma (cases: elective bone surgery; controls: sprain, toe fracture). Cases were 12 patients (11 diabetic subjects) with severe painless neuropathy and chronic foot pathology. Controls were 13 non-neuropathic persons. Over 1 week after the trauma, cutaneous pressure pain perception threshold (CPPPT) and deep pressure pain perception threshold (DPPPT) were measured repeatedly, adjacent to the injury and at the opposite foot (pinprick stimulators, Algometer II®). Results In the control group, post-traumatic DPPPT (but not CPPPT) at the injured foot was reduced by about 15–25%. In the case group, pre- and post-operative CPPPT and DPPPT were supranormal. Although DPPPT fell post-operatively by about 15–20%, it remained always higher than the post-traumatic DPPPT in the control group: over musculus abductor hallucis 615 kPa (kilopascal) versus 422 kPa, and over metatarsophalangeal joint 518 kPa versus 375 kPa (medians; case vs. control group); CPPPT did not decrease post-operatively. Conclusion Physiological nociception and post-traumatic hyperalgesia to pressure are diminished at the foot with severe painless (diabetic) neuropathy. A degree of post-traumatic hypersensitivity required to ‘pull away’ from any one, even innocuous, mechanical impact in order to avoid additional damage is, therefore, lacking. PMID:25397867

Effect of painless diabetic neuropathy on pressure pain hypersensitivity (hyperalgesia) after acute foot trauma.

Science.gov (United States)

Wienemann, Tobias; Chantelau, Ernst A; Koller, Armin

2014-01-01

Acute injury transiently lowers local mechanical pain thresholds at a limb. To elucidate the impact of painless (diabetic) neuropathy on this post-traumatic hyperalgesia, pressure pain perception thresholds after a skeletal foot trauma were studied in consecutive persons without and with neuropathy (i.e. history of foot ulcer or Charcot arthropathy). A case-control study was done on 25 unselected clinical routine patients with acute unilateral foot trauma (cases: elective bone surgery; controls: sprain, toe fracture). Cases were 12 patients (11 diabetic subjects) with severe painless neuropathy and chronic foot pathology. Controls were 13 non-neuropathic persons. Over 1 week after the trauma, cutaneous pressure pain perception threshold (CPPPT) and deep pressure pain perception threshold (DPPPT) were measured repeatedly, adjacent to the injury and at the opposite foot (pinprick stimulators, Algometer II(®)). In the control group, post-traumatic DPPPT (but not CPPPT) at the injured foot was reduced by about 15-25%. In the case group, pre- and post-operative CPPPT and DPPPT were supranormal. Although DPPPT fell post-operatively by about 15-20%, it remained always higher than the post-traumatic DPPPT in the control group: over musculus abductor hallucis 615 kPa (kilopascal) versus 422 kPa, and over metatarsophalangeal joint 518 kPa versus 375 kPa (medians; case vs. control group); CPPPT did not decrease post-operatively. Physiological nociception and post-traumatic hyperalgesia to pressure are diminished at the foot with severe painless (diabetic) neuropathy. A degree of post-traumatic hypersensitivity required to 'pull away' from any one, even innocuous, mechanical impact in order to avoid additional damage is, therefore, lacking.

The Peripheral Whole Blood Transcriptome of Acute Pyelonephritis in Human Pregnancy

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Madan, Ichchha; Than, Nandor Gabor; Romero, Roberto; Chaemsaithong, Piya; Miranda, Jezid; Tarca, Adi L.; Bhatti, Gaurav; Draghici, Sorin; Yeo, Lami; Mazor, Moshe; Hassan, Sonia S.; Chaiworapongsa, Tinnakorn

2018-01-01

Objective Human pregnancy is characterized by activation of the innate immune response and suppression of adaptive immunity. The former is thought to provide protection against infection to the mother, and the latter, tolerance against paternal antigens expressed in fetal cells. Acute pyelonephritis is associated with an increased risk of acute respiratory distress syndrome and sepsis in pregnant (vs. nonpregnant) women. The objective of this study was to describe the gene expression profile (transcriptome) of maternal whole blood in acute pyelonephritis. Method A case-control study was conducted to include pregnant women with acute pyelonephritis (n=15) and women with a normal pregnancy (n=34). Affymetrix HG-U133 Plus 2.0 arrays (Affymetrix, Santa Clara, CA, USA) were used for gene expression profiling. A linear model was used to test the association between the presence of pyelonephritis and gene expression levels while controlling for white blood cell count and gestational age. A fold change of 1.5 was considered significant at a false discovery rate of 0.1. A subset of differentially expressed genes (n=56) was tested with real-time quantitative reverse transcription-polymerase chain reaction (qRT-PCR) (cases, n=19; controls, n=59). Gene ontology and pathway analysis were applied. Results A total of 983 genes were differentially expressed in acute pyelonephritis: 457 were up-regulated and 526 were down-regulated. Significant enrichment of 300 biological processes and 63 molecular functions was found in pyelonephritis. Significantly impacted pathways in pyelonephritis included a) cytokine-cytokine receptor interaction; b) T-cell receptor signaling; c) Jak-STAT signaling; and d) complement and coagulation cascades. Of 56 genes tested by qRT-PCR, 48 (85.7%) had confirmation of differential expression. Conclusion This is the first study of the transcriptomic signature of whole blood in pregnant women with acute pyelonephritis. Acute infection during pregnancy is

Involvement of melatonin metabolites in the long-term inhibitory effect of the hormone on rat spinal nociceptive transmission.

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Mondaca, Mauricio; Hernández, Alejandro; Valladares, Luis; Sierralta, Walter; Noseda, Rodrigo; Soto-Moyano, Rubén

2004-02-01

There is evidence that melatonin and its metabolites could bind to nuclear sites in neurones, suggesting that this hormone is able to exert long-term functional effects in the central nervous system via genomic mechanisms. This study was designed to investigate (i) whether systemically administered melatonin can exert long-term effects on spinal cord windup activity, and (ii) whether blockade of melatonin degradation with eserine could prevent this effect. Rats receiving melatonin (10 mg/kg ip), the same dose of melatonin plus eserine (0.5 mg/kg ip), or saline were studied. Seven days after administration of the drugs or saline, spinal windup of rats was assessed in a C-fiber reflex response paradigm. Results show that rats receiving melatonin exhibited a reduction in spinal windup activity. This was not observed in the animals receiving melatonin plus eserine or saline, suggesting a role for melatonin metabolites in long-term changes of nociceptive transmission in the rat spinal cord.

Bone signal abnormality, as seen on knee joint MRI : relationship between its location and associated injury

International Nuclear Information System (INIS)

Kim, Young Nam; Kim, Baek Hyun; Jung, Hoe Seok; Na, Eui Sung; Seol, Hye Young; Cha, In Ho; Lim, Hong Chul

1998-01-01

The purpose of the study was to evaluate the relationship between the location of bone signal abnormality and associated injury, as seen on MR, in patients with acute knee joint injury. Materials and Methods: Thirty-six patients with acute knee injury and bone signal abnormalities on MR were included in this study. The femur and tibia were each divided into six compartments, namely the anteromedial, medial, posteromedial,anterolateral, lateral, and posterolateral ; these were obtained in each knee joint. We evaluated the location of bone signal abnormality and the corresponding arthroscopic or operative findings of injury to ligaments and menisci. Cases with signal abnormalities involving more than three compartments were excluded. Results : Bone signal abnormalities were demonstrated in 51 compartments. Most(84%, 43/51) were noted in the lateral half of the knee joint, the most common location being the tibio- posterolateral compartment(13/51). The femoro-lateral(11/51) and tibio- anterolateral compartment(8/51) were the next most common locations. All cases(13/13)with bone signal abnormality in the tibio- posterolateral compartment had tears at the anterior cruciate ligament,while 9 of 11 cases(81%) with abnormality in the femoro- lateral compartment had tears at the anterior cruciate ligament. Six of eight cases(75%) with signal abnormality in the tibio- anterolateral compartment had tears at the posterior cruciate ligament ; 31 of 43 cases (72%) with abnormality in the lateral half of the knee joint had tears at the medial collateral ligament. Six of eight cases(75%) with signal abnormality in the medial half of the knee joint had tears at the medial meniscus, but no lateral meniscal tear was found. Among patients with signal abnormality in the lateral half of the knee joint, the tear was lateral meniscal in nine of 43 cases(21%) and medial meniscal in six of 43(14%). Conclusion : The location of bone signal abnormality, as seen on knee MR, inpatients with

Dynamic Regulation of Delta-Opioid Receptor in Rat Trigeminal Ganglion Neurons by Lipopolysaccharide-induced Acute Pulpitis.

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Huang, Jin; Lv, Yiheng; Fu, Yunjie; Ren, Lili; Wang, Pan; Liu, Baozhu; Huang, Keqiang; Bi, Jing

2015-12-01

Delta-opioid receptor (DOR) and its endogenous ligands distribute in trigeminal system and play a very important role in modulating peripheral inflammatory pain. DOR activation can trigger p44/42 mitogen-activated protein kinase (ERK1/2) and Akt signaling pathways, which participate in anti-inflammatory and neuroprotective effects. In this study, our purpose was to determine the dynamic changes of DOR in trigeminal ganglion (TG) neurons during the process of acute dental pulp inflammation and elucidate its possible mechanism. Forty rats were used to generate lipopolysaccharide-induced acute pulpitis animal models at 6, 12, and 24 hours and sham-operated groups. Acute pulpitis was confirmed by hematoxylin-eosin staining, and TG neuron activation was determined by anti-c-Fos immunohistochemistry. DOR protein and gene expression in TG was investigated by immunohistochemistry, Western blotting, and real-time polymerase chain reaction, and DOR expression in trigeminal nerves and dental pulp was also determined by immunohistochemistry. To further investigate the mechanism of DOR modulating acute inflammation, the change of pErk1/2 and pAkt in TG was examined by immunohistochemistry. Lipopolysaccharide could successfully induce acute pulpitis and activated TG neurons. Acute pulpitis could dynamically increase DOR protein and gene expression at 6, 12, and 24 hours in TG, and DOR dimerization was significantly increased at 12 and 24 hours. Acute pulpitis also induced the dynamic change of DOR protein in trigeminal nerve and dental pulp. Furthermore, ERK1/2 and Akt signaling pathways were inhibited in TG after acute pulpitis. Increased DOR expression and dimerization may play important roles in peripheral acute inflammatory pain. Copyright © 2015 American Association of Endodontists. Published by Elsevier Inc. All rights reserved.

Reduced acute nociception and chronic pain in Shank2 ?/? mice

OpenAIRE

Ko, Hyoung-Gon; Oh, Seog-Bae; Zhuo, Min; Kaang, Bong-Kiun

2016-01-01

Autism spectrum disorder is a debilitating mental illness and social issue. Autism spectrum disorder patients suffer from social isolation, cognitive deficits, compulsive behavior, and sensory deficits, including hyposensitivity to pain. However, recent studies argued that autism spectrum disorder patients show physiological pain response and, in some cases, even extremely intense pain response to harmless stimulation. Recently, Shank gene family was reported as one of the genetic risk factor...

Acute Pancreatitis in acute viral hepatitis

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S K.C.

2011-03-01

Full Text Available Introduction: The association of acute viral hepatitis and acute pancreatitis is well described. This study was conducted to find out the frequency of pancreatic involvement in acute viral hepatitis in the Nepalese population. Methods: Consecutive patients of acute viral hepatitis presenting with severe abdominal pain between January 2005 and April 2010 were studied. Patients with history of significant alcohol consumption and gall stones were excluded. Acute viral hepatitis was diagnosed by clinical examination, liver function test, ultrasound examination and confirmed by viral serology. Pancreatitis was diagnosed by clinical presentation, biochemistry, ultrasound examination and CT scan. Results: Severe abdominal pain was present in 38 of 382 serologically-confirmed acute viral hepatitis patients. Twenty five patients were diagnosed to have acute pancreatitis. The pancreatitis was mild in 14 and severe in 11 patients. The etiology of pancreatitis was hepatitis E virus in 18 and hepatitis A virus in 7 patients. Two patients died of complications secondary to shock. The remaining patients recovered from both pancreatitis and hepatitis on conservative treatment. Conclusions: Acute pancreatitis occurred in 6.5 % of patients with acute viral hepatitis. Cholelithiasis and gastric ulcers are the other causes of severe abdominal pain. The majority of the patients recover with conservative management. Keywords: acute viral hepatitis, acute pancreatitis, pain abdomen, hepatitis E, hepatitis A, endemic zone

Chronic stress exacerbates neuropathic pain via the integration of stress-affect-related information with nociceptive information in the central nucleus of the amygdala.

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Li, Ming-Jia; Liu, Ling-Yu; Chen, Lin; Cai, Jie; Wan, You; Xing, Guo-Gang

2017-04-01

Exacerbation of pain by chronic stress and comorbidity of pain with stress-related psychiatric disorders, including anxiety and depression, represent significant clinical challenges. However, the underlying mechanisms still remain unclear. Here, we investigated whether chronic forced swim stress (CFSS)-induced exacerbation of neuropathic pain is mediated by the integration of stress-affect-related information with nociceptive information in the central nucleus of the amygdala (CeA). We first demonstrated that CFSS indeed produces both depressive-like behaviors and exacerbation of spared nerve injury (SNI)-induced mechanical allodynia in rats. Moreover, we revealed that CFSS induces both sensitization of basolateral amygdala (BLA) neurons and augmentation of long-term potentiation (LTP) at the BLA-CeA synapse and meanwhile, exaggerates both SNI-induced sensitization of CeA neurons and LTP at the parabrachial (PB)-CeA synapse. In addition, we discovered that CFSS elevates SNI-induced functional up-regulation of GluN2B-containing NMDA (GluN2B-NMDA) receptors in the CeA, which is proved to be necessary for CFSS-induced augmentation of LTP at the PB-CeA synapse and exacerbation of pain hypersensitivity in SNI rats. Suppression of CFSS-elicited depressive-like behaviors by antidepressants imipramine or ifenprodil inhibits the CFSS-induced exacerbation of neuropathic pain. Collectively, our findings suggest that CFSS potentiates synaptic efficiency of the BLA-CeA pathway, leading to the activation of GluN2B-NMDA receptors and sensitization of CeA neurons, which subsequently facilitate pain-related synaptic plasticity of the PB-CeA pathway, thereby exacerbating SNI-induced neuropathic pain. We conclude that chronic stress exacerbates neuropathic pain via the integration of stress-affect-related information with nociceptive information in the CeA.

Usefulness of 2D PC MRA of the circle of willis in the evaluation of acute cerebral infarction

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Kwon, Oh Han; Lee, Jae Hee; Kim, Ki Ju; Lee, Sung Yong [Our Lady of Mercy Hospital, Seoul (Korea, Republic of); Choi, Kyu Ho [The Catholic Univ. of Korea, Seoul (Korea, Republic of)

1999-11-01

To evaluate the usefulness of axial 2-D PC MRA of the circle of Willis in the evaluation of acute cerebral infarction We evaluated 42 patients with acute cerebral infarction who had undergone T2-weighted and diffusion weighted MR imaging (T2WI, DWI) and 2-D PC MRA of the circle of Willis within 72 hours of the onset of symptoms. In conjunction with high-signal lesions on DWI, the findings of 2-D PC MRA were classified as normal, stenotic, or indicative of arterial occlusion;negative 2-D PC MRA was not considered useful. In addition, the signal intensity of T2WI and DWI was compared. (The findings of 2-D PC MRA showed that 15 cases(35.7%) were normal, 13(31%) were stenotic, and that in 14 (33.3%), occlusion was present). Thus, 2-D PC MRA detected vascular abnormality in 27 cases(64.3%). On T2WI, six cases (14.3%) showed no signal change and 36(85.7%) showed high signal change. In six cases without signal change, MR images were obtained within 12 hours of ictus;in one of these patients MRA findings were normal, one had stenosis, and in four, occlusion was noted. 2-D PC MRA is a useful modality for the detection of vascular abnormality in patients with acute cerebral infarct.

Phytochemicals from Ruta graveolens Activate TAS2R Bitter Taste Receptors and TRP Channels Involved in Gustation and Nociception.

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Mancuso, Giuseppe; Borgonovo, Gigliola; Scaglioni, Leonardo; Bassoli, Angela

2015-10-16

Ruta graveolens (rue) is a spontaneous plant in the Mediterranean area with a strong aroma and a very intense bitter taste, used in gastronomy and in folk medicine. From the leaves, stems and fruits of rue, we isolated rutin, rutamarin, three furanocoumarins, two quinolinic alkaloids, a dicoumarin and two long chain ketones. Bitter taste and chemesthetic properties have been evaluated by in vitro assays with twenty receptors of the TAS2R family and four TRP ion channels involved in gustation and nociception. Among the alkaloids, skimmianine was active as a specific agonist of T2R14, whereas kokusaginin did not activate any of the tested receptors. The furanocoumarins activates TAS2R10, 14, and 49 with different degrees of selectivity, as well as the TRPA1 somatosensory ion channel. Rutamarin is an agonist of TRPM5 and TRPV1 and a strong antagonist of TRPM8 ion channels.

Adaptation of signal transduction and muscle proteome in trained horses

NARCIS (Netherlands)

Ginneken, Mireille Maria Elisabeth van

2006-01-01

In the present thesis the localization and activation of signaling proteins, known from human studies, in equine muscle were investigated under conditions of rest, after an acute bout of exercise and before and after a period of (intensified) training. Proteins of interest (protein kinase C (PKC),

MRI evaluation of acute articular cartilage injury of knee

International Nuclear Information System (INIS)

Zhang Jun; Wu Zhenhua; Fan Guoguang; Pan Shinong; Guo Qiyong

2003-01-01

Objective: To study the MRI manifestation of acute articular cartilage injury of knee for evaluating the extension and degree of the injury and guiding treatment. Methods: MRI of 34 patients with acute articular cartilage injury of knee within one day to fifteen days confirmed by arthroscopy and arthrotomy was reviewed and analyzed, with emphasis on articular cartilage and subchondral lesion. And every manifestation on MRI and that of arthroscopy and operation was compared. Results: The articular cartilage injury was diagnosed on MRI in 29 of 34 cases. Cartilage signal changes were found only in 4. The changes of cartilage shape were variable. Thinning of focal cartilage was showed in 3, osteochondral impaction in 3, creases of cartilage in 3, disrupted cartilage with fissuring in 13, cracks cartilage in 2, and cracks cartilage with displaced fragment in 1. Bone bruise and occult fracture were found only on MRI. Conclusion: The assessment of MRI and arthroscopy in acute articular cartilage injury are consistent. Combined with arthroscopy, MRI can succeed in assessing the extension and degree of acute articular injury and allowing treatment planning

IFN-γ signaling to astrocytes protects from autoimmune mediated neurological disability.

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Claudia Hindinger

Full Text Available Demyelination and axonal degeneration are determinants of progressive neurological disability in patients with multiple sclerosis (MS. Cells resident within the central nervous system (CNS are active participants in development, progression and subsequent control of autoimmune disease; however, their individual contributions are not well understood. Astrocytes, the most abundant CNS cell type, are highly sensitive to environmental cues and are implicated in both detrimental and protective outcomes during autoimmune demyelination. Experimental autoimmune encephalomyelitis (EAE was induced in transgenic mice expressing signaling defective dominant-negative interferon gamma (IFN-γ receptors on astrocytes to determine the influence of inflammation on astrocyte activity. Inhibition of IFN-γ signaling to astrocytes did not influence disease incidence, onset, initial progression of symptoms, blood brain barrier (BBB integrity or the composition of the acute CNS inflammatory response. Nevertheless, increased demyelination at peak acute disease in the absence of IFN-γ signaling to astrocytes correlated with sustained clinical symptoms. Following peak disease, diminished clinical remission, increased mortality and sustained astrocyte activation within the gray matter demonstrate a critical role of IFN-γ signaling to astrocytes in neuroprotection. Diminished disease remission was associated with escalating demyelination, axonal degeneration and sustained inflammation. The CNS infiltrating leukocyte composition was not altered; however, decreased IL-10 and IL-27 correlated with sustained disease. These data indicate that astrocytes play a critical role in limiting CNS autoimmune disease dependent upon a neuroprotective signaling pathway mediated by engagement of IFN-γ receptors.

Effects of CD44 Ligation on Signaling and Metabolic Pathways in Acute Myeloid Leukemia

KAUST Repository

Madhoun, Nour Y.

2017-01-01

Acute myeloid leukemia (AML) is characterized by a blockage in the differentiation of myeloid cells at different stages. CD44-ligation using anti-CD44 monoclonal antibodies (mAbs) has been shown to reverse the blockage of differentiation

Evaluation of anti-nociceptive and anti-inflammatory activities of hydroalcoholic extract derived from root of Apium graveolens L. in mice

Directory of Open Access Journals (Sweden)

2017-11-01

Full Text Available Background and objectives: Apium graveolens L. (celery has been considered as sedative, analgesic, carminative, antispasmodic and diuretic plant in traditional Iranian medicine. The aim of the present study was to evaluate the anti-nociceptive and anti-inflammatory effect of celery root in mice. Methods: Analgesic effect of celery root was determined by two animal models of hot plate and acetic acid writhing test. Anti-inflammatory potential of the extract was also determined by formalin induced ear edema and xylene induced paw edema tests.  Results: The result showed no significant difference between the positive control group and the test group in hot plate test and the most effective dose of celery root was 200 mg/kg, while the frequency of writhings was significantly different in whole test groups in comparison with control group (p

Role of olfactory reactions, nociception, and immunoendocrine shifts in addictive disorders.

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Masterova, Elena; Nevidimova, Tatiana; Savochkina, Dariya; Nikitina, Valentina; Lobacheva, Olga; Vetlugina, Tamara; Bokhan, Nikolay

2017-09-01

Addictive pathology is associated with nervous, immune, and endocrine shifts. Meanwhile, the nature of intersystemic relationship lying beneath addictive disorders remains unclear. The purpose of the study was to identify neuroimmunoendocrine markers of addictive disorders in male subjects defining the nature of their interaction. The study enrolled 69 subjects aged 18-43 years: 59 males and 10 females divided into those with addictive disorders (n = 39) and conditionally healthy subjects (n = 30). EEG testing with olfactory stimulation, olfactometric, and pressure algometric examinations was carried out. Multiplex technique was applied to determine mitogen-induced production of cytokines IL-10, IL-1, IL-1RA, IL-2, IFN-gamma, TNF-alpha. ELISA method was applied to measure serum cortisol and testosterone levels. Olfactory responses to isopropanol with open eyes in addicted patients manifested as increase in alpha-rhythm and beta1-rhythm, with closed eyes presentation of this odorant was accompanied by increase of theta-rhythm in opioid-addicted patients. Male subjects with addictive disorders showed reduced alpha-rhythm in terms of olfactory stimulation with modified emotional evaluation of the odorant, deficient mitogen-induced production of IFN-gamma, and reduced pain sensitivity. Male subjects with opioid addiction had reduced beta1-rhythm in terms of olfactory stimulation, mitogen-induced production of IFN-gamma, and elevated testosterone level. The findings obtained verify potential involvement of nociception, olfaction, and cytokine production in addiction pathogenesis evidencing their various roles depending on the range of psychoactive substances (PAS) and pathology progression. The data obtained may provide background for unification of reward circuit and inhibitory control concepts in regulation of addictive behavior. (Am J Addict 2017;26:640-648). © 2017 American Academy of Addiction Psychiatry.

Ezh2 Controls an Early Hematopoietic Program and Growth and Survival Signaling in Early T Cell Precursor Acute Lymphoblastic Leukemia

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Etienne Danis

2016-03-01

Full Text Available Early T cell precursor acute lymphoblastic leukemia (ETP-ALL is an aggressive subtype of ALL distinguished by stem-cell-associated and myeloid transcriptional programs. Inactivating alterations of Polycomb repressive complex 2 components are frequent in human ETP-ALL, but their functional role is largely undefined. We have studied the involvement of Ezh2 in a murine model of NRASQ61K-driven leukemia that recapitulates phenotypic and transcriptional features of ETP-ALL. Homozygous inactivation of Ezh2 cooperated with oncogenic NRASQ61K to accelerate leukemia onset. Inactivation of Ezh2 accentuated expression of genes highly expressed in human ETP-ALL and in normal murine early thymic progenitors. Moreover, we found that Ezh2 contributes to the silencing of stem-cell- and early-progenitor-cell-associated genes. Loss of Ezh2 also resulted in increased activation of STAT3 by tyrosine 705 phosphorylation. Our data mechanistically link Ezh2 inactivation to stem-cell-associated transcriptional programs and increased growth/survival signaling, features that convey an adverse prognosis in patients.

Research Paper ISSN 0189-6016©2008

African Journals Online (AJOL)

Prof. Adewunmi

The ethanol extracts of Syzygium aromaticum flower bud were tested for ... the anti-nociceptive activity produced significant effects (P<0.05) at all the three doses of ... induced by subplantar injection of formalin was use as the measure of acute ... The signs of toxicity were first noticed after 2-6 hours of extract administration.

Gastric electrical stimulation decreases gastric distension-induced central nociception response through direct action on primary afferents.

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Wassila Ouelaa

Full Text Available BACKGROUND & AIMS: Gastric electrical stimulation (GES is an effective therapy to treat patients with chronic dyspepsia refractory to medical management. However, its mechanisms of action remain poorly understood. METHODS: Gastric pain was induced by performing gastric distension (GD in anesthetized rats. Pain response was monitored by measuring the pseudo-affective reflex (e.g., blood pressure variation, while neuronal activation was determined using c-fos immunochemistry in the central nervous system. Involvement of primary afferents was assessed by measuring phosphorylation of ERK1/2 in dorsal root ganglia. RESULTS: GES decreased blood pressure variation induced by GD, and prevented GD-induced neuronal activation in the dorsal horn of the spinal cord (T9-T10, the nucleus of the solitary tract and in CRF neurons of the hypothalamic paraventricular nucleus. This effect remained unaltered within the spinal cord when sectioning the medulla at the T5 level. Furthermore, GES prevented GD-induced phosphorylation of ERK1/2 in dorsal root ganglia. CONCLUSIONS: GES decreases GD-induced pain and/or discomfort likely through a direct modulation of gastric spinal afferents reducing central processing of visceral nociception.

Transcranial Direct Current Stimulation (tDCS) Targeting Left Dorsolateral Prefrontal Cortex Modulates Task-Induced Acute Pain in Healthy Volunteers.

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Mariano, Timothy Y; Van't Wout, Mascha; Garnaat, Sarah L; Rasmussen, Steven A; Greenberg, Benjamin D

2016-04-01

Current chronic pain treatments target nociception rather than affective "suffering" and its associated functional and psychiatric comorbidities. The left dorsolateral prefrontal cortex (DLPFC) has been implicated in affective, cognitive, and attentional aspects of pain and is a primary target of neuromodulation for affective disorders. Transcranial direct current stimulation (tDCS) can non-invasively modulate cortical activity. The present study tests whether anodal tDCS targeting the left DLPFC will increase tolerability of acute painful stimuli vs cathodal tDCS. Forty tDCS-naive healthy volunteers received anodal and cathodal stimulation targeting the left DLPFC in two randomized and counterbalanced sessions. During stimulation, each participant performed cold pressor (CP) and breath holding (BH) tasks. We measured pain intensity with the Defense and Veterans Pain Rating Scale (DVPRS) before and after each task. Mixed ANOVA revealed no main effect of stimulation polarity for mean CP threshold, tolerance, or endurance, or mean BH time (allP > 0.27). However, DVPRS rise associated with CP was significantly smaller with anodal vs cathodal tDCS (P = 0.024). We further observed a significant tDCS polarity × stimulation order interaction (P = 0.042) on CP threshold, suggesting task sensitization. Although our results do not suggest that polarity of tDCS targeting the left DLPFC differentially modulates the tolerability of CP- and BH-related pain distress in healthy volunteers, there was a significant effect on DVPRS pain ratings. This contrasts with our previous findings that tDCS targeting the left dorsal anterior cingulate cortex showed a trend toward higher mean CP tolerance with cathodal vs anodal stimulation. The present results may suggest tDCS-related effects on nociception or DLPFC-mediated attention, or preferential modulation of the affective valence of pain as captured by the DVPRS. Sham-controlled clinical studies are needed. © 2015

Mathematical modeling of gonadotropin-releasing hormone signaling.

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Pratap, Amitesh; Garner, Kathryn L; Voliotis, Margaritis; Tsaneva-Atanasova, Krasimira; McArdle, Craig A

2017-07-05

Gonadotropin-releasing hormone (GnRH) acts via G-protein coupled receptors on pituitary gonadotropes to control reproduction. These are G q -coupled receptors that mediate acute effects of GnRH on the exocytotic secretion of luteinizing hormone (LH) and follicle-stimulating hormone (FSH), as well as the chronic regulation of their synthesis. GnRH is secreted in short pulses and GnRH effects on its target cells are dependent upon the dynamics of these pulses. Here we overview GnRH receptors and their signaling network, placing emphasis on pulsatile signaling, and how mechanistic mathematical models and an information theoretic approach have helped further this field. Copyright © 2016 The Authors. Published by Elsevier B.V. All rights reserved.

Mechanical nociception thresholds in lame sows: evidence of hyperalgesia as measured by two different methods.

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Nalon, E; Maes, D; Piepers, S; van Riet, M M J; Janssens, G P J; Millet, S; Tuyttens, F A M

2013-11-01

Lameness is a frequently occurring, painful condition of breeding sows that may result in hyperalgesia, i.e., an increased sensitivity to pain. In this study a mechanical nociception threshold (MT) test was used (1) to determine if hyperalgesia occurs in sows with naturally-occurring lameness; (2) to compare measurements obtained with a hand-held probe and a limb-mounted actuator connected to a digital algometer; and (3) to investigate the systematic left-to-right and cranial-to-caudal differences in MT. Twenty-eight pregnant sows were investigated, of which 14 were moderately lame and 14 were not lame. Over three testing sessions, repeated measurements were taken at 5 min intervals on the dorsal aspects of the metatarsi and metacarpi of all limbs. The MT was defined as the force in Newtons (N) that elicited an avoidance response, and this parameter was found to be lower in limbs affected by lameness than in normal limbs (Ptesting sessions (P<0.001), as well as between days (P<0.001). The findings provide evidence that lame sows experience hyperalgesia. Systematic differences between forelimb and hindlimb MT must be taken into account when such assessments are performed. Copyright © 2013 Elsevier Ltd. All rights reserved.

Electroacupuncture in conscious free-moving mice reduces pain by ameliorating peripheral and central nociceptive mechanisms

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Wang, Ying; Lei, Jianxun; Gupta, Mihir; Peng, Fei; Lam, Sarah; Jha, Ritu; Raduenz, Ellis; Beitz, Al J.; Gupta, Kalpna

2016-01-01

Integrative approaches such as electroacupuncture, devoid of drug effects are gaining prominence for treating pain. Understanding the mechanisms of electroacupuncture induced analgesia would benefit chronic pain conditions such as sickle cell disease (SCD), for which patients may require opioid analgesics throughout life. Mouse models are instructive in developing a mechanistic understanding of pain, but the anesthesia/restraint required to administer electroacupuncture may alter the underlying mechanisms. To overcome these limitations, we developed a method to perform electroacupuncture in conscious, freely moving, unrestrained mice. Using this technique we demonstrate a significant analgesic effect in transgenic mouse models of SCD and cancer as well as complete Freund’s adjuvant-induced pain. We demonstrate a comprehensive antinociceptive effect on mechanical, cold and deep tissue hyperalagesia in both genders. Interestingly, individual mice showed a variable response to electroacupuncture, categorized into high-, moderate-, and non-responders. Mechanistically, electroacupuncture significantly ameliorated inflammatory and nociceptive mediators both peripherally and centrally in sickle mice correlative to the antinociceptive response. Application of sub-optimal doses of morphine in electroacupuncture-treated moderate-responders produced equivalent antinociception as obtained in high-responders. Electroacupuncture in conscious freely moving mice offers an effective approach to develop a mechanism-based understanding of analgesia devoid of the influence of anesthetics or restraints. PMID:27687125

Experimental models of hepatotoxicity related to acute liver failure

Energy Technology Data Exchange (ETDEWEB)

Maes, Michaël [Department of In Vitro Toxicology and Dermato-Cosmetology, Vrije Universiteit Brussel, Brussels (Belgium); Vinken, Mathieu, E-mail: mvinken@vub.ac.be [Department of In Vitro Toxicology and Dermato-Cosmetology, Vrije Universiteit Brussel, Brussels (Belgium); Jaeschke, Hartmut [Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City (United States)

2016-01-01

Acute liver failure can be the consequence of various etiologies, with most cases arising from drug-induced hepatotoxicity in Western countries. Despite advances in this field, the management of acute liver failure continues to be one of the most challenging problems in clinical medicine. The availability of adequate experimental models is of crucial importance to provide a better understanding of this condition and to allow identification of novel drug targets, testing the efficacy of new therapeutic interventions and acting as models for assessing mechanisms of toxicity. Experimental models of hepatotoxicity related to acute liver failure rely on surgical procedures, chemical exposure or viral infection. Each of these models has a number of strengths and weaknesses. This paper specifically reviews commonly used chemical in vivo and in vitro models of hepatotoxicity associated with acute liver failure. - Highlights: • The murine APAP model is very close to what is observed in patients. • The Gal/ET model is useful to study TNFα-mediated apoptotic signaling mechanisms. • Fas receptor activation is an effective model of apoptosis and secondary necrosis. • The ConA model is a relevant model of auto-immune hepatitis and viral hepatitis. • Multiple time point evaluation needed in experimental models of acute liver injury.

Phytochemicals from Ruta graveolens Activate TAS2R Bitter Taste Receptors and TRP Channels Involved in Gustation and Nociception

Directory of Open Access Journals (Sweden)

Giuseppe Mancuso