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File list: InP.Neu.50.AllAg.Forebrain [Chip-atlas[Archive

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Towards a mechanism-based approach to pain diagnosis

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Vardeh, Daniel

2016-01-01

The last few decades have witnessed a huge leap forward in our understanding of the mechanistic underpinnings of pain, both in normal states where it helps protect from injury, and in pathological states where pain evolves from a symptom reflecting tissue injury to become the disease itself. However, despite these scientific advances, chronic pain remains extremely challenging to manage clinically. While the number of potential treatment targets has grown substantially and a strong case has been made for a mechanism-based and individualized approach to pain therapy, arguably clinicians are not much more advanced now than 20 years ago, in their capacity to either diagnose or effectively treat their patients. The gulf between pain research and pain management is as wide as ever. We are still currently unable to apply an evidence-based approach to chronic pain management that reflects mechanistic understanding, and instead, clinical practice remains an empirical and often unsatisfactory journey for patients, whose individual response to treatment cannot be predicted. Here we take a common and difficult to treat pain condition, chronic low back pain, and use its presentation in clinical practice as a framework to highlight what is known about pathophysiological pain mechanisms and how we could potentially detect these to drive rational treatment choice. We discuss how present methods of assessment and management still fall well short, however, of any mechanism-based or precision-medicine approach. Nevertheless, substantial improvements in chronic pain management could be possible if a more strategic and coordinated approach were to evolve, one designed to identify the specific mechanisms driving the presenting pain phenotype. We present an analysis of such an approach, highlighting the major problems in identifying mechanisms in patients, and develop a framework for a pain diagnostic ladder that may prove useful in the future, consisting of successive identification of

Microglia Modulate Wiring of the Embryonic Forebrain

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Paola Squarzoni

2014-09-01

Full Text Available Dysfunction of microglia, the tissue macrophages of the brain, has been associated with the etiology of several neuropsychiatric disorders. Consistently, microglia have been shown to regulate neurogenesis and synaptic maturation at perinatal and postnatal stages. However, microglia invade the brain during mid-embryogenesis and thus could play an earlier prenatal role. Here, we show that embryonic microglia, which display a transiently uneven distribution, regulate the wiring of forebrain circuits. Using multiple mouse models, including cell-depletion approaches and cx3cr1−/−, CR3−/−, and DAP12−/− mutants, we find that perturbing microglial activity affects the outgrowth of dopaminergic axons in the forebrain and the laminar positioning of subsets of neocortical interneurons. Since defects in both dopamine innervation and cortical networks have been linked to neuropsychiatric diseases, our study provides insights into how microglial dysfunction can impact forebrain connectivity and reveals roles for immune cells during normal assembly of brain circuits.

How diagnostic tests help to disentangle the mechanisms underlying neuropathic pain symptoms in painful neuropathies.

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Truini, Andrea; Cruccu, Giorgio

2016-02-01

Neuropathic pain, ie, pain arising directly from a lesion or disease affecting the somatosensory afferent pathway, manifests with various symptoms, the commonest being ongoing burning pain, electrical shock-like sensations, and dynamic mechanical allodynia. Reliable insights into the mechanisms underlying neuropathic pain symptoms come from diagnostic tests documenting and quantifying somatosensory afferent pathway damage in patients with painful neuropathies. Neurophysiological investigation and skin biopsy studies suggest that ongoing burning pain primarily reflects spontaneous activity in nociceptive-fiber pathways. Electrical shock-like sensations presumably arise from high-frequency ectopic bursts generated in demyelinated, nonnociceptive, Aβ fibers. Although the mechanisms underlying dynamic mechanical allodynia remain debatable, normally innocuous stimuli might cause pain by activating spared and sensitized nociceptive afferents. Extending the mechanistic approach to neuropathic pain symptoms might advance targeted therapy for the individual patient and improve testing for new drugs.

Forebrain neurogenesis: From embryo to adult.

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Dennis, Daniel; Picketts, David; Slack, Ruth S; Schuurmans, Carol

2016-01-01

A satellite symposium to the Canadian Developmental Biology Conference 2016 was held on March 16-17, 2016 in Banff, Alberta, Canada, entitled Forebrain Neurogenesis : From embryo to adult . The Forebrain Neurogenesis symposium was a focused, high-intensity meeting, bringing together the top Canadian and international researchers in the field. This symposium reported the latest breaking news, along with 'state of the art' techniques to answer fundamental questions in developmental neurobiology. Topics covered ranged from stem cell regulation to neurocircuitry development, culminating with a session focused on neuropsychiatric disorders. Understanding the underlying causes of neurodevelopmental disorders such as autism spectrum disorder (ASD) and attention deficit/hyperactivity disorder (ADHD) is of great interest as diagnoses of these conditions are climbing at alarming rates. For instance, in 2012, the Centers for Disease Control reported that the prevalence rate of ASD in the U.S. was 1 in 88; while more recent data indicate that the number is as high as 1 in 68 (Centers for Disease Control and Prevention MMWR Surveillance Summaries. Vol. 63. No. 2). Similarly, the incidence of ASD is on the rise in Canada, increasing from 1 in 150 in 2000 to 1 in 63 in 2012 in southeastern Ontario (Centers for Disease Control and Prevention). Currently very little is known regarding the deficits underlying these neurodevelopmental conditions. Moreover, the development of effective therapies is further limited by major gaps in our understanding of the fundamental processes that regulate forebrain development and adult neurogenesis. The Forebrain Neurogenesis satellite symposium was thus timely, and it played a key role in advancing research in this important field, while also fostering collaborations between international leaders, and inspiring young researchers.

Pain and pain mechanisms in patients with inflammatory arthritis

DEFF Research Database (Denmark)

Rifbjerg-Madsen, S; Christensen, A W; Christensen, R

2017-01-01

completed the PDQ (RA: 3,826, PsA: 1,180, SpA: 1,093). 52% of all patients and 63% of PDQ-completers had VAS pain score ≥ 30 mm. The distribution of the PDQ classification-groups (18) were; RA: 56%/24%/20%. PsA: 45%/ 27%/ 28%. SpA: 55% / 24%/ 21%. More patients with PsA had PDQ score >18....... The objectives were to quantify and characterize pain phenotypes (non-neuropathic vs. neuropathic features) among Danish arthritis patients using the PDQ, and to assess the association with on-going inflammation. METHODS: The PDQ was included onto the DANBIO touch screens at 22 departments of Rheumatology......28-CRP and VAS pain but not with indicators of peripheral inflammation (CRP and SJC). Thus, pain classification by PDQ may assist in mechanism-based pain treatment....

Mechanisms of, and Adjuvants for, Bone Pain.

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Figura, Nicholas; Smith, Joshua; Yu, Hsiang-Hsuan Michael

2018-06-01

Metastatic bone pain is a complex, poorly understood process. Understanding the unique mechanisms causing cancer-induced bone pain may lead to potential therapeutic targets. This article discusses the effects of osteoclast overstimulation within the tumor microenvironment; the role of inflammatory factors at the tumor-nociceptor interface; the development of structural instability, causing mechanical nerve damage; and, ultimately, the neuroplastic changes in the setting of sustained pain. Several adjuvant therapies are available to attenuate metastatic bone pain. This article discusses the role of pharmacologic therapies, surgery, kyphoplasty, vertebroplasty, and radiofrequency ablation. Copyright © 2018 Elsevier Inc. All rights reserved.

Pain-related psychological issues in hand therapy.

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Hamasaki, Tokiko; Pelletier, René; Bourbonnais, Daniel; Harris, Patrick; Choinière, Manon

Literature review. Pain is a subjective experience that results from the modulation of nociception conveyed to the brain via the nervous system. Perception of pain takes place when potential or actual noxious stimuli are appraised as threats of injury. This appraisal is influenced by one's cognitions and emotions based on her/his pain-related experiences, which are processed in the forebrain and limbic areas of the brain. Unarguably, patients' psychological factors such as cognitions (eg, pain catastrophizing), emotions (eg, depression), and pain-related behaviors (eg, avoidance) can influence perceived pain intensity, disability, and treatment outcomes. Therefore, hand therapists should address the patient pain experience using a biopsychosocial approach. However, in hand therapy, a biomedical perspective predominates in pain management by focusing solely on tissue healing. This review aims to raise awareness among hand therapists of the impact of pain-related psychological factors. This literature review allowed to describe (1) how the neurophysiological mechanisms of pain can be influenced by various psychological factors, (2) several evidence-based interventions that can be integrated into hand therapy to address these psychological issues, and (3) some approaches of psychotherapy for patients with maladaptive pain experiences. Restoration of sensory and motor functions as well as alleviating pain is at the core of hand therapy. Numerous psychological factors including patients' beliefs, cognitions, and emotions alter their pain experience and may impact on their outcomes. Decoding the biopsychosocial components of the patients' pain is thus essential for hand therapists. Copyright © 2018 Hanley & Belfus. Published by Elsevier Inc. All rights reserved.

Mechanisms of Acupuncture-Electroacupuncture on Persistent Pain

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Zhang, Ruixin; Lao, Lixing; Ren, Ke; Berman, Brian M.

2014-01-01

In the last decade, preclinical investigations of electroacupuncture mechanisms on persistent tissue-injury (inflammatory), nerve-injury (neuropathic), cancer, and visceral pain have increased. These studies show that electroacupuncture activates the nervous system differently in health than in pain conditions, alleviates both sensory and affective inflammatory pain, and inhibits inflammatory and neuropathic pain more effectively at 2–10 Hz than at 100 Hz. Electroacupuncture blocks pain by activating a variety of bioactive chemicals through peripheral, spinal, and supraspinal mechanisms. These include opioids, which desensitize peripheral nociceptors and reduce pro-inflammatory cytokines peripherally and in the spinal cord, and serotonin and norepinephrine, which decrease spinal n-methyl-d-aspartate receptor subunit GluN1 phosphorylation. Additional studies suggest that electroacupuncture, when combined with low dosages of conventional analgesics, provides effective pain management that can forestall the side effects of often-debilitating pharmaceuticals. PMID:24322588

Neural and psychosocial mechanisms of pain sensitivity in fibromyalgia.

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English, Brian

2014-06-01

Fibromyalgia is a chronic musculoskeletal pain disorder that affects an estimated 5 million adults in the U.S. The hallmark is burning, searing, tingling, shooting, stabbing, deep aching, or sharp pain. Fibromyalgia is generally considered to be a "central sensitivity syndrome" where central sensitization is regarded as the cause of pain in its own right. Nonetheless, the case continues to be made that all central and spatially distributed peripheral components of fibromyalgia pain would fade if the peripheral generators could be silenced. Although neural mechanisms are clearly important in pain sensitivity, cognitive and social mechanisms also need to be considered. The aim of this review is to examine four mechanisms responsible for heightened pain sensitivity in fibromyalgia: peripheral sensitization, central sensitization, cognitive-emotional sensitization, and interpersonal sensitization. The purpose of framing the review in terms of pain sensitivity in fibromyalgia is to highlight that different mechanisms of sensitization are appropriately regarded as intervening variables when it comes to understanding individual differences in the experience of pain. The paper concludes by considering the implications of the findings of the review for explanations of fibromyalgia pain by nurses working in multidisciplinary teams. The trend appears to be able to explain the cause of fibromyalgia pain in terms of sensitization per se. The recommended alternative is to explain fibromyalgia pain in terms of changes in pain sensitivity and the role of underlying neural and psychosocial mechanisms. Copyright © 2014 American Society for Pain Management Nursing. Published by Elsevier Inc. All rights reserved.

Ablation of ferroptosis regulator glutathione peroxidase 4 in forebrain neurons promotes cognitive impairment and neurodegeneration

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William Sealy Hambright

2017-08-01

Full Text Available Synaptic loss and neuron death are the underlying cause of neurodegenerative diseases such as Alzheimer's disease (AD; however, the modalities of cell death in those diseases remain unclear. Ferroptosis, a newly identified oxidative cell death mechanism triggered by massive lipid peroxidation, is implicated in the degeneration of neurons populations such as spinal motor neurons and midbrain neurons. Here, we investigated whether neurons in forebrain regions (cerebral cortex and hippocampus that are severely afflicted in AD patients might be vulnerable to ferroptosis. To this end, we generated Gpx4BIKO mouse, a mouse model with conditional deletion in forebrain neurons of glutathione peroxidase 4 (Gpx4, a key regulator of ferroptosis, and showed that treatment with tamoxifen led to deletion of Gpx4 primarily in forebrain neurons of adult Gpx4BIKO mice. Starting at 12 weeks after tamoxifen treatment, Gpx4BIKO mice exhibited significant deficits in spatial learning and memory function versus Control mice as determined by the Morris water maze task. Further examinations revealed that the cognitively impaired Gpx4BIKO mice exhibited hippocampal neurodegeneration. Notably, markers associated with ferroptosis, such as elevated lipid peroxidation, ERK activation and augmented neuroinflammation, were observed in Gpx4BIKO mice. We also showed that Gpx4BIKO mice fed a diet deficient in vitamin E, a lipid soluble antioxidant with anti-ferroptosis activity, had an expedited rate of hippocampal neurodegeneration and behavior dysfunction, and that treatment with a small-molecule ferroptosis inhibitor ameliorated neurodegeneration in those mice. Taken together, our results indicate that forebrain neurons are susceptible to ferroptosis, suggesting that ferroptosis may be an important neurodegenerative mechanism in diseases such as AD. Keywords: Ferroptosis, Neurodegeneration, Cognitive impairment, Alzheimer's disease, Glutathione peroxidase 4, Transgenic mice

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

Mechanisms of Osteoarthritic Pain. Studies in Humans and Experimental Models

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Annett Eitner

2017-11-01

Full Text Available Pain due to osteoarthritis (OA is one of the most frequent causes of chronic pain. However, the mechanisms of OA pain are poorly understood. This review addresses the mechanisms which are thought to be involved in OA pain, derived from studies on pain mechanisms in humans and in experimental models of OA. Three areas will be considered, namely local processes in the joint associated with OA pain, neuronal mechanisms involved in OA pain, and general factors which influence OA pain. Except the cartilage all structures of the joints are innervated by nociceptors. Although the hallmark of OA is the degradation of the cartilage, OA joints show multiple structural alterations of cartilage, bone and synovial tissue. In particular synovitis and bone marrow lesions have been proposed to determine OA pain whereas the contribution of the other pathologies to pain generation has been studied less. Concerning the peripheral neuronal mechanisms of OA pain, peripheral nociceptive sensitization was shown, and neuropathic mechanisms may be involved at some stages. Structural changes of joint innervation such as local loss and/or sprouting of nerve fibers were shown. In addition, central sensitization, reduction of descending inhibition, descending excitation and cortical atrophies were observed in OA. The combination of different neuronal mechanisms may define the particular pain phenotype in an OA patient. Among mediators involved in OA pain, nerve growth factor (NGF is in the focus because antibodies against NGF significantly reduce OA pain. Several studies show that neutralization of interleukin-1β and TNF may reduce OA pain. Many patients with OA exhibit comorbidities such as obesity, low grade systemic inflammation and diabetes mellitus. These comorbidities can significantly influence the course of OA, and pain research just began to study the significance of such factors in pain generation. In addition, psychologic and socioeconomic factors may aggravate

Usefulness of the Pain Tracking Technique in Acute Mechanical Low Back Pain

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Tania Bravo Acosta

2015-01-01

Full Text Available Objective. To evaluate the usefulness of the pain tracking technique in acute mechanical low back pain. Method. We performed an experimental prospective (longitudinal explanatory study between January 2011 and September 2012. The sample was randomly divided into two groups. Patients were assessed at the start and end of the treatment using the visual analogue scale and the Waddell test. Treatment consisted in applying the pain tracking technique to the study group and interferential current therapy to the control group. At the end of treatment, cryotherapy was applied for 10 minutes. The Wilcoxon signed-rank test and the Mann Whitney test were used. They were performed with a predetermined significance level of p≤0.05. Results. Pain was triggered by prolonged static posture and intense physical labor and intensified through trunk movements and when sitting and standing. The greatest relief was reported in lateral decubitus position and in William’s position. The majority of the patients had contracture. Pain and disability were modified with the rehabilitation treatment in both groups. Conclusions. Both the pain tracking and interferential current techniques combined with cryotherapy are useful treatments for acute mechanical low back pain. The onset of analgesia is faster when using the pain tracking technique.

Serotonin 5-HT4 receptors and forebrain cholinergic system: receptor expression in identified cell populations.

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Peñas-Cazorla, Raúl; Vilaró, M Teresa

2015-11-01

Activation of serotonin 5-HT4 receptors has pro-cognitive effects on memory performance. The proposed underlying neurochemical mechanism is the enhancement of acetylcholine release in frontal cortex and hippocampus elicited by 5-HT4 agonists. Although 5-HT4 receptors are present in brain areas related to cognition, e.g., hippocampus and cortex, the cellular localization of the receptors that might modulate acetylcholine release is unknown at present. We have analyzed, using dual label in situ hybridization, the cellular localization of 5-HT4 receptor mRNA in identified neuronal populations of the rat basal forebrain, which is the source of the cholinergic innervation to cortex and hippocampus. 5-HT4 receptor mRNA was visualized with isotopically labeled oligonucleotide probes, whereas cholinergic, glutamatergic, GABAergic and parvalbumin-synthesizing neurons were identified with digoxigenin-labeled oligonucleotide probes. 5-HT4 receptor mRNA was not detected in the basal forebrain cholinergic cell population. In contrast, basal forebrain GABAergic, parvalbumin synthesizing, and glutamatergic cells contained 5-HT4 receptor mRNA. Hippocampal and cortical glutamatergic neurons also express this receptor. These results indicate that 5-HT4 receptors are not synthesized by cholinergic cells, and thus would be absent from cholinergic terminals. In contrast, several non-cholinergic cell populations within the basal forebrain and its target hippocampal and cortical areas express these receptors and are thus likely to mediate the enhancement of acetylcholine release elicited by 5-HT4 agonists.

Why Social Pain Can Live on: Different Neural Mechanisms Are Associated with Reliving Social and Physical Pain.

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Meyer, Meghan L; Williams, Kipling D; Eisenberger, Naomi I

2015-01-01

Although social and physical pain recruit overlapping neural activity in regions associated with the affective component of pain, the two pains can diverge in their phenomenology. Most notably, feelings of social pain can be re-experienced or "relived," even when the painful episode has long passed, whereas feelings of physical pain cannot be easily relived once the painful episode subsides. Here, we observed that reliving social (vs. physical) pain led to greater self-reported re-experienced pain and greater activity in affective pain regions (dorsal anterior cingulate cortex and anterior insula). Moreover, the degree of relived pain correlated positively with affective pain system activity. In contrast, reliving physical (vs. social) pain led to greater activity in the sensory-discriminative pain system (primary and secondary somatosensory cortex and posterior insula), which did not correlate with relived pain. Preferential engagement of these different pain mechanisms may reflect the use of different top-down neurocognitive pathways to elicit the pain. Social pain reliving recruited dorsomedial prefrontal cortex, often associated with mental state processing, which functionally correlated with affective pain system responses. In contrast, physical pain reliving recruited inferior frontal gyrus, known to be involved in body state processing, which functionally correlated with activation in the sensory pain system. These results update the physical-social pain overlap hypothesis: while overlapping mechanisms support live social and physical pain, distinct mechanisms guide internally-generated pain.

Lesions of the basal forebrain cholinergic system in mice disrupt idiothetic navigation.

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Adam S Hamlin

Full Text Available Loss of integrity of the basal forebrain cholinergic neurons is a consistent feature of Alzheimer's disease, and measurement of basal forebrain degeneration by magnetic resonance imaging is emerging as a sensitive diagnostic marker for prodromal disease. It is also known that Alzheimer's disease patients perform poorly on both real space and computerized cued (allothetic or uncued (idiothetic recall navigation tasks. Although the hippocampus is required for allothetic navigation, lesions of this region only mildly affect idiothetic navigation. Here we tested the hypothesis that the cholinergic medial septo-hippocampal circuit is important for idiothetic navigation. Basal forebrain cholinergic neurons were selectively lesioned in mice using the toxin saporin conjugated to a basal forebrain cholinergic neuronal marker, the p75 neurotrophin receptor. Control animals were able to learn and remember spatial information when tested on a modified version of the passive place avoidance test where all extramaze cues were removed, and animals had to rely on idiothetic signals. However, the exploratory behaviour of mice with cholinergic basal forebrain lesions was highly disorganized during this test. By contrast, the lesioned animals performed no differently from controls in tasks involving contextual fear conditioning and spatial working memory (Y maze, and displayed no deficits in potentially confounding behaviours such as motor performance, anxiety, or disturbed sleep/wake cycles. These data suggest that the basal forebrain cholinergic system plays a specific role in idiothetic navigation, a modality that is impaired early in Alzheimer's disease.

Forebrain CRF1 Modulates Early-Life Stress-Programmed Cognitive Deficits

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Wang, Xiao-Dong; Rammes, Gerhard; Kraev, Igor; Wolf, Miriam; Liebl, Claudia; Scharf, Sebastian H.; Rice, Courtney J.; Wurst, Wolfgang; Holsboer, Florian; Deussing, Jan M.; Baram, Tallie Z.; Stewart, Michael G.; Müller, Marianne B.; Schmidt, Mathias V.

2012-01-01

Childhood traumatic events hamper the development of the hippocampus and impair declarative memory in susceptible individuals. Persistent elevations of hippocampal corticotropin-releasing factor (CRF), acting through CRF receptor 1 (CRF1), in experimental models of early-life stress have suggested a role for this endogenous stress hormone in the resulting structural modifications and cognitive dysfunction. However, direct testing of this possibility has been difficult. In the current study, we subjected conditional forebrain CRF1 knock-out (CRF1-CKO) mice to an impoverished postnatal environment and examined the role of forebrain CRF1 in the long-lasting effects of early-life stress on learning and memory. Early-life stress impaired spatial learning and memory in wild-type mice, and postnatal forebrain CRF overexpression reproduced these deleterious effects. Cognitive deficits in stressed wild-type mice were associated with disrupted long-term potentiation (LTP) and a reduced number of dendritic spines in area CA3 but not in CA1. Forebrain CRF1 deficiency restored cognitive function, LTP and spine density in area CA3, and augmented CA1 LTP and spine density in stressed mice. In addition, early-life stress differentially regulated the amount of hippocampal excitatory and inhibitory synapses in wild-type and CRF1-CKO mice, accompanied by alterations in the neurexin-neuroligin complex. These data suggest that the functional, structural and molecular changes evoked by early-life stress are at least partly dependent on persistent forebrain CRF1 signaling, providing a molecular target for the prevention of cognitive deficits in adults with a history of early-life adversity. PMID:21940453

Neuromodulatory treatments for chronic pain: efficacy and mechanisms

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Jensen, Mark P.; Day, Melissa A.; Miró, Jordi

2017-01-01

Chronic pain is common, and the available treatments do not provide adequate relief for most patients. Neuromodulatory interventions that modify brain processes underlying the experience of pain have the potential to provide substantial relief for some of these patients. The purpose of this Review is to summarize the state of knowledge regarding the efficacy and mechanisms of noninvasive neuromodulatory treatments for chronic pain. The findings provide support for the efficacy and positive side-effect profile of hypnosis, and limited evidence for the potential efficacy of meditation training, noninvasive electrical stimulation procedures, and neurofeedback procedures. Mechanisms research indicates that hypnosis influences multiple neurophysiological processes involved in the experience of pain. Evidence also indicates that mindfulness meditation has both immediate and long-term effects on cortical structures and activity involved in attention, emotional responding and pain. Less is known about the mechanisms of other neuromodulatory treatments. On the basis of the data discussed in this Review, training in the use of self-hypnosis might be considered a viable ‘first-line’ approach to treat chronic pain. More-definitive research regarding the benefits and costs of meditation training, noninvasive brain stimulation and neurofeedback is needed before these treatments can be recommended for the treatment of chronic pain. PMID:24535464

Cholinergic basal forebrain structures are not essential for mediation of the arousing action of glutamate.

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Lelkes, Zoltán; Abdurakhmanova, Shamsiiat; Porkka-Heiskanen, Tarja

2017-09-18

The cholinergic basal forebrain contributes to cortical activation and receives rich innervations from the ascending activating system. It is involved in the mediation of the arousing actions of noradrenaline and histamine. Glutamatergic stimulation in the basal forebrain results in cortical acetylcholine release and suppression of sleep. However, it is not known to what extent the cholinergic versus non-cholinergic basal forebrain projection neurones contribute to the arousing action of glutamate. To clarify this question, we administered N-methyl-D-aspartate (NMDA), a glutamate agonist, into the basal forebrain in intact rats and after destruction of the cholinergic cells in the basal forebrain with 192 immunoglobulin (Ig)G-saporin. In eight Han-Wistar rats with implanted electroencephalogram/electromyogram (EEG/EMG) electrodes and guide cannulas for microdialysis probes, 0.23 μg 192 IgG-saporin was administered into the basal forebrain, while the eight control animals received artificial cerebrospinal fluid. Two weeks later, a microdialysis probe targeted into the basal forebrain was perfused with cerebrospinal fluid on the baseline day and for 3 h with 0.3 mmNMDA on the subsequent day. Sleep-wake activity was recorded for 24 h on both days. NMDA exhibited a robust arousing effect in both the intact and the lesioned rats. Wakefulness was increased and both non-REM and REM sleep were decreased significantly during the 3-h NMDA perfusion. Destruction of the basal forebrain cholinergic neurones did not abolish the wake-enhancing action of NMDA. Thus, the cholinergic basal forebrain structures are not essential for the mediation of the arousing action of glutamate. © 2017 European Sleep Research Society.

Systematic mechanism-orientated approach to chronic pancreatitis pain.

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Bouwense, Stefan A W; de Vries, Marjan; Schreuder, Luuk T W; Olesen, Søren S; Frøkjær, Jens B; Drewes, Asbjørn M; van Goor, Harry; Wilder-Smith, Oliver H G

2015-01-07

Pain in chronic pancreatitis (CP) shows similarities with other visceral pain syndromes (i.e., inflammatory bowel disease and esophagitis), which should thus be managed in a similar fashion. Typical causes of CP pain include increased intrapancreatic pressure, pancreatic inflammation and pancreatic/extrapancreatic complications. Unfortunately, CP pain continues to be a major clinical challenge. It is recognized that ongoing pain may induce altered central pain processing, e.g., central sensitization or pro-nociceptive pain modulation. When this is present conventional pain treatment targeting the nociceptive focus, e.g., opioid analgesia or surgical/endoscopic intervention, often fails even if technically successful. If central nervous system pain processing is altered, specific treatment targeting these changes should be instituted (e.g., gabapentinoids, ketamine or tricyclic antidepressants). Suitable tools are now available to make altered central processing visible, including quantitative sensory testing, electroencephalograpy and (functional) magnetic resonance imaging. These techniques are potentially clinically useful diagnostic tools to analyze central pain processing and thus define optimum management approaches for pain in CP and other visceral pain syndromes. The present review proposes a systematic mechanism-orientated approach to pain management in CP based on a holistic view of the mechanisms involved. Future research should address the circumstances under which central nervous system pain processing changes in CP, and how this is influenced by ongoing nociceptive input and therapies. Thus we hope to predict which patients are at risk for developing chronic pain or not responding to therapy, leading to improved treatment of chronic pain in CP and other visceral pain disorders.

Midbrain and forebrain patterning delivers immunocytochemically and functionally similar populations of neuropeptide Y containing GABAergic neurons.

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Khaira, S K; Nefzger, C M; Beh, S J; Pouton, C W; Haynes, J M

2011-09-01

Neurons differentiated in vitro from embryonic stem cells (ESCs) have the potential to serve both as models of disease states and in drug discovery programs. In this study, we use sonic hedgehog (SHH) and fibroblast growth factor 8 (FGF-8) to enrich for forebrain and midbrain phenotypes from mouse ESCs. We then investigate, using Ca(2+) imaging and [(3)H]-GABA release studies, whether the GABAergic neurons produced exhibit distinct functional phenotypes. At day 24 of differentiation, reverse transcriptase-PCR showed the presence of both forebrain (Bf-1, Hesx1, Pgc-1α, Six3) and midbrain (GATA2, GATA3) selective mRNA markers in developing forebrain-enriched cultures. All markers were present in midbrain cultures except for Bf-1 and Pgc-1α. Irrespective of culture conditions all GABA immunoreactive neurons were also immunoreactive to neuropeptide Y (NPY) antibodies. Forebrain and midbrain GABAergic neurons responded to ATP (1 mM), L-glutamate (30 μM), noradrenaline (30 μM), acetylcholine (30 μM) and dopamine (30 μM), with similar elevations of intracellular Ca(2+)([Ca(2+)](i)). The presence of GABA(A) and GABA(B) antagonists, bicuculline (30 μM) and CGP55845 (1 μM), increased the elevation of [Ca(2+)](i) in response to dopamine (30 μM) in midbrain, but not forebrain GABAergic neurons. All agonists, except dopamine, elicited similar [(3)H]-GABA release from forebrain and midbrain cultures. Dopamine (30 μM) did not stimulate significant [(3)H]-GABA release in midbrain cultures, although it was effective in forebrain cultures. This study shows that differentiating neurons toward a midbrain fate restricts the expression of forebrain markers. Forebrain differentiation results in the expression of forebrain and midbrain markers. All GABA(+) neurons contain NPY, and show similar agonist-induced elevations of [Ca(2+)](i) and [(3)H]-GABA release. This study indicates that the pharmacological phenotype of these particular neurons may be independent of the addition of

Mechanisms of chronic pain - key considerations for appropriate physical therapy management.

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Courtney, Carol A; Fernández-de-Las-Peñas, César; Bond, Samantha

2017-07-01

In last decades, knowledge of nociceptive pain mechanisms has expanded rapidly. The use of quantitative sensory testing has provided evidence that peripheral and central sensitization mechanisms play a relevant role in localized and widespread chronic pain syndromes. In fact, almost any patient suffering with a chronic pain condition will demonstrate impairments in the central nervous system. In addition, it is accepted that pain is associated with different types of trigger factors including social, physiological, and psychological. This rational has provoked a change in the understanding of potential mechanisms of manual therapies, changing from a biomechanical/medical viewpoint, to a neurophysiological/nociceptive viewpoint. Therefore, interventions for patients with chronic pain should be applied based on current knowledge of nociceptive mechanisms since determining potential drivers of the sensitization process is critical for effective management. The current paper reviews mechanisms of chronic pain from a clinical and neurophysiological point of view and summarizes key messages for clinicians for proper management of individuals with chronic pain.

Mechanism of Chronic Pain in Rodent Brain Imaging

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Chang, Pei-Ching

Chronic pain is a significant health problem that greatly impacts the quality of life of individuals and imparts high costs to society. Despite intense research effort in understanding of the mechanism of pain, chronic pain remains a clinical problem that has few effective therapies. The advent of human brain imaging research in recent years has changed the way that chronic pain is viewed. To further extend the use of human brain imaging techniques for better therapies, the adoption of imaging technique onto the animal pain models is essential, in which underlying brain mechanisms can be systematically studied using various combination of imaging and invasive techniques. The general goal of this thesis is to addresses how brain develops and maintains chronic pain in an animal model using fMRI. We demonstrate that nucleus accumbens, the central component of mesolimbic circuitry, is essential in development of chronic pain. To advance our imaging technique, we develop an innovative methodology to carry out fMRI in awake, conscious rat. Using this cutting-edge technique, we show that allodynia is assoicated with shift brain response toward neural circuits associated nucleus accumbens and prefrontal cortex that regulate affective and cognitive component of pain. Taken together, this thesis provides a deeper understanding of how brain mediates pain. It builds on the existing body of knowledge through maximizing the depth of insight into brain imaging of chronic pain.

Mindfulness meditation-related pain relief: Evidence for unique brain mechanisms in the regulation of pain

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Zeidan, F.; Grant, J.A.; Brown, C.A.; McHaffie, J.G.; Coghill, R.C.

2013-01-01

The cognitive modulation of pain is influenced by a number of factors ranging from attention, beliefs, conditioning, expectations, mood, and the regulation of emotional responses to noxious sensory events. Recently, mindfulness meditation has been found attenuate pain through some of these mechanisms including enhanced cognitive and emotional control, as well as altering the contextual evaluation of sensory events. This review discusses the brain mechanisms involved in mindfulness meditation-related pain relief across different meditative techniques, expertise and training levels, experimental procedures, and neuroimaging methodologies. Converging lines of neuroimaging evidence reveal that mindfulness meditation-related pain relief is associated with unique appraisal cognitive processes depending on expertise level and meditation tradition. Moreover, it is postulated that mindfulness meditation-related pain relief may share a common final pathway with other cognitive techniques in the modulation of pain. PMID:22487846

Brain Mechanisms Supporting Modulation of Pain by Mindfulness Meditation

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Zeidan, F.; Martucci, K.T.; Kraft, R.A.; Gordon, N.S.; McHaffie, J.G.; Coghill, R.C.

2011-01-01

The subjective experience of one’s environment is constructed by interactions among sensory, cognitive, and affective processes. For centuries, meditation has been thought to influence such processes by enabling a non-evaluative representation of sensory events. To better understand how meditation influences the sensory experience, we employed arterial spin labeling (ASL) functional magnetic resonance imaging to assess the neural mechanisms by which mindfulness meditation influences pain in healthy human participants. After four-days of mindfulness meditation training, meditating in the presence of noxious stimulation significantly reduced pain-unpleasantness by 57% and pain-intensity ratings by 40% when compared to rest. A two factor repeated measures analysis of variance was used to identify interactions between meditation and pain-related brain activation. Meditation reduced pain-related activation of the contra lateral primary somatosensory cortex. Multiple regression analysis was used to identify brain regions associated with individual differences in the magnitude of meditation-related pain reductions. Meditation-induced reductions in pain intensity ratings were associated with increased activity in the anterior cingulate cortex and anterior insula, areas involved in the cognitive regulation of nociceptive processing. Reductions in pain unpleasantness ratings were associated with orbitofrontal cortex activation, an area implicated in reframing the contextual evaluation of sensory events. Moreover, reductions in pain unpleasantness also were associated with thalamic deactivation, which may reflect a limbic gating mechanism involved in modifying interactions between afferent in put and executive-order brain areas. Taken together, these data indicate that meditation engages multiple brain mechanisms that alter the construction of the subjectively available pain experience from afferent information. PMID:21471390

Conservative Management of Mechanical Neck Pain in a Helicopter Pilot.

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Alagha, Babak

2015-10-01

Acute and chronic spinal symptoms such as neck pain may limit flying performance significantly and disqualify the pilot from flight duty. Mechanical neck pain is very common among pilots because of their exposure to vibration, +GZ forces, helmet weight, poor neck posture during air combat maneuvers, previous neck injuries, and poor treatment plans for such injuries. Successful treatment of such injuries requires appropriate therapeutic procedures as well as an aeromedical assessment. The aim of this case study was to demonstrate the benefits of conservative procedures such as spinal manipulation and mobilization therapy (SMMT) and exercise therapy (ET) in treating chronic mechanical neck pain in an Iranian commercial helicopter pilot. A 36-yr-old male patient presented to the clinic with moderate, intermittent nonradicular chronic neck pain and limited range of motion over a 2-yr period. The patient was treated with cervical and upper thoracic SMMT followed by home ET for 5 wk. After this period, the patient reported significant recovery and improvement in range of motion in his neck. Mechanical neck pain is very common among helicopter pilots. Although Air Force and Navy waiver guides recommend nonsteroidal anti-inflammatory medications as well as SMMT and ET, there are currently very few published studies that examine the benefits of manual and exercise therapy for treating mechanical neck pain in commercial and military pilots. Based on the results of this study, it seems that SMMT and ET may be a safe and effective in treatment of uncomplicated mechanical neck pain in helicopter pilots. Alagha B. Conservative management of mechanical neck pain in a helicopter pilot.

Dissociating basal forebrain and medial temporal amnesic syndromes: insights from classical conditioning.

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Myer, Catherine E; Bryant, Deborah; DeLuca, John; Gluck, Mark A

2002-01-01

In humans, anterograde amnesia can result from damage to the medial temporal (MT) lobes (including hippocampus), as well as to other brain areas such as basal forebrain. Results from animal classical conditioning studies suggest that there may be qualitative differences in the memory impairment following MT vs. basal forebrain damage. Specifically, delay eyeblink conditioning is spared after MT damage in animals and humans, but impaired in animals with basal forebrain damage. Recently, we have likewise shown delay eyeblink conditioning impairment in humans with amnesia following anterior communicating artery (ACoA) aneurysm rupture, which damages the basal forebrain. Another associative learning task, a computer-based concurrent visual discrimination, also appears to be spared in MT amnesia while ACoA amnesics are slower to learn the discriminations. Conversely, animal and computational models suggest that, even though MT amnesics may learn quickly, they may learn qualitatively differently from controls, and these differences may result in impaired transfer when familiar information is presented in novel combinations. Our initial data suggests such a two-phase learning and transfer task may provide a double dissociation between MT amnesics (spared initial learning but impaired transfer) and ACoA amnesics (slow initial learning but spared transfer). Together, these emerging data suggest that there are subtle but dissociable differences in the amnesic syndrome following damage to the MT lobes vs. basal forebrain, and that these differences may be most visible in non-declarative tasks such as eyeblink classical conditioning and simple associative learning.

Transcriptional maturation of the mouse auditory forebrain.

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Hackett, Troy A; Guo, Yan; Clause, Amanda; Hackett, Nicholas J; Garbett, Krassimira; Zhang, Pan; Polley, Daniel B; Mirnics, Karoly

2015-08-14

The maturation of the brain involves the coordinated expression of thousands of genes, proteins and regulatory elements over time. In sensory pathways, gene expression profiles are modified by age and sensory experience in a manner that differs between brain regions and cell types. In the auditory system of altricial animals, neuronal activity increases markedly after the opening of the ear canals, initiating events that culminate in the maturation of auditory circuitry in the brain. This window provides a unique opportunity to study how gene expression patterns are modified by the onset of sensory experience through maturity. As a tool for capturing these features, next-generation sequencing of total RNA (RNAseq) has tremendous utility, because the entire transcriptome can be screened to index expression of any gene. To date, whole transcriptome profiles have not been generated for any central auditory structure in any species at any age. In the present study, RNAseq was used to profile two regions of the mouse auditory forebrain (A1, primary auditory cortex; MG, medial geniculate) at key stages of postnatal development (P7, P14, P21, adult) before and after the onset of hearing (~P12). Hierarchical clustering, differential expression, and functional geneset enrichment analyses (GSEA) were used to profile the expression patterns of all genes. Selected genesets related to neurotransmission, developmental plasticity, critical periods and brain structure were highlighted. An accessible repository of the entire dataset was also constructed that permits extraction and screening of all data from the global through single-gene levels. To our knowledge, this is the first whole transcriptome sequencing study of the forebrain of any mammalian sensory system. Although the data are most relevant for the auditory system, they are generally applicable to forebrain structures in the visual and somatosensory systems, as well. The main findings were: (1) Global gene expression

A forebrain atlas of the lizard Gekko gecko.

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Smeets, W J; Hoogland, P V; Lohman, A H

1986-12-01

An atlas of the forebrain of the lizard Gekko gecko has been provided, which will serve as the basis for subsequent experimental tracing and immunohistochemical studies. Apart from a strongly developed medial cortex and septal area, the Tokay gecko shows all the main features of the forebrain of the lacertid-type lizards. When its convenience as an experimental animal is also taken into account, this species seems to be very suitable for studying the limbic system in reptiles. The atlas comprises topographical reconstructions of the telencephalon and diencephalon and a series of transverse sections of which the levels have been indicated in the reconstructions. The results obtained in the Gekko are briefly compared with those found in other lizards studied.

Adult forebrain NMDA receptors gate social motivation and social memory.

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Jacobs, Stephanie; Tsien, Joe Z

2017-02-01

Motivation to engage in social interaction is critical to ensure normal social behaviors, whereas dysregulation in social motivation can contribute to psychiatric diseases such as schizophrenia, autism, social anxiety disorders and post-traumatic stress disorder (PTSD). While dopamine is well known to regulate motivation, its downstream targets are poorly understood. Given the fact that the dopamine 1 (D1) receptors are often physically coupled with the NMDA receptors, we hypothesize that the NMDA receptor activity in the adult forebrain principal neurons are crucial not only for learning and memory, but also for the proper gating of social motivation. Here, we tested this hypothesis by examining sociability and social memory in inducible forebrain-specific NR1 knockout mice. These mice are ideal for exploring the role of the NR1 subunit in social behavior because the NR1 subunit can be selectively knocked out after the critical developmental period, in which NR1 is required for normal development. We found that the inducible deletion of the NMDA receptors prior to behavioral assays impaired, not only object and social recognition memory tests, but also resulted in profound deficits in social motivation. Mice with ablated NR1 subunits in the forebrain demonstrated significant decreases in sociability compared to their wild type counterparts. These results suggest that in addition to its crucial role in learning and memory, the NMDA receptors in the adult forebrain principal neurons gate social motivation, independent of neuronal development. Copyright © 2016 Elsevier Inc. All rights reserved.

Corneal Mechanical Thresholds Negatively Associate With Dry Eye and Ocular Pain Symptoms.

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Spierer, Oriel; Felix, Elizabeth R; McClellan, Allison L; Parel, Jean Marie; Gonzalez, Alex; Feuer, William J; Sarantopoulos, Constantine D; Levitt, Roy C; Ehrmann, Klaus; Galor, Anat

2016-02-01

To examine associations between corneal mechanical thresholds and metrics of dry eye. This was a cross-sectional study of individuals seen in the Miami Veterans Affairs eye clinic. The evaluation consisted of questionnaires regarding dry eye symptoms and ocular pain, corneal mechanical detection and pain thresholds, and a comprehensive ocular surface examination. The main outcome measures were correlations between corneal thresholds and signs and symptoms of dry eye and ocular pain. A total of 129 subjects participated in the study (mean age 64 ± 10 years). Mechanical detection and pain thresholds on the cornea correlated with age (Spearman's ρ = 0.26, 0.23, respectively; both P Dry eye symptom severity scores and Neuropathic Pain Symptom Inventory (modified for the eye) scores negatively correlated with corneal detection and pain thresholds (range, r = -0.13 to -0.27, P eye pain (pain to wind, light, temperature) and explained approximately 32% of measurement variability (R = 0.57). Mechanical detection and pain thresholds measured on the cornea are correlated with dry eye symptoms and ocular pain. This suggests hypersensitivity within the corneal somatosensory pathways in patients with greater dry eye and ocular pain complaints.

Corneal Mechanical Thresholds Negatively Associate With Dry Eye and Ocular Pain Symptoms

Science.gov (United States)

Spierer, Oriel; Felix, Elizabeth R.; McClellan, Allison L.; Parel, Jean Marie; Gonzalez, Alex; Feuer, William J.; Sarantopoulos, Constantine D.; Levitt, Roy C.; Ehrmann, Klaus; Galor, Anat

2016-01-01

Purpose To examine associations between corneal mechanical thresholds and metrics of dry eye. Methods This was a cross-sectional study of individuals seen in the Miami Veterans Affairs eye clinic. The evaluation consisted of questionnaires regarding dry eye symptoms and ocular pain, corneal mechanical detection and pain thresholds, and a comprehensive ocular surface examination. The main outcome measures were correlations between corneal thresholds and signs and symptoms of dry eye and ocular pain. Results A total of 129 subjects participated in the study (mean age 64 ± 10 years). Mechanical detection and pain thresholds on the cornea correlated with age (Spearman's ρ = 0.26, 0.23, respectively; both P Dry eye symptom severity scores and Neuropathic Pain Symptom Inventory (modified for the eye) scores negatively correlated with corneal detection and pain thresholds (range, r = −0.13 to −0.27, P eye pain (pain to wind, light, temperature) and explained approximately 32% of measurement variability (R = 0.57). Conclusions Mechanical detection and pain thresholds measured on the cornea are correlated with dry eye symptoms and ocular pain. This suggests hypersensitivity within the corneal somatosensory pathways in patients with greater dry eye and ocular pain complaints. PMID:26886896

A Review of Neuropathic Pain: From Diagnostic Tests to Mechanisms

OpenAIRE

Truini, Andrea

2017-01-01

Neuropathic pain develops when the somatosensory nervous system is affected by a lesion or disease. Diagnostic tests aimed at assessing somatosensory afferent pathway damage are therefore useful for diagnosing neuropathic pain. Neuropathic pain manifests with a range of different symptoms such as ongoing burning pain, squeezing or pressure pain, paroxysmal electric shock-like sensations, stabbing pain, or mechanical dynamic allodynia. The various types of neuropathic pain are associated with ...

Higher sensitivity to cadmium induced cell death of basal forebrain cholinergic neurons: A cholinesterase dependent mechanism

International Nuclear Information System (INIS)

Del Pino, Javier; Zeballos, Garbriela; Anadon, María José; Capo, Miguel Andrés; Díaz, María Jesús; García, Jimena; Frejo, María Teresa

2014-01-01

Cadmium is an environmental pollutant, which is a cause of concern because it can be greatly concentrated in the organism causing severe damage to a variety of organs including the nervous system which is one of the most affected. Cadmium has been reported to produce learning and memory dysfunctions and Alzheimer like symptoms, though the mechanism is unknown. On the other hand, cholinergic system in central nervous system (CNS) is implicated on learning and memory regulation, and it has been reported that cadmium can affect cholinergic transmission and it can also induce selective toxicity on cholinergic system at peripheral level, producing cholinergic neurons loss, which may explain cadmium effects on learning and memory processes if produced on central level. The present study is aimed at researching the selective neurotoxicity induced by cadmium on cholinergic system in CNS. For this purpose we evaluated, in basal forebrain region, the cadmium toxic effects on neuronal viability and the cholinergic mechanisms related to it on NS56 cholinergic mourine septal cell line. This study proves that cadmium induces a more pronounced, but not selective, cell death on acetylcholinesterase (AChE) on cholinergic neurons. Moreover, MTT and LDH assays showed a dose dependent decrease of cell viability in NS56 cells. The ACh treatment of SN56 cells did not revert cell viability reduction induced by cadmium, but siRNA transfection against AChE partially reduced it. Our present results provide new understanding of the mechanisms contributing to the harmful effects of cadmium on the function and viability of neurons, and the possible relevance of cadmium in the pathogenesis of neurodegenerative diseases

Mechanisms-based classifications of musculoskeletal pain: part 3 of 3: symptoms and signs of nociceptive pain in patients with low back (± leg) pain.

LENUS (Irish Health Repository)

Smart, Keith M

2012-08-01

As a mechanisms-based classification of pain \\'nociceptive pain\\' (NP) refers to pain attributable to the activation of the peripheral receptive terminals of primary afferent neurones in response to noxious chemical, mechanical or thermal stimuli. The symptoms and signs associated with clinical classifications of NP have not been extensively studied. The purpose of this study was to identify symptoms and signs associated with a clinical classification of NP in patients with low back (± leg) pain. Using a cross-sectional, between-subjects design; four hundred and sixty-four patients with low back (± leg) pain were assessed using a standardised assessment protocol after which their pain was assigned a mechanisms-based classification based on experienced clinical judgement. Clinicians then completed a clinical criteria checklist indicating the presence\\/absence of various symptoms and signs. A regression analysis identified a cluster of seven clinical criteria predictive of NP, including: \\'Pain localised to the area of injury\\/dysfunction\\

Effects of heavy ions on rabbit tissues: damage to the forebrain

International Nuclear Information System (INIS)

Cox, A.B.; Keng, P.C.; Lee, A.C.; Lett, J.T.

1982-01-01

As part of a study of progressive radiation effects in normal tissues, the forebrains of New Zealand white rabbits (Oryctolagus cuniculus) (about 6 weeks old) were irradiated locally with single acute doses of 60 Co γ-photons (LETsub(infinity)=0.3 keV/μm), Ne ions (LETsub(infinity)=35+-3 keV/μm) or Ar ions (LETsub(infinity)=90+-5 keV/μm). Other rabbits received fractionated doses of 60 Co γ-photons according to a standard radiotherapeutic protocol. Irradiated rabbits and appropriately aged controls were sacrificed at selected intervals, and whole sagittal sections of their brains were examined for pathological changes. Forebrain damage was scored with subjective indices based on histological differences between the anterior (irradiated) and posterior (unirradiated) regions of the brain. Those indices ranged from zero (no apparent damage) to five (severe infarctions, etc.). At intermediate levels of forebrain damage, the relative biological effectiveness (r.b.e.) of each heavy ion was similar to that found for alopecia and cataractogenesis, and the early expression of the damage was also accelerated as the LETsub(infinity) increased. Late deterioration of the forebrain appeared also to be accelerated by increasing LETsub(infinity), although its accurate quantification was not possible because other priorities in the overall experimental design limited systematic sacrifice of the animals. (author)

Cytotoxicity of synthetic cannabinoids on primary neuronal cells of the forebrain: the involvement of cannabinoid CB1 receptors and apoptotic cell death

International Nuclear Information System (INIS)

Tomiyama, Ken-ichi; Funada, Masahiko

2014-01-01

The abuse of herbal products containing synthetic cannabinoids has become an issue of public concern. The purpose of this paper was to evaluate the acute cytotoxicity of synthetic cannabinoids on mouse brain neuronal cells. Cytotoxicity induced by synthetic cannabinoid (CP-55,940, CP-47,497, CP-47,497-C8, HU-210, JWH-018, JWH-210, AM-2201, and MAM-2201) was examined using forebrain neuronal cultures. These synthetic cannabinoids induced cytotoxicity in the forebrain cultures in a concentration-dependent manner. The cytotoxicity was suppressed by preincubation with the selective CB 1 receptor antagonist AM251, but not with the selective CB 2 receptor antagonist AM630. Furthermore, annexin-V-positive cells were found among the treated forebrain cells. Synthetic cannabinoid treatment induced the activation of caspase-3, and preincubation with a caspase-3 inhibitor significantly suppressed the cytotoxicity. These synthetic cannabinoids induced apoptosis through a caspase-3-dependent mechanism in the forebrain cultures. Our results indicate that the cytotoxicity of synthetic cannabinoids towards primary neuronal cells is mediated by the CB 1 receptor, but not by the CB 2 receptor, and further suggest that caspase cascades may play an important role in the apoptosis induced by these synthetic cannabinoids. In conclusion, excessive synthetic cannabinoid abuse may present a serious acute health concern due to neuronal damage or deficits in the brain. - Highlights: • Synthetic cannabinoids (classical cannabinoids, non-classical cannabinoids, and aminoalkylindole derivatives) induce cytotoxicity in mouse forebrain cultures. • Synthetic cannabinoid-induced cytotoxicity towards forebrain cultures is mediated by the CB 1 receptor, but not by the CB 2 receptor, and involves caspase-dependent apoptosis. • A high concentration of synthetic cannabinoids may be toxic to neuronal cells that express CB 1 receptors

Regulation of gene expression and pain states by epigenetic mechanisms.

Science.gov (United States)

Géranton, Sandrine M; Tochiki, Keri K

2015-01-01

The induction of inflammatory or neuropathic pain states is known to involve molecular activity in the spinal superficial dorsal horn and dorsal root ganglia, including intracellular signaling events which lead to changes in gene expression. These changes ultimately cause alterations in macromolecular synthesis, synaptic transmission, and structural architecture which support central sensitization, a process required for the establishment of long-term pain states. Epigenetic mechanisms are essential for long-term synaptic plasticity and modulation of gene expression. This is because epigenetic modifications are known to regulate gene transcription by aiding the physical relaxation or condensation of chromatin. These processes are therefore potential regulators of the molecular changes underlying permanent pain states. A handful of studies have emerged in the field of pain epigenetics; however, the field is still very much in its infancy. This chapter draws upon other specialities which have extensively investigated epigenetic mechanisms, such as learning and memory and oncology. After defining epigenetics as well as the recent field of "neuroepigenetics" and the main molecular mechanisms involved, this chapter describes the role of these mechanisms in the synaptic plasticity seen in learning and memory, and address those epigenetic mechanisms that have been linked with the development of acute and prolonged pain states. Finally, the idea that long-lasting epigenetic modifications could contribute to the transition from acute to chronic pain states by supporting maladaptive molecular changes is discussed. © 2015 Elsevier Inc. All rights reserved.

Ascending connections to the forebrain in the Tegu lizard.

Science.gov (United States)

Lohman, A H; van Woerden-Verkley, I

1978-12-01

The ascending connections to the striatum and the cortex of the Tegu lizard, Tupinambis nigropunctatus, were studied by means of anterograde fiber degeneration and retrograde axonal transport. The striatum receives projections by way of the dorsal peduncle of the lateral forebrain bundle from four dorsal thalamic nuclei: nucleus rotundus, nucleus reuniens, the posterior part of the dorsal lateral geniculate nucleus and nucleus dorsomedialis. The former three nuclei project to circumscribed areas of the dorsal striatum, whereas nucleus dorsomedialis has a distribution to the whole dorsal striatum. Other sources of origin to the striatum are the mesencephalic reticular formation, substantia nigra and nucleus cerebelli lateralis. With the exception of the latter afferentation all these projections are ipsilateral. The ascending connections to the pallium originate for the major part from nucleus dorsolateralis anterior of the dorsal thalamus. The fibers course in both the medial forebrain bundle and the dorsal peduncle of the lateral forebrain bundle and terminate ipsilaterally in the middle of the molecular layer of the small-celled part of the mediodorsal cortex and bilaterally above the intermediate region of the dorsal cortex. The latter area is reached also by fibers from the septal area. The large-celled part of the mediodorsal cortex receives projections from nucleus raphes superior and the corpus mammillare.

Cellular localization of transforming growth factor-alpha mRNA in rat forebrain.

Science.gov (United States)

Seroogy, K B; Lundgren, K H; Lee, D C; Guthrie, K M; Gall, C M

1993-05-01

The cellular localization of transforming growth factor-alpha (TGF alpha) mRNA in juvenile and adult rat forebrain was examined using in situ hybridization with a 35S-labeled cRNA probe. TGF alpha cRNA-labeled neuronal perikarya were distributed across many forebrain regions including the olfactory bulb, caudate-putamen, nucleus accumbens, olfactory tubercle, ventral pallidum, amygdala, hippocampal stratum granulosum and CA3 stratum pyramidale, and piriform, entorhinal, and retrosplenial cortices. TGF alpha cRNA-hybridizing cells were also localized to several thalamic nuclei and to the suprachiasmatic, dorsomedial, and ventromedial nuclei of the hypothalamus. In addition, labeled cells were present in regions of white matter including the corpus callosum, anterior commissure, internal and external capsules, optic tract, and lateral olfactory tract. Thus, both neurons and glia appear to synthesize TGF alpha in normal brain. Hybridization densities were greater in neuronal fields at 2 weeks of age compared with the adult, suggesting a role for TGF alpha in the development of several forebrain systems. Our results demonstrating the prominent and wide-spread expression of TGF alpha mRNA in forebrain, combined with the extremely low abundance of epidermal growth factor mRNA in brain, support the argument that TGF alpha is the principal endogenous ligand for the epidermal growth factor receptor in normal brain.

Medial forebrain bundle lesions fail to structurally and functionally disconnect the ventral tegmental area from many ipsilateral forebrain nuclei: implications for the neural substrate of brain stimulation reward.

Science.gov (United States)

Simmons, J M; Ackermann, R F; Gallistel, C R

1998-10-15

Lesions in the medial forebrain bundle rostral to a stimulating electrode have variable effects on the rewarding efficacy of self-stimulation. We attempted to account for this variability by measuring the anatomical and functional effects of electrolytic lesions at the level of the lateral hypothalamus (LH) and by correlating these effects to postlesion changes in threshold pulse frequency (pps) for self-stimulation in the ventral tegmental area (VTA). We implanted True Blue in the VTA and compared cell labeling patterns in forebrain regions of intact and lesioned animals. We also compared stimulation-induced regional [14C]deoxyglucose (DG) accumulation patterns in the forebrains of intact and lesioned animals. As expected, postlesion threshold shifts varied: threshold pps remained the same or decreased in eight animals, increased by small but significant amounts in three rats, and increased substantially in six subjects. Unexpectedly, LH lesions did not anatomically or functionally disconnect all forebrain nuclei from the VTA. Most septal and preoptic regions contained equivalent levels of True Blue label in intact and lesioned animals. In both intact and lesioned groups, VTA stimulation increased metabolic activity in the fundus of the striatum (FS), the nucleus of the diagonal band, and the medial preoptic area. On the other hand, True Blue labeling demonstrated anatomical disconnection of the accumbens, FS, substantia innominata/magnocellular preoptic nucleus (SI/MA), and bed nucleus of the stria terminalis. [14C]DG autoradiography indicated functional disconnection of the lateral preoptic area and SI/MA. Correlations between patterns of True Blue labeling or [14C]deoxyglucose accumulation and postlesion shifts in threshold pulse frequency were weak and generally negative. These direct measures of connectivity concord with the behavioral measures in suggesting a diffuse net-like connection between forebrain nuclei and the VTA.

Pain in the Blood? Envisioning Mechanism-Based Diagnoses and Biomarkers in Clinical Pain Medicine

Directory of Open Access Journals (Sweden)

Emmanuel Bäckryd

2015-03-01

Full Text Available Chronic pain is highly prevalent, and pain medicine lacks objective biomarkers to guide diagnosis and choice of treatment. The current U.S. “opioid epidemic” is a reminder of the paucity of effective and safe treatment options. Traditional pain diagnoses according to the International Classification of Diseases are often unspecific, and analgesics are often prescribed on a trial-and-error basis. In contrast to this current state of affairs, the vision of future mechanism-based diagnoses of chronic pain conditions is presented in this non-technical paper, focusing on the need for biomarkers and the theoretical complexity of the task. Pain is and will remain a subjective experience, and as such is not objectively measurable. Therefore, the concept of “noci-marker” is presented as an alternative to “pain biomarker”, the goal being to find objective, measurable correlates of the pathophysiological processes involved in different chronic pain conditions. This vision entails a call for more translational pain research in order to bridge the gap between clinical pain medicine and preclinical science.

Psychosocial factors partially mediate the relationship between mechanical hyperalgesia and self-reported pain.

Science.gov (United States)

Mason, Kayleigh J; O'Neill, Terence W; Lunt, Mark; Jones, Anthony K P; McBeth, John

2018-01-26

Amplification of sensory signalling within the nervous system along with psychosocial factors contributes to the variation and severity of knee pain. Quantitative sensory testing (QST) is a non-invasive test battery that assesses sensory perception of thermal, pressure, mechanical and vibration stimuli used in the assessment of pain. Psychosocial factors also have an important role in explaining the occurrence of pain. The aim was to determine whether QST measures were associated with self-reported pain, and whether those associations were mediated by psychosocial factors. Participants with knee pain identified from a population-based cohort completed a tender point count and a reduced QST battery of thermal, mechanical and pressure pain thresholds, temporal summation, mechanical pain sensitivity (MPS), dynamic mechanical allodynia (DMA) and vibration detection threshold performed following the protocol by the German Research Network on Neuropathic Pain. QST assessments were performed at the most painful knee and opposite forearm (if pain-free). Participants were asked to score for their global and knee pain intensities within the past month (range 0-10), and complete questionnaire items investigating anxiety, depression, illness perceptions, pain catastrophising, and physical functioning. QST measures (independent variable) significantly correlated (Spearman's rho) with self-reported pain intensity (dependent variable) were included in structural equation models with psychosocial factors (latent mediators). Seventy-two participants were recruited with 61 participants (36 women; median age 64 years) with complete data included in subsequent analyses. Tender point count was significantly correlated with global pain intensity. DMA at the knee and MPS at the most painful knee and opposite pain-free forearm were significantly correlated with both global pain and knee pain intensities. Psychosocial factors including pain catastrophising sub-scales (rumination and

Cytotoxicity of synthetic cannabinoids on primary neuronal cells of the forebrain: the involvement of cannabinoid CB{sub 1} receptors and apoptotic cell death

Energy Technology Data Exchange (ETDEWEB)

Tomiyama, Ken-ichi; Funada, Masahiko, E-mail: mfunada@ncnp.go.jp

2014-01-01

The abuse of herbal products containing synthetic cannabinoids has become an issue of public concern. The purpose of this paper was to evaluate the acute cytotoxicity of synthetic cannabinoids on mouse brain neuronal cells. Cytotoxicity induced by synthetic cannabinoid (CP-55,940, CP-47,497, CP-47,497-C8, HU-210, JWH-018, JWH-210, AM-2201, and MAM-2201) was examined using forebrain neuronal cultures. These synthetic cannabinoids induced cytotoxicity in the forebrain cultures in a concentration-dependent manner. The cytotoxicity was suppressed by preincubation with the selective CB{sub 1} receptor antagonist AM251, but not with the selective CB{sub 2} receptor antagonist AM630. Furthermore, annexin-V-positive cells were found among the treated forebrain cells. Synthetic cannabinoid treatment induced the activation of caspase-3, and preincubation with a caspase-3 inhibitor significantly suppressed the cytotoxicity. These synthetic cannabinoids induced apoptosis through a caspase-3-dependent mechanism in the forebrain cultures. Our results indicate that the cytotoxicity of synthetic cannabinoids towards primary neuronal cells is mediated by the CB{sub 1} receptor, but not by the CB{sub 2} receptor, and further suggest that caspase cascades may play an important role in the apoptosis induced by these synthetic cannabinoids. In conclusion, excessive synthetic cannabinoid abuse may present a serious acute health concern due to neuronal damage or deficits in the brain. - Highlights: • Synthetic cannabinoids (classical cannabinoids, non-classical cannabinoids, and aminoalkylindole derivatives) induce cytotoxicity in mouse forebrain cultures. • Synthetic cannabinoid-induced cytotoxicity towards forebrain cultures is mediated by the CB{sub 1} receptor, but not by the CB{sub 2} receptor, and involves caspase-dependent apoptosis. • A high concentration of synthetic cannabinoids may be toxic to neuronal cells that express CB{sub 1} receptors.

Mechanism-based classification of pain for physical therapy management in palliative care: A clinical commentary

Directory of Open Access Journals (Sweden)

Senthil P Kumar

2011-01-01

Full Text Available Pain relief is a major goal for palliative care in India so much that most palliative care interventions necessarily begin first with pain relief. Physical therapists play an important role in palliative care and they are regarded as highly proficient members of a multidisciplinary healthcare team towards management of chronic pain. Pain necessarily involves three different levels of classification-based upon pain symptoms, pain mechanisms and pain syndromes. Mechanism-based treatments are most likely to succeed compared to symptomatic treatments or diagnosis-based treatments. The objective of this clinical commentary is to update the physical therapists working in palliative care, on the mechanism-based classification of pain and its interpretation, with available therapeutic evidence for providing optimal patient care using physical therapy. The paper describes the evolution of mechanism-based classification of pain, the five mechanisms (central sensitization, peripheral neuropathic, nociceptive, sympathetically maintained pain and cognitive-affective are explained with recent evidence for physical therapy treatments for each of the mechanisms.

Mast cells in the sheep, hedgehog and rat forebrain

Science.gov (United States)

MICHALOUDI, HELEN C.; PAPADOPOULOS, GEORGIOS C.

1999-01-01

The study was designed to reveal the distribution of various mast cell types in the forebrain of the adult sheep, hedgehog and rat. Based on their histochemical and immunocytochemical characteristics, mast cells were categorised as (1) connective tissue-type mast cells, staining metachromatically purple with the toluidine blue method, or pale red with the Alcian blue/safranin method, (2) mucosal-type or immature mast cells staining blue with the Alcian blue/safranin method and (3) serotonin immunopositive mast cells. All 3 types of brain mast cells in all species studied were located in both white and grey matter, often associated with intraparenchymal blood vessels. Their distribution pattern exhibited interspecies differences, while their number varied considerably not only between species but also between individuals of each species. A distributional left-right asymmetry, with more cells present on the left side, was observed in all species studied but it was most prominent in the sheep brain. In the sheep, mast cells were abundantly distributed in forebrain areas, while in the hedgehog and the rat forebrain, mast cells were less widely distributed and were relatively or substantially fewer in number respectively. A limited number of brain mast cells, in all 3 species, but primarily in the rat, were found to react both immunocytochemically to 5-HT antibody and histochemically with Alcian blue/safranin staining. PMID:10634696

Ionic mechanisms in peripheral pain.

Science.gov (United States)

Fransén, Erik

2014-01-01

Chronic pain constitutes an important and growing problem in society with large unmet needs with respect to treatment and clear implications for quality of life. Computational modeling is used to complement experimental studies to elucidate mechanisms involved in pain states. Models representing the peripheral nerve ending often address questions related to sensitization or reduction in pain detection threshold. In models of the axon or the cell body of the unmyelinated C-fiber, a large body of work concerns the role of particular sodium channels and mutations of these. Furthermore, in central structures: spinal cord or higher structures, sensitization often refers not only to enhanced synaptic efficacy but also to elevated intrinsic neuronal excitability. One of the recent developments in computational neuroscience is the emergence of computational neuropharmacology. In this area, computational modeling is used to study mechanisms of pathology with the objective of finding the means of restoring healthy function. This research has received increased attention from the pharmaceutical industry as ion channels have gained increased interest as drug targets. Computational modeling has several advantages, notably the ability to provide mechanistic links between molecular and cellular levels on the one hand and functions at the systems level on the other hand. These characteristics make computational modeling an additional tool to be used in the process of selecting pharmaceutical targets. Furthermore, large-scale simulations can provide a framework to systematically study the effects of several interacting disease parameters or effects from combinations of drugs. © 2014 Elsevier Inc. All rights reserved.

Physical Therapy in the Treatment of Central Pain Mechanisms for Female Sexual Pain.

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Vandyken, Carolyn; Hilton, Sandra

2017-01-01

The complexity of female sexual pain requires an interdisciplinary approach. Physical therapists trained in pelvic health conditions are well positioned to be active members of an interdisciplinary team addressing the assessment and treatment of female sexual pain. Changes within physical therapy practice in the last ten years have resulted in significant utilization of pelvic floor muscle relaxation and manual therapy techniques to address a variety of pelvic pain conditions, including female sexual pain. However, sexual pain is a complex issue giving credence to the necessity of addressing all of the drivers of the pain experience- biological, psychological and social. This review aims to reconcile current pain science with a plan for integrating a biopsychosocial approach into the evaluation and subsequent treatment for female sexual pain for physical therapists. A literature review of the important components of skilled physical therapy interventions is presented including the physical examination, pain biology education, cognitive behavioral influences in treatment design, motivational interviewing as an adjunct to empathetic practice, and the integration of non-threatening movement and mindfulness into treatment. A single case study is used to demonstrate the biopsychosocial framework utilized in this approach. Appropriate measures for assessing psychosocial factors are readily available and inform a reasoned approach for physical therapy design that addresses both peripheral and central pain mechanisms. Decades of research support the integration of a biopsychosocial approach in the treatment of complex pain, including female sexual pain. It is reasonable for physical therapists to utilize evidence based strategies such as CBT, pain biology education, Mindfulness Based Stress Reduction (MBSR), yoga and imagery based exercises to address the biopsychosocial components of female sexual pain. Copyright © 2016 International Society for Sexual Medicine

The signaling lipid sphingosine 1-phosphate regulates mechanical pain

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Hill, Rose Z; Hoffman, Benjamin U; Morita, Takeshi; Campos, Stephanie M; Lumpkin, Ellen A; Brem, Rachel B

2018-01-01

Somatosensory neurons mediate responses to diverse mechanical stimuli, from innocuous touch to noxious pain. While recent studies have identified distinct populations of A mechanonociceptors (AMs) that are required for mechanical pain, the molecular underpinnings of mechanonociception remain unknown. Here, we show that the bioactive lipid sphingosine 1-phosphate (S1P) and S1P Receptor 3 (S1PR3) are critical regulators of acute mechanonociception. Genetic or pharmacological ablation of S1PR3, or blockade of S1P production, significantly impaired the behavioral response to noxious mechanical stimuli, with no effect on responses to innocuous touch or thermal stimuli. These effects are mediated by fast-conducting A mechanonociceptors, which displayed a significant decrease in mechanosensitivity in S1PR3 mutant mice. We show that S1PR3 signaling tunes mechanonociceptor excitability via modulation of KCNQ2/3 channels. Our findings define a new role for S1PR3 in regulating neuronal excitability and establish the importance of S1P/S1PR3 signaling in the setting of mechanical pain thresholds. PMID:29561262

Receptors for GRP/bombesin-like peptides in the rat forebrain

International Nuclear Information System (INIS)

Wolf, S.S.; Moody, T.W.

1985-01-01

Binding sites in the rat forebrain were characterized using ( 125 I-Tyr4)bombesin as a receptor probe. Pharmacology experiments indicate that gastrin releasing peptide (GRP) and the GRP fragments GRP as well as Ac-GRP inhibited radiolabeled (Tyr4)bombesin binding with high affinity. Biochemistry experiments indicated that heat, N-ethyl maleimide or trypsin greatly reduced radiolabeled (Tyr4)bombesin binding. Also, autoradiographic studies indicated that highest grain densities were present in the stria terminalis, periventricular and suprachiasmatic nucleus of the hypothalamus, dorsomedial and rhomboid thalamus, dentate gyrus, hippocampus and medial amygdaloid nucleus. The data suggest that CNS protein receptors, which are discretely distributed in the rat forebrain, may mediate the action of endogenous GRP/bombesin-like peptides

Regulatory interactions of stress and reward on rat forebrain opioidergic and GABAergic circuitry.

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Christiansen, A M; Herman, J P; Ulrich-Lai, Y M

2011-03-01

Palatable food intake reduces stress responses, suggesting that individuals may consume such ?comfort? food as self-medication for stress relief. The mechanism by which palatable foods provide stress relief is not known, but likely lies at the intersection of forebrain reward and stress regulatory circuits. Forebrain opioidergic and gamma-aminobutyric acid ergic signaling is critical for both reward and stress regulation, suggesting that these systems are prime candidates for mediating stress relief by palatable foods. Thus, the present study (1) determines how palatable ?comfort? food alters stress-induced changes in the mRNA expression of inhibitory neurotransmitters in reward and stress neurocircuitry and (2) identifies candidate brain regions that may underlie comfort food-mediated stress reduction. We used a model of palatable ?snacking? in combination with a model of chronic variable stress followed by in situ hybridization to determine forebrain levels of pro-opioid and glutamic acid decarboxylase (GAD) mRNA. The data identify regions within the extended amygdala, striatum, and hypothalamus as potential regions for mediating hypothalamic-pituitary-adrenal axis buffering following palatable snacking. Specifically, palatable snacking alone decreased pro-enkephalin-A (ENK) mRNA expression in the anterior bed nucleus of the stria terminalis (BST) and the nucleus accumbens, and decreased GAD65 mRNA in the posterior BST. Chronic stress alone increased ENK mRNA in the hypothalamus, nucleus accumbens, amygdala, and hippocampus; increased dynorphin mRNA in the nucleus accumbens; increased GAD65 mRNA in the anterior hypothalamus and BST; and decreased GAD65 mRNA in the dorsal hypothalamus. Importantly, palatable food intake prevented stress-induced gene expression changes in subregions of the hypothalamus, BST, and nucleus accumbens. Overall, these data suggest that complex interactions exist between brain reward and stress pathways and that palatable snacking can

Pain in Patients with Pancreatic Cancer: Prevalence, Mechanisms, Management and Future Developments.

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Koulouris, Andreas I; Banim, Paul; Hart, Andrew R

2017-04-01

Pain affects approximately 80% of patients with pancreatic cancer, with half requiring strong opioid analgesia, namely: morphine-based drugs on step three of the WHO analgesic ladder (as opposed to the weak opioids: codeine and tramadol). The presence of pain is associated with reduced survival. This article reviews the literature regarding pain: prevalence, mechanisms, pharmacological, and endoscopic treatments and identifies areas for research to develop individualized patient pain management pathways. The online literature review was conducted through: PubMed, Clinical Key, Uptodate, and NICE Evidence. There are two principal mechanisms for pain: pancreatic duct obstruction and pancreatic neuropathy which, respectively, activate mechanical and chemical nociceptors. In pancreatic neuropathy, several histological, molecular, and immunological changes occur which correlate with pain including: transient receptor potential cation channel activation and mast cell infiltration. Current pain management is empirical rather etiology-based and is informed by the WHO analgesic ladder for first-line therapies, and then endoscopic ultrasound-guided celiac plexus neurolysis (EUS-CPN) in patients with resistant pain. For EUS-CPN, there is only one clinical trial reporting a benefit, which has limited generalizability. Case series report pancreatic duct stenting gives effective analgesia, but there are no clinical trials. Progress in understanding the mechanisms for pain and when this occurs in the natural history, together with assessing new therapies both pharmacological and endoscopic, will enable individualized care and may improve patients' quality of life and survival.

A Screening Mechanism Differentiating True from False Pain during Empathy.

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Sun, Ya-Bin; Lin, Xiao-Xiao; Ye, Wen; Wang, Ning; Wang, Jin-Yan; Luo, Fei

2017-09-13

Empathizing with another's suffering is important in social interactions. Empathic behavior is selectively elicited from genuine, meaningful pain but not from fake, meaningless scenarios. However, the brain's screening mechanism of false information from meaningful events and the time course for the screening process remains unclear. Using EEG combined with principle components analysis (PCA) techniques, here we compared temporal neurodynamics between the observation of pain and no-pain pictures as well as between true (painful expressions and needle-penetrated arms) and false (needle-penetrated faces with neutral expressions) pain pictures. The results revealed that pain vs. no-pain information is differentiated in the very early ERP components, i.e., the N1/P1 for the face and arm pictures categories and the VPP/N170 for the facial expression category while the mid-latency ERP components, N2 and P3, played key roles in differentiating true from false situations. The complex of N2 and P3 components may serve as a screening mechanism through which observers allocate their attentions to more important or relevant events and screen out false environmental information. This is the first study to describe and provide a time course of the screening process during pain empathy. These findings shed new light on the understanding of empathic processing.

IMMEDIATE EFFECT OF CERVICAL MANIPULATION ON PAIN AND RANGE OF MOTION IN PATIENTS WITH CHRONIC MECHANICAL NECK PAIN

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Kabir Isah Mayana

2017-06-01

Full Text Available Background: Neck pain has been reported as a prevalent musculoskeletal disorder globally with more than half of the general population being affected once or more within their life span. Methods: A randomized clinical trial research design was used which investigated the immediate effect of cervical manipulation on neck pain and cervical range of motion among patients with chronic mechanical neck pain. 20 male and female participants between the ages of 26 to 60 years with chronic mechanical neck pain attending physiotherapy clinics were recruited. They were randomly assigned into two groups (A and B of 10 patients each. Group A received soft tissue massage, and cervical manipulation and group B served as the control group, and they received only soft tissue massage. There were two outcomes measured; Pain intensity was rated using visual analog scale (VAS before and immediately after the intervention. Pre and Post intervention measurements of cervical spine range of motion using Goniometer were also taken. Results: Findings of the study revealed significant immediate improvement of pain and Cervical Range of Motions (p<0.05 in all dimensions in the experimental group while Pain, flexion and right side Cervical flexion significantly improved in the control group. It was also found out after comparing the outcomes between the two groups that, the experimental group had significantly (p<0.05 better improvement than the control group in post-intervention pain, cervical flexion, cervical extension and cervical (right and left lateral rotations. Conclusion: Cervical manipulation is effective in immediate pain relief and improvement in cervical range of motion in patients with mechanical neck pain

Facilitatory and inhibitory pain mechanisms are altered in patients with carpal tunnel syndrome.

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Benjamin Soon

Full Text Available Preliminary evidence from studies using quantitative sensory testing suggests the presence of central mechanisms in patients with carpal tunnel syndrome (CTS as apparent by widespread hyperalgesia. Hallmarks of central mechanisms after nerve injuries include nociceptive facilitation and reduced endogenous pain inhibition. Methods to study nociceptive facilitation in CTS so far have been limited to quantitative sensory testing and the integrity of endogenous inhibition remains unexamined. The aim of this study was therefore to investigate changes in facilitatory and inhibitory processing in patients with CTS by studying hypersensitivity following experimentally induced pain (facilitatory mechanisms and the efficacy of conditioned pain modulation (CPM, inhibitory mechanisms. Twenty-five patients with mild to moderate CTS and 25 age and sex matched control participants without CTS were recruited. Increased pain facilitation was evaluated via injection of hypertonic saline into the upper trapezius. Altered pain inhibition through CPM was investigated through cold water immersion of the foot as the conditioning stimulus and pressure pain threshold over the thenar and hypothenar eminence bilaterally as the test stimulus. The results demonstrated that patients with CTS showed a greater duration (p = 0.047, intensity (p = 0.044 and area (p = 0.012 of pain in response to experimentally induced pain in the upper trapezius and impaired CPM compared to the control participants (p = 0.006. Although typically considered to be driven by peripheral mechanisms, these findings indicate that CTS demonstrates characteristics of altered central processing with increased pain facilitation and reduced endogenous pain inhibition.

Functional Connectome Analysis of Dopamine Neuron Glutamatergic Connections in Forebrain Regions.

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Mingote, Susana; Chuhma, Nao; Kusnoor, Sheila V; Field, Bianca; Deutch, Ariel Y; Rayport, Stephen

2015-12-09

In the ventral tegmental area (VTA), a subpopulation of dopamine neurons express vesicular glutamate transporter 2 and make glutamatergic connections to nucleus accumbens (NAc) and olfactory tubercle (OT) neurons. However, their glutamatergic connections across the forebrain have not been explored systematically. To visualize dopamine neuron forebrain projections and to enable photostimulation of their axons independent of transmitter status, we virally transfected VTA neurons with channelrhodopsin-2 fused to enhanced yellow fluorescent protein (ChR2-EYFP) and used DAT(IREScre) mice to restrict expression to dopamine neurons. ChR2-EYFP-expressing neurons almost invariably stained for tyrosine hydroxylase, identifying them as dopaminergic. Dopamine neuron axons visualized by ChR2-EYFP fluorescence projected most densely to the striatum, moderately to the amygdala and entorhinal cortex (ERC), sparsely to prefrontal and cingulate cortices, and rarely to the hippocampus. Guided by ChR2-EYFP fluorescence, we recorded systematically from putative principal neurons in target areas and determined the incidence and strength of glutamatergic connections by activating all dopamine neuron terminals impinging on recorded neurons with wide-field photostimulation. This revealed strong glutamatergic connections in the NAc, OT, and ERC; moderate strength connections in the central amygdala; and weak connections in the cingulate cortex. No glutamatergic connections were found in the dorsal striatum, hippocampus, basolateral amygdala, or prefrontal cortex. These results indicate that VTA dopamine neurons elicit widespread, but regionally distinct, glutamatergic signals in the forebrain and begin to define the dopamine neuron excitatory functional connectome. Dopamine neurons are important for the control of motivated behavior and are involved in the pathophysiology of several major neuropsychiatric disorders. Recent studies have shown that some ventral midbrain dopamine neurons are

Effect of thermal stresses on the mechanism of tooth pain.

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Oskui, Iman Z; Ashtiani, Mohammed N; Hashemi, Ata; Jafarzadeh, Hamid

2014-11-01

Daily hot and cold thermal loadings on teeth may result in structural deformation, mechanical stress, and pain signaling. The aim of this study was to compare the adverse effects of hot and cold beverages on an intact tooth and, then, to provide physical evidence to support the hydrodynamic theory of tooth pain sensation mechanism. Three-dimensional finite element analysis was performed on a premolar model subjected to hot and cold thermal loadings. Elapsed times for heat diffusion and stress detection at the pulp-dentin junction were calculated as measures of the pain sensation. Extreme tensile stress within the enamel resulted in damage in cold loadings. Also, extreme values of stress at the pulpal wall occurred 21.6 seconds earlier than extreme temperatures in hot and cold loadings. The intact tooth was remarkably vulnerable to cold loading. Earlier changes in mechanical stress rather than temperature at the pulp-dentin junction indicate that the dental pain caused by hot or cold beverages may be based on the hydrodynamic theory. Copyright © 2014 American Association of Endodontists. Published by Elsevier Inc. All rights reserved.

Mechanisms-based classifications of musculoskeletal pain: part 2 of 3: symptoms and signs of peripheral neuropathic pain in patients with low back (± leg) pain.

LENUS (Irish Health Repository)

Smart, Keith M

2012-08-01

As a mechanisms-based classification of pain \\'peripheral neuropathic pain\\' (PNP) refers to pain arising from a primary lesion or dysfunction in the peripheral nervous system. Symptoms and signs associated with an assumed dominance of PNP in patients attending for physiotherapy have not been extensively studied. The purpose of this study was to identify symptoms and signs associated with a clinical classification of PNP in patients with low back (± leg) pain. Using a cross-sectional, between-subjects design; four hundred and sixty-four patients with low back (± leg) pain were assessed using a standardised assessment protocol. Patients\\' pain was assigned a mechanisms-based classification based on experienced clinical judgement. Clinicians then completed a clinical criteria checklist specifying the presence or absence of various clinical criteria. A binary logistic regression analysis with Bayesian model averaging identified a cluster of two symptoms and one sign predictive of PNP, including: \\'Pain referred in a dermatomal or cutaneous distribution\\

Pain in Breast Cancer Treatment: Aggravating Factors and Coping Mechanisms

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Maria de Fatima Guerreiro Godoy

2014-01-01

Full Text Available The objective of this study was to evaluate pain in women with breast cancer-related lymphedema and the characteristics of aggravating factors and coping mechanisms. The study was conducted in the Clinica Godoy, São Jose do Rio Preto, with a group of 46 women who had undergone surgery for the treatment of breast cancer. The following variables were evaluated: type and length of surgery; number of radiotherapy and chemotherapy sessions; continued feeling of the removed breast (phantom limb, infection, intensity of pain, and factors that improve and worsen the pain. The percentage of events was used for statistical analysis. About half the participants (52.1% performed modified radical surgery, with 91.3% removing only one breast; 82.6% of the participants did not perform breast reconstruction surgery. Insignificant pain was reported by 32.60% of the women and 67.3% said they suffered pain; it was mild in 28.8% of the cases (scale 1–5, moderate in 34.8% (scale 6–9, and severe in 4.3%. The main mechanisms used to cope with pain were painkillers in 41.30% of participants, rest in 21.73%, religious ceremonies in 17.39%, and chatting with friends in 8.69%. In conclusion, many mastectomized patients with lymphedema complain of pain, but pain is often underrecognized and undertreated.

Molecular Mechanisms That Contribute to Bone Marrow Pain

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Jason J. Ivanusic

2017-09-01

Full Text Available Pain associated a bony pathology puts a significant burden on individuals, society, and the health-care systems worldwide. Pathology that involves the bone marrow activates sensory nerve terminal endings of peripheral bone marrow nociceptors, and is the likely trigger for pain. This review presents our current understanding of how bone marrow nociceptors are influenced by noxious stimuli presented in pathology associated with bone marrow. A number of ion channels and receptors are emerging as important modulators of the activity of peripheral bone marrow nociceptors. Nerve growth factor (NGF sequestration has been trialed for the management of inflammatory bone pain (osteoarthritis, and there is significant evidence for interaction of NGF with bone marrow nociceptors. Activation of transient receptor potential cation channel subfamily V member 1 sensitizes bone marrow nociceptors and could contribute to increased sensitivity of patients to noxious stimuli in various bony pathologies. Acid-sensing ion channels sense changes to tissue pH in the bone marrow microenvironment and could be targeted to treat pathology that involves acidosis of the bone marrow. Piezo2 is a mechanically gated ion channel that has recently been reported to be expressed by most myelinated bone marrow nociceptors and might be a target for treatments directed against mechanically induced bone pain. These ion channels and receptors could be useful targets for the development of peripherally acting drugs to treat pain of bony origin.

Differential effect of ketamine and lidocaine on spontaneous and mechanical evoked pain in patients with nerve injury pain

DEFF Research Database (Denmark)

Gottrup, Hanne; Bach, Flemming Winther; Juhl, Gitte Irene

2006-01-01

ketamine, an N-methyl-D-aspartate receptor antagonist and lidocaine, a sodium channel blocker, on spontaneous pain, brush-evoked pain, and pinprick-evoked pain in patients with nerve injury pain. METHODS: Twenty patients participated in two randomized, double-blinded, placebo-controlled, crossover...... experiments in which they, on four different days, received a 30-minute intravenous infusion of ketamine (0.24 mg/kg), lidocaine (5 mg/kg), or saline. Ongoing pain, pain evoked by brush and repetitive pinprick stimuli, and acetone was measured before, during, and after infusion. RESULTS: Ketamine...... significantly reduced ongoing pain and evoked pain to brush and pinprick, whereas lidocaine only reduced evoked pain to repetitive pinprick stimuli. In individual patients, there was no correlation between the pain-relieving effect of lidocaine and ketamine on ongoing or mechanically evoked pains. CONCLUSIONS...

Human brain activity associated with painful mechanical stimulation to muscle and bone.

Science.gov (United States)

Maeda, Lynn; Ono, Mayu; Koyama, Tetsuo; Oshiro, Yoshitetsu; Sumitani, Masahiko; Mashimo, Takashi; Shibata, Masahiko

2011-08-01

The purpose of this study was to elucidate the central processing of painful mechanical stimulation to muscle and bone by measuring blood oxygen level-dependent signal changes using functional magnetic resonance imaging (fMRI). Twelve healthy volunteers were enrolled. Mechanical pressure on muscle and bone were applied at the right lower leg by an algometer. Intensities were adjusted to cause weak and strong pain sensation at either target site in preliminary testing. Brain activation in response to mechanical nociceptive stimulation targeting muscle and bone were measured by fMRI and analyzed. Painful mechanical stimulation targeting muscle and bone activated the common areas including bilateral insula, anterior cingulate cortex, posterior cingulate cortex, secondary somatosensory cortex (S2), inferior parietal lobe, and basal ganglia. The contralateral S2 was more activated by strong stimulation than by weak stimulation. Some areas in the basal ganglia (bilateral putamen and caudate nucleus) were more activated by muscle stimulation than by bone stimulation. The putamen and caudate nucleus may have a more significant role in brain processing of muscle pain compared with bone pain.

Adolescent Intermittent Alcohol Exposure: Deficits in Object Recognition Memory and Forebrain Cholinergic Markers.

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H Scott Swartzwelder

Full Text Available The long-term effects of intermittent ethanol exposure during adolescence (AIE are of intensive interest and investigation. The effects of AIE on learning and memory and the neural functions that drive them are of particular interest as clinical findings suggest enduring deficits in those cognitive domains in humans after ethanol abuse during adolescence. Although studies of such deficits after AIE hold much promise for identifying mechanisms and therapeutic interventions, the findings are sparse and inconclusive. The present results identify a specific deficit in memory function after AIE and establish a possible neural mechanism of that deficit that may be of translational significance. Male rats (starting at PND-30 received exposure to AIE (5g/kg, i.g. or vehicle and were allowed to mature into adulthood. At PND-71, one group of animals was assessed using the spatial-temporal object recognition (stOR test to evaluate memory function. A separate group of animals was used to assess the density of cholinergic neurons in forebrain areas Ch1-4 using immunohistochemistry. AIE exposed animals manifested deficits in the temporal component of the stOR task relative to controls, and a significant decrease in the number of ChAT labeled neurons in forebrain areas Ch1-4. These findings add to the growing literature indicating long-lasting neural and behavioral effects of AIE that persist into adulthood and indicate that memory-related deficits after AIE depend upon the tasks employed, and possibly their degree of complexity. Finally, the parallel finding of diminished cholinergic neuron density suggests a possible mechanism underlying the effects of AIE on memory and hippocampal function as well as possible therapeutic or preventive strategies for AIE.

Acute Responses of Strength and Running Mechanics to Increasing and Decreasing Pain in Patients With Patellofemoral Pain

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Bazett-Jones, David M.; Huddleston, Wendy; Cobb, Stephen; O'Connor, Kristian; Earl-Boehm, Jennifer E.

2017-01-01

Context:  Patellofemoral pain (PFP) is typically exacerbated by repetitive activities that load the patellofemoral joint, such as running. Understanding the mediating effects of changes in pain in individuals with PFP might inform injury progression, rehabilitation, or both. Objective:  To investigate the effects of changing pain on muscular strength and running biomechanics in those with PFP. Design:  Crossover study. Setting:  University research laboratory. Patients or Other Participants:  Seventeen participants (10 men, 7 women) with PFP. Intervention(s):  Each participant completed knee pain-reducing and pain-inducing protocols in random order. The pain-reducing protocol consisted of 15 minutes of transcutaneous electric nerve stimulation (TENS) around the patella. The pain-inducing protocol was sets of 20 repeated single-legged squats (RSLS). Participants completed RSLS sets until either their pain was within at least 1 cm of their pain during an exhaustive run or they reached 10 sets. Main Outcome Measure(s):  Pain, isometric hip and trunk strength, and running mechanics were assessed before and after the protocols. Dependent variables were pain, normalized strength (abduction, extension, external rotation, lateral trunk flexion), and peak lower extremity kinematics and kinetics in all planes. Pain scores were analyzed using a Friedman test. Strength and mechanical variables were analyzed using repeated-measures analyses of variance. The α level was set at P < .05. Results:  Pain was decreased after the TENS (pretest: 3.10 ± 1.95, posttest: 1.89 ± 2.33) and increased after the RSLS (baseline: 3.10 ± 1.95, posttest: 4.38 ± 2.40) protocols (each P < .05). The RSLS protocol resulted in a decrease in hip-extension strength (baseline: 0.355 ± 0.08 kg/kg, posttest: 0.309 ± 0.09 kg/kg; P < .001). Peak plantar-flexion angle was decreased after RSLS (baseline: −13.97° ± 6.41°, posttest: −12.84° ± 6.45°; P = .003). Peak hip

Targeted electroporation of defined lateral ventricular walls: a novel and rapid method to study fate specification during postnatal forebrain neurogenesis

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Cremer Harold

2011-04-01

Full Text Available Abstract Background Postnatal olfactory bulb (OB neurogenesis involves the generation of granule and periglomerular cells by neural stem cells (NSCs located in the walls of the lateral ventricle (LV. Recent studies show that NSCs located in different regions of the LV give rise to different types of OB neurons. However, the molecular mechanisms governing neuronal specification remain largely unknown and new methods to approach these questions are needed. Results In this study, we refine electroporation of the postnatal forebrain as a technique to perform precise and accurate delivery of transgenes to NSCs located in distinct walls of the LV in the mouse. Using this method, we confirm and expand previous studies showing that NSCs in distinct walls of the LV produce neurons that invade different layers of the OB. Fate mapping of the progeny of radial glial cells located in these distinct LV walls reveals their specification into defined subtypes of granule and periglomerular neurons. Conclusions Our results provide a baseline with which future studies aiming at investigating the role of factors in postnatal forebrain neuronal specification can be compared. Targeted electroporation of defined LV NSC populations will prove valuable to study the genetic factors involved in forebrain neuronal specification.

Prosomeric map of the lamprey forebrain based on calretinin immunocytochemistry, Nissl stain, and ancillary markers.

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Pombal, M A; Puelles, L

1999-11-22

The structural organization of the lamprey extratelencephalic forebrain is re-examined from the perspective of the prosomeric segmental paradigm. The question asked was whether the prosomeric forebrain model used for gnathostomes is of material advantage for interpreting subdivisions in the lamprey forebrain. To this aim, the main longitudinal and transverse landmarks recognized by the prosomeric model in other vertebrates were identified in Nissl-stained lamprey material. Lines of cytoarchitectural discontinuity and contours of migrated neuronal groups were mapped in a two-dimensional sagittal representation and were also classified according to their radial position. Immunocytochemical mapping of calretinin expression in adjacent sections served to define particular structural units better, in particular, the dorsal thalamus. These data were complemented by numerous other chemoarchitectonic observations obtained with ancillary markers, which identified additional specific formations, subdivisions, or boundaries. Emphasis was placed on studying whether such chemically defined neuronal groups showed boundaries aligned with the postulated inter- or intraprosomeric boundaries. The course of diverse axonal tracts was studied also with regard to their prosomeric topography. This analysis showed that the full prosomeric model applies straightforwardly to the lamprey forebrain. This finding implies that a common segmental and longitudinal organization of the neural tube may be primitive for all vertebrates. Interesting novel aspects appear in the interpretation of the lamprey pretectum, the dorsal and ventral thalami, and the hypothalamus. The topologic continuity of the prosomeric forebrain regions with evaginated or non-evaginated portions of the telencephalon was also examined. Copyright 1999 Wiley-Liss, Inc.

Relationship between mechanical sensitivity and postamputation pain: A prospective study

DEFF Research Database (Denmark)

Nikolajsen, Lone; IlKjær, Susanne; Jensen, Troels Staehelin

2000-01-01

of the limb and early (after 1 week) and late (after 6 months) phantom pain. Thirty-five patients scheduled for amputation of the lower limb were examined before, 1 week and 6 months after amputation. On all three examination days pressure-pain thresholds were measured and compared with the simultaneous...... recording of ongoing pain intensity assessed on a visual analogue scale (VAS). There was a weak but significant inverse relationship between preamputation thresholds and early stump and phantom pain. There was no relationship between preamputation thresholds and late stump and phantom pain. One week after...... amputation there was a significant and inverse relationship between mechanical thresholds and phantom pain but no relationship was found after 6 months. The findings suggest that although tenderness of the limb before and after amputation is related to early stump and phantom pain, the relationship is weak...

Sleep-wake sensitive mechanisms of adenosine release in the basal forebrain of rodents: an in vitro study.

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Robert Edward Sims

Full Text Available Adenosine acting in the basal forebrain is a key mediator of sleep homeostasis. Extracellular adenosine concentrations increase during wakefulness, especially during prolonged wakefulness and lead to increased sleep pressure and subsequent rebound sleep. The release of endogenous adenosine during the sleep-wake cycle has mainly been studied in vivo with microdialysis techniques. The biochemical changes that accompany sleep-wake status may be preserved in vitro. We have therefore used adenosine-sensitive biosensors in slices of the basal forebrain (BFB to study both depolarization-evoked adenosine release and the steady state adenosine tone in rats, mice and hamsters. Adenosine release was evoked by high K(+, AMPA, NMDA and mGlu receptor agonists, but not by other transmitters associated with wakefulness such as orexin, histamine or neurotensin. Evoked and basal adenosine release in the BFB in vitro exhibited three key features: the magnitude of each varied systematically with the diurnal time at which the animal was sacrificed; sleep deprivation prior to sacrifice greatly increased both evoked adenosine release and the basal tone; and the enhancement of evoked adenosine release and basal tone resulting from sleep deprivation was reversed by the inducible nitric oxide synthase (iNOS inhibitor, 1400 W. These data indicate that characteristics of adenosine release recorded in the BFB in vitro reflect those that have been linked in vivo to the homeostatic control of sleep. Our results provide methodologically independent support for a key role for induction of iNOS as a trigger for enhanced adenosine release following sleep deprivation and suggest that this induction may constitute a biochemical memory of this state.

Ionic mechanisms of action of prion protein fragment PrP(106-126) in rat basal forebrain neurons.

Science.gov (United States)

Alier, Kwai; Li, Zongming; Mactavish, David; Westaway, David; Jhamandas, Jack H

2010-08-01

Prion diseases are neurodegenerative disorders that are characterized by the presence of the misfolded prion protein (PrP). Neurotoxicity in these diseases may result from prion-induced modulation of ion channel function, changes in neuronal excitability, and consequent disruption of cellular homeostasis. We therefore examined PrP effects on a suite of potassium (K(+)) conductances that govern excitability of basal forebrain neurons. Our study examined the effects of a PrP fragment [PrP(106-126), 50 nM] on rat neurons using the patch clamp technique. In this paradigm, PrP(106-126) peptide, but not the "scrambled" sequence of PrP(106-126), evoked a reduction of whole-cell outward currents in a voltage range between -30 and +30 mV. Reduction of whole-cell outward currents was significantly attenuated in Ca(2+)-free external media and also in the presence of iberiotoxin, a blocker of calcium-activated potassium conductance. PrP(106-126) application also evoked a depression of the delayed rectifier (I(K)) and transient outward (I(A)) potassium currents. By using single cell RT-PCR, we identified the presence of two neuronal chemical phenotypes, GABAergic and cholinergic, in cells from which we recorded. Furthermore, cholinergic and GABAergic neurons were shown to express K(v)4.2 channels. Our data establish that the central region of PrP, defined by the PrP(106-126) peptide used at nanomolar concentrations, induces a reduction of specific K(+) channel conductances in basal forebrain neurons. These findings suggest novel links between PrP signalling partners inferred from genetic experiments, K(+) channels, and PrP-mediated neurotoxicity.

NCAM deficiency in the mouse forebrain impairs innate and learned avoidance behaviours.

Science.gov (United States)

Brandewiede, J; Stork, O; Schachner, M

2014-06-01

The neural cell adhesion molecule (NCAM) has been implicated in the development and plasticity of neural circuits and the control of hippocampus- and amygdala-dependent learning and behaviour. Previous studies in constitutive NCAM null mutants identified emotional behaviour deficits related to disturbances of hippocampal and amygdala functions. Here, we studied these behaviours in mice conditionally deficient in NCAM in the postmigratory forebrain neurons. We report deficits in both innate and learned avoidance behaviours, as observed in elevated plus maze and passive avoidance tasks. In contrast, general locomotor activity, trait anxiety or neophobia were unaffected by the mutation. Altered avoidance behaviour of the conditional NCAM mutants was associated with a deficit in serotonergic signalling, as indicated by their reduced responsiveness to (±)-8-hydroxy-2-(dipropylamino)-tetralin-induced hypothermia. Another serotonin-dependent behaviour, namely intermale aggression that is massively increased in constitutively NCAM-deficient mice, was not affected in the forebrain-specific mutants. Our data suggest that genetically or environmentally induced changes of NCAM expression in the late postnatal and mature forebrain determine avoidance behaviour and serotonin (5-HT)1A receptor signalling. © 2014 John Wiley & Sons Ltd and International Behavioural and Neural Genetics Society.

Thermal and mechanical pain sensitization in patients with osteoarthritis of the knee.

Science.gov (United States)

Bevilaqua-Grossi, Debora; Zanin, Marilia; Benedetti, Camila; Florencio, Lidiane; Oliveira, Anamaria

2018-02-26

The aim was to assess sensitization using quantitative sensory testing in mechanical and thermal modes in individuals with and without osteoarthritis (OA) of the knee. Pain thresholds were correlated with functionality, symptoms of depression and intensity of pain. Thirty control volunteers and 30 patients with OA of the knee were assessed. Punctate pain thresholds using Von Frey filaments and thermal pain thresholds using a Thermal Sensory Analyzer were evaluated in the periarticular region of the knee and forearm. Using a digital pressure algometer, pressure pain thresholds were assessed in the periarticular region of the knee and on the root exit zone on the lumbar and sacral spine. Punctate, pressure, and thermal pain thresholds differed significantly between participants with and without OA (p pain sensitization. Pressure pain thresholds also showed moderate and negative correlations with data on functionality, symptoms of depression and intensity of pain (-0.36  -0.56), contributing up to 30% of their variability. Allodynia and hyperalgesia were demonstrated in the OA group, suggesting central sensitization in patients with mild to moderate severity of joint damage. Correlation between mechanical hypersensitivity and psychosocial factors seems to be small, despite of its significance.

Work and back pain: a prospective study of psychological, social and mechanical predictors of back pain severity.

Science.gov (United States)

Christensen, J O; Knardahl, S

2012-07-01

Studies relating occupational psychological and social factors to back pain have traditionally investigated a small number of exposure factors. The current study explored longitudinally a comprehensive set of specific psychological/social and mechanical work factors as predictors of back pain severity (defined as the product of back pain intensity and duration). Employees from 28 organizations in Norway, representing a wide variety of occupations, were surveyed with a follow-up period of 2 years. Several designs were tested: (1) cross-sectional analyses at baseline and follow-up; (2) prospective analyses with baseline exposure; (3) prospective analyses with average exposure over time [(T1+T2)/2]; and (4) prospective analyses with measures of change in exposure from T1 to T2. A total of 2808 employees responded at both time points. Fourteen psychological/social and two mechanical exposures were measured. Odds ratios (ORs) were computed by ordinal logistic regressions. Several psychological/social factors predicted back pain severity. After adjustment for age, sex, skill level, back pain severity at T1 and other exposure factors estimated to be potential confounders, the most consistent predictors of back pain were the protective factors decision control [lowest OR 0.68; 99% confidence interval (CI): 0.49-0.95], empowering leadership (lowest OR 0.59; 99% CI: 0.38-0.91) and fair leadership (lowest OR 0.54; 99% CI: 0.34-0.87). Some of the most important predictors included in this study were factors that have previously received little attention in back pain research. This emphasizes the importance of extending the list of factors possibly contributing to back pain. © 2011 National Institute of Occupational Health, Norway European Journal of Pain © 2011 European Federation of International Association for the Study of Pain Chapters.

Modulation of learning and memory by the targeted deletion of the circadian clock gene Bmal1 in forebrain circuits.

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Snider, Kaitlin H; Dziema, Heather; Aten, Sydney; Loeser, Jacob; Norona, Frances E; Hoyt, Kari; Obrietan, Karl

2016-07-15

A large body of literature has shown that the disruption of circadian clock timing has profound effects on mood, memory and complex thinking. Central to this time keeping process is the master circadian pacemaker located within the suprachiasmatic nucleus (SCN). Of note, within the central nervous system, clock timing is not exclusive to the SCN, but rather, ancillary oscillatory capacity has been detected in a wide range of cell types and brain regions, including forebrain circuits that underlie complex cognitive processes. These observations raise questions about the hierarchical and functional relationship between the SCN and forebrain oscillators, and, relatedly, about the underlying clock-gated synaptic circuitry that modulates cognition. Here, we utilized a clock knockout strategy in which the essential circadian timing gene Bmal1 was selectively deleted from excitatory forebrain neurons, whilst the SCN clock remained intact, to test the role of forebrain clock timing in learning, memory, anxiety, and behavioral despair. With this model system, we observed numerous effects on hippocampus-dependent measures of cognition. Mice lacking forebrain Bmal1 exhibited deficits in both acquisition and recall on the Barnes maze. Notably, loss of forebrain Bmal1 abrogated time-of-day dependent novel object location memory. However, the loss of Bmal1 did not alter performance on the elevated plus maze, open field assay, and tail suspension test, indicating that this phenotype specifically impairs cognition but not affect. Together, these data suggest that forebrain clock timing plays a critical role in shaping the efficiency of learning and memory retrieval over the circadian day. Copyright © 2016 Elsevier B.V. All rights reserved.

Decreased levels of free D-aspartic acid in the forebrain of serine racemase (Srr) knock-out mice.

Science.gov (United States)

Horio, Mao; Ishima, Tamaki; Fujita, Yuko; Inoue, Ran; Mori, Hisashi; Hashimoto, Kenji

2013-05-01

d-Serine, an endogenous co-agonist of the N-methyl-d-aspartate (NMDA) receptor is synthesized from l-serine by serine racemase (SRR). A previous study of Srr knockout (Srr-KO) mice showed that levels of d-serine in forebrain regions, such as frontal cortex, hippocampus, and striatum, but not cerebellum, of mutant mice are significantly lower than those of wild-type (WT) mice, suggesting that SRR is responsible for d-serine production in the forebrain. In this study, we attempted to determine whether SRR affects the level of other amino acids in brain tissue. We found that tissue levels of d-aspartic acid in the forebrains (frontal cortex, hippocampus and striatum) of Srr-KO mice were significantly lower than in WT mice, whereas levels of d-aspartic acid in the cerebellum were not altered. Levels of d-alanine, l-alanine, l-aspartic acid, taurine, asparagine, arginine, threonine, γ-amino butyric acid (GABA) and methionine, remained the same in frontal cortex, hippocampus, striatum and cerebellum of WT and mutant mice. Furthermore, no differences in d-aspartate oxidase (DDO) activity were detected in the forebrains of WT and Srr-KO mice. These results suggest that SRR and/or d-serine may be involved in the production of d-aspartic acid in mouse forebrains, although further detailed studies will be necessary to confirm this finding. Copyright © 2013 Elsevier Ltd. All rights reserved.

Temporomandibular disorders and painful comorbidities: clinical association and underlying mechanisms.

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Costa, Yuri Martins; Conti, Paulo César Rodrigues; de Faria, Flavio Augusto Cardoso; Bonjardim, Leonardo Rigoldi

2017-03-01

The association between temporomandibular disorders (TMDs) and headaches, cervical spine dysfunction, and fibromyalgia is not artefactual. The aim of this review is to describe the comorbid relationship between TMD and these three major painful conditions and to discuss the clinical implications and the underlying pain mechanisms involved in these relationships. Common neuronal pathways and central sensitization processes are acknowledged as the main factors for the association between TMD and primary headaches, although the establishment of cause-effect mechanisms requires further clarification and characterization. The biomechanical aspects are not the main factors involved in the comorbid relationship between TMD and cervical spine dysfunction, which can be better explained by the neuronal convergence of the trigeminal and cervical spine sensory pathways as well as by central sensitization processes. The association between TMD and fibromyalgia also has supporting evidence in the literature, and the proposed main mechanism underlying this relationship is the impairment of the descending pain inhibitory system. In this particular scenario, a cause-effect relationship is more likely to occur in one direction, that is, fibromyalgia as a risk factor for TMD. Therefore, clinical awareness of the association between TMD and painful comorbidities and the support of multidisciplinary approaches are required to recognize these related conditions. Copyright © 2016 Elsevier Inc. All rights reserved.

Neuroprotective effects of ebselen following forebrain ischemia: involvement of glutamate and nitric oxide.

Science.gov (United States)

Koizumi, Hiroyasu; Fujisawa, Hirosuke; Suehiro, Eiichi; Shirao, Satoshi; Suzuki, Michiyasu

2011-01-01

Ebselen is a mimic of glutathione peroxidase that reacts with peroxynitrite and inhibits nitric oxide (NO) synthase. Ebselen has beneficial effects on the neurological outcome of patients with stroke. In this study, the mechanisms by which ebselen can elicit neuroprotective effects against ischemic brain injury were investigated in male Wistar rats. Experimental forebrain ischemia was induced by bilateral common carotid artery occlusion with hemorrhagic hypotension. Ebselen was administered to animals in the treatment group 2 hours prior to the induction of forebrain ischemia, and placebo was administered in the control group. Cerebral blood flow (CBF) was measured by the hydrogen clearance method. Cortical extracellular levels of excitatory amino acids (EAAs) and NO were evaluated using in vivo microdialysis. Neuronal damage in the CA1 subfield of the hippocampus was assessed in brains harvested after a 24-hour period of survival. CBF did not recover to normal physiological levels after ischemic insults in either the control or treatment groups. The differences in the sequential changes in extracellular EAA and NO levels between groups were not statistically significant. There was a significantly larger mean density of intact, undamaged neurons in the CA1 subfield in the treatment group than in the control group. The neuroprotective effects of ebselen were reflected in the histological findings, without significant inhibition of glutamate release or NO synthesis during the acute phase of experimentally induced cerebral ischemia.

Mechanisms Mediating Vibration-induced Chronic Musculoskeletal Pain Analyzed in the Rat

OpenAIRE

Dina, Olayinka A.; Joseph, Elizabeth K.; Levine, Jon D.; Green, Paul G.

2009-01-01

While occupational exposure to vibration is a common cause of acute and chronic musculoskeletal pain, eliminating exposure produces limited symptomatic improvement, and re-exposure precipitates rapid recurrence or exacerbation. To evaluate mechanisms underlying these pain syndromes, we have developed a model in the rat, in which exposure to vibration (60–80 Hz) induces, in skeletal muscle, both acute mechanical hyperalgesia as well as long-term changes characterized by enhanced hyperalgesia t...

Optogenetic fMRI and electrophysiological identification of region-specific connectivity between the cerebellar cortex and forebrain.

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Choe, Katrina Y; Sanchez, Carlos F; Harris, Neil G; Otis, Thomas S; Mathews, Paul J

2018-06-01

Complex animal behavior is produced by dynamic interactions between discrete regions of the brain. As such, defining functional connections between brain regions is critical in gaining a full understanding of how the brain generates behavior. Evidence suggests that discrete regions of the cerebellar cortex functionally project to the forebrain, mediating long-range communication potentially important in motor and non-motor behaviors. However, the connectivity map remains largely incomplete owing to the challenge of driving both reliable and selective output from the cerebellar cortex, as well as the need for methods to detect region specific activation across the entire forebrain. Here we utilize a paired optogenetic and fMRI (ofMRI) approach to elucidate the downstream forebrain regions modulated by activating a region of the cerebellum that induces stereotypical, ipsilateral forelimb movements. We demonstrate with ofMRI, that activating this forelimb motor region of the cerebellar cortex results in functional activation of a variety of forebrain and midbrain areas of the brain, including the hippocampus and primary motor, retrosplenial and anterior cingulate cortices. We further validate these findings using optogenetic stimulation paired with multi-electrode array recordings and post-hoc staining for molecular markers of activated neurons (i.e. c-Fos). Together, these findings demonstrate that a single discrete region of the cerebellar cortex is capable of influencing motor output and the activity of a number of downstream forebrain as well as midbrain regions thought to be involved in different aspects of behavior. Copyright © 2018 Elsevier Inc. All rights reserved.

Bone hyperalgesia after mechanical impact stimulation: a human experimental pain model.

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Finocchietti, Sara; Graven-Nielsen, Thomas; Arendt-Nielsen, Lars

2014-12-01

Hyperalgesia in different musculoskeletal structures including bones is a major clinical problem. An experimental bone hyperalgesia model was developed in the present study. Hyperalgesia was induced by three different weights impacted on the shinbone in 16 healthy male and female subjects. The mechanical impact pain threshold (IPT) was measured as the height from which three weights (165, 330, and 660 g) should be dropped to elicit pain at the shinbone. Temporal summation of pain to repeated impact stimuli was assessed. All these stimuli caused bone hyperalgesia. The pressure pain threshold (PPT) was assessed by a computerized pressure algometer using two different probes (1.0 and 0.5 cm(2)). All parameters were recorded before (0), 24, 72, and 96 h after the initial stimulations. The IPTs were lowest 24 h after hyperalgesia induction for all three weights and the effect lasted up to 72 h (p pain and hyperalgesia model may provide the basis for studying this fundamental mechanism of bone-related hyperalgesia and be used for profiling compounds developed for this target.

Advances in mechanism research of pain in Parkinson's disease

Directory of Open Access Journals (Sweden)

Hui LIU

2017-09-01

Full Text Available Parkinson's disease (PD, a neurodegenerative disease, is very common in middle aged and older people. There are two kinds of symptoms: motor symptoms and non - motor symptoms (NMS. Pain, a commonly reported NMS of PD, can significantly affect the quality of life, thus causing more attention. However, mechanisms of pain in PD is not clear, and need to be further researched. DOI: 10.3969/j.issn.1672-6731.2017.08.006

A preconditioning nerve lesion inhibits mechanical pain hypersensitivity following subsequent neuropathic injury

Directory of Open Access Journals (Sweden)

Wu Ann

2011-01-01

Full Text Available Abstract Background A preconditioning stimulus can trigger a neuroprotective phenotype in the nervous system - a preconditioning nerve lesion causes a significant increase in axonal regeneration, and cerebral preconditioning protects against subsequent ischemia. We hypothesized that a preconditioning nerve lesion induces gene/protein modifications, neuronal changes, and immune activation that may affect pain sensation following subsequent nerve injury. We examined whether a preconditioning lesion affects neuropathic pain and neuroinflammation after peripheral nerve injury. Results We found that a preconditioning crush injury to a terminal branch of the sciatic nerve seven days before partial ligation of the sciatic nerve (PSNL; a model of neuropathic pain induced a significant attenuation of pain hypersensitivity, particularly mechanical allodynia. A preconditioning lesion of the tibial nerve induced a long-term significant increase in paw-withdrawal threshold to mechanical stimuli and paw-withdrawal latency to thermal stimuli, after PSNL. A preconditioning lesion of the common peroneal induced a smaller but significant short-term increase in paw-withdrawal threshold to mechanical stimuli, after PSNL. There was no difference between preconditioned and unconditioned animals in neuronal damage and macrophage and T-cell infiltration into the dorsal root ganglia (DRGs or in astrocyte and microglia activation in the spinal dorsal and ventral horns. Conclusions These results suggest that prior exposure to a mild nerve lesion protects against adverse effects of subsequent neuropathic injury, and that this conditioning-induced inhibition of pain hypersensitivity is not dependent on neuroinflammation in DRGs and spinal cord. Identifying the underlying mechanisms may have important implications for the understanding of neuropathic pain due to nerve injury.

Mechanisms mediating vibration-induced chronic musculoskeletal pain analyzed in the rat.

Science.gov (United States)

Dina, Olayinka A; Joseph, Elizabeth K; Levine, Jon D; Green, Paul G

2010-04-01

While occupational exposure to vibration is a common cause of acute and chronic musculoskeletal pain, eliminating exposure produces limited symptomatic improvement, and reexposure precipitates rapid recurrence or exacerbation. To evaluate mechanisms underlying these pain syndromes, we have developed a model in the rat, in which exposure to vibration (60-80Hz) induces, in skeletal muscle, both acute mechanical hyperalgesia as well as long-term changes characterized by enhanced hyperalgesia to a proinflammatory cytokine or reexposure to vibration. Exposure of a hind limb to vibration-produced mechanical hyperalgesia measured in the gastrocnemius muscle of the exposed hind limb, which persisted for approximately 2 weeks. When nociceptive thresholds had returned to baseline, exposure to a proinflammatory cytokine or reexposure to vibration produced markedly prolonged hyperalgesia. The chronic prolongation of vibration- and cytokine-hyperalgesia was prevented by spinal intrathecal injection of oligodeoxynucleotide (ODN) antisense to protein kinase Cepsilon, a second messenger in nociceptors implicated in the induction and maintenance of chronic pain. Vibration-induced hyperalgesia was inhibited by spinal intrathecal administration of ODN antisense to receptors for the type-1 tumor necrosis factor-alpha (TNFalpha) receptor. Finally, in TNFalpha-pretreated muscle, subsequent vibration-induced hyperalgesia was markedly prolonged. These studies establish a model of vibration-induced acute and chronic musculoskeletal pain, and identify the proinflammatory cytokine TNFalpha and the second messenger protein kinase Cepsilon as targets against which therapies might be directed to prevent and/or treat this common and very debilitating chronic pain syndrome. Copyright 2010 American Pain Society. All rights reserved.

Selective spider toxins reveal a role for Nav1.1 channel in mechanical pain

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Osteen, Jeremiah D.; Herzig, Volker; Gilchrist, John; Emrick, Joshua J.; Zhang, Chuchu; Wang, Xidao; Castro, Joel; Garcia-Caraballo, Sonia; Grundy, Luke; Rychkov, Grigori Y.; Weyer, Andy D.; Dekan, Zoltan; Undheim, Eivind A. B.; Alewood, Paul; Stucky, Cheryl L.; Brierley, Stuart M.; Basbaum, Allan I.; Bosmans, Frank; King, Glenn F.; Julius, David

2016-01-01

Voltage-gated sodium (Nav) channels initiate action potentials in most neurons, including primary afferent nerve fibers of the pain pathway. Local anesthetics block pain through non-specific actions at all Nav channels, but the discovery of selective modulators would facilitate the analysis of individual subtypes and their contributions to chemical, mechanical, or thermal pain. Here, we identify and characterize spider toxins that selectively activate the Nav1.1 subtype, whose role in nociception and pain has not been explored. We exploit these probes to demonstrate that Nav1.1-expressing fibers are modality-specific nociceptors: their activation elicits robust pain behaviors without neurogenic inflammation and produces profound hypersensitivity to mechanical, but not thermal, stimuli. In the gut, high-threshold mechanosensitive fibers also express Nav1.1 and show enhanced toxin sensitivity in a model of irritable bowel syndrome. Altogether, these findings establish an unexpected role for Nav1.1 in regulating the excitability of sensory nerve fibers that underlie mechanical pain. PMID:27281198

Mechanisms-based classifications of musculoskeletal pain: part 1 of 3: symptoms and signs of central sensitisation in patients with low back (± leg) pain.

LENUS (Irish Health Repository)

Smart, Keith M

2012-08-01

As a mechanisms-based classification of pain \\'central sensitisation pain\\' (CSP) refers to pain arising from a dominance of neurophysiological dysfunction within the central nervous system. Symptoms and signs associated with an assumed dominance of CSP in patients attending for physiotherapy have not been extensively studied. The purpose of this study was to identify symptoms and signs associated with a clinical classification of CSP in patients with low back (± leg) pain. Using a cross-sectional, between-subjects design; four hundred and sixty-four patients with low back (± leg) pain were assessed using a standardised assessment protocol. Patients\\' pain was assigned a mechanisms-based classification based on experienced clinical judgement. Clinicians then completed a clinical criteria checklist specifying the presence or absence of various clinical criteria. A binary logistic regression analysis with Bayesian model averaging identified a cluster of three symptoms and one sign predictive of CSP, including: \\'Disproportionate, non-mechanical, unpredictable pattern of pain provocation in response to multiple\\/non-specific aggravating\\/easing factors\\

Enhanced quantal release of excitatory transmitter in anterior cingulate cortex of adult mice with chronic pain

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Zhao Ming-Gao

2009-01-01

Full Text Available Abstract The anterior cingulate cortex (ACC is a forebrain structure that plays important roles in emotion, learning, memory and persistent pain. Our previous studies have demonstrated that the enhancement of excitatory synaptic transmission was induced by peripheral inflammation and nerve injury in ACC synapses. However, little information is available on their presynaptic mechanisms, since the source of the enhanced synaptic transmission could include the enhanced probability of neurotransmitter release at existing release sites and/or increases in the number of available vesicles. The present study aims to perform quantal analysis of excitatory synapses in the ACC with chronic pain to examine the source of these increases. The quantal analysis revealed that both probability of transmitter release and number of available vesicles were increased in a mouse model of peripheral inflammation, whereas only probability of transmitter release but not number of available vesicles was enhanced in a mouse model of neuropathic pain. In addition, we compared the miniature excitatory postsynaptic potentials (mEPSCs in ACC synapses with those in other pain-related brain areas such as the amygdala and spinal cord. Interestingly, the rate and amplitude of mEPSCs in ACC synapses were significantly lower than those in the amygdala and spinal cord. Our studies provide strong evidences that chronic inflammatory pain increases both probability of transmitter release and number of available vesicles, whereas neuropathic pain increases only probability of transmitter release in the ACC synapses.

IMPACT OF REFLEXOLOGY ON MECHANICAL LOW BACK PAIN

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Salwa El-Gendy

2015-10-01

Full Text Available Background: Low-back pain (LBP is one of the highest common and costly musculoskeletal conditions in current society. Seventy to 85% of the populations will exhibits LBP at some time in their lives. There is little known about specific manual therapy techniques used to treat chronic LBP. Reflexology is a treatment that involves using gentle pressure to reflex points located on all of the outsides of the feet and hands. The aim of the study was to investigate the efficacy of reflexology technique in subjects with chronic low back pain (CLBP. Methods: Twenty patients with nonspecific chronic low back pain were included in the study and were assessed regarding range of motion via goniometer and pain threshold (via modified Oswestery scale and visual analogue scale, the 20 patients were allocated into two groups 10 patients in each group. Group A received reflexology sittings at rate of 3 days per week, and the duration of each sitting was 30 minutes. While group B were control. The study was continued for 3 weeks Results: According to VAS, the results revealed a non-significant variance between the study group and control group before intervention (p= 0.43. While after intervention, there was a significant decline of pain in the study group compared to that of the control group (p=0.000. Moreover, there was a very highly significant decrease in pain within the study group after treatment (p= 0.005. Conclusion: The present study indicated that the reflexology technique was effective and safe to be applied for cases of mechanical low back pain. It results in a significant decrease in pain within the study group after treatment.

Loss of MeCP2 From Forebrain Excitatory Neurons Leads to Cortical Hyperexcitation and Seizures

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Zhang, Wen; Peterson, Matthew; Beyer, Barbara; Frankel, Wayne N.

2014-01-01

Mutations of MECP2 cause Rett syndrome (RTT), a neurodevelopmental disorder leading to loss of motor and cognitive functions, impaired social interactions, and seizure at young ages. Defects of neuronal circuit development and function are thought to be responsible for the symptoms of RTT. The majority of RTT patients show recurrent seizures, indicating that neuronal hyperexcitation is a common feature of RTT. However, mechanisms underlying hyperexcitation in RTT are poorly understood. Here we show that deletion of Mecp2 from cortical excitatory neurons but not forebrain inhibitory neurons in the mouse leads to spontaneous seizures. Selective deletion of Mecp2 from excitatory but not inhibitory neurons in the forebrain reduces GABAergic transmission in layer 5 pyramidal neurons in the prefrontal and somatosensory cortices. Loss of MeCP2 from cortical excitatory neurons reduces the number of GABAergic synapses in the cortex, and enhances the excitability of layer 5 pyramidal neurons. Using single-cell deletion of Mecp2 in layer 2/3 pyramidal neurons, we show that GABAergic transmission is reduced in neurons without MeCP2, but is normal in neighboring neurons with MeCP2. Together, these results suggest that MeCP2 in cortical excitatory neurons plays a critical role in the regulation of GABAergic transmission and cortical excitability. PMID:24523563

Early life vincristine exposure evokes mechanical pain hypersensitivity in the developing rat.

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Schappacher, Katie A; Styczynski, Lauren; Baccei, Mark L

2017-09-01

Vincristine (VNC) is commonly used to treat pediatric cancers, including the most prevalent childhood malignancy, acute lymphoblastic leukemia. Although clinical evidence suggests that VNC causes peripheral neuropathy in children, the degree to which pediatric chemotherapeutic regimens influence pain sensitivity throughout life remains unclear, in part because of the lack of an established animal model of chemotherapy-induced neuropathic pain during early life. Therefore, this study investigated the effects of VNC exposure between postnatal days (P) 11 and 21 on mechanical and thermal pain sensitivity in the developing rat. Low doses of VNC (15 or 30 μg/kg) failed to alter nociceptive withdrawal reflexes at any age examined compared with vehicle-injected littermate controls. Meanwhile, high dose VNC (60 μg/kg) evoked mechanical hypersensitivity in both sexes beginning at P26 that persisted until adulthood and included both static and dynamic mechanical allodynia. Hind paw withdrawal latencies to noxious heat and cold were unaffected by high doses of VNC, suggesting a selective effect of neonatal VNC on mechanical pain sensitivity. Gross and fine motor function appeared normal after VNC treatment, although a small decrease in weight gain was observed. The VNC regimen also produced a significant decrease in intraepidermal nerve fiber density in the hind paw skin by P33. Overall, the present results demonstrate that high-dose administration of VNC during the early postnatal period selectively evokes a mechanical hypersensitivity that is slow to emerge during adolescence, providing further evidence that aberrant sensory input during early life can have prolonged consequences for pain processing.

Morphometric Studies Of The Cerebellum And Forebrain Of The ...

African Journals Online (AJOL)

Morphometric studies were undertaken using the brains of six African giant rats. The mean of weights and lengths (tip of the olfactory bulb to the caudal border of the cerebellum) were observed tobe 4.88 0.183g and 4.40 0.193g, respectively. Similarly, the mean weight and length of the cerebellum and the forebrain ...

Effect of Lumbar Stabilization Exercises Versus Kinesiotaping on Chronic Mechanical Low Back Pain

International Nuclear Information System (INIS)

Abdellatif, M.M.; Kamel, M.R.; Ahmed, H.H.; Diab, H.R.

2016-01-01

Background: Low back pain (LBP) is one of the most common musculoskeletal problems in modern society. Approximately two third of the adults are affected by mechanical low back pain. Lumbar stabilization exercise is a therapeutic technique that uses a progressive sequence of training in coordination, balance, endurance and strengthening. It helps increasing the range of joint motion and reducing associated pain. Kinesiotape is an adhesive tape which has approximately the same elasticity as skin. The flexibility of the tape will lift the skin to create space between the skin and the muscle, prompting improvement of blood circulation and lymphatic fluids drainage in the taped area, and this will decrease pain, increase Range Of Motion (ROM) and improve Activities of Daily Level (ADL). Purpose: This study was conducted to compare the effect of lumbar stabilization exercises and Kinesiotape in patients with Chronic Mechanical Low Back Pain. Design of the study: Thirty patients were divided randomly into two equal groups. Group A was received lumber stabilization exercises and Infrared Radiation and Group B was received kinesiotape and Infrared Radiation. Method: Visual Analogue Scale (VAS) was used to measure the pain intensity level and Dual Inclinometer was used to measure ROM of the lumbar spine. Results: There was a high significant decrease in pain level in both groups Group A (p < 0.0001) and Group B (p < 0.0001). There was a high significant improvement in Lumbar ROM in both groups A and B where Group A: Flexion (p < 0.0001), extension (p < 0.0001), lateral flexion (p < 0.0001) and rotation (p < 0.0001), Group B: Flexion (p < 0.0001), extension (p < 0.0001), later al flexion (p < 0.0001) and rotation (p < 0.0001). Conclusion: There was no significant difference between the Lumbar Stabilization Exercise and kinesiotaping for the patients with chronic mechanical low back pain in increasing lumbar ROM and pain relief after treatment and during the follow up after

Peripheral Receptor Mechanisms Underlying Orofacial Muscle Pain and Hyperalgesia

Science.gov (United States)

Saloman, Jami L.

Musculoskeletal pain conditions, particularly those associated with temporomandibular joint and muscle disorders (TMD) are severely debilitating and affect approximately 12% of the population. Identifying peripheral nociceptive mechanisms underlying mechanical hyperalgesia, a prominent feature of persistent muscle pain, could contribute to the development of new treatment strategies for the management of TMD and other muscle pain conditions. This study provides evidence of functional interactions between ligand-gated channels, P2X3 and TRPV1/TRPA1, in trigeminal sensory neurons, and proposes that these interactions underlie the development of mechanical hyperalgesia. In the masseter muscle, direct P2X3 activation, via the selective agonist αβmeATP, induced a dose- and time-dependent hyperalgesia. Importantly, the αβmeATP-induced hyperalgesia was prevented by pretreatment of the muscle with a TRPV1 antagonist, AMG9810, or the TRPA1 antagonist, AP18. P2X3 was co-expressed with both TRPV1 and TRPA1 in masseter muscle afferents confirming the possibility for intracellular interactions. Moreover, in a subpopulation of P2X3 /TRPV1 positive neurons, capsaicin-induced Ca2+ transients were significantly potentiated following P2X3 activation. Inhibition of Ca2+-dependent kinases, PKC and CaMKII, prevented P2X3-mechanical hyperalgesia whereas blockade of Ca2+-independent PKA did not. Finally, activation of P2X3 induced phosphorylation of serine, but not threonine, residues in TRPV1 in trigeminal sensory neurons. Significant phosphorylation was observed at 15 minutes, the time point at which behavioral hyperalgesia was prominent. Similar data were obtained regarding another nonselective cation channel, the NMDA receptor (NMDAR). Our data propose P2X3 and NMDARs interact with TRPV1 in a facilitatory manner, which could contribute to the peripheral sensitization underlying masseter hyperalgesia. This study offers novel mechanisms by which individual pro-nociceptive ligand

Central sensitization as the mechanism underlying pain in joint hypermobility syndrome/Ehlers-Danlos syndrome, hypermobility type.

Science.gov (United States)

Di Stefano, G; Celletti, C; Baron, R; Castori, M; Di Franco, M; La Cesa, S; Leone, C; Pepe, A; Cruccu, G; Truini, A; Camerota, F

2016-09-01

Patients with joint hypermobility syndrome/Ehlers-Danlos syndrome, hypermobility type (JHS/EDS-HT) commonly suffer from pain. How this hereditary connective tissue disorder causes pain remains unclear although previous studies suggested it shares similar mechanisms with neuropathic pain and fibromyalgia. In this prospective study seeking information on the mechanisms underlying pain in patients with JHS/EDS-HT, we enrolled 27 consecutive patients with this connective tissue disorder. Patients underwent a detailed clinical examination, including the neuropathic pain questionnaire DN4 and the fibromyalgia rapid screening tool. As quantitative sensory testing methods, we included thermal-pain perceptive thresholds and the wind-up ratio and recorded a standard nerve conduction study to assess non-nociceptive fibres and laser-evoked potentials, assessing nociceptive fibres. Clinical examination and diagnostic tests disclosed no somatosensory nervous system damage. Conversely, most patients suffered from widespread pain, the fibromyalgia rapid screening tool elicited positive findings, and quantitative sensory testing showed lowered cold and heat pain thresholds and an increased wind-up ratio. While the lack of somatosensory nervous system damage is incompatible with neuropathic pain as the mechanism underlying pain in JHS/EDS-HT, the lowered cold and heat pain thresholds and increased wind-up ratio imply that pain in JHS/EDS-HT might arise through central sensitization. Hence, this connective tissue disorder and fibromyalgia share similar pain mechanisms. WHAT DOES THIS STUDY ADD?: In patients with JHS/EDS-HT, the persistent nociceptive input due to joint abnormalities probably triggers central sensitization in the dorsal horn neurons and causes widespread pain. © 2016 European Pain Federation - EFIC®

Towards a mechanism-based approach to pain management in osteoarthritis.

Science.gov (United States)

Malfait, Anne-Marie; Schnitzer, Thomas J

2013-11-01

Pain is the defining symptom of osteoarthritis (OA), yet available treatment options, of which NSAIDs are the most common, provide inadequate pain relief and are associated with serious health risks when used long term. Chronic pain pathways are subject to complex levels of control and modulation, both in the periphery and in the central nervous system. Ongoing clinical and basic research is uncovering how these pathways operate in OA. Indeed, clinical investigation into the types of pain associated with progressive OA, the presence of central sensitization, the correlation with structural changes in the joint, and the efficacy of novel analgesics affords new insights into the pathophysiology of OA pain. Moreover, studies in disease-specific animal models enable the unravelling of the cellular and molecular pathways involved. We expect that increased understanding of the mechanisms by which chronic OA-associated pain is generated and maintained will offer opportunities for targeting and improving the safety of analgesia. In addition, using clinical and genetic approaches, it might become possible to identify subsets of patients with pain of different pathophysiology, thus enabling a tailored approach to pain management.

Entropy as a new measure of mechanical pain sensitivity in the masseter muscle

DEFF Research Database (Denmark)

Castrillon, Eduardo; Sato, Hitoshi; Tanosoto, Tomohiro

ENTROPY AS A NEW MEASURE OF MECHANICAL PAIN SENSITIVITY IN THE MASSETER MUSCLE Author Block: E. E. Castrillon1, H. Sato2,3, T. Tanosoto4, T. Arima4, L. Baad-Hansen1, P. Svensson1, 1Clinical Oral Physiology, Århus Univ., Aarhus, Denmark, 2Dept. of Dentistry & Oral Physiology, Sch. of Med., Keio Un...... injections (Pmechanical pain sensitivity that captures new aspects of spatial characteristics and could therefore complement more classical assessments of TMD pain patients.......ENTROPY AS A NEW MEASURE OF MECHANICAL PAIN SENSITIVITY IN THE MASSETER MUSCLE Author Block: E. E. Castrillon1, H. Sato2,3, T. Tanosoto4, T. Arima4, L. Baad-Hansen1, P. Svensson1, 1Clinical Oral Physiology, Århus Univ., Aarhus, Denmark, 2Dept. of Dentistry & Oral Physiology, Sch. of Med., Keio Univ......., Tokyo, Japan, 3Japan Society for the Promotion of Sci., Tokyo, Japan, 4Dept. of Oral Rehabilitation, Graduate Sch. of Dental Med., Hokkaido Univ., Sapporo, Japan : Aim of Investigation: Manual palpation is a psychophysical technique to evaluate mechanical pain sensitivity in craniofacial muscles...

Self-reported pain severity, quality of life, disability, anxiety and depression in patients classified with 'nociceptive', 'peripheral neuropathic' and 'central sensitisation' pain. The discriminant validity of mechanisms-based classifications of low back (±leg) pain.

LENUS (Irish Health Repository)

Smart, Keith M

2012-04-01

Evidence of validity is required to support the use of mechanisms-based classifications of pain clinically. The purpose of this study was to evaluate the discriminant validity of \\'nociceptive\\' (NP), \\'peripheral neuropathic\\' (PNP) and \\'central sensitisation\\' (CSP) as mechanisms-based classifications of pain in patients with low back (±leg) pain by evaluating the extent to which patients classified in this way differ from one another according to health measures associated with various dimensions of pain. This study employed a cross-sectional, between-subjects design. Four hundred and sixty-four patients with low back (±leg) pain were assessed using a standardised assessment protocol. Clinicians classified each patient\\'s pain using a mechanisms-based classification approach. Patients completed a number of self-report measures associated with pain severity, health-related quality of life, functional disability, anxiety and depression. Discriminant validity was evaluated using a multivariate analysis of variance. There was a statistically significant difference between pain classifications on the combined self-report measures, (p = .001; Pillai\\'s Trace = .33; partial eta squared = .16). Patients classified with CSP (n = 106) reported significantly more severe pain, poorer general health-related quality of life, and greater levels of back pain-related disability, depression and anxiety compared to those classified with PNP (n = 102) and NP (n = 256). A similar pattern was found in patients with PNP compared to NP. Mechanisms-based pain classifications may reflect meaningful differences in attributes underlying the multidimensionality of pain. Further studies are required to evaluate the construct and criterion validity of mechanisms-based classifications of musculoskeletal pain.

Computational Modeling and Analysis of Mechanically Painful Stimulations

DEFF Research Database (Denmark)

Manafi Khanian, Bahram

Cuff algometry is used for quantitative assessment of deep-tissue sensitivity. The main purpose of this PhD dissertation is to provide a novel insight into the intrinsic and extrinsic factors which are involved in mechanically induced pain during cuff pressure algometry. A computational 3D finite...

Ontogenetic distribution of the transcription factor Nkx2.2 in the developing forebrain of Xenopus laevis

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Laura eDominguez

2011-03-01

Full Text Available The expression of the Nkx2.2 gene is involved in the organization of the alar-basal boundary in the forebrain of vertebrates. Its expression in different diencephalic and telencephalic regions, helped to define distinct progenitor domains in mouse and chick. Here we investigated the pattern of Nkx2.2 protein distribution throughout the development of the forebrain of the anuran amphibian, Xenopus laevis. We used immunohistochemical and in situ hybridization techniques for its detection in combination with other essential territorial markers in the forebrain. No expression was observed in the telencephalon. In the alar hypothalamus, Nkx2.2 positive cells were scattered in the suprachiasmatic territory, but also in the supraoptoparaventricular area, as defined by the expression of the transcription factor Otp and the lack of xDll4. In the basal hypothalamus Nkx2.2 expressing cells were localized in the tuberal region, with the exception of the arcuate nucleus, rich in Otp expressing cells. In the diencephalon it was expressed in all three prosomeres (P1-P3 and not in the zona limitans intrathalamica. The presence of Nkx2.2 expressing cells in P3 was restricted to the alar portion, as well as in prosomere P2, whereas in P1 the Nkx2.2 expressing cells were located in the basal plate and identified the alar/basal boundary. These results showed that Nkx2.2 and Sonic hedgehog are expressed in parallel adjacent stripes along the anterior-posterior axis. The results of this study showed a conserved distribution pattern of Nkx2.2 among vertebrates, crucial to recognize subdivisions that are otherwise indistinct, and supported the relevance of this transcription factor in the organization of the forebrain, particularly in the delineation of the alar/basal boundary of the forebrain.

R-Flurbiprofen Reduces Neuropathic Pain in Rodents by Restoring Endogenous Cannabinoids

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Marian, Claudiu; Häussler, Annett; Wijnvoord, Nina; Ziebell, Simone; Metzner, Julia; Koch, Marco; Myrczek, Thekla; Bechmann, Ingo; Kuner, Rohini; Costigan, Michael; Dehghani, Faramarz; Geisslinger, Gerd; Tegeder, Irmgard

2010-01-01

Background R-flurbiprofen, one of the enantiomers of flurbiprofen racemate, is inactive with respect to cyclooxygenase inhibition, but shows analgesic properties without relevant toxicity. Its mode of action is still unclear. Methodology/Principal Findings We show that R-flurbiprofen reduces glutamate release in the dorsal horn of the spinal cord evoked by sciatic nerve injury and thereby alleviates pain in sciatic nerve injury models of neuropathic pain in rats and mice. This is mediated by restoring the balance of endocannabinoids (eCB), which is disturbed following peripheral nerve injury in the DRGs, spinal cord and forebrain. The imbalance results from transcriptional adaptations of fatty acid amide hydrolase (FAAH) and NAPE-phospholipase D, i.e. the major enzymes involved in anandamide metabolism and synthesis, respectively. R-flurbiprofen inhibits FAAH activity and normalizes NAPE-PLD expression. As a consequence, R-Flurbiprofen improves endogenous cannabinoid mediated effects, indicated by the reduction of glutamate release, increased activity of the anti-inflammatory transcription factor PPARγ and attenuation of microglia activation. Antinociceptive effects are lost by combined inhibition of CB1 and CB2 receptors and partially abolished in CB1 receptor deficient mice. R-flurbiprofen does however not cause changes of core body temperature which is a typical indicator of central effects of cannabinoid-1 receptor agonists. Conclusion Our results suggest that R-flurbiprofen improves the endogenous mechanisms to regain stability after axonal injury and to fend off chronic neuropathic pain by modulating the endocannabinoid system and thus constitutes an attractive, novel therapeutic agent in the treatment of chronic, intractable pain. PMID:20498712

R-flurbiprofen reduces neuropathic pain in rodents by restoring endogenous cannabinoids.

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Philipp Bishay

Full Text Available BACKGROUND: R-flurbiprofen, one of the enantiomers of flurbiprofen racemate, is inactive with respect to cyclooxygenase inhibition, but shows analgesic properties without relevant toxicity. Its mode of action is still unclear. METHODOLOGY/PRINCIPAL FINDINGS: We show that R-flurbiprofen reduces glutamate release in the dorsal horn of the spinal cord evoked by sciatic nerve injury and thereby alleviates pain in sciatic nerve injury models of neuropathic pain in rats and mice. This is mediated by restoring the balance of endocannabinoids (eCB, which is disturbed following peripheral nerve injury in the DRGs, spinal cord and forebrain. The imbalance results from transcriptional adaptations of fatty acid amide hydrolase (FAAH and NAPE-phospholipase D, i.e. the major enzymes involved in anandamide metabolism and synthesis, respectively. R-flurbiprofen inhibits FAAH activity and normalizes NAPE-PLD expression. As a consequence, R-Flurbiprofen improves endogenous cannabinoid mediated effects, indicated by the reduction of glutamate release, increased activity of the anti-inflammatory transcription factor PPARgamma and attenuation of microglia activation. Antinociceptive effects are lost by combined inhibition of CB1 and CB2 receptors and partially abolished in CB1 receptor deficient mice. R-flurbiprofen does however not cause changes of core body temperature which is a typical indicator of central effects of cannabinoid-1 receptor agonists. CONCLUSION: Our results suggest that R-flurbiprofen improves the endogenous mechanisms to regain stability after axonal injury and to fend off chronic neuropathic pain by modulating the endocannabinoid system and thus constitutes an attractive, novel therapeutic agent in the treatment of chronic, intractable pain.

The Effect of Traditional Cupping on Pain and Mechanical Thresholds in Patients with Chronic Nonspecific Neck Pain: A Randomised Controlled Pilot Study

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Lauche, Romy; Cramer, Holger; Hohmann, Claudia; Choi, Kyung-Eun; Rampp, Thomas; Saha, Felix Joyonto; Musial, Frauke; Langhorst, Jost; Dobos, Gustav

2012-01-01

Introduction. Cupping has been used since antiquity in the treatment of pain conditions. In this pilot study, we investigated the effect of traditional cupping therapy on chronic nonspecific neck pain (CNP) and mechanical sensory thresholds. Methods. Fifty CNP patients were randomly assigned to treatment (TG, n = 25) or waiting list control group (WL, n = 25). TG received a single cupping treatment. Pain at rest (PR), pain related to movement (PM), quality of life (SF-36), Neck Disability Index (NDI), mechanical detection (MDT), vibration detection (MDT), and pressure pain thresholds (PPT) were measured before and three days after a single cupping treatment. Patients also kept a pain and medication diary (PaDi, MeDi) during the study. Results. Baseline characteristics were similar in the two groups. After cupping TG reported significantly less pain (PR: −17.9 mm VAS, 95%CI −29.2 to −6.6; PM: −19.7, 95%CI −32.2 to −7.2; PaDi: −1.5 points on NRS, 95%CI −2.5 to −0.4; all P cupping might be an effective treatment for improving pain, quality of life, and hyperalgesia in CNP. PMID:22203873

Human brain activity associated with painful mechanical stimulation to muscle and bone

OpenAIRE

Maeda, Lynn; Ono, Mayu; Koyama, Tetsuo; Oshiro, Yoshitetsu; Sumitani, Masahiko; Mashimo, Takashi; Shibata, Masahiko

2011-01-01

Purpose The purpose of this study was to elucidate the central processing of painful mechanical stimulation to muscle and bone by measuring blood oxygen level-dependent signal changes using functional magnetic resonance imaging (fMRI). Methods Twelve healthy volunteers were enrolled. Mechanical pressure on muscle and bone were applied at the right lower leg by an algometer. Intensities were adjusted to cause weak and strong pain sensation at either target site in preliminary testing. Brain ac...

The Pain System in Oesophageal Disorders: Mechanisms, Clinical Characteristics, and Treatment

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Christian Lottrup

2011-01-01

Full Text Available Pain is common in gastroenterology. This review aims at giving an overview of pain mechanisms, clinical features, and treatment options in oesophageal disorders. The oesophagus has sensory receptors specific for different stimuli. Painful stimuli are encoded by nociceptors and communicated via afferent nerves to the central nervous system. The pain stimulus is further processed and modulated in specific pain centres in the brain, which may undergo plastic alterations. Hence, tissue inflammation and long-term exposure to pain can cause sensitisation and hypersensitivity. Oesophageal sensitivity can be evaluated ,for example, with the oesophageal multimodal probe. Treatment should target the cause of the patient's symptoms. In gastro-oesophageal reflux diseases, proton pump inhibitors are the primary treatment option, surgery being reserved for patients with severe disease resistant to drug therapy. Functional oesophageal disorders are treated with analgesics, antidepressants, and psychological therapy. Lifestyle changes are another option with less documentation.

Basal Forebrain Cholinergic Deficits Reduce Glucose Metabolism and Function of Cholinergic and GABAergic Systems in the Cingulate Cortex.

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Jeong, Da Un; Oh, Jin Hwan; Lee, Ji Eun; Lee, Jihyeon; Cho, Zang Hee; Chang, Jin Woo; Chang, Won Seok

2016-01-01

Reduced brain glucose metabolism and basal forebrain cholinergic neuron degeneration are common features of Alzheimer's disease and have been correlated with memory function. Although regions representing glucose hypometabolism in patients with Alzheimer's disease are targets of cholinergic basal forebrain neurons, the interaction between cholinergic denervation and glucose hypometabolism is still unclear. The aim of the present study was to evaluate glucose metabolism changes caused by cholinergic deficits. We lesioned basal forebrain cholinergic neurons in rats using 192 immunoglobulin G-saporin. After 3 weeks, lesioned animals underwent water maze testing or were analyzed by ¹⁸F-2-fluoro-2-deoxyglucose positron emission tomography. During water maze probe testing, performance of the lesioned group decreased with respect to time spent in the target quadrant and platform zone. Cingulate cortex glucose metabolism in the lesioned group decreased, compared with the normal group. Additionally, acetylcholinesterase activity and glutamate decarboxylase 65/67 expression declined in the cingulate cortex. Our results reveal that spatial memory impairment in animals with selective basal forebrain cholinergic neuron damage is associated with a functional decline in the GABAergic and cholinergic system associated with cingulate cortex glucose hypometabolism.

Effect of basal forebrain stimulation on extracellular acetylcholine release and blood flow in the olfactory bulb.

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Uchida, Sae; Kagitani, Fusako

2017-05-12

The olfactory bulb receives cholinergic basal forebrain input, as does the neocortex; however, the in vivo physiological functions regarding the release of extracellular acetylcholine and regulation of regional blood flow in the olfactory bulb are unclear. We used in vivo microdialysis to measure the extracellular acetylcholine levels in the olfactory bulb of urethane-anesthetized rats. Focal chemical stimulation by microinjection of L-glutamate into the horizontal limb of the diagonal band of Broca (HDB) in the basal forebrain, which is the main source of cholinergic input to the olfactory bulb, increased extracellular acetylcholine release in the ipsilateral olfactory bulb. When the regional cerebral blood flow was measured using laser speckle contrast imaging, the focal chemical stimulation of the HDB did not significantly alter the blood flow in the olfactory bulb, while increases were observed in the neocortex. Our results suggest a functional difference between the olfactory bulb and neocortex regarding cerebral blood flow regulation through the release of acetylcholine by cholinergic basal forebrain input.

Widespread expression of BDNF but not NT3 by target areas of basal forebrain cholinergic neurons

Energy Technology Data Exchange (ETDEWEB)

Phillips, H.S.; Hains, J.M.; Laramee, G.R.; Rosenthal, A.; Winslow, J.W. (Genentech, San Francisco, CA (USA))

1990-10-12

Brain-derived neurotrophic factor (BDNF) and neurotrophin-3 (NT3) are homologs of the well-known neurotrophic factor nerve growth factor. The three members of this family display distinct patterns of target specificity. To examine the distribution in brain of messenger RNA for these molecules, in situ hybridization was performed. Cells hybridizing intensely to antisense BDNF probe were located throughout the major targets of the rat basal forebrain cholinergic system, that is, the hippocampus, amygdala, and neocortex. Strongly hybridizing cells were also observed in structures associated with the olfactory system. The distribution of NT3 mRNA in forebrain was much more limited. Within the hippocampus, labeled cells were restricted to CA2, the most medial portion of CA1, and the dentate gyrus. In human hippocampus, cells expressing BDNF and mRNA are distributed in a fashion similar to that observed in the rat. These findings point to both basal forebrain cholinergic cells and olfactory pathways as potential central targets for BDNF.

Widespread expression of BDNF but not NT3 by target areas of basal forebrain cholinergic neurons

International Nuclear Information System (INIS)

Phillips, H.S.; Hains, J.M.; Laramee, G.R.; Rosenthal, A.; Winslow, J.W.

1990-01-01

Brain-derived neurotrophic factor (BDNF) and neurotrophin-3 (NT3) are homologs of the well-known neurotrophic factor nerve growth factor. The three members of this family display distinct patterns of target specificity. To examine the distribution in brain of messenger RNA for these molecules, in situ hybridization was performed. Cells hybridizing intensely to antisense BDNF probe were located throughout the major targets of the rat basal forebrain cholinergic system, that is, the hippocampus, amygdala, and neocortex. Strongly hybridizing cells were also observed in structures associated with the olfactory system. The distribution of NT3 mRNA in forebrain was much more limited. Within the hippocampus, labeled cells were restricted to CA2, the most medial portion of CA1, and the dentate gyrus. In human hippocampus, cells expressing BDNF and mRNA are distributed in a fashion similar to that observed in the rat. These findings point to both basal forebrain cholinergic cells and olfactory pathways as potential central targets for BDNF

Agmatine protection against chlorpromazine-induced forebrain cortex injury in rats.

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Dejanovic, Bratislav; Stevanovic, Ivana; Ninkovic, Milica; Stojanovic, Ivana; Lavrnja, Irena; Radicevic, Tatjana; Pavlovic, Milos

2016-03-01

This study was conducted to investigate whether agmatine (AGM) provides protection against oxidative stress induced by treatment with chlorpromazine (CPZ) in Wistar rats. In addition, the role of reactive oxygen species and efficiency of antioxidant protection in the brain homogenates of forebrain cortexes prepared 48 h after treatment were investigated. Chlorpromazine was applied intraperitoneally (i.p.) in single dose of 38.7 mg/kg body weight (BW) The second group was treated with both CPZ and AGM (75 mg/kg BW). The control group was treated with 0.9% saline solution in the same manner. All tested compounds were administered i.p. in a single dose. Rats were sacrificed by decapitation 48 h after treatment Treatment with AGM significantly attenuated the oxidative stress parameters and restored antioxidant capacity in the forebrain cortex. The data indicated that i.p. administered AGM exerted antioxidant action in CPZ-treated animals. Moreover, reactive astrocytes and microglia may contribute to secondary nerve-cell damage and participate in the balance of destructive vs. protective actions involved in the pathogenesis after poisoning.

Basal Forebrain Cholinergic Deficits Reduce Glucose Metabolism and Function of Cholinergic and GABAergic Systems in the Cingulate Cortex

OpenAIRE

Jeong, Da Un; Oh, Jin Hwan; Lee, Ji Eun; Lee, Jihyeon; Cho, Zang Hee; Chang, Jin Woo; Chang, Won Seok

2015-01-01

Purpose Reduced brain glucose metabolism and basal forebrain cholinergic neuron degeneration are common features of Alzheimer's disease and have been correlated with memory function. Although regions representing glucose hypometabolism in patients with Alzheimer's disease are targets of cholinergic basal forebrain neurons, the interaction between cholinergic denervation and glucose hypometabolism is still unclear. The aim of the present study was to evaluate glucose metabolism changes caused ...

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.

Numbness in clinical and experimental pain--a cross-sectional study exploring the mechanisms of reduced tactile function.

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Geber, Christian; Magerl, Walter; Fondel, Ricarda; Fechir, Marcel; Rolke, Roman; Vogt, Thomas; Treede, Rolf-Detlef; Birklein, Frank

2008-09-30

Pain patients often report distinct numbness of the painful skin although no structural peripheral or central nerve lesion is obvious. In this cross-sectional study we assessed the reduction of tactile function and studied underlying mechanisms in patients with chronic pain and in healthy participants exposed to phasic and tonic experimental nociceptive stimulation. Mechanical detection (MDT) and pain thresholds (MPT) were assessed in the painful area and the non-painful contralateral side in 10 patients with unilateral musculoskeletal pain. Additionally, 10 healthy participants were exposed to nociceptive stimulation applied to the volar forearms (capsaicin; electrical stimulation, twice each). Areas of tactile hypaesthesia and mechanical hyperalgesia were assessed. MDT and MPT were quantified adjacent to the stimulation site. Tactile hypaesthesia in pain patients and in experimental pain (MDT-z-scores: -0.66+/-0.30 and -0.42+/-0.15, respectively, both p<0.01) was paralleled by mechanical hyperalgesia (MPT-z-scores: +0.51+/-0.27, p<0.05; and +0.48+/-0.10, p<0.001). However, hypaesthesia and hyperalgesia were not correlated. Although 9 patients reported numbness, only 3 of them were able to delineate circumscript areas of tactile hypaesthesia. In experimental pain, the area of tactile hypaesthesia could be mapped in 31/40 experiments (78%). Irrespective of the mode of nociceptive stimulation (phasic vs. tonic) tactile hypaesthesia and hyperalgesia developed with a similar time course and disappeared within approximately 1 day. Hypaesthesia (numbness) often encountered in clinical pain can be reproduced by experimental nociceptive stimulation. The time course of effects suggests a mechanism involving central plasticity.

Mechanisms of Sucrose and Non-Nutritive Sucking in Procedural Pain Management in Infants

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Sharyn Gibbins

2001-01-01

Full Text Available The administration of sucrose with and without non-nutritive sucking (NNS has been examined for relieving procedural pain in newborn infants. The calming and pain-relieving effects of sucrose are thought to be mediated by endogenous opioid pathways activated by sweet taste. The orogustatory effects of sucrose have been demonstrated in animal newborns, and in preterm and full term human infants during painful procedures. In contrast to sucrose, the analgesic effects of NNS are hypothesized to be activated through nonopioid pathways by stimulation of orotactile and mechanoreceptor mechanisms. Although there is uncertainty as to whether the effects of sucrose and NNS are synergistic or additive, there is sufficient evidence to support the efficacy of combining the two interventions for procedural pain relief in infants. In this review article, the underlying mechanisms of sucrose and NNS, separately and in combination for relieving procedural pain in preterm and full term infants, are examined. Clinical and research implications are addressed.

Mechanisms and Management of Diabetic Painful Distal Symmetrical Polyneuropathy

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Tesfaye, Solomon; Boulton, Andrew J.M.; Dickenson, Anthony H.

2013-01-01

Although a number of the diabetic neuropathies may result in painful symptomatology, this review focuses on the most common: chronic sensorimotor distal symmetrical polyneuropathy (DSPN). It is estimated that 15–20% of diabetic patients may have painful DSPN, but not all of these will require therapy. In practice, the diagnosis of DSPN is a clinical one, whereas for longitudinal studies and clinical trials, quantitative sensory testing and electrophysiological assessment are usually necessary. A number of simple numeric rating scales are available to assess the frequency and severity of neuropathic pain. Although the exact pathophysiological processes that result in diabetic neuropathic pain remain enigmatic, both peripheral and central mechanisms have been implicated, and extend from altered channel function in peripheral nerve through enhanced spinal processing and changes in many higher centers. A number of pharmacological agents have proven efficacy in painful DSPN, but all are prone to side effects, and none impact the underlying pathophysiological abnormalities because they are only symptomatic therapy. The two first-line therapies approved by regulatory authorities for painful neuropathy are duloxetine and pregabalin. α-Lipoic acid, an antioxidant and pathogenic therapy, has evidence of efficacy but is not licensed in the U.S. and several European countries. All patients with DSPN are at increased risk of foot ulceration and require foot care, education, and if possible, regular podiatry assessment. PMID:23970715

Hierarchical prediction errors in midbrain and basal forebrain during sensory learning.

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Iglesias, Sandra; Mathys, Christoph; Brodersen, Kay H; Kasper, Lars; Piccirelli, Marco; den Ouden, Hanneke E M; Stephan, Klaas E

2013-10-16

In Bayesian brain theories, hierarchically related prediction errors (PEs) play a central role for predicting sensory inputs and inferring their underlying causes, e.g., the probabilistic structure of the environment and its volatility. Notably, PEs at different hierarchical levels may be encoded by different neuromodulatory transmitters. Here, we tested this possibility in computational fMRI studies of audio-visual learning. Using a hierarchical Bayesian model, we found that low-level PEs about visual stimulus outcome were reflected by widespread activity in visual and supramodal areas but also in the midbrain. In contrast, high-level PEs about stimulus probabilities were encoded by the basal forebrain. These findings were replicated in two groups of healthy volunteers. While our fMRI measures do not reveal the exact neuron types activated in midbrain and basal forebrain, they suggest a dichotomy between neuromodulatory systems, linking dopamine to low-level PEs about stimulus outcome and acetylcholine to more abstract PEs about stimulus probabilities. Copyright © 2013 Elsevier Inc. All rights reserved.

Treatment for chronic low back pain: the focus should change to multimodal management that reflects the underlying pain mechanisms.

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Müller-Schwefe, Gerhard; Morlion, Bart; Ahlbeck, Karsten; Alon, Eli; Coaccioli, Stefano; Coluzzi, Flaminia; Huygen, Frank; Jaksch, Wolfgang; Kalso, Eija; Kocot-Kępska, Magdalena; Kress, Hans-Georg; Mangas, Ana Cristina; Margarit Ferri, Cesar; Mavrocordatos, Philippe; Nicolaou, Andrew; Hernández, Concepción Pérez; Pergolizzi, Joseph; Schäfer, Michael; Sichère, Patrick

2017-07-01

Chronic low back pain: Chronic pain is the most common cause for people to utilize healthcare resources and has a considerable impact upon patients' lives. The most prevalent chronic pain condition is chronic low back pain (CLBP). CLBP may be nociceptive or neuropathic, or may incorporate both components. The presence of a neuropathic component is associated with more intense pain of longer duration, and a higher prevalence of co-morbidities. However, many physicians' knowledge of chronic pain mechanisms is currently limited and there are no universally accepted treatment guidelines, so the condition is not particularly well managed. Diagnosis should begin with a focused medical history and physical examination, to exclude serious spinal pathology that may require evaluation by an appropriate specialist. Most patients have non-specific CLBP, which cannot be attributed to a particular cause. It is important to try and establish whether a neuropathic component is present, by combining the findings of physical and neurological examinations with the patient's history. This may prove difficult, however, even when using screening instruments. Multimodal management: The multifactorial nature of CLBP indicates that the most logical treatment approach is multimodal: i.e. integrated multidisciplinary therapy with co-ordinated somatic and psychotherapeutic elements. As both nociceptive and neuropathic components may be present, combining analgesic agents with different mechanisms of action is a rational treatment modality. Individually tailored combination therapy can improve analgesia whilst reducing the doses of constituent agents, thereby lessening the incidence of side effects. This paper outlines the development of CLBP and the underlying mechanisms involved, as well as providing information on diagnosis and the use of a wide range of pharmaceutical agents in managing the condition (including NSAIDs, COX-2 inhibitors, tricyclic antidepressants, opioids and

Muscular heat and mechanical pain sensitivity after lengthening contractions in humans and animals.

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Queme, Fernando; Taguchi, Toru; Mizumura, Kazue; Graven-Nielsen, Thomas

2013-11-01

Mechanical sensitivity of muscle nociceptors was previously shown to increase 2 days after lengthening contractions (LC), but heat sensitivity was not different despite nerve growth factor (NGF) being upregulated in the muscle during delayed-onset muscle soreness (DOMS). The discrepancy of these results and lack of other reports drove us to assess heat sensitivity during DOMS in humans and to evaluate the effect of NGF on the heat response of muscle C-fibers. Pressure pain thresholds and pain intensity scores to intramuscular injection of isotonic saline at 48°C and capsaicin were recorded in humans after inducing DOMS. The response of single unmyelinated afferents to mechanical and heat stimulations applied to their receptive field was recorded from muscle-nerve preparations in vitro. In humans, pressure pain thresholds were reduced but heat and capsaicin pain responses were not increased during DOMS. In rats, the mechanical but not the heat sensitivity of muscle C-fibers was increased in the LC group. NGF applied to the receptive field facilitated the heat sensitivity relative to the control. The absence of facilitated heat sensitivity after LC, despite the NGF sensitization, may be explained if the NGF concentration produced after LC is not sufficient to sensitize nociceptor response to heat. This article presents new findings on the basic mechanisms underlying hyperalgesia during DOMS, which is a useful model to study myofascial pain syndrome, and the role of NGF on muscular nociception. This might be useful in the search for new pharmacologic targets and therapeutic approaches. Copyright © 2013 American Pain Society. Published by Elsevier Inc. All rights reserved.

Cluster Analysis of an International Pressure Pain Threshold Database Identifies 4 Meaningful Subgroups of Adults With Mechanical Neck Pain

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Walton, David M; Kwok, Timothy S H; Mehta, Swati

2017-01-01

OBJECTIVE: To determine pressure pain detection threshold (PPDT) related phenotypes of individuals with mechanical neck pain that may be identifiable in clinical practice. METHODS: This report describes a secondary analysis of 5 independent, international mechanical neck pain databases of PPDT...... values taken at both a local and distal region (total N=1176). Minor systematic differences in mean PPDT values across cohorts necessitated z-transformation before analysis, and each cohort was split into male and female sexes. Latent profile analysis (LPA) using the k-means approach was undertaken...... to identify the most parsimonious set of PPDT-based phenotypes that were both statistically and clinically meaningful. RESULTS: LPA revealed 4 distinct clusters named according to PPDT levels at the local and distal zones: low-low PPDT (67%), mod-mod (25%), mod-high (4%), and high-high (4%). Secondary...

Role of Shp2 in forebrain neurons in regulating metabolic and cardiovascular functions and responses to leptin.

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do Carmo, J M; da Silva, A A; Sessums, P O; Ebaady, S H; Pace, B R; Rushing, J S; Davis, M T; Hall, J E

2014-06-01

We examined whether deficiency of Src homology 2 containing phosphatase (Shp2) signaling in forebrain neurons alters metabolic and cardiovascular regulation under various conditions and if it attenuates the anorexic and cardiovascular effects of leptin. We also tested whether forebrain Shp2 deficiency alters blood pressure (BP) and heart rate (HR) responses to acute stress. Forebrain Shp2(-/-) mice were generated by crossing Shp2(flox/flox) mice with CamKIIα-cre mice. At 22-24 weeks of age, the mice were instrumented for telemetry for measurement of BP, HR and body temperature (BT). Oxygen consumption (VO2), energy expenditure and motor activity were monitored by indirect calorimetry. Shp2/CamKIIα-cre mice were heavier (46±3 vs 32±1 g), hyperglycemic, hyperleptinemic, hyperinsulinemic and hyperphagic compared to Shp2(flox/flox) control mice. Shp2/CamKIIα-cre mice exhibited reduced food intake responses to fasting/refeeding and impaired regulation of BT when exposed to 15 and 30 °C ambient temperatures. Despite being obese and having many features of metabolic syndrome, Shp2/CamKIIα-cre mice had similar daily average BP and HR compared to Shp2(flox/flox) mice (112±2 vs 113±1 mm Hg and 595±34 vs 650±40 b.p.m.), but exhibited increased BP and HR responses to cold exposure and acute air-jet stress test. Leptin's ability to reduce food intake and to raise BP were markedly attenuated in Shp2/CamKIIα-cre mice. These results suggest that forebrain Shp2 signaling regulates food intake, appetite responses to caloric deprivation and thermogenic control of body temperature during variations in ambient temperature. Deficiency of Shp2 signaling in the forebrain is associated with augmented cardiovascular responses to cold and acute stress but attenuated BP responses to leptin.

Short-term changes in neck pain, widespread pressure pain sensitivity, and cervical range of motion after the application of trigger point dry needling in patients with acute mechanical neck pain: a randomized clinical trial.

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Mejuto-Vázquez, María J; Salom-Moreno, Jaime; Ortega-Santiago, Ricardo; Truyols-Domínguez, Sebastián; Fernández-de-Las-Peñas, César

2014-04-01

Randomized clinical trial. To determine the effects of trigger point dry needling (TrPDN) on neck pain, widespread pressure pain sensitivity, and cervical range of motion in patients with acute mechanical neck pain and active trigger points in the upper trapezius muscle. TrPDN seems to be effective for decreasing pain in individuals with upper-quadrant pain syndromes. Potential effects of TrPDN for decreasing pain and sensitization in individuals with acute mechanical neck pain are needed. Methods Seventeen patients (53% female) were randomly assigned to 1 of 2 groups: a single session of TrPDN or no intervention (waiting list). Pressure pain thresholds over the C5-6 zygapophyseal joint, second metacarpal, and tibialis anterior muscle; neck pain intensity; and cervical spine range-of-motion data were collected at baseline (pretreatment) and 10 minutes and 1 week after the intervention by an assessor blinded to the treatment allocation of the patient. Mixed-model analyses of variance were used to examine the effects of treatment on each outcome variable. Patients treated with 1 session of TrPDN experienced greater decreases in neck pain, greater increases in pressure pain threshold, and higher increases in cervical range of motion than those who did not receive an intervention at both 10 minutes and 1 week after the intervention (Ppain intensity and widespread pressure pain sensitivity, and also increase active cervical range of motion, in patients with acute mechanical neck pain. Changes in pain, pressure pain threshold, and cervical range of motion surpassed their respective minimal detectable change values, supporting clinically relevant treatment effects. Level of Evidence Therapy, level 1b-.

Influence of Gluteus Maximus Inhibition on Upper Trapezius Overactivity in Chronic Mechanical Neck Pain with Radiculopathy

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Ghada Mohamed Koura

2017-03-01

Full Text Available Background: Mechanical neck pain is the most common type of neck pain and commonly to accompany with radiculopathy. Patients of neck pain exhibit greater activation of accessory muscles, (sternocleidomastoid, anterior scalene, and upper trapezius muscles and may also show changed patterns of motor control of other postural muscles as pelvic muscles for reducing activation of painful muscles of neck. Aim of the study: To determine if there is an association between gluteus maximus inhibition and overactivity of upper fibres of trapezius in patients with chronic mechanical neck pain with radiculopathy. Materials and Methods: Forty female patients participated in this study diagnosed as chronic mechanical neck pain with radiculopathy. Amplitude and onset of muscle activation were assessed by using the surface electromyography (EMG during prone hip extension test. Results: The results of this study demonstrated that there is no correlation between the amplitude of EMG activity of right and left gluteus maximus and the amplitude of EMG activity of right and left upper trapezius (P<0.05. Conclusion: It can be concluded that the overactivity of the upper trapezius muscle in patients with chronic mechanical neck pain with radiculopathy is not related to the inhibition of the gluteus maximus muscle during prone hip extension test.

Imaging in mechanical back pain

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Hansen, Bjarke Brandt; Hansen, Philip; Carrino, John A

2016-01-01

Low back pain is common and relates to a variety of overlapping pathologies. Within the last few decades, almost every medical imaging modality has been applied in the evaluation of low back pain. Imaging of the spine has a high priority in the assessment of patients with low back pain, who seem ...

[Effectiveness of an individualised physiotherapy program versus group therapy on neck pain and disability in patients with acute and subacute mechanical neck pain].

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Antúnez Sánchez, Leonardo Gregorio; de la Casa Almeida, María; Rebollo Roldán, Jesús; Ramírez Manzano, Antonio; Martín Valero, Rocío; Suárez Serrano, Carmen

To compare the efficacy in reducing neck pain and disability in an individualised physiotherapy treatment with group treatment in acute and subacute mechanical neck pain. Randomised clinical trial. Health Area of University Hospital Virgen del Rocío, Seville, Spain. A total of 90 patients diagnosed with mechanical neck pain of up to one month onset, distributed randomly into two groups: (i)individualised treatment; (ii)group treatment. The treatment consisted of 15 sessions of about 60minutes for both groups. Individual treatment consisted of 15minutes of infrared heat therapy, 17minutes of massage, and analytical passive stretching of the trapezius muscles and angle of the scapula. The group treatment consisted of a program of active mobilisation, isometric contractions, self-stretching, and postural recommendations. Pain was measured at the beginning and end of treatment pain using a Visual Analogue Scale (VAS) and an algometer applied on the trapezius muscles and angle of the scapula, and neck disability using the Neck Disability Index. Both treatments were statistically significant (P<.001) in improving all variables. Statistically significant differences (P<.001) were found for all of them in favour of individualised treatment compared to group treatment. Patients with acute or subacute mechanical neck pain experienced an improvement in pain and neck disability after receiving either of the physiotherapy treatments used in our study, with the individual treatment being more effective than collective. Copyright © 2016 Elsevier España, S.L.U. All rights reserved.

Mindfulness Meditation-Based Pain Relief Employs Different Neural Mechanisms Than Placebo and Sham Mindfulness Meditation-Induced Analgesia

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Emerson, Nichole M.; Farris, Suzan R.; Ray, Jenna N.; Jung, Youngkyoo; McHaffie, John G.; Coghill, Robert C.

2015-01-01

Mindfulness meditation reduces pain in experimental and clinical settings. However, it remains unknown whether mindfulness meditation engages pain-relieving mechanisms other than those associated with the placebo effect (e.g., conditioning, psychosocial context, beliefs). To determine whether the analgesic mechanisms of mindfulness meditation are different from placebo, we randomly assigned 75 healthy, human volunteers to 4 d of the following: (1) mindfulness meditation, (2) placebo conditioning, (3) sham mindfulness meditation, or (4) book-listening control intervention. We assessed intervention efficacy using psychophysical evaluation of experimental pain and functional neuroimaging. Importantly, all cognitive manipulations (i.e., mindfulness meditation, placebo conditioning, sham mindfulness meditation) significantly attenuated pain intensity and unpleasantness ratings when compared to rest and the control condition (p Mindfulness meditation reduced pain intensity (p = 0.032) and pain unpleasantness (p Mindfulness meditation also reduced pain intensity (p = 0.030) and pain unpleasantness (p = 0.043) ratings more than sham mindfulness meditation. Mindfulness-meditation-related pain relief was associated with greater activation in brain regions associated with the cognitive modulation of pain, including the orbitofrontal, subgenual anterior cingulate, and anterior insular cortex. In contrast, placebo analgesia was associated with activation of the dorsolateral prefrontal cortex and deactivation of sensory processing regions (secondary somatosensory cortex). Sham mindfulness meditation-induced analgesia was not correlated with significant neural activity, but rather by greater reductions in respiration rate. This study is the first to demonstrate that mindfulness-related pain relief is mechanistically distinct from placebo analgesia. The elucidation of this distinction confirms the existence of multiple, cognitively driven, supraspinal mechanisms for pain

Mindfulness Meditation-Based Pain Relief Employs Different Neural Mechanisms Than Placebo and Sham Mindfulness Meditation-Induced Analgesia.

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Zeidan, Fadel; Emerson, Nichole M; Farris, Suzan R; Ray, Jenna N; Jung, Youngkyoo; McHaffie, John G; Coghill, Robert C

2015-11-18

Mindfulness meditation reduces pain in experimental and clinical settings. However, it remains unknown whether mindfulness meditation engages pain-relieving mechanisms other than those associated with the placebo effect (e.g., conditioning, psychosocial context, beliefs). To determine whether the analgesic mechanisms of mindfulness meditation are different from placebo, we randomly assigned 75 healthy, human volunteers to 4 d of the following: (1) mindfulness meditation, (2) placebo conditioning, (3) sham mindfulness meditation, or (4) book-listening control intervention. We assessed intervention efficacy using psychophysical evaluation of experimental pain and functional neuroimaging. Importantly, all cognitive manipulations (i.e., mindfulness meditation, placebo conditioning, sham mindfulness meditation) significantly attenuated pain intensity and unpleasantness ratings when compared to rest and the control condition (p pain intensity (p = 0.032) and pain unpleasantness (p pain intensity (p = 0.030) and pain unpleasantness (p = 0.043) ratings more than sham mindfulness meditation. Mindfulness-meditation-related pain relief was associated with greater activation in brain regions associated with the cognitive modulation of pain, including the orbitofrontal, subgenual anterior cingulate, and anterior insular cortex. In contrast, placebo analgesia was associated with activation of the dorsolateral prefrontal cortex and deactivation of sensory processing regions (secondary somatosensory cortex). Sham mindfulness meditation-induced analgesia was not correlated with significant neural activity, but rather by greater reductions in respiration rate. This study is the first to demonstrate that mindfulness-related pain relief is mechanistically distinct from placebo analgesia. The elucidation of this distinction confirms the existence of multiple, cognitively driven, supraspinal mechanisms for pain modulation. Recent findings have demonstrated that mindfulness meditation

Mechanism, Assessment and Management of Pain in Chronic Pancreatitis: Recommendations of a Multidisciplinary Study Group

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Anderson, Michelle A; Akshintala, Venkata; Albers, Kathryn M; Amann, Stephen T.; Belfer, Inna; Brand, Randall; Chari, Suresh; Cote, Greg; Davis, Brian M.; Frulloni, Luca; Gelrud, Andres; Guda, Nalini; Humar, Abhinav; Liddle, Rodger A.; Slivka, Adam; Gupta, Rachelle Stopczynski; Szigethy, Eva; Talluri, Jyothsna; Wassef, Wahid; Wilcox, C Mel; Windsor, John; Yadav, Dhiraj; Whitcomb, David C.

2015-01-01

Description Pain in patients with chronic pancreatitis (CP) remains the primary clinical complaint and source of poor quality of life. However, clear guidance on evaluation and treatment is lacking. Methods Pancreatic Pain working groups reviewed information on pain mechanisms, clinical pain assessment and pain treatment in CP. Levels of evidence were assigned using the Oxford system, and consensus was based on GRADE. A consensus meeting was held during PancreasFest 2012 with substantial post-meeting discussion, debate, and manuscript refinement. Results Twelve discussion questions and proposed guidance statements were presented. Conference participates concluded: Disease Mechanism: Pain etiology is multifactorial, but data are lacking to effectively link symptoms with pathologic feature and molecular subtypes. Assessment of Pain: Pain should be assessed at each clinical visit, but evidence to support an optimal approach to assessing pain character, frequency and severity is lacking. Management: There was general agreement on the roles for endoscopic and surgical therapies, but less agreement on optimal patient selection for medical, psychological, endoscopic, surgical and other therapies. Conclusions Progress is occurring in pain biology and treatment options, but pain in patients with CP remains a major problem that is inadequately understood, measured and managed. The growing body of information needs to be translated into more effective clinical care. PMID:26620965

Pain Measurement in Mechanically Ventilated Patients After Cardiac Surgery: Comparison of the Behavioral Pain Scale (BPS) and the Critical-Care Pain Observation Tool (CPOT).

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Rijkenberg, Saskia; Stilma, Willemke; Bosman, Robert J; van der Meer, Nardo J; van der Voort, Peter H J

2017-08-01

The Behavioral Pain Scale (BPS) and Critical-Care Pain Observation Tool (CPOT) are behavioral pain assessment tools for sedated and unconscious critically ill patients. The aim of this study was to compare the reliability, internal consistency, and discriminant validation of the BPS and the CPOT simultaneously in mechanically ventilated patients after cardiac surgery. A prospective, observational cohort study. A 20-bed closed-format intensive care unit with mixed medical, surgical, and cardiac surgery patients in a teaching hospital in Amsterdam, The Netherlands. The study comprised 72 consecutive intubated and mechanically ventilated patients after cardiac surgery who were not able to self-report pain. Two nurses assessed the BPS and CPOT simultaneously and independently at the following 4 moments: rest, a nonpainful procedure (oral care), rest, and a painful procedure (turning). Both scores showed a significant increase of 2 points between rest and turning. The median BPS score of nurse 1 showed a significant increase of 1 point between rest and the nonpainful procedure (oral care), whereas both median CPOT scores did not change. The interrater reliability of the BPS and CPOT showed fair-to-good agreement of 0.74 overall. During the periods of rest 1 and rest 2, values ranged from 0.24 to 0.46. Cronbach's alpha values for the BPS were 0.62 (nurse 1) and 0.59 (nurse 2) compared with 0.65 and 0.58, respectively, for the CPOT. The BPS and CPOT are reliable and valid pain assessment tools in a daily clinical setting. However, the discriminant validation of both scores seems less satisfactory in sedated or agitated patients and this topic requires further investigation. Copyright © 2017 Elsevier Inc. All rights reserved.

Mechanisms of Stress-Induced Visceral Pain: Implications in Irritable Bowel Syndrome.

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Greenwood-Van Meerveld, B; Moloney, R D; Johnson, A C; Vicario, M

2016-08-01

Visceral pain is a term describing pain originating from the internal organs of the body and is a common feature of many disorders, including irritable bowel syndrome (IBS). Stress is implicated in the development and exacerbation of many visceral pain disorders. Recent evidence suggests that stress and the gut microbiota can interact through complementary or opposing factors to influence visceral nociceptive behaviours. The Young Investigator Forum at the International Society of Psychoneuroendocrinology (ISPNE) annual meeting reported experimental evidence suggesting the gut microbiota can affect the stress response to affect visceral pain. Building upon human imaging data showing abnormalities in the central processing of visceral stimuli in patients with IBS and knowledge that the amygdala plays a pivotal role in facilitating the stress axis, the latest experimental evidence supporting amygdala-mediated mechanisms in stress-induced visceral pain was reviewed. The final part of the session at ISPNE reviewed experimental evidence suggesting that visceral pain in IBS may be a result, at least in part, of afferent nerve sensitisation following increases in epithelial permeability and mucosal immune activation. © 2016 British Society for Neuroendocrinology.

The efficacy of mechanical vibration analgesia for relief of heel stick pain in neonates: a novel approach.

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Baba, Lisa R; McGrath, Jacqueline M; Liu, Jiexin

2010-01-01

Hospitalized infants are often exposed to many painful procedures as a result of their illness or disease process. Untreated or poorly treated pain can have deleterious effects on normal nociceptive pain development as well as future development of pain pathways. Mechanical vibration has been found to be efficacious in adult and pediatric populations for the relief of mild-to-moderate acute and chronic pain. However, little is known about the efficacy of this intervention in the neonatal population. The purpose of this study was to test the hypothesis that mechanical vibration would be efficacious in the relief of pain associated with heel sticks in neonates. Heel sticks are one of the most common painful procedures during neonatal hospitalization. A random-sequencing crossover design was used with infants acting as their own controls. Newborn infants of 35 weeks' gestation or greater (N = 20) met the inclusion criteria for the study. Pain during heel stick was measured with the Neonatal Infant Pain Scale. The Neonatal Infant Pain Scale is a nonintrusive tool with extensive evidence of its reliability and validity in the neonatal population, when used by trained observers. Mechanical vibration produced an analgesic effect for infants who had previously experienced painful heel sticks that approached statistical significance. The apparent limitations of mechanical vibration as analgesia may be due to the concurrent use of sucrose and pacifier, the effects of order (ie, habituation), or type II error. Because vibration produced the predicted positive effect in some circumstances, further investigation in larger samples within a randomized clinical trial is warranted.

Cholinergic Inputs from Basal Forebrain Add an Excitatory Bias to Odor Coding in the Olfactory Bulb

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Rothermel, Markus; Carey, Ryan M.; Puche, Adam; Shipley, Michael T.

2014-01-01

Cholinergic modulation of central circuits is associated with active sensation, attention, and learning, yet the neural circuits and temporal dynamics underlying cholinergic effects on sensory processing remain unclear. Understanding the effects of cholinergic modulation on particular circuits is complicated by the widespread projections of cholinergic neurons to telencephalic structures that themselves are highly interconnected. Here we examined how cholinergic projections from basal forebrain to the olfactory bulb (OB) modulate output from the first stage of sensory processing in the mouse olfactory system. By optogenetically activating their axons directly in the OB, we found that cholinergic projections from basal forebrain regulate OB output by increasing the spike output of presumptive mitral/tufted cells. Cholinergic stimulation increased mitral/tufted cell spiking in the absence of inhalation-driven sensory input and further increased spiking responses to inhalation of odorless air and to odorants. This modulation was rapid and transient, was dependent on local cholinergic signaling in the OB, and differed from modulation by optogenetic activation of cholinergic neurons in basal forebrain, which led to a mixture of mitral/tufted cell excitation and suppression. Finally, bulbar cholinergic enhancement of mitral/tufted cell odorant responses was robust and occurred independent of the strength or even polarity of the odorant-evoked response, indicating that cholinergic modulation adds an excitatory bias to mitral/tufted cells as opposed to increasing response gain or sharpening response spectra. These results are consistent with a role for the basal forebrain cholinergic system in dynamically regulating the sensitivity to or salience of odors during active sensing of the olfactory environment. PMID:24672011

The Effect of Traditional Cupping on Pain and Mechanical Thresholds in Patients with Chronic Nonspecific Neck Pain: A Randomised Controlled Pilot Study

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Romy Lauche

2012-01-01

Full Text Available Introduction. Cupping has been used since antiquity in the treatment of pain conditions. In this pilot study, we investigated the effect of traditional cupping therapy on chronic nonspecific neck pain (CNP and mechanical sensory thresholds. Methods. Fifty CNP patients were randomly assigned to treatment (TG, n=25 or waiting list control group (WL, n=25. TG received a single cupping treatment. Pain at rest (PR, pain related to movement (PM, quality of life (SF-36, Neck Disability Index (NDI, mechanical detection (MDT, vibration detection (MDT, and pressure pain thresholds (PPT were measured before and three days after a single cupping treatment. Patients also kept a pain and medication diary (PaDi, MeDi during the study. Results. Baseline characteristics were similar in the two groups. After cupping TG reported significantly less pain (PR: −17.9 mm VAS, 95%CI −29.2 to −6.6; PM: −19.7, 95%CI −32.2 to −7.2; PaDi: −1.5 points on NRS, 95%CI −2.5 to −0.4; all P<0.05 and higher quality of life than WL (SF-36, Physical Functioning: 7.5, 95%CI 1.4 to 13.5; Bodily Pain: 14.9, 95%CI 4.4 to 25.4; Physical Component Score: 5.0, 95%CI 1.4 to 8.5; all P<0.05. No significant effect was found for NDI, MDT, or VDT, but TG showed significantly higher PPT at pain-areas than WL (in lg(kPa; pain-maximum: 0.088, 95%CI 0.029 to 0.148, pain-adjacent: 0.118, 95%CI 0.038 to 0.199; both P<0.01. Conclusion. A single application of traditional cupping might be an effective treatment for improving pain, quality of life, and hyperalgesia in CNP.

Cellular, molecular, and epigenetic mechanisms in non-associative conditioning: implications for pain and memory.

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Rahn, Elizabeth J; Guzman-Karlsson, Mikael C; David Sweatt, J

2013-10-01

Sensitization is a form of non-associative conditioning in which amplification of behavioral responses can occur following presentation of an aversive or noxious stimulus. Understanding the cellular and molecular underpinnings of sensitization has been an overarching theme spanning the field of learning and memory as well as that of pain research. In this review we examine how sensitization, both in the context of learning as well as pain processing, shares evolutionarily conserved behavioral, cellular/synaptic, and epigenetic mechanisms across phyla. First, we characterize the behavioral phenomenon of sensitization both in invertebrates and vertebrates. Particular emphasis is placed on long-term sensitization (LTS) of withdrawal reflexes in Aplysia following aversive stimulation or injury, although additional invertebrate models are also covered. In the context of vertebrates, sensitization of mammalian hyperarousal in a model of post-traumatic stress disorder (PTSD), as well as mammalian models of inflammatory and neuropathic pain is characterized. Second, we investigate the cellular and synaptic mechanisms underlying these behaviors. We focus our discussion on serotonin-mediated long-term facilitation (LTF) and axotomy-mediated long-term hyperexcitability (LTH) in reduced Aplysia systems, as well as mammalian spinal plasticity mechanisms of central sensitization. Third, we explore recent evidence implicating epigenetic mechanisms in learning- and pain-related sensitization. This review illustrates the fundamental and functional overlay of the learning and memory field with the pain field which argues for homologous persistent plasticity mechanisms in response to sensitizing stimuli or injury across phyla. Copyright © 2013 Elsevier Inc. All rights reserved.

Recent advances in acute pain management: understanding the mechanisms of acute pain, the prescription of opioids, and the role of multimodal pain therapy [version 1; referees: 3 approved

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Richa Wardhan

2017-11-01

Full Text Available In this review, we discuss advances in acute pain management, including the recent report of the joint American Pain Society and American Academy of Pain Medicine task force on the classification of acute pain, the role of psychosocial factors, multimodal pain management, new non-opioid therapy, and the effect of the “opioid epidemic”. In this regard, we propose that a fundamental principle in acute pain management is identifying patients who are most at risk and providing an “opioid free anesthesia and postoperative analgesia”. This can be achieved by using a multimodal approach that includes regional anesthesia and minimizing the dose and the duration of opioid prescription. This allows prescribing medications that work through different mechanisms. We shall also look at the recent pharmacologic and treatment advances made in acute pain and regional anesthesia.

The hallucinogen d-lysergic acid diethylamide (d-LSD) induces the immediate-early gene c-Fos in rat forebrain.

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Frankel, Paul S; Cunningham, Kathryn A

2002-12-27

The hallucinogen d-lysergic acid diethylamide (d-LSD) evokes dramatic somatic and psychological effects. In order to analyze the neural activation induced by this unique psychoactive drug, we tested the hypothesis that expression of the immediate-early gene product c-Fos is induced in specific regions of the rat forebrain by a relatively low, behaviorally active, dose of d-LSD (0.16 mg/kg, i.p.); c-Fos protein expression was assessed at 30 min, and 1, 2 and 4 h following d-LSD injection. A time- and region-dependent expression of c-Fos was observed with a significant increase (PLSD administration. These data demonstrate a unique pattern of c-Fos expression in the rat forebrain following a relatively low dose of d-LSD and suggest that activation of these forebrain regions contributes to the unique behavioral effects of d-LSD. Copyright 2002 Elsevier Science B.V.

An evaluation of instruments for scoring physiological and behavioral cues of pain, non-pain related distress, and adequacy of analgesia and sedation in pediatric mechanically ventilated patients: A systematic review.

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Dorfman, Tamara L; Sumamo Schellenberg, Elizabeth; Rempel, Gwen R; Scott, Shannon D; Hartling, Lisa

2014-04-01

Advancing technology allows for successful treatment of children with life-threatening illnesses. Effectively assessing and optimally treating a child's distress during their stay in the Pediatric Intensive Care Unit (PICU) is paramount. Objective measures of distress in mechanically ventilated pediatric patients are increasingly available but few have been evaluated. The objectives of this systematic review were to identify available instruments appropriate for measuring physiological and behavioral cues of pain, non-pain related distress, and adequacy of analgesia and sedation in mechanically ventilated pediatric patients, and evaluate these instruments in terms of their psychometric properties. A systematic review of original and validation reports of objective instruments to measure pain and non-pain related distress, and adequacy of analgesia and sedation in mechanically ventilated PICU patients was undertaken. A comprehensive search was conducted in 10 databases from January 1970 to June 2011. Reference lists of relevant articles were reviewed to identify additional articles. Studies were included in the review if they met pre-established eligibility criteria. Two independent reviewers reviewed studies for inclusion, assessed quality, and extracted data. Twenty-five articles were included, identifying 15 instruments. The instruments had different foci including: assessing pain, non-pain related distress, and sedation (n=2); assessing pain exclusively (n=4); assessing sedation exclusively (n=7), assessing sedation in mechanically ventilated muscle relaxed PICU patients (n=1); and assessing delirium in mechanically ventilated PICU patients (n=1). The Comfort Scale demonstrated the greatest clinical utility in the assessment of pain, non-pain related distress, and sedation in mechanically ventilated pediatric patients. Modified FLACC and the MAPS are more appropriate, however, for the assessment of procedural pain and other brief painful events. More work is

The major brain endocannabinoid 2-AG controls neuropathic pain and mechanical hyperalgesia in patients with neuromyelitis optica.

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Hannah L Pellkofer

Full Text Available Recurrent myelitis is one of the predominant characteristics in patients with neuromyelitis optica (NMO. While paresis, visual loss, sensory deficits, and bladder dysfunction are well known symptoms in NMO patients, pain has been recognized only recently as another key symptom of the disease. Although spinal cord inflammation is a defining aspect of neuromyelitis, there is an almost complete lack of data on altered somatosensory function, including pain. Therefore, eleven consecutive patients with NMO were investigated regarding the presence and clinical characteristics of pain. All patients were examined clinically as well as by Quantitative Sensory Testing (QST following the protocol of the German Research Network on Neuropathic Pain (DFNS. Additionally, plasma endocannabinoid levels and signs of chronic stress and depression were determined. Almost all patients (10/11 suffered from NMO-associated neuropathic pain for the last three months, and 8 out of 11 patients indicated relevant pain at the time of examination. Symptoms of neuropathic pain were reported in the vast majority of patients with NMO. Psychological testing revealed signs of marked depression. Compared to age and gender-matched healthy controls, QST revealed pronounced mechanical and thermal sensory loss, strongly correlated to ongoing pain suggesting the presence of deafferentation-induced neuropathic pain. Thermal hyperalgesia correlated to MRI-verified signs of spinal cord lesion. Heat hyperalgesia was highly correlated to the time since last relapse of NMO. Patients with NMO exhibited significant mechanical and thermal dysesthesia, namely dynamic mechanical allodynia and paradoxical heat sensation. Moreover, they presented frequently with either abnormal mechanical hypoalgesia or hyperalgesia, which depended significantly on plasma levels of the endogenous cannabinoid 2-arachidonoylglycerole (2-AG. These data emphasize the high prevalence of neuropathic pain and hyperalgesia

Forebrain-Specific Loss of BMPRII in Mice Reduces Anxiety and Increases Object Exploration.

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McBrayer, Zofeyah L; Dimova, Jiva; Pisansky, Marc T; Sun, Mu; Beppu, Hideyuki; Gewirtz, Jonathan C; O'Connor, Michael B

2015-01-01

To investigate the role of Bone Morphogenic Protein Receptor Type II (BMPRII) in learning, memory, and exploratory behavior in mice, a tissue-specific knockout of BMPRII in the post-natal hippocampus and forebrain was generated. We found that BMPRII mutant mice had normal spatial learning and memory in the Morris water maze, but showed significantly reduced swimming speeds with increased floating behavior. Further analysis using the Porsolt Swim Test to investigate behavioral despair did not reveal any differences in immobility between mutants and controls. In the Elevated Plus Maze, BMPRII mutants and Smad4 mutants showed reduced anxiety, while in exploratory tests, BMPRII mutants showed more interest in object exploration. These results suggest that loss of BMPRII in the mouse hippocampus and forebrain does not disrupt spatial learning and memory encoding, but instead impacts exploratory and anxiety-related behaviors.

Forebrain-Specific Loss of BMPRII in Mice Reduces Anxiety and Increases Object Exploration.

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Zofeyah L McBrayer

Full Text Available To investigate the role of Bone Morphogenic Protein Receptor Type II (BMPRII in learning, memory, and exploratory behavior in mice, a tissue-specific knockout of BMPRII in the post-natal hippocampus and forebrain was generated. We found that BMPRII mutant mice had normal spatial learning and memory in the Morris water maze, but showed significantly reduced swimming speeds with increased floating behavior. Further analysis using the Porsolt Swim Test to investigate behavioral despair did not reveal any differences in immobility between mutants and controls. In the Elevated Plus Maze, BMPRII mutants and Smad4 mutants showed reduced anxiety, while in exploratory tests, BMPRII mutants showed more interest in object exploration. These results suggest that loss of BMPRII in the mouse hippocampus and forebrain does not disrupt spatial learning and memory encoding, but instead impacts exploratory and anxiety-related behaviors.

Neuropathic Pain Following Spinal Cord Injury: Mechanism, Assessment and Treatment

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Gul Mete Civelek

2016-04-01

Full Text Available Spinal cord injury (SCI is a devastating disease which may cause physical, psychological and social dysfunction. Neuropathic pain (NP after SCI is common, can be seen in varying degrees and is one of the most difficultly treated problems developing after SCI. With the addition of the NP to loss of function after SCI, sleep patterns, moods and daily activities of patients are adversely affected. In order to treat pain effectively, classification of pain after SCI must be done carefully and correctly. According to classification of International Pain Study Group, pain after SCI is divided into two main groups as nociceptive and neuropathic pain. Neuropathic pain is defined as %u201Cpain occuring as a direct result of a disease or lesion directly affecting somato-sensorial system%u201D. NP after SCI can be classified according to anatomical region (above the level of lesion, at the level of lesion, below the level of lesion. Treatment of NP after SCI is often challenging and receiving response to treatment may take long time. Therefore, treatment of NP after SCI should be multifactorial. Treatment options include pharmochologic treatment, application of transcutanous electrical nerve stimulation, psychiatric treatment approaches, and surgical approaches in selected cases. In pharmachologic treatment, first line agents are tricyclic antidepresants, pregabalin and gabapentin. In this review, mechanisms and assessment and treatment of NP after SCI is discussed with the guide of current literature.

Deep Dyspareunia in Endometriosis: A Proposed Framework Based on Pain Mechanisms and Genito-Pelvic Pain Penetration Disorder.

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Yong, Paul J

2017-10-01

Endometriosis is a common chronic disease affecting 1 in 10 women of reproductive age, with half of women with endometriosis experiencing deep dyspareunia. A review of research studies on endometriosis indicates a need for a validated question or questionnaire for deep dyspareunia. Moreover, placebo-controlled randomized trials have yet to demonstrate a clear benefit for traditional treatments of endometriosis for the outcome of deep dyspareunia. The reason some patients might not respond to traditional treatments is the multifactorial nature of deep dyspareunia in endometriosis, which can include comorbid conditions (eg, interstitial cystitis and bladder pain syndrome) and central sensitization underlying genito-pelvic pain penetration disorder. In general, there is a lack of a framework that integrates these multifactorial causes to provide a standardized approach to deep dyspareunia in endometriosis. To propose a clinical framework for deep dyspareunia based on a synthesis of pain mechanisms with genito-pelvic pain penetration disorder according to the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition. Narrative review after literature search with the terms (endometriosis AND dyspareunia) OR (dyspareunia AND deep) and after analysis of placebo-controlled randomized trials. Deep dyspareunia presence or absence or deep dyspareunia severity on a numeric rating scale or visual analog scale. Four types of deep dyspareunia are proposed in women with endometriosis: type I that is directly due to endometriosis; type II that is related to a comorbid condition; type III in which genito-pelvic pain penetration disorder is primary; and type IV that is secondary to a combination of types I to III. Four types of deep dyspareunia in endometriosis are proposed, which can be used as a framework in research studies and in clinical practice. Research trials could phenotype or stratify patients by each type. The framework also could give rise to more personalized

Painful faces-induced attentional blink modulated by top-down and bottom-up mechanisms

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Chun eZheng

2015-06-01

Full Text Available Pain-related stimuli can capture attention in an automatic (bottom-up or intentional (top-down fashion. Previous studies have examined attentional capture by pain-related information using spatial attention paradigms that involve mainly a bottom-up mechanism. In the current study, we investigated the pain information–induced attentional blink (AB using a rapid serial visual presentation (RSVP task, and compared the effects of task-irrelevant and task-relevant pain distractors. Relationships between accuracy of target identification and individual traits (i.e., empathy and catastrophizing thinking about pain were also examined. The results demonstrated that task-relevant painful faces had a significant pain information–induced AB effect, whereas task-irrelevant faces a near-significant trend of this effect, supporting the notion that pain-related stimuli can influence the temporal dynamics of attention. Furthermore, we found a significant negative correlation between response accuracy and pain catastrophizing score in task-relevant trials. These findings suggest that active scanning of environmental information related to pain produces greater deficits in cognition than does unintentional attention toward pain, which may represent the different ways in which healthy individuals and patients with chronic pain process pain-relevant information. These results may provide insight into the understanding of maladaptive attentional processing in patients with chronic pain.

Dcc regulates asymmetric outgrowth of forebrain neurons in zebrafish.

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Jingxia Gao

Full Text Available The guidance receptor DCC (deleted in colorectal cancer ortholog UNC-40 regulates neuronal asymmetry development in Caenorhabditis elegans, but it is not known whether DCC plays a role in the specification of neuronal polarity in vertebrates. To examine the roles of DCC in neuronal asymmetry regulation in vertebrates, we studied zebrafish anterior dorsal telencephalon (ADt neuronal axons. We generated transgenic zebrafish animals expressing the photo-convertible fluorescent protein Kaede in ADt neurons and then photo-converted Kaede to label specifically the ADt neuron axons. We found that ADt axons normally project ventrally. Knock down of Dcc function by injecting antisense morpholino oligonucleotides caused the ADt neurons to project axons dorsally. To examine the axon projection pattern of individual ADt neurons, we labeled single ADt neurons using a forebrain-specific promoter to drive fluorescent protein expression. We found that individual ADt neurons projected axons dorsally or formed multiple processes after morpholino knock down of Dcc function. We further found that knock down of the Dcc ligand, Netrin1, also caused ADt neurons to project axons dorsally. Knockdown of Neogenin1, a guidance receptor closely related to Dcc, enhanced the formation of aberrant dorsal axons in embryos injected with Dcc morpholino. These experiments provide the first evidence that Dcc regulates polarized axon initiation and asymmetric outgrowth of forebrain neurons in vertebrates.

Effects of Natural Sounds on Pain: A Randomized Controlled Trial with Patients Receiving Mechanical Ventilation Support.

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Saadatmand, Vahid; Rejeh, Nahid; Heravi-Karimooi, Majideh; Tadrisi, Sayed Davood; Vaismoradi, Mojtaba; Jordan, Sue

2015-08-01

Nonpharmacologic pain management in patients receiving mechanical ventilation support in critical care units is under investigated. Natural sounds may help reduce the potentially harmful effects of anxiety and pain in hospitalized patients. The aim of this study was to examine the effect of pleasant, natural sounds on self-reported pain in patients receiving mechanical ventilation support, using a pragmatic parallel-arm, randomized controlled trial. The study was conducted in a general adult intensive care unit of a high-turnover teaching hospital, in Tehran, Iran. Between October 2011 and June 2012, we recruited 60 patients receiving mechanical ventilation support to the intervention (n = 30) and control arms (n = 30) of a pragmatic parallel-group, randomized controlled trial. Participants in both arms wore headphones for 90 minutes. Those in the intervention arm heard pleasant, natural sounds, whereas those in the control arm heard nothing. Outcome measures included the self-reported visual analog scale for pain at baseline; 30, 60, and 90 minutes into the intervention; and 30 minutes post-intervention. All patients approached agreed to participate. The trial arms were similar at baseline. Pain scores in the intervention arm fell and were significantly lower than in the control arm at each time point (p natural sounds via headphones is a simple, safe, nonpharmacologic nursing intervention that may be used to allay pain for up to 120 minutes in patients receiving mechanical ventilation support. Copyright © 2015 American Society for Pain Management Nursing. Published by Elsevier Inc. All rights reserved.

Burning Eye Syndrome: Do Neuropathic Pain Mechanisms Underlie Chronic Dry Eye?

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Kalangara, Jerry P; Galor, Anat; Levitt, Roy C; Felix, Elizabeth R; Alegret, Ramon; Sarantopoulos, Constantine D

2016-04-01

Dry eye is a multi-factorial disorder that manifests with painful ocular symptoms and visual disturbances, which can only be partly attributed to tear dysfunction. This disorder may also involve neuroplasticity in response to neuronal injury. This review will emphasize the key characteristics of dry eye pain and its pathologic mechanisms, making the argument that a subset of dry eye represents a neuropathic pain disorder of the eye, more appropriately called "burning eye syndrome." A literature review was conducted using a PubMed search focusing on dry eye, corneal nociception, and neuropathic pain. Articles were reviewed and those discussing clinical course, pathophysiology, and neuronal regulation of chronic ocular pain as related to dry eye were summarized. We found that there is a discordance between ocular pain and dryness on the ocular surface. Although tear dysfunction may be one of the initial insults, its persistence may be associated with repeated ocular sensory nerve injury leading to an acute-to-chronic pain transition associated with neuropathologic changes (peripheral and central sensitization), neuronal dysfunction, and spontaneous ocular pain. Dry eye is becoming a major health concern due to its increasing incidence, significant morbidity, and economic burden. Recent evidence suggests that a subset of dry eye may be better represented as a chronic neuropathic pain disorder due to its features of dysesthesia, spontaneous pain, allodynia, and hyperalgesia. Future therapies targeted at the underlying neuroplasticity may yield improved efficacy for patients with this subset of dry eye, which we term "burning eye syndrome." © 2015 American Academy of Pain Medicine. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

ESC-Derived Basal Forebrain Cholinergic Neurons Ameliorate the Cognitive Symptoms Associated with Alzheimer’s Disease in Mouse Models

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Wei Yue

2015-11-01

Full Text Available Degeneration of basal forebrain cholinergic neurons (BFCNs is associated with cognitive impairments of Alzheimer’s disease (AD, implying that BFCNs hold potentials in exploring stem cell-based replacement therapy for AD. However, studies on derivation of BFCNs from embryonic stem cells (ESCs are limited, and the application of ESC-derived BFCNs remains to be determined. Here, we report on differentiation approaches for directing both mouse and human ESCs into mature BFCNs. These ESC-derived BFCNs exhibit features similar to those of their in vivo counterparts and acquire appropriate functional properties. After transplantation into the basal forebrain of AD model mice, ESC-derived BFCN progenitors predominantly differentiate into mature cholinergic neurons that functionally integrate into the endogenous basal forebrain cholinergic projection system. The AD mice grafted with mouse or human BFCNs exhibit improvements in learning and memory performances. Our findings suggest a promising perspective of ESC-derived BFCNs in the development of stem cell-based therapies for treatment of AD.

Song exposure regulates known and novel microRNAs in the zebra finch auditory forebrain

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Kim Jong H

2011-05-01

Full Text Available Abstract Background In an important model for neuroscience, songbirds learn to discriminate songs they hear during tape-recorded playbacks, as demonstrated by song-specific habituation of both behavioral and neurogenomic responses in the auditory forebrain. We hypothesized that microRNAs (miRNAs or miRs may participate in the changing pattern of gene expression induced by song exposure. To test this, we used massively parallel Illumina sequencing to analyse small RNAs from auditory forebrain of adult zebra finches exposed to tape-recorded birdsong or silence. Results In the auditory forebrain, we identified 121 known miRNAs conserved in other vertebrates. We also identified 34 novel miRNAs that do not align to human or chicken genomes. Five conserved miRNAs showed significant and consistent changes in copy number after song exposure across three biological replications of the song-silence comparison, with two increasing (tgu-miR-25, tgu-miR-192 and three decreasing (tgu-miR-92, tgu-miR-124, tgu-miR-129-5p. We also detected a locus on the Z sex chromosome that produces three different novel miRNAs, with supporting evidence from Northern blot and TaqMan qPCR assays for differential expression in males and females and in response to song playbacks. One of these, tgu-miR-2954-3p, is predicted (by TargetScan to regulate eight song-responsive mRNAs that all have functions in cellular proliferation and neuronal differentiation. Conclusions The experience of hearing another bird singing alters the profile of miRNAs in the auditory forebrain of zebra finches. The response involves both known conserved miRNAs and novel miRNAs described so far only in the zebra finch, including a novel sex-linked, song-responsive miRNA. These results indicate that miRNAs are likely to contribute to the unique behavioural biology of learned song communication in songbirds.

Mechanism-based classification and physical therapy management of persons with cancer pain: A prospective case series

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Senthil P Kumar

2013-01-01

Full Text Available Context: Mechanism-based classification (MBC was established with current evidence and physical therapy (PT management methods for both cancer and for noncancer pain. Aims: This study aims to describe the efficacy of MBC-based PT in persons with primary complaints of cancer pain. Settings and Design: A prospective case series of patients who attended the physiotherapy department of a multispecialty university-affiliated teaching hospital. Material and Methods: A total of 24 adults (18 female, 6 male aged 47.5 ± 10.6 years, with primary diagnosis of heterogeneous group of cancer, chief complaints of chronic disabling pain were included in the study on their consent for participation The patients were evaluated and classified on the basis of five predominant mechanisms for pain. Physical therapy interventions were recommended based on mechanisms identified and home program was prescribed with a patient log to ensure compliance. Treatments were given in five consecutive weekly sessions for five weeks each of 30 min duration. Statistical Analysis Used: Pre-post comparisons for pain severity (PS and pain interference (PI subscales of Brief pain inventory-Cancer pain (BPI-CP and, European organization for research and treatment in cancer-quality of life questionnaire (EORTC-QLQ-C30 were done using Wilcoxon signed-rank test at 95% confidence interval using SPSS for Windows version 16.0 (SPSS Inc, Chicago, IL. Results: There were statistically significant ( P < 0.05 reduction in pain severity, pain interference and total BPI-CP scores, and the EORTC-QLQ-C30. Conclusion: MBC-PT was effective for improving BPI-CP and EORTC-QLQ-C30 scores in people with cancer pain.

Psychological flexibility and catastrophizing as associated change mechanisms during online Acceptance & Commitment Therapy for chronic pain

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Trompetter, H.R.; Bohlmeijer, Ernst Thomas; Fox, Gerardus J.A.; Schreurs, Karlein Maria Gertrudis

2015-01-01

The underlying mechanisms of the effectiveness of cognitive behavioural interventions for chronic pain need further clarification. The role of, and associations between, pain-related psychological flexibility (PF) and pain catastrophizing (PC) were examined during a randomized controlled trial on

Effect of pain chronification and chronic pain on an endogenous pain modulation circuit in rats.

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Miranda, J; Lamana, S M S; Dias, E V; Athie, M; Parada, C A; Tambeli, C H

2015-02-12

We tested the hypothesis that chronic pain development (pain chronification) and ongoing chronic pain (chronic pain) reduce the activity and induce plastic changes in an endogenous analgesia circuit, the ascending nociceptive control. An important mechanism mediating this form of endogenous analgesia, referred to as capsaicin-induced analgesia, is its dependence on nucleus accumbens μ-opioid receptor mechanisms. Therefore, we also investigated whether pain chronification and chronic pain alter the requirement for nucleus accumbens μ-opioid receptor mechanisms in capsaicin-induced analgesia. We used an animal model of pain chronification in which daily subcutaneous prostaglandin E2 (PGE2) injections into the rat's hind paw for 14 days, referred to as the induction period of persistent hyperalgesia, induce a long-lasting state of nociceptor sensitization referred to as the maintenance period of persistent hyperalgesia, that lasts for at least 30 days following the cessation of the PGE2 treatment. The nociceptor hypersensitivity was measured by the shortening of the time interval for the animal to respond to a mechanical stimulation of the hind paw. We found a significant reduction in the duration of capsaicin-induced analgesia during the induction and maintenance period of persistent mechanical hyperalgesia. Intra-accumbens injection of the μ-opioid receptor selective antagonist Cys(2),Tyr(3),Orn(5),Pen(7)amide (CTOP) 10 min before the subcutaneous injection of capsaicin into the rat's fore paw blocked capsaicin-induced analgesia. Taken together, these findings indicate that pain chronification and chronic pain reduce the duration of capsaicin-induced analgesia, without affecting its dependence on nucleus accumbens μ-opioid receptor mechanisms. The attenuation of endogenous analgesia during pain chronification and chronic pain suggests that endogenous pain circuits play an important role in the development and maintenance of chronic pain. Copyright © 2014 IBRO

Visual training paired with electrical stimulation of the basal forebrain improves orientation-selective visual acuity in the rat.

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Kang, Jun Il; Groleau, Marianne; Dotigny, Florence; Giguère, Hugo; Vaucher, Elvire

2014-07-01

The cholinergic afferents from the basal forebrain to the primary visual cortex play a key role in visual attention and cortical plasticity. These afferent fibers modulate acute and long-term responses of visual neurons to specific stimuli. The present study evaluates whether this cholinergic modulation of visual neurons results in cortical activity and visual perception changes. Awake adult rats were exposed repeatedly for 2 weeks to an orientation-specific grating with or without coupling this visual stimulation to an electrical stimulation of the basal forebrain. The visual acuity, as measured using a visual water maze before and after the exposure to the orientation-specific grating, was increased in the group of trained rats with simultaneous basal forebrain/visual stimulation. The increase in visual acuity was not observed when visual training or basal forebrain stimulation was performed separately or when cholinergic fibers were selectively lesioned prior to the visual stimulation. The visual evoked potentials show a long-lasting increase in cortical reactivity of the primary visual cortex after coupled visual/cholinergic stimulation, as well as c-Fos immunoreactivity of both pyramidal and GABAergic interneuron. These findings demonstrate that when coupled with visual training, the cholinergic system improves visual performance for the trained orientation probably through enhancement of attentional processes and cortical plasticity in V1 related to the ratio of excitatory/inhibitory inputs. This study opens the possibility of establishing efficient rehabilitation strategies for facilitating visual capacity.

Down-regulation of NR2B receptors partially contributes to analgesic effects of Gentiopicroside in persistent inflammatory pain.

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Chen, Lei; Liu, Jin-cheng; Zhang, Xiao-nan; Guo, Yan-yan; Xu, Zhao-hui; Cao, Wei; Sun, Xiao-li; Sun, Wen-ji; Zhao, Ming-Gao

2008-06-01

Gentiopicroside is one of the secoiridoid compound isolated from Gentiana lutea. It exhibits analgesic activities in the mice. The anterior cingulate cortex (ACC) is a forebrain structure known for its roles in pain transmission and modulation. Painful stimuli potentiate the prefrontal synaptic transmission and induce glutamate NMDA NR2B receptor expression in the ACC. But little is known about Gentiopicroside on the persistent inflammatory pain and chronic pain-induced synaptic transmission changes in the ACC. The present study was undertaken to investigate its analgesic activities and central synaptic modulation to the peripheral painful inflammation. Gentiopicroside produced significant analgesic effects against persistent inflammatory pain stimuli in mice. Systemic administration of Gentiopicroside significantly reversed NR2B over-expression during the chronic phases of persistent inflammation caused by hind-paw administration of complete Freunds adjuvant (CFA) in mice. Whole-cell patch clamp recordings revealed that Gentiopicroside significantly reduced NR2B receptors mediated postsynaptic currents in the ACC. Our findings provide strong evidence that analgesic effects of Gentiopicroside involve down-regulation of NR2B receptors in the ACC to persistent inflammatory pain.

Associations of Musculoskeletal Pain With Mobility in Older Adults: Potential Cerebral Mechanisms.

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Cruz-Almeida, Yenisel; Rosso, Andrea; Marcum, Zachary; Harris, Tamara; Newman, Anne B; Nevitt, Michael; Satterfield, Suzanne; Yaffe, Kristine; Rosano, Caterina

2017-09-01

Musculoskeletal pain is highly prevalent and limits mobility in older adults. A potential mechanism by which pain affects mobility could be through its negative impact on the brain. We examined whether structural integrity of cerebral gray and white matter (WM) mediated the relationship between pain and mobility in community-dwelling older adults. Musculoskeletal pain, gait speed, and neuroimaging data were obtained concurrently from the Health ABC study (mean age = 83/56% female, n = 212). Microstructural gray matter integrity was measured by mean diffusivity (MD), WM microstructure and macrostructure were measured by fractional anisotropy (FA) and WM hyperintensities (WMH), respectively. Regression models were adjusted for gray matter atrophy, age, gender, medication use, and obesity. Bootstrapped mediation methods were used (1,000 bootstrapped samples, 95% confidence intervals). The associations of musculoskeletal pain with WMH (β = .19, p mobility, although pre-existing WM integrity may also simultaneously amplify pain and decrease mobility. Future studies are needed to further understand whether successful pain management may significantly improve both brain health and mobility. © The Author 2017. Published by Oxford University Press on behalf of The Gerontological Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

Immediate changes in widespread pressure pain sensitivity, neck pain, and cervical range of motion after cervical or thoracic thrust manipulation in patients with bilateral chronic mechanical neck pain: a randomized clinical trial.

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Martínez-Segura, Raquel; De-la-Llave-Rincón, Ana I; Ortega-Santiago, Ricardo; Cleland, Joshua A; Fernández-de-Las-Peñas, César

2012-09-01

Randomized clinical trial. To compare the effects of cervical versus thoracic thrust manipulation in patients with bilateral chronic mechanical neck pain on pressure pain sensitivity, neck pain, and cervical range of motion (CROM). Evidence suggests that spinal interventions can stimulate descending inhibitory pain pathways. To our knowledge, no study has investigated the neurophysiological effects of thoracic thrust manipulation in individuals with bilateral chronic mechanical neck pain, including widespread changes on pressure sensitivity. Ninety patients (51% female) were randomly assigned to 1 of 3 groups: cervical thrust manipulation on the right, cervical thrust manipulation on the left, or thoracic thrust manipulation. Pressure pain thresholds (PPTs) over the C5-6 zygapophyseal joint, lateral epicondyle, and tibialis anterior muscle, neck pain (11-point numeric pain rating scale), and cervical spine range of motion (CROM) were collected at baseline and 10 minutes after the intervention by an assessor blinded to the treatment allocation of the patients. Mixed-model analyses of covariance were used to examine the effects of the treatment on each outcome variable, with group as the between-subjects variable, time and side as the within-subject variables, and gender as the covariate. The primary analysis was the group-by-time interaction. No significant interactions were found with the mixed-model analyses of covariance for PPT level (C5-6, P>.210; lateral epicondyle, P>.186; tibialis anterior muscle, P>.268), neck pain intensity (P = .923), or CROM (flexion, P = .700; extension, P = .387; lateral flexion, P>.672; rotation, P>.192) as dependent variables. All groups exhibited similar changes in PPT, neck pain, and CROM (all, P.10). The results of the current randomized clinical trial suggest that cervical and thoracic thrust manipulation induce similar changes in PPT, neck pain intensity, and CROM in individuals with bilateral chronic mechanical neck pain

Chronic Pain and Mental Health Disorders: Shared Neural Mechanisms, Epidemiology, and Treatment.

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Hooten, W Michael

2016-07-01

Chronic pain and mental health disorders are common in the general population, and epidemiological studies suggest that a bidirectional relationship exists between these 2 conditions. The observations from functional imaging studies suggest that this bidirectional relationship is due in part to shared neural mechanisms. In addition to depression, anxiety, and substance use disorders, individuals with chronic pain are at risk of other mental health problems including suicide and cigarette smoking and many have sustained sexual violence. Within the broader biopsychosocial model of pain, the fear-avoidance model explains how behavioral factors affect the temporal course of chronic pain and provides the framework for an array of efficacious behavioral interventions including cognitive-behavioral therapy, acceptance-based therapies, and multidisciplinary pain rehabilitation. Concomitant pain and mental health disorders often complicate pharmacological management, but several drug classes, including serotonin-norepinephrine reuptake inhibitors, tricyclic antidepressants, and anticonvulsants, have efficacy for both conditions and should be considered first-line treatment agents. Copyright © 2016 Mayo Foundation for Medical Education and Research. Published by Elsevier Inc. All rights reserved.

FMRP acts as a key messenger for dopamine modulation in the forebrain.

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Wang, Hansen; Wu, Long-Jun; Kim, Susan S; Lee, Frank J S; Gong, Bo; Toyoda, Hiroki; Ren, Ming; Shang, Yu-Ze; Xu, Hui; Liu, Fang; Zhao, Ming-Gao; Zhuo, Min

2008-08-28

The fragile X mental retardation protein (FMRP) is an RNA-binding protein that controls translational efficiency and regulates synaptic plasticity. Here, we report that FMRP is involved in dopamine (DA) modulation of synaptic potentiation. AMPA glutamate receptor subtype 1 (GluR1) surface expression and phosphorylation in response to D1 receptor stimulation were reduced in cultured Fmr1(-/-) prefrontal cortex (PFC) neurons. Furthermore, D1 receptor signaling was impaired, accompanied by D1 receptor hyperphosphorylation at serine sites and subcellular redistribution of G protein-coupled receptor kinase 2 (GRK2) in both PFC and striatum of Fmr1(-/-) mice. FMRP interacted with GRK2, and pharmacological inhibition of GRK2 rescued D1 receptor signaling in Fmr1(-/-) neurons. Finally, D1 receptor agonist partially rescued hyperactivity and enhanced the motor function of Fmr1(-/-) mice. Our study has identified FMRP as a key messenger for DA modulation in the forebrain and may provide insights into the cellular and molecular mechanisms underlying fragile X syndrome.

Peripheral Mechanisms of Dental Pain: The Role of Substance P

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Paola Sacerdote

2012-01-01

Full Text Available Current evidence supports the central role of neuropeptides in the molecular mechanisms underlying dental pain. In particular, substance P, a neuropeptide produced in neuron cell bodies localised in dorsal root and trigeminal ganglia, contributes to the transmission and maintenance of noxious stimuli and inflammatory processes. The major role of substance P in the onset of dental pain and inflammation is increasingly being recognised. Well-grounded experimental and clinical observations have documented an increase in substance P concentration in patients affected by caries, pulpitis, or granulomas and in those undergoing standard orthodontic or orthodontic/dental care procedures. This paper focuses on the role of substance P in the induction and maintenance of inflammation and dental pain, in order to define future lines of research for the evaluation of therapeutic strategies aimed at modulating the complex effects of this mediator in oral tissues.

Selective spider toxins reveal a role for Nav1.1 channel in mechanical pain

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Osteen, Jeremiah D.; Herzig, Volker; Gilchrist, John; Emrick, Joshua J.; Zhang, Chuchu; Wang, Xidao; Castro, Joel; Garcia-Caraballo, Sonia; Grundy, Luke; Rychkov, Grigori Y.; Weyer, Andy D.; Dekan, Zoltan; Undheim, Eivind A. B.; Alewood, Paul; Stucky, Cheryl L.

2016-01-01

Voltage-gated sodium (Nav) channels initiate action potentials in most neurons, including primary afferent nerve fibers of the pain pathway. Local anesthetics block pain through non-specific actions at all Nav channels, but the discovery of selective modulators would facilitate the analysis of individual subtypes and their contributions to chemical, mechanical, or thermal pain. Here, we identify and characterize spider toxins that selectively activate the Nav1.1 subtype, whose role in nocicep...

Mechanisms of the placebo response in pain in osteoarthritis.

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Abhishek, A; Doherty, M

2013-09-01

Administration of a placebo associates with symptomatic improvement in many conditions--the so-called placebo response. In this review we explain the concept of placebo response, examine the data that supports existence in osteoarthritis (OA), and discuss its possible mechanisms and determinants. A Pubmed literature search was carried out. Key articles were identified, and their findings discussed in a narrative review. Pain, stiffness, self-reported function and physician-global assessment in OA clearly improve in response to placebo. However, more objective measures such as quadriceps strength and radiographic progression appear less responsive. Although not directly studied in OA, contextual effects, patient expectation and conditioning are believed to be the main mechanisms. Neurotransmitter changes that mediate placebo-induced analgesia include increased endogenous opioid levels, increased dopamine levels, and reduced levels of cholecystokinin. Almost all parts of the brain involved in pain processing are influenced during placebo-induced analgesia. Determinants of the magnitude of placebo response include the patient-practitioner interaction, treatment response expectancy, knowledge of being treated, patient personality traits and placebo specific factors such as the route and frequency of administration, branding, and treatment costs. Clearer understanding of the neurobiology of placebo response validates its existence as a real phenomenon. Although routine administration of placebo for symptomatic improvement is difficult to justify, contextual factors that enhance treatment response should be employed in the management of chronic painful conditions such as OA where available treatments have only modest efficacy. Copyright © 2013 Osteoarthritis Research Society International. Published by Elsevier Ltd. All rights reserved.

The influence of a series of five dry cupping treatments on pain and mechanical thresholds in patients with chronic non-specific neck pain - a randomised controlled pilot study

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2011-01-01

Background In this preliminary trial we investigated the effects of dry cupping, an ancient method for treating pain syndromes, on patients with chronic non-specific neck pain. Sensory mechanical thresholds and the participants' self-reported outcome measures of pain and quality of life were evaluated. Methods Fifty patients (50.5 ± 11.9 years) were randomised to a treatment group (TG) or a waiting-list control group (WL). Patients in the TG received a series of 5 cupping treatments over a period of 2 weeks; the control group did not. Self-reported outcome measures before and after the cupping series included the following: Pain at rest (PR) and maximal pain related to movement (PM) on a 100-mm visual analogue scale (VAS), pain diary (PD) data on a 0-10 numeric rating scale (NRS), Neck Disability Index (NDI), and health-related quality of life (SF-36). In addition, the mechanical-detection thresholds (MDT), vibration-detection thresholds (VDT), and pressure-pain thresholds (PPT) were determined at pain-related and control areas. Results Patients of the TG had significantly less pain after cupping therapy than patients of the WL group (PR: Δ-22.5 mm, p = 0.00002; PM: Δ-17.8 mm, p = 0.01). Pain diaries (PD) revealed that neck pain decreased gradually in the TG patients and that pain reported by the two groups differed significantly after the fifth cupping session (Δ-1.1, p = 0.001). There were also significant differences in the SF-36 subscales for bodily pain (Δ13.8, p = 0.006) and vitality (Δ10.2, p = 0.006). Group differences in PPT were significant at pain-related and control areas (all p cupping treatments appeared to be effective in relieving chronic non-specific neck pain. Not only subjective measures improved, but also mechanical pain sensitivity differed significantly between the two groups, suggesting that cupping has an influence on functional pain processing. Trial registration The trial was registered at clinicaltrials.gov (NCT01289964). PMID

The influence of a series of five dry cupping treatments on pain and mechanical thresholds in patients with chronic non-specific neck pain - a randomised controlled pilot study

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Dobos Gustav J

2011-08-01

Full Text Available Abstract Background In this preliminary trial we investigated the effects of dry cupping, an ancient method for treating pain syndromes, on patients with chronic non-specific neck pain. Sensory mechanical thresholds and the participants' self-reported outcome measures of pain and quality of life were evaluated. Methods Fifty patients (50.5 ± 11.9 years were randomised to a treatment group (TG or a waiting-list control group (WL. Patients in the TG received a series of 5 cupping treatments over a period of 2 weeks; the control group did not. Self-reported outcome measures before and after the cupping series included the following: Pain at rest (PR and maximal pain related to movement (PM on a 100-mm visual analogue scale (VAS, pain diary (PD data on a 0-10 numeric rating scale (NRS, Neck Disability Index (NDI, and health-related quality of life (SF-36. In addition, the mechanical-detection thresholds (MDT, vibration-detection thresholds (VDT, and pressure-pain thresholds (PPT were determined at pain-related and control areas. Results Patients of the TG had significantly less pain after cupping therapy than patients of the WL group (PR: Δ-22.5 mm, p = 0.00002; PM: Δ-17.8 mm, p = 0.01. Pain diaries (PD revealed that neck pain decreased gradually in the TG patients and that pain reported by the two groups differed significantly after the fifth cupping session (Δ-1.1, p = 0.001. There were also significant differences in the SF-36 subscales for bodily pain (Δ13.8, p = 0.006 and vitality (Δ10.2, p = 0.006. Group differences in PPT were significant at pain-related and control areas (all p Conclusions A series of five dry cupping treatments appeared to be effective in relieving chronic non-specific neck pain. Not only subjective measures improved, but also mechanical pain sensitivity differed significantly between the two groups, suggesting that cupping has an influence on functional pain processing. Trial registration The trial was registered at

The influence of a series of five dry cupping treatments on pain and mechanical thresholds in patients with chronic non-specific neck pain--a randomised controlled pilot study.

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Lauche, Romy; Cramer, Holger; Choi, Kyung-Eun; Rampp, Thomas; Saha, Felix Joyonto; Dobos, Gustav J; Musial, Frauke

2011-08-15

In this preliminary trial we investigated the effects of dry cupping, an ancient method for treating pain syndromes, on patients with chronic non-specific neck pain. Sensory mechanical thresholds and the participants' self-reported outcome measures of pain and quality of life were evaluated. Fifty patients (50.5 ± 11.9 years) were randomised to a treatment group (TG) or a waiting-list control group (WL). Patients in the TG received a series of 5 cupping treatments over a period of 2 weeks; the control group did not. Self-reported outcome measures before and after the cupping series included the following: Pain at rest (PR) and maximal pain related to movement (PM) on a 100-mm visual analogue scale (VAS), pain diary (PD) data on a 0-10 numeric rating scale (NRS), Neck Disability Index (NDI), and health-related quality of life (SF-36). In addition, the mechanical-detection thresholds (MDT), vibration-detection thresholds (VDT), and pressure-pain thresholds (PPT) were determined at pain-related and control areas. Patients of the TG had significantly less pain after cupping therapy than patients of the WL group (PR: Δ-22.5 mm, p = 0.00002; PM: Δ-17.8 mm, p = 0.01). Pain diaries (PD) revealed that neck pain decreased gradually in the TG patients and that pain reported by the two groups differed significantly after the fifth cupping session (Δ-1.1, p = 0.001). There were also significant differences in the SF-36 subscales for bodily pain (Δ13.8, p = 0.006) and vitality (Δ10.2, p = 0.006). Group differences in PPT were significant at pain-related and control areas (all p cupping treatments appeared to be effective in relieving chronic non-specific neck pain. Not only subjective measures improved, but also mechanical pain sensitivity differed significantly between the two groups, suggesting that cupping has an influence on functional pain processing. The trial was registered at clinicaltrials.gov (NCT01289964).

Effectiveness of the Pilates Method in the Treatment of Chronic Mechanical Neck Pain: A Randomized Controlled Trial.

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de Araujo Cazotti, Luciana; Jones, Anamaria; Roger-Silva, Diego; Ribeiro, Luiza Helena Coutinho; Natour, Jamil

2018-05-09

To assess the effectiveness of the Pilates method on pain, function, quality of life, and consumption of pain medication in patients with mechanical neck pain. The design was a randomized controlled trial, with a blinded assessor and intention-to-treat analysis. The study took place in the outpatient clinic of the rheumatology department, referral center. Sixty-four patients with chronic mechanical neck pain were randomly allocated into 2 groups: the Pilates group (PG) and control group (CG). The PG attended 2 sessions of Pilates per week, for 12 weeks. The protocol included Pilates exercises performed on a mat and on equipment and was adapted depending on the physical fitness of each participant; the repetitions varied from 6 to 12, respecting patient reports of fatigue and pain, using a single series for each exercise. The CG received only the standard pharmacological treatment. Both groups were instructed to use acetaminophen 750 mg if necessary. Patients were evaluated at baseline after 45, 90, and 180 days. We used the numerical pain scale (NPS) for pain; the neck disability index (NDI) for function, and the SF-36 questionnaire for quality of life. The groups were homogeneous at baseline, the only exception being body mass index (BMI), with the PG showing higher BMI. Regarding the assessment between groups over time (ANOVA), statistical differences were identified for pain (p Pilates method for the treatment of chronic mechanical neck pain, resulting in improvement of pain, function, quality of life, and reduction of the use of analgesics. Copyright © 2018. Published by Elsevier Inc.

Central representation of muscle pain and mechanical hyperesthesia in the orofacial region: a positron emission tomography study

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Kupers, Rron; Svensson, Peter; Jensen, Troels Staehlin

2004-01-01

Functional neuroimaging studies of the human brain have revealed a network of brain regions involved in the processing of nociceptive information. However, little is known of the cerebral processing of pain originating from muscles. The aim of this study was to investigate the cerebral activation...... pattern evoked by experimental jaw-muscle pain and its interference by simultaneous mechanical stimuli, which has been shown to evoke hyperesthesia. Ten healthy subjects participated in a PET study and jaw-muscle pain was induced by bolus injections of 5% hypertonic saline into the right masseter muscle....... Repeated von Frey hair stimulation (0.5 Hz) of the skin above the masseter muscle was used as the mechanical stimulus. Hypertonic saline injections caused strong muscle pain spreading to adjacent areas. von Frey stimulation was rated as non-painful but produced hyperesthesia during jaw-muscle pain. Jaw...

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

Forebrain development in fetal MRI: evaluation of anatomical landmarks before gestational week 27

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Schmook, Maria T.; Weber, Michael; Kasprian, Gregor; Nemec, Stefan; Prayer, Daniela; Brugger, Peter C.; Krampl-Bettelheim, Elisabeth

2010-01-01

Forebrain malformations include some of the most severe developmental anomalies and require early diagnosis. The proof of normal or abnormal prosencephalic development may have an influence on further management in the event of a suspected fetal malformation. The purpose of this retrospective study was to evaluate the detectability of anatomical landmarks of forebrain development using in vivo fetal magnetic resonance imaging (MRI) before gestational week (gw) 27. MRI studies of 83 singleton fetuses (gw 16-26, average ±sd: gw 22 ± 2) performed at 1.5 Tesla were assessed. T2-weighted (w) fast spin echo, T1w gradient-echo and diffusion-weighted sequences were screened for the detectability of anatomical landmarks as listed below. The interhemispheric fissure, ocular bulbs, corpus callosum, infundibulum, chiasm, septum pellucidum (SP), profile, and palate were detectable in 95%, 95%, 89%, 87%, 82%, 81%, 78%, 78% of cases. Olfactory tracts were more easily delineated than bulbs and sulci (37% versus 18% and 8%), with significantly higher detection rates in the coronal plane. The pituitary gland could be detected on T1w images in 60% with an increasing diameter with gestational age (p=0.041). The delineation of olfactory tracts (coronal plane), chiasm, SP and pituitary gland were significantly increased after week 21 (p<0.05). Pathologies were found in 28% of cases. This study provides detection rates for anatomical landmarks of forebrain development with fetal MRI before gw 27. Several anatomical structures are readily detectable with routine fetal MRI sequences; thus, if these landmarks are not delineable, it should raise the suspicion of a pathology. Recommendations regarding favorable sequences/planes are provided. (orig.)

Forebrain development in fetal MRI: evaluation of anatomical landmarks before gestational week 27

Energy Technology Data Exchange (ETDEWEB)

Schmook, Maria T.; Weber, Michael; Kasprian, Gregor; Nemec, Stefan; Prayer, Daniela [Medical University of Vienna, Department of Radiology/Division of Neuro- and Musculoskeletal Radiology, Vienna (Austria); Brugger, Peter C. [Medical University of Vienna, Integrative Morphology Group, Center for Anatomy and Cell Biology, Vienna (Austria); Krampl-Bettelheim, Elisabeth [Department of Obstetrics and Gynecology / Division of Obstetrics and Feto-maternal Medicine, Vienna (Austria)

2010-06-15

Forebrain malformations include some of the most severe developmental anomalies and require early diagnosis. The proof of normal or abnormal prosencephalic development may have an influence on further management in the event of a suspected fetal malformation. The purpose of this retrospective study was to evaluate the detectability of anatomical landmarks of forebrain development using in vivo fetal magnetic resonance imaging (MRI) before gestational week (gw) 27. MRI studies of 83 singleton fetuses (gw 16-26, average {+-}sd: gw 22 {+-} 2) performed at 1.5 Tesla were assessed. T2-weighted (w) fast spin echo, T1w gradient-echo and diffusion-weighted sequences were screened for the detectability of anatomical landmarks as listed below. The interhemispheric fissure, ocular bulbs, corpus callosum, infundibulum, chiasm, septum pellucidum (SP), profile, and palate were detectable in 95%, 95%, 89%, 87%, 82%, 81%, 78%, 78% of cases. Olfactory tracts were more easily delineated than bulbs and sulci (37% versus 18% and 8%), with significantly higher detection rates in the coronal plane. The pituitary gland could be detected on T1w images in 60% with an increasing diameter with gestational age (p=0.041). The delineation of olfactory tracts (coronal plane), chiasm, SP and pituitary gland were significantly increased after week 21 (p<0.05). Pathologies were found in 28% of cases. This study provides detection rates for anatomical landmarks of forebrain development with fetal MRI before gw 27. Several anatomical structures are readily detectable with routine fetal MRI sequences; thus, if these landmarks are not delineable, it should raise the suspicion of a pathology. Recommendations regarding favorable sequences/planes are provided. (orig.)

Delineating inflammatory and mechanical sub-types of low back pain: a pilot survey of fifty low back pain patients in a chiropractic setting

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Riksman Janine S

2011-02-01

Full Text Available Abstract Background An instrument known as the Mechanical and Inflammatory Low Back Pain (MAIL Scale was drafted using the results of a previous expert opinion study. A pilot survey was conducted to test the feasibility of a larger study designed to determine the MAIL Scale's ability to distinguish two potential subgroups of low back pain: inflammatory and mechanical. Methods Patients with a primary complaint of low back pain (LBP presenting to chiropractic clinics in Perth, Western Australia were asked to fill out the MAIL Scale questionnaire. The instrument's ability to separate patients into inflammatory and mechanical subgroups of LBP was examined using the mean score of each notional subgroup as an arbitrary cut-off point. Results Data were collected from 50 patients. The MAIL Scale did not appear to separate cases of LBP into the two notionally distinct groups of inflammatory (n = 6 or mechanical (n = 5. A larger "mixed symptom" group (n = 39 was revealed. Conclusions In this pilot study the MAIL Scale was unable to clearly discriminate between what is thought to be mechanical and inflammatory LBP in 50 cases seen in a chiropractic setting. However, the small sample size means any conclusions must be viewed with caution. Further research within a larger study population may be warranted and feasible.

The stress response to surgery: release mechanisms and the modifying effect of pain relief

DEFF Research Database (Denmark)

Kehlet, H

1989-01-01

This short review updates information on the release mechanisms of the systemic response to surgical injury and the modifying effect of pain relief. Initiation of the response is primarily due to afferent nerve impulses combined with release of humoral substances (such as prostaglandins, kinins...... in releasing the classical endocrine catabolic response, while humoral factors are important for the hyperthermic response, changes in coagulation and fibrinolysis immunofunction, and capillary permeability. The modifying effect of pain relief on the surgical stress response is dependent upon the technique...... on the stress response. In summary, pain alleviation itself may not necessarily lead to an important modification of the stress response, and a combined approach with inhibition of the neural and humoral release mechanisms is necessary for a pronounced inhibition or prevention of the response to surgical injury....

Contribution of Pro-Inflammatory Cytokine Signaling within Midbrain Periaqueductal Gray to Pain Sensitivity in Parkinson's disease via GABAergic Pathway

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Xianbo Zhuang

2016-07-01

Full Text Available Background/Aims: Hypersensitive pain response is often observed in patients with Parkinson's disease (PD; however, the mechanisms responsible for hyperalgesia are not well understood. Chronic neuroinflammation is one of the hallmarks of PD pathophysiology. Since the midbrain periaqueductal gray (PAG is an important component of the descending inhibitory pathway controlling on central pain transmission, we examined the role for pro-inflammatory cytokines (PICs system of PAG in regulating exaggerated pain evoked by PD. Methods: We used a rat model of PD to perform the experimental protocols. PD was induced by microinjection of 6-hydroxydopamine to lesion the left medial forebrain bundle. Pain responses to mechanical and thermal stimulation were first examined in control rats and PD rats. Then, ELISA and Western Blot analysis were used to determine PIC levels and their receptors expression. Results: Protein expression of IL-1β, IL-6 and TNF-α receptors (namely, IL-1R, IL-6R and TNFR subtype TNFR1 in the plasma membrane PAG of PD rats was upregulated, whereas the total expression of PIC receptors was not significantly altered. The ratio of membrane protein and total protein (IL-1R, IL-6R and TNFR1 was 1.48±0.15, 1.59±0.18 and 1.67±0.16 in PAG of PD rats (P < 0.05 vs. their respective controls. This was accompanied with increases of PICs of PAG, and decreases of GABA (623±21 ng/mg in control rats and 418±18 ng/mg in PD rats; P < 0.05 vs. control rats and withdrawal thresholds to mechanical and thermal stimuli. Our data further showed that the concentrations of GABA and withdrawal thresholds were largely restored by blocking those PIC receptors in PAG of PD rats. Stimulation of GABA receptors in PAG of PD rats also blunted a decrease in withdrawal thresholds. Conclusions: Our data suggest that upregulation of the membrane PIC receptor in the PAG of PD rats is likely to impair the descending inhibitory pathways in regulating pain transmission

Extensive Lesions of Cholinergic Basal Forebrain Neurons Do Not Impair Spatial Working Memory

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Vuckovich, Joseph A.; Semel, Mara E.; Baxter, Mark G.

2004-01-01

A recent study suggests that lesions to all major areas of the cholinergic basal forebrain in the rat (medial septum, horizontal limb of the diagonal band of Broca, and nucleus basalis magnocellularis) impair a spatial working memory task. However, this experiment used a surgical technique that may have damaged cerebellar Purkinje cells. The…

Determining Brain Mechanisms that Underpin Analgesia Induced by the Use of Pain Coping Skills.

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Cole, Leonie J; Bennell, Kim L; Ahamed, Yasmin; Bryant, Christina; Keefe, Francis; Moseley, G Lorimer; Hodges, Paul; Farrell, Michael J

2018-02-16

Cognitive behavioral therapies decrease pain and improve mood and function in people with osteoarthritis. This study assessed the effects of coping strategies on the central processing of knee pain in people with osteoarthritis of the knees. Mechanical pressure was applied to exacerbate knee pain in 28 people with osteoarthritis of the knee. Reports of pain intensity and functional magnetic resonance imaging measures of pain-related brain activity were recorded with and without the concurrent use of pain coping skills. Coping skills led to a significant reduction in pain report (Coping = 2.64 ± 0.17, Not Coping = 3.28 ± 0.15, P strategies were associated with increased activation in pain modulatory regions of the brain (medial prefrontal and rostral anterior cingulate cortices, Pcorrected strategies was found to be proportional to the decrease in pain-related activation in brain regions that code the aversive/emotional dimension of pain (anterior insula, inferior frontal gyrus, orbitofrontal cortex, Pcorrected skills. However, training in coping skills reduced the extent to which brain responses to noxious input were influenced by anxiety. The results of this study support previous reports of pain modulation by cognitive pain coping strategies and contribute to the current understanding of how analgesia associated with the use of pain coping strategies is represented in the brain.

Spinal astrocytic activation contributes to mechanical allodynia in a rat chemotherapy-induced neuropathic pain model.

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Xi-Tuan Ji

Full Text Available Chemotherapy-induced neuropathic pain (CNP is the major dose-limiting factor in cancer chemotherapy. However, the neural mechanisms underlying CNP remain enigmatic. Accumulating evidence implicates the involvement of spinal glia in some neuropathic pain models. In this study, using a vincristine-evoked CNP rat model with obvious mechanical allodynia, we found that spinal astrocyte rather than microglia was dramatically activated. The mechanical allodynia was dose-dependently attenuated by intrathecal administratration of L-α-aminoadipate (astrocytic specific inhibitor; whereas minocycline (microglial specific inhibitor had no such effect, indicating that spinal astrocytic activation contributes to allodynia in CNP rat. Furthermore, oxidative stress mediated the development of spinal astrocytic activation, and activated astrocytes dramatically increased interleukin-1β expression which induced N-methyl-D-aspartic acid receptor (NMDAR phosphorylation in spinal neurons to strengthen pain transmission. Taken together, our findings suggest that spinal activated astrocytes may be a crucial component of the pathophysiology of CNP and "Astrocyte-Cytokine-NMDAR-neuron" pathway may be one detailed neural mechanisms underlying CNP. Thus, inhibiting spinal astrocytic activation may represent a novel therapeutic strategy for treating CNP.

Silencing of FKBP51 alleviates the mechanical pain threshold, inhibits DRG inflammatory factors and pain mediators through the NF-kappaB signaling pathway.

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Yu, Hong-Mei; Wang, Qi; Sun, Wen-Bo

2017-09-05

Neuropathic pain is chronic pain caused by lesions or diseases of the somatosensory system, currently available analgesics provide only temporal relief. The precise role of FK506 binding protein 51 (FKBP51) in neuropathic pain induced by chronic constriction injury (CCI) is not clear. The purpose of the present study was to investigate the effects and possible mechanisms of FKBP51 in neuropathic pain in the rat model of CCI. Our results showed that FKBP51 was obviously upregulated in a time-dependent manner in the dorsal root ganglion (DRG) of CCI rats. Additionally, silencing of FKBP51 remarkably attenuated mechanical allodynia and thermal hyperalgesia as reflected by paw withdrawal threshold (PWT) and paw withdrawal latency (PWL) in CCI rats. Moreover, knockdown of FKBP51 reduced the production of pro-inflammatory cytokines (TNF-α, IL-1β and IL-6), nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF) expression in the DRG of CCI rats. Furthermore, we revealed that inhibition of FKBP51 greatly suppressed the activation of the NF-kappaB (NF-κB) signaling in the DRG of CCI rats. Interestingly, similar to the FKBP51 siRNA (si-FKBP51), ammonium pyrrolidinedithiocarbamate (PDTC, an inhibitor of NF-κB) also alleviated neuropathic pain and neuro-inflammation, indicating that knockdown of FKBP51 alleviated neuropathic pain development of CCI rats by inhibiting the activation of NF-κB signaling pathway. Taken together, our findings indicate that FKBP51 may serve as a novel therapeutic target for neuropathic pain. Copyright © 2017. Published by Elsevier B.V.

Effectiveness of a new cervical pillow on pain and sleep quality in recreational athletes with chronic mechanical neck pain: a preliminary comparative study.

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DI Cagno, Alessandra; Minganti, Carlo; Quaranta, Federico; Pistone, Eugenio M; Fagnani, Federica; Fiorilli, Giovanni; Giombini, Arrigo

2017-09-01

The aim of this intervention study was to determine the effects of a new experimental cervical pillow, on symptomatic adults affected by chronic mechanical neck pain. Twelve recreational athletes of both sexes (mean age 40.5 years; range 35-55), affected by grade II chronic mechanical neck pain, were evaluated with a daily diary type of self-report questionnaire, which incorporated an 11-point Numerical Rating Pain Scale, to collect the primary outcome measures of pre- and post-sleep neck pain and with the Neck Pain Disability Scale. Tympanic temperature, heart rate (HR) variability continuous monitoring during sleep, overnight pillow comfort and sleep quality were assessed. Average weekly scores in overall questionnaires, tympanic temperature and the HR low frequency (LF) / high frequency (HF) ratio were significantly lower (Ppain, improving LF/HF ratio and enhancing-vagal activity, promoting deeper stages during the sleep. The shape of this pillow maintains an appropriate cervical curvature, reduces intra-disc pressure allowing a better distribution of loads between cervical discs. The round shaped portion of the pillow, facilitates breathing and avoids the narrowing of the airway due to the incorrect position during the sleep. The peculiar material of the DM2 pillow, contributed to lower brain temperature promoting dry heat loss from the head to the pillow, reducing sweating.

Mechanisms Underlying the Analgesic Effect of Moxibustion on Visceral Pain in Irritable Bowel Syndrome: A Review

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Renjia Huang

2014-01-01

Full Text Available Irritable bowel syndrome (IBS is a functional bowel disorder that causes recurrent abdominal (visceral pain. Epidemiological data show that the incidence rate of IBS is as high as 25%. Most of the medications may lead to tolerance, addiction and toxic side effects. Moxibustion is an important component of traditional Chinese medicine and has been used to treat IBS-like abdominal pain for several thousand years in China. As a mild treatment, moxibustion has been widely applied in clinical treatment of visceral pain in IBS. In recent years, it has played an irreplaceable role in alternative medicine. Extensive clinical studies have demonstrated that moxibustion for treatment of visceral pain is simple, convenient, and inexpensive, and it is being accepted by an increasing number of patients. There have not been many studies investigating the analgesic mechanisms of moxibustion. Studies exploring the analgesic mechanisms have mainly focused on visceral hypersensitivity, brain-gut axis neuroendocrine system, and immune system. This paper reviews the latest developments in moxibustion use for treatment of visceral pain in IBS from these perspectives. It also evaluates potential problems in relevant studies on the mechanisms of moxibustion therapy to promote the application of moxibustion in the treatment of IBS.

Dynamic gene and protein expression patterns of the autism-associated met receptor tyrosine kinase in the developing mouse forebrain.

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Judson, Matthew C; Bergman, Mica Y; Campbell, Daniel B; Eagleson, Kathie L; Levitt, Pat

2009-04-10

The establishment of appropriate neural circuitry depends on the coordination of multiple developmental events across space and time. These events include proliferation, migration, differentiation, and survival-all of which can be mediated by hepatocyte growth factor (HGF) signaling through the Met receptor tyrosine kinase. We previously found a functional promoter variant of the MET gene to be associated with autism spectrum disorder, suggesting that forebrain circuits governing social and emotional function may be especially vulnerable to developmental disruptions in HGF/Met signaling. However, little is known about the spatiotemporal distribution of Met expression in the forebrain during the development of such circuits. To advance our understanding of the neurodevelopmental influences of Met activation, we employed complementary Western blotting, in situ hybridization, and immunohistochemistry to comprehensively map Met transcript and protein expression throughout perinatal and postnatal development of the mouse forebrain. Our studies reveal complex and dynamic spatiotemporal patterns of expression during this period. Spatially, Met transcript is localized primarily to specific populations of projection neurons within the neocortex and in structures of the limbic system, including the amygdala, hippocampus, and septum. Met protein appears to be principally located in axon tracts. Temporally, peak expression of transcript and protein occurs during the second postnatal week. This period is characterized by extensive neurite outgrowth and synaptogenesis, supporting a role for the receptor in these processes. Collectively, these data suggest that Met signaling may be necessary for the appropriate wiring of forebrain circuits, with particular relevance to the social and emotional dimensions of behavior. (c) 2009 Wiley-Liss, Inc.

Overlapping mechanisms of stress-induced relapse to opioid use disorder and chronic pain: Clinical implications

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Udi E Ghitza

2016-05-01

Full Text Available Over the past two decades, a steeply growing number of persons with chronic non-cancer pain have been using opioid analgesics chronically to treat it, accompanied by a markedly increased prevalence of individuals with opioid-related misuse, opioid use disorders, emergency department visits, hospitalizations, admissions to drug treatment programs, and drug overdose deaths. This opioid misuse and overdose epidemic calls for well-designed randomized-controlled clinical trials into more skillful and appropriate pain management and for developing effective analgesics which have lower abuse liability and are protective against stress induced by chronic non-cancer pain. However, incomplete knowledge regarding effective approaches to treat various types of pain has been worsened by an under-appreciation of overlapping neurobiological mechanisms of stress, stress-induced relapse to opioid use, and chronic non-cancer pain in patients presenting for care for these conditions. This insufficient knowledge base has unfortunately encouraged common prescription of conveniently-available opioid pain-relieving drugs with abuse liability, as opposed to treating underlying problems using team-based multidisciplinary, patient-centered, collaborative-care approaches for addressing pain and co-occurring stress and risk for opioid use disorder. This paper reviews recent neurobiological findings regarding overlapping mechanisms of stress-induced relapse to opioid misuse and chronic non-cancer pain, and then discusses these in the context of key outstanding evidence gaps and clinical-treatment research directions which may be pursued to fill these gaps. Such research directions, if conducted through well-designed randomized controlled trials, may substantively inform clinical practice in general medical settings on how to effectively care for patients presenting with pain-related distress and these common co-occurring conditions.

Psychometric validation of the behavioral indicators of pain scale for the assessment of pain in mechanically ventilated and unable to self-report critical care patients.

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Latorre-Marco, I; Acevedo-Nuevo, M; Solís-Muñoz, M; Hernández-Sánchez, L; López-López, C; Sánchez-Sánchez, M M; Wojtysiak-Wojcicka, M; de Las Pozas-Abril, J; Robleda-Font, G; Frade-Mera, M J; De Blas-García, R; Górgolas-Ortiz, C; De la Figuera-Bayón, J; Cavia-García, C

2016-11-01

To assess the psychometric properties of the behavioral indicators of pain scale (ESCID) when applied to a wide range of medical and surgical critical patients. A multicentre, prospective observational study was designed to validate a scale measuring instrument. Twenty Intensive Care Units of 14 hospitals belonging to the Spanish National Health System. A total of 286 mechanically ventilated, unable to self-report critically ill medical and surgical adult patients. Pain levels were measured by two independent evaluators simultaneously, using two scales: ESCID and the behavioral pain scale (BPS). Pain was observed before, during, and after two painful procedures (turning, tracheal suctioning) and one non-painful procedure. ESCID reliability was measured on the basis of internal consistency using the Cronbach-α coefficient. Inter-rater and intra-rater agreement were measured. The Spearman correlation coefficient was used to assess the correlation between ESCID and BPS. A total of 4386 observations were made in 286 patients (62% medical and 38% surgical). High correlation was found between ESCID and BPS (r=0.94-0.99; p<0.001), together with high intra-rater and inter-rater concordance. ESCID was internally reliable, with a Cronbach-α value of 0.85 (95%CI 0.81-0.88). Cronbach-α coefficients for ESCID domains were high: facial expression 0.87 (95%CI 0.84-0.89), calmness 0.84 (95%CI 0.81-0.87), muscle tone 0.80 (95%CI 0.75-0.84), compliance with mechanical ventilation 0.70 (95%CI 0.63-0.75) and consolability 0.85 (95%CI 0.81-0.88). ESCID is valid and reliable for measuring pain in mechanically ventilated unable to self-report medical and surgical critical care patients. CLINICALTRIALS.GOV: NCT01744717. Copyright © 2016 The Authors. Publicado por Elsevier España, S.L.U. All rights reserved.

Postoperative pain after manual and mechanical glide path: a randomized clinical trial.

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Pasqualini, Damiano; Mollo, Livio; Scotti, Nicola; Cantatore, Giuseppe; Castellucci, Arnaldo; Migliaretti, Giuseppe; Berutti, Elio

2012-01-01

This prospective randomized clinical trial evaluated the incidence of postoperative pain after glide path performed with PathFile (PF) (Dentsply Maillefer, Ballaigues, Switzerland) versus stainless-steel K-file (KF). In 149 subjects, the mechanical glide path was performed with nickel-titanium (NiTi) rotary PF; in 146 subjects, the manual glide path was performed with stainless-steel KFs. Postoperative pain, analgesics consumption, and the number of days to complete pain resolution were evaluated in the following 7 days. An analysis of variance model for repeated measures was used to compare the variation of pain-scale values (P < .05). The Student's t test for continuous variables normally distributed, the nonparametric Mann-Whitney U test for the nonnormally distributed variables, and the chi-square test for dichotomous variables were used (P < .05). Despite homogeneous baseline conditions at diagnosis, tooth type, pain prevalence, and scores, the postoperative pain prevalence curves in PF group evidenced a more favorable trend in terms of time to pain resolution compared with the KF group (P = .004). The difference was also evident in the model adjusted for analgesics consumption in both groups (P = .012). The mean analgesics intake per subject was significantly higher in the KF group (3.7 ± 2.2) compared with the PF group (2 ± 1.7) (P < .001). Mean pain stop values were also significantly higher in the KF group (2.7) compared with the PF group (1.7) (P = .001). The glide path with NiTi Rotary PF leads to less postoperative pain and faster symptom resolution. Copyright © 2012 American Association of Endodontists. Published by Elsevier Inc. All rights reserved.

[Possible changes in energy-minimizer mechanisms of locomotion due to chronic low back pain - a literature review].

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de Carvalho, Alberito Rodrigo; Andrade, Alexandro; Peyré-Tartaruga, Leonardo Alexandre

2015-01-01

One goal of the locomotion is to move the body in the space at the most economical way possible. However, little is known about the mechanical and energetic aspects of locomotion that are affected by low back pain. And in case of occurring some damage, little is known about how the mechanical and energetic characteristics of the locomotion are manifested in functional activities, especially with respect to the energy-minimizer mechanisms during locomotion. This study aimed: a) to describe the main energy-minimizer mechanisms of locomotion; b) to check if there are signs of damage on the mechanical and energetic characteristics of the locomotion due to chronic low back pain (CLBP) which may endanger the energy-minimizer mechanisms. This study is characterized as a narrative literature review. The main theory that explains the minimization of energy expenditure during the locomotion is the inverted pendulum mechanism, by which the energy-minimizer mechanism converts kinetic energy into potential energy of the center of mass and vice-versa during the step. This mechanism is strongly influenced by spatio-temporal gait (locomotion) parameters such as step length and preferred walking speed, which, in turn, may be severely altered in patients with chronic low back pain. However, much remains to be understood about the effects of chronic low back pain on the individual's ability to practice an economic locomotion, because functional impairment may compromise the mechanical and energetic characteristics of this type of gait, making it more costly. Thus, there are indications that such changes may compromise the functional energy-minimizer mechanisms. Copyright © 2014 Elsevier Editora Ltda. All rights reserved.

Generalized mechanical pain sensitivity over nerve tissues in patients with strictly unilateral migraine.

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Fernández-de-las-Peñas, César; Arendt-Nielsen, Lars; Cuadrado, María Luz; Pareja, Juan A

2009-06-01

No study has previously analyzed pressure pain sensitivity of nerve trunks in migraine. This study aimed to examine the differences in mechanical pain sensitivity over specific nerves between patients with unilateral migraine and healthy controls. Blinded investigators assessed pressure pain thresholds (PPT) over the supra-orbital nerves (V1) and peripheral nerve trunks of both upper extremities (median, radial, and ulnar nerves) in 20 patients with strictly unilateral migraine and 20 healthy matched controls. Pain intensity after palpation over both supra-orbital nerves was also assessed. A pressure algometer was used to quantify PPT, whereas a 10-point numerical pain rate scale was used to evaluate pain to palpation over the supra-orbital nerve. The analysis of covariance revealed that pain to palpation over the supra-orbital nerve was significantly higher (P0.6). In patients with unilateral migraine, we found increased mechano-sensitivity of the supra-orbital nerve on the symptomatic side of the head. Outside the head, the same patients showed increased mechano-sensitivity of the main peripheral nerves of both upper limbs, without asymmetries. Such diffuse hypersensitivity of the peripheral nerves lends further evidence to the presence of a state of hyperexcitability of the central nervous system in patients with unilateral migraine.

Melatonin Alters the Mechanical and Thermal Hyperalgesia Induced by Orofacial Pain Model in Rats.

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Scarabelot, Vanessa Leal; Medeiros, Liciane Fernandes; de Oliveira, Carla; Adachi, Lauren Naomi Spezia; de Macedo, Isabel Cristina; Cioato, Stefania Giotti; de Freitas, Joice S; de Souza, Andressa; Quevedo, Alexandre; Caumo, Wolnei; Torres, Iraci Lucena da Silva

2016-10-01

Melatonin is a neuroendocrine hormone that presents a wide range of physiological functions including regulating circadian rhythms and sleep, enhancing immune function, sleep improvement, and antioxidant effects. In addition, melatonin has received special attention in pain treatment since it is effective and presents few adverse effects. In this study, we evaluated the effect of acute dose of melatonin upon hyperalgesia induced by complete Freund's adjuvant in a chronic orofacial pain model in Sprague-Dawley rats. Nociceptive behavior was assessed by facial Von Frey and the hot plate tests at baseline and thereafter 30, 60, and 120 min, 24 h, and 7 days after melatonin treatment. We demonstrated that acute melatonin administration alters mechanical and thermal hyperalgesia induced by an orofacial pain model (TMD), highlighting that the melatonin effect upon mechanical hyperalgesia remained until 7 days after its administration. Besides, we observed specific tissue profiles of neuroimmunomodulators linked to pain conditions and/or melatonin effect (brain-derived neurotrophic factor, nerve growth factor, and interleukins 6 and 10) in the brainstem levels, and its effects were state-dependent of the baseline of these animals.

Individual Participant Data Meta-Analysis of Mechanical Workplace Risk Factors and Low Back Pain

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Shannon, Harry S.; Wells, Richard P.; Walter, Stephen D.; Cole, Donald C.; Côté, Pierre; Frank, John; Hogg-Johnson, Sheilah; Langlois, Lacey E.

2012-01-01

Objectives. We used individual participant data from multiple studies to conduct a comprehensive meta-analysis of mechanical exposures in the workplace and low back pain. Methods. We conducted a systematic literature search and contacted an author of each study to request their individual participant data. Because outcome definitions and exposure measures were not uniform across studies, we conducted 2 substudies: (1) to identify sets of outcome definitions that could be combined in a meta-analysis and (2) to develop methods to translate mechanical exposure onto a common metric. We used generalized estimating equation regression to analyze the data. Results. The odds ratios (ORs) for posture exposures ranged from 1.1 to 2.0. Force exposure ORs ranged from 1.4 to 2.1. The magnitudes of the ORs differed according to the definition of low back pain, and heterogeneity was associated with both study-level and individual-level characteristics. Conclusions. We found small to moderate ORs for the association of mechanical exposures and low back pain, although the relationships were complex. The presence of individual-level OR modifiers in such an area can be best understood by conducting a meta-analysis of individual participant data. PMID:22390445

VIPER: Chronic Pain after Amputation: Inflammatory Mechanisms, Novel Analgesic Pathways, and Improved Patient Safety

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2016-10-01

Whitney U test for evaluating differences in inflammatory mediators between groups (Case vs. Control) and used nonparametric correlations (Spearman’s rho...responses to acute pain. PAIN 2008;140:135–144. [10] Gordon S, Martinez FO. Alternative activation of macrophages: mechanism and functions...Concentrations in Cases vs. Controls. Mediator Case (n=36) Median (Range) Control (n=40) Median (Range) Mann- Whitney U Test (p value) IFN

Chronic Widespread Back Pain is Distinct From Chronic Local Back Pain: Evidence From Quantitative Sensory Testing, Pain Drawings, and Psychometrics.

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Gerhardt, Andreas; Eich, Wolfgang; Janke, Susanne; Leisner, Sabine; Treede, Rolf-Detlef; Tesarz, Jonas

2016-07-01

Whether chronic localized pain (CLP) and chronic widespread pain (CWP) have different mechanisms or to what extent they overlap in their pathophysiology is controversial. The study compared quantitative sensory testing profiles of nonspecific chronic back pain patients with CLP (n=48) and CWP (n=29) with and fibromyalgia syndrome (FMS) patients (n=90) and pain-free controls (n = 40). The quantitative sensory testing protocol of the "German-Research-Network-on-Neuropathic-Pain" was used to measure evoked pain on the painful area in the lower back and the pain-free hand (thermal and mechanical detection and pain thresholds, vibration threshold, pain sensitivity to sharp and blunt mechanical stimuli). Ongoing pain and psychometrics were captured with pain drawings and questionnaires. CLP patients did not differ from pain-free controls, except for lower pressure pain threshold (PPT) on the back. CWP and FMS patients showed lower heat pain threshold and higher wind-up ratio on the back and lower heat pain threshold and cold pain threshold on the hand. FMS showed lower PPT on back and hand, and higher comorbidity of anxiety and depression and more functional impairment than all other groups. Even after long duration CLP presents with a local hypersensitivity for PPT, suggesting a somatotopically specific sensitization of nociceptive processing. However, CWP patients show widespread ongoing pain and hyperalgesia for different stimuli that is generalized in space, suggesting the involvement of descending control systems, as also suggested for FMS patients. Because mechanisms in nonspecific chronic back pain with CLP and CWP differ, these patients should be distinguished in future research and allocated to different treatments.

Topographic Organization of Cholinergic Innervation From the Basal Forebrain to the Visual Cortex in the Rat

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Frédéric Huppé-Gourgues

2018-03-01

Full Text Available Acetylcholine is an important neurotransmitter for the regulation of visual attention, plasticity, and perceptual learning. It is released in the visual cortex predominantly by cholinergic projections from the basal forebrain, where stimulation may produce potentiation of visual processes. However, little is known about the fine organization of these corticopetal projections, such as whether basal forebrain neurons projecting to the primary and secondary visual cortical areas (V1 and V2, respectively are organized retinotopically. The aim of this study was to map these basal forebrain-V1/V2 projections. Microinjections of the fluorescent retrograde tracer cholera toxin b fragment in different sites within V1 and V2 in Long–Evans rats were performed. Retrogradely labeled cell bodies in the horizontal and vertical limbs of the diagonal band of Broca (HDB and VDB, respectively, nucleus basalis magnocellularis, and substantia innominata (SI, were mapped ex vivo with a computer-assisted microscope stage controlled by stereological software. Choline acetyltranferase immunohistochemistry was used to identify cholinergic cells. Our results showed a predominance of cholinergic projections coming from the HDB. These projections were not retinotopically organized but projections to V1 arised from neurons located in the anterior HDB/SI whereas projections to V2 arised from neurons located throughout the whole extent of HDB/SI. The absence of a clear topography of these projections suggests that BF activation can stimulate visual cortices broadly.

Neuropeptide Y in the forebrain of the adult male cichlid fish Oreochromis mossambicus: distribution, effects of castration and testosterone replacement.

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Sakharkar, Amul J; Singru, Praful S; Sarkar, Koustav; Subhedar, Nishikant K

2005-08-22

We studied the organization of the neuropeptide Y (NPY)-immunoreactive system in the forebrain of adult male cichlid fish Oreochromis mossambicus and its response to castration and testosterone replacement by using morphometric methods. Immunoreactivity for NPY was widely distributed in the forebrain, and the pattern generally resembled that in other teleosts. Whereas immunoreactivity was conspicuous in the ganglia of nervus terminalis (NT; or nucleus olfactoretinalis), a weak reaction was detected in some granule cells in the olfactory bulb and in the cells of area ventralis telencephali pars lateralis (Vl). Moderately to intensely immunoreactive cells were distinctly seen in the nucleus entopeduncularis (NE), nucleus preopticus (NPO), nucleus lateralis tuberis (NLT), paraventricular organ (PVO), and midbrain tegmentum (MT). NPY fibers were widely distributed in the forebrain. Castration for 10/15 days resulted in a drastic loss of immunoreactivity in the cells of NE (P<0.001) and a significant decrease (P<0.01) in their cell nuclear size. However, cell nuclei of the NT neurons showed a significant increase in size. A highly significant reduction in the NPY-immunoreactive fiber density (P<0.001) was observed in several areas of the forebrain. Although testosterone replacement reversed these changes, fibers in some areas showed supranormal responses. Immunoreactive cells in Vl, NPO, NLT, PVO, and MT and fiber density in some other areas did not respond to castration. We suggest that the NPY-immunoreactive elements that respond to castration and testosterone replacement may serve as the substrate for processing the positive feedback action of the steroid hormone. (c) 2005 Wiley-Liss, Inc.

Chronic inflammatory pain: new molecules & mechanisms

NARCIS (Netherlands)

Willemen, H.L.D.M.

2013-01-01

Pain is an important self-protecting signal. The pain system detects and reacts to (withdrawal reflex) the presence of an acute potentially injurious stimulus such as heat, pressure, tissue damage or inflammation to avoid possible (further) tissue damage. However, after inflammation or tissue damage

Mechanisms and management of functional abdominal pain.

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Farmer, Adam D; Aziz, Qasim

2014-09-01

Functional abdominal pain syndrome is characterised by frequent or continuous abdominal pain associated with a degree of loss of daily activity. It has a reported population prevalence of between 0.5% and 1.7%, with a female preponderance. The pathophysiology of functional abdominal pain is incompletely understood although it has been postulated that peripheral sensitisation of visceral afferents, central sensitisation of the spinal dorsal horn and aberrancies within descending modulatory systems may have an important role. The management of patients with functional abdominal pain requires a tailored multidisciplinary approach in a supportive and empathetic environment in order to develop an effective therapeutic relationship. Patient education directed towards an explanation of the pathophysiology of functional abdominal pain is in our opinion a prerequisite step and provides the rationale for the introduction of interventions. Interventions can usefully be categorised into general measures, pharmacotherapy, psychological interventions and 'step-up' treatments. Pharmacotherapeutic/step-up options include tricyclic antidepressants, serotonin noradrenergic reuptake inhibitors and the gabapentinoids. Psychological treatments include cognitive behavioural therapy and hypnotherapy. However, the objective evidence base for these interventions is largely derived from other chronic pain syndrome, and further research is warranted in adult patients with functional abdominal pain. © The Royal Society of Medicine.

Increases in extracellular serotonin and dopamine metabolite levels in the basal forebrain during sleep deprivation

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Zant, J.C.; Leenaars, C.H.; Kostin, A.; van Someren, E.J.W.; Porrka-Heiskanen, T.

2011-01-01

The basal forebrain (BF) is an important mediator of cortical arousal, which is innervated by all ascending arousal systems. During sleep deprivation (SD) a site-specific accumulation of sleep factors in the BF results in increased sleep pressure (Kalinchuk et al., 2006; Porkka-Heiskanen et al.,

Selective immunotoxic lesions of basal forebrain cholinergic cells: effects on learning and memory in rats.

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Baxter, Mark G; Bucci, David J; Gorman, Linda K; Wiley, Ronald G; Gallagher, Michela

2013-10-01

Male Long-Evans rats were given injections of either 192 IgG-saporin, an apparently selective toxin for basal forebrain cholinergic neurons (LES), or vehicle (CON) into either the medial septum and vertical limb of the diagonal band (MS/VDB) or bilaterally into the nucleus basalis magnocellularis and substantia innominata (nBM/SI). Place discrimination in the Morris water maze assessed spatial learning, and a trial-unique matching-to-place task in the water maze assessed memory for place information over varying delays. MS/VDB-LES and nBM/SI-LES rats were not impaired relative to CON rats in acquisition of the place discrimination, but were mildly impaired relative to CON rats in performance of the memory task even at the shortest delay, suggesting a nonmnemonic deficit. These results contrast with effects of less selective lesions, which have been taken to support a role for basal forebrain cholinergic neurons in learning and memory. 2013 APA, all rights reserved

Spontaneous sleep-wake cycle and sleep deprivation differently induce Bdnf1, Bdnf4 and Bdnf9a DNA methylation and transcripts levels in the basal forebrain and frontal cortex in rats.

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Ventskovska, Olena; Porkka-Heiskanen, Tarja; Karpova, Nina N

2015-04-01

Brain-derived neurotrophic factor (Bdnf) regulates neuronal plasticity, slow wave activity and sleep homeostasis. Environmental stimuli control Bdnf expression through epigenetic mechanisms, but there are no data on epigenetic regulation of Bdnf by sleep or sleep deprivation. Here we investigated whether 5-methylcytosine (5mC) DNA modification at Bdnf promoters p1, p4 and p9 influences Bdnf1, Bdnf4 and Bdnf9a expression during the normal inactive phase or after sleep deprivation (SD) (3, 6 and 12 h, end-times being ZT3, ZT6 and ZT12) in rats in two brain areas involved in sleep regulation, the basal forebrain and cortex. We found a daytime variation in cortical Bdnf expression: Bdnf1 expression was highest at ZT6 and Bdnf4 lowest at ZT12. Such variation was not observed in the basal forebrain. Also Bdnf p1 and p9 methylation levels differed only in the cortex, while Bdnf p4 methylation did not vary in either area. Factorial analysis revealed that sleep deprivation significantly induced Bdnf1 and Bdnf4 with the similar pattern for Bdnf9a in both basal forebrain and cortex; 12 h of sleep deprivation decreased 5mC levels at the cortical Bdnf p4 and p9. Regression analysis between the 5mC promoter levels and the corresponding Bdnf transcript expression revealed significant negative correlations for the basal forebrain Bdnf1 and cortical Bdnf9a transcripts in only non-deprived rats, while these correlations were lost after sleep deprivation. Our results suggest that Bdnf transcription during the light phase of undisturbed sleep-wake cycle but not after SD is regulated at least partially by brain site-specific DNA methylation. © 2014 European Sleep Research Society.

Pain genes.

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Tom Foulkes

2008-07-01

Full Text Available Pain, which afflicts up to 20% of the population at any time, provides both a massive therapeutic challenge and a route to understanding mechanisms in the nervous system. Specialised sensory neurons (nociceptors signal the existence of tissue damage to the central nervous system (CNS, where pain is represented in a complex matrix involving many CNS structures. Genetic approaches to investigating pain pathways using model organisms have identified the molecular nature of the transducers, regulatory mechanisms involved in changing neuronal activity, as well as the critical role of immune system cells in driving pain pathways. In man, mapping of human pain mutants as well as twin studies and association studies of altered pain behaviour have identified important regulators of the pain system. In turn, new drug targets for chronic pain treatment have been validated in transgenic mouse studies. Thus, genetic studies of pain pathways have complemented the traditional neuroscience approaches of electrophysiology and pharmacology to give us fresh insights into the molecular basis of pain perception.

Neuroregulatory and neuroendocrine GnRH pathways in the hypothalamus and forebrain of the baboon.

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Marshall, P E; Goldsmith, P C

1980-07-14

The distribution of neurons containing gonadotropin-releasing hormone (GnRH) in the baboon hypothalamus and forebrain was studied immunocytochemically by light and electron microscopy. GnRH was present in the perikarya, axonal and dendritic processes of immunoreactive neurons. Three populations of GnRH neurons could be distinguished. Most of the GnRH neurons which are assumed to directly influence the anterior pituitary were in the medial basal hypothalamus. Other cells that projected to the median eminence were found scattered throughout the hypothalamus. A second, larger population of neurons apparently was not involved with control of the anterior pituitary. These neurons were generally found within afferent and efferent pathways of the hypothalamus and forebrain, and may receive external information affecting reproduction. A few neurons projecting to the median eminence were also observed sending collaterals to other brain areas. Thus, in addition to their neuroendocrine role, these cells possibly have neuroregulatory functions. The inference is made that these bifunctional neurons, together with the widely observed GnRH-GnRH cellular interactions may help to synchronize ovulation and sexual behavior.

Localized Sympathectomy Reduces Mechanical Hypersensitivity by Restoring Normal Immune Homeostasis in Rat Models of Inflammatory Pain.

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Xie, Wenrui; Chen, Sisi; Strong, Judith A; Li, Ai-Ling; Lewkowich, Ian P; Zhang, Jun-Ming

2016-08-17

Some forms of chronic pain are maintained or enhanced by activity in the sympathetic nervous system (SNS), but attempts to model this have yielded conflicting findings. The SNS has both pro- and anti-inflammatory effects on immunity, confounding the interpretation of experiments using global sympathectomy methods. We performed a "microsympathectomy" by cutting the ipsilateral gray rami where they entered the spinal nerves near the L4 and L5 DRG. This led to profound sustained reductions in pain behaviors induced by local DRG inflammation (a rat model of low back pain) and by a peripheral paw inflammation model. Effects of microsympathectomy were evident within one day, making it unlikely that blocking sympathetic sprouting in the local DRGs or hindpaw was the sole mechanism. Prior microsympathectomy greatly reduced hyperexcitability of sensory neurons induced by local DRG inflammation observed 4 d later. Microsympathectomy reduced local inflammation and macrophage density in the affected tissues (as indicated by paw swelling and histochemical staining). Cytokine profiling in locally inflamed DRG showed increases in pro-inflammatory Type 1 cytokines and decreases in the Type 2 cytokines present at baseline, changes that were mitigated by microsympathectomy. Microsympathectomy was also effective in reducing established pain behaviors in the local DRG inflammation model. We conclude that the effect of sympathetic fibers in the L4/L5 gray rami in these models is pro-inflammatory. This raises the possibility that therapeutic interventions targeting gray rami might be useful in some chronic inflammatory pain conditions. Sympathetic blockade is used for many pain conditions, but preclinical studies show both pro- and anti-nociceptive effects. The sympathetic nervous system also has both pro- and anti-inflammatory effects on immune tissues and cells. We examined effects of a very localized sympathectomy. By cutting the gray rami to the spinal nerves near the lumbar sensory

Thermal and mechanical quantitative sensory testing in Chinese patients with burning mouth syndrome--a probable neuropathic pain condition?

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Mo, Xueyin; Zhang, Jinglu; Fan, Yuan; Svensson, Peter; Wang, Kelun

2015-01-01

To explore the hypothesis that burning mouth syndrome (BMS) probably is a neuropathic pain condition, thermal and mechanical sensory and pain thresholds were tested and compared with age- and gender-matched control participants using a standardized battery of psychophysical techniques. Twenty-five BMS patients (men: 8, women: 17, age: 49.5 ± 11.4 years) and 19 age- and gender-matched healthy control participants were included. The cold detection threshold (CDT), warm detection threshold (WDT), cold pain threshold (CPT), heat pain threshold (HPT), mechanical detection threshold (MDT) and mechanical pain threshold (MPT), in accordance with the German Network of Neuropathic Pain guidelines, were measured at the following four sites: the dorsum of the left hand (hand), the skin at the mental foramen (chin), on the tip of the tongue (tongue), and the mucosa of the lower lip (lip). Statistical analysis was performed using ANOVA with repeated measures to compare the means within and between groups. Furthermore, Z-score profiles were generated, and exploratory correlation analyses between QST and clinical variables were performed. Two-tailed tests with a significance level of 5 % were used throughout. CDTs (P < 0.02) were significantly lower (less sensitivity) and HPTs (P < 0.001) were significantly higher (less sensitivity) at the tongue and lip in BMS patients compared to control participants. WDT (P = 0.007) was also significantly higher at the tongue in BMS patients compared to control subjects . There were no significant differences in MDT and MPT between the BMS patients and healthy subjects at any of the four test sites. Z-scores showed that significant loss of function can be identified for CDT (Z-scores = -0.9±1.1) and HPT (Z-scores = 1.5±0.4). There were no significant correlations between QST and clinical variables (pain intensity, duration, depressions scores). BMS patients had a significant loss of thermal function but not

Expert clinical reasoning and pain assessment in mechanically ventilated patients: A descriptive study.

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Gerber, Anne; Thevoz, Anne-Laure; Ramelet, Anne-Sylvie

2015-02-01

Pain assessment in mechanically ventilated patients is challenging, because nurses need to decode pain behaviour, interpret pain scores, and make appropriate decisions. This clinical reasoning process is inherent to advanced nursing practice, but is poorly understood. A better understanding of this process could contribute to improved pain assessment and management. This study aimed to describe the indicators that influence expert nurses' clinical reasoning when assessing pain in critically ill nonverbal patients. This descriptive observational study was conducted in the adult intensive care unit (ICU) of a tertiary referral hospital in Western Switzerland. A purposive sample of expert nurses, caring for nonverbal ventilated patients who received sedation and analgesia, were invited to participate in the study. Data were collected in "real life" using recorded think-aloud combined with direct non-participant observation and brief interviews. Data were analysed using deductive and inductive content analyses using a theoretical framework related to clinical reasoning and pain. Seven expert nurses with an average of 7.85 (±3.1) years of critical care experience participated in the study. The patients had respiratory distress (n=2), cardiac arrest (n=2), sub-arachnoid bleeding (n=1), and multi-trauma (n=2). A total of 1344 quotes in five categories were identified. Patients' physiological stability was the principal indicator for making decision in relation to pain management. Results also showed that it is a permanent challenge for nurses to discriminate situations requiring sedation from situations requiring analgesia. Expert nurses mainly used working knowledge and patterns to anticipate and prevent pain. Patient's clinical condition is important for making decision about pain in critically ill nonverbal patients. The concept of pain cannot be assessed in isolation and its assessment should take the patient's clinical stability and sedation into account. Further

Regional glucose utilization and blood flow following graded forebrain ischemia in the rat: correlation with neuropathology

International Nuclear Information System (INIS)

Ginsberg, M.D.; Graham, D.I.; Busto, R.

1985-01-01

Regional patterns of cerebral glucose utilization (rCMRglc) and blood flow (rCBF) were examined in the early recovery period following transient forebrain ischemia in order to correlate early postischemic physiological events with regionally selective patterns of ischemic neuropathology. Wistar rats were subjected to 30 or 60 minutes of graded forebrain ischemia by a method combining unilateral occlusion of the common carotid artery with moderate elevation of intracranial pressure and mild hypotension; this procedure results in a high-grade ischemic deficit affecting chiefly the lateral neocortex, striatum, and hippocampus ipsilateral to the carotid occlusion. Simultaneous measurements of rCMRglc and rCBF made in regional tissue samples after 2 and 4 hours of postischemic recirculation using a double-tracer radioisotopic strategy revealed a disproportionately high level of glucose metabolism relative to blood flow in the early postischemic striatum, owing to the resumption of nearly normal rCMRglc in the face of depressed flow. In contrast, the neocortex, which had been equally ischemic, showed parallel depressions of both metabolism and blood flow during early recovery. Light microscopy at 4 and 8 hours after recovery revealed the striatum to be the predominant locus of ischemic neuronal alterations, whereas neocortical lesions were much less prominent in extent and severity at this time. The resumption of normal levels of metabolism in the setting of a disproportionate depression of rCBF in the early postischemic period may accentuate the process of neuronal injury initiated by ischemia and may contribute to the genesis of neuronal necrosis in selectively vulnerable areas of the forebrain

Mast cell deficiency attenuates acupuncture analgesia for mechanical pain using c-kit gene mutant rats.

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Cui, Xiang; Liu, Kun; Xu, Dandan; Zhang, Youyou; He, Xun; Liu, Hao; Gao, Xinyan; Zhu, Bing

2018-01-01

Acupuncture therapy plays a pivotal role in pain relief, and increasing evidence demonstrates that mast cells (MCs) may mediate acupuncture analgesia. The present study aims to investigate the role of MCs in acupuncture analgesia using c-kit gene mutant-induced MC-deficient rats. WsRC-Ws/Ws rats and their wild-type (WT) littermates (WsRC-+/+) were used. The number of MCs in skin of ST36 area was compared in two rats after immunofluorescence labeling. Mechanical withdrawal latency (MWL), mechanical withdrawal threshold (MWT), and thermal withdrawal latency (TWL) were measured on bilateral plantar for pain threshold evaluation before and after each stimulus. Acupuncture- and moxibustion-like stimuli (43°C, 46°C heat, 1 mA electroacupuncture [EA], 3 mA EA, and manual acupuncture [MA]) were applied randomly on different days. Fewer MCs were observed in the skin of ST36 in mutant rats compared to WT rats ( P 0.05). Bilateral MWL and MWT in WsRC-+/+ rats increased significantly after each stimulus compared to baseline ( P <0.01, P <0.001). In WsRC-Ws/Ws rats, only noxious stimuli could produce anti-nociceptive effects for mechanical pain (46°C, 3 mA EA, MA) ( P <0.01, P <0.001). Additionally, the net increases in MWL and MWT induced by most stimuli were greater in WT than in mutant rats ( P <0.05). For thermal nociception, either high- or low-intensity stimuli could significantly augment TWL in two rats ( P <0.001), and the net increases of TWL evoked by most stimuli were to the same extent in two genetic variants. MCs influence the basic mechanical but not thermal pain threshold. MCs participate in acupuncture analgesia in mechanical but not in thermal nociception, in that MC deficiency may attenuate the mechanical analgesia evoked by high-intensity stimuli and eliminate analgesia provoked by low-intensity stimuli.

Mechanisms and management of functional abdominal pain

OpenAIRE

Farmer, Adam D; Aziz, Qasim

2014-01-01

Functional abdominal pain syndrome is characterised by frequent or continuous abdominal pain associated with a degree of loss of daily activity. It has a reported population prevalence of between 0.5% and 1.7%, with a female preponderance. The pathophysiology of functional abdominal pain is incompletely understood although it has been postulated that peripheral sensitisation of visceral afferents, central sensitisation of the spinal dorsal horn and aberrancies within descending modulatory sys...

Electromagnetic Field Devices and Their Effects on Nociception and Peripheral Inflammatory Pain Mechanisms.

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Ross, Christina L; Teli, Thaleia; Harrison, Benjamin S

2016-03-01

Context • During cell-communication processes, endogenous and exogenous signaling affects normal and pathological developmental conditions. Exogenous influences, such as extra-low-frequency (ELF) electromagnetic fields (EMFs) have been shown to affect pain and inflammation by modulating G-protein coupling receptors (GPCRs), downregulating cyclooxygenase-2 (Cox-2) activity, and downregulating inflammatory modulators, such as tumor necrosis factor alpha (TNF-α) and interleukin 1 beta (IL-1β) as well as the transcription factor nuclear factor kappa B (NF-κB). EMF devices could help clinicians who seek an alternative or complementary treatment for relief of patients chronic pain and disability. Objective • The research team intended to review the literature on the effects of EMFs on inflammatory pain mechanisms. Design • We used a literature search of articles published in PubMed using the following key words: low-frequency electromagnetic field therapy, inflammatory pain markers, cyclic adenosine monophosphate (cAMP), cyclic guanosine monophosphate (cGMP), opioid receptors, G-protein coupling receptors, and enzymes. Setting • The study took place at the Wake Forest School of Medicine in Winston-Salem, NC, USA. Results • The mechanistic pathway most often considered for the biological effects of EMF is the plasma membrane, across which the EMF signal induces a voltage change. Oscillating EMF exerts forces on free ions that are present on both sides of the plasma membrane and that move across the cell surface through transmembrane proteins. The ions create a forced intracellular vibration that is responsible for phenomena such as the influx of extracellular calcium (Ca2+) and the binding affinity of calmodulin (CaM), which is the primary transduction pathway to the secondary messengers, cAMP and cGMP, which have been found to influence inflammatory pain. Conclusions • An emerging body of evidence indicates the existence of a frequency

Dysfunctional pain modulation in somatoform pain disorder patients.

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Klug, Stefanie; Stefanie, Klug; Anderer, Peter; Peter, Anderer; Saletu-Zyhlarz, Gerda; Gerda, Saletu-Zyhlarz; Freidl, Marion; Marion, Freidl; Saletu, Bernd; Bernd, Saletu; Prause, Wolfgang; Wolfgang, Prause; Aigner, Martin; Martin, Aigner

2011-06-01

To date, pain perception is thought to be a creative process of modulation carried out by an interplay of pro- and anti-nociceptive mechanisms. Recent research demonstrates that pain experience constitutes the result of top-down processes represented in cortical descending pain modulation. Cortical, mainly medial and frontal areas, as well as subcortical structures such as the brain stem, medulla and thalamus seem to be key players in pain modulation. An imbalance of pro- and anti-nociceptive mechanisms are assumed to cause chronic pain disorders, which are associated with spontaneous pain perception without physiologic scaffolding or exaggerated cortical activation in response to pain exposure. In contrast to recent investigations, the aim of the present study was to elucidate cortical activation of somatoform pain disorder patients during baseline condition. Scalp EEG, quantitative Fourier-spectral analyses and LORETA were employed to compare patient group (N = 15) to age- and sex-matched controls (N = 15) at rest. SI, SII, ACC, SMA, PFC, PPC, insular, amygdale and hippocampus displayed significant spectral power reductions within the beta band range (12-30 Hz). These results suggest decreased cortical baseline arousal in somatoform pain disorder patients. We finally conclude that obtained results may point to an altered baseline activity, maybe characteristic for chronic somatoform pain disorder.

The peripheral and central mechanisms of transition of acute to chronic pain and the possible role of cyclooxygenase-2 inhibition in the prevention of pain syndrome chronization

Directory of Open Access Journals (Sweden)

O. S. Davydov

2016-01-01

Full Text Available Chronic pain syndromes as a cause of suffering, short-term or persistent disability, and social losses greatly worsen quality of life. The mechanisms leading to the occurrence and maintenance of chronic pain are traditionally of interest for in-depth study since each of them is potentially a target for pharmacotherapy. Peripheral and central sensitizations, as well as disinhibition make different contributions to the development of chronic pain. The fact that cyclooxygenase-2 (COX-2 inhibitors may affect at both the peripheral and central, spinal levels, by modulating such a phenomenon as central sensitization, has been recently discussed. There are theoretical prerequisites for a discussion of this action of COX-2 inhibitors; however, clinical findings supporting this hypothesis have been scarce so far. In this connection, of interest is the clinical trial published in 2016, which may suggest to a high degree of accuracy that some analgesic effect of the selective COX-2 inhibitor etoricoxib is realized through the central mechanisms of pain modulation. 

Lack of cross-tolerance between haloperidol and clozapine towards Fos-protein induction in rat forebrain regions

NARCIS (Netherlands)

Sebens, JB; Koch, T; Korf, J

1996-01-01

We investigated whether the acute effects of haloperidol and clozapine on Fos expression in the rat forebrain are mediated by the same receptors through evaluation of cross-tolerance, particularly in the commonly affected areas. Acutely administered haloperidol (1 mg/kg, i.p.) and clozapine (20

Food-Derived Natural Compounds for Pain Relief in Neuropathic Pain.

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Lim, Eun Yeong; Kim, Yun Tai

2016-01-01

Neuropathic pain, defined as pain caused by a lesion or disease of the somatosensory nervous system, is characterized by dysesthesia, hyperalgesia, and allodynia. The number of patients with this type of pain has increased rapidly in recent years. Yet, available neuropathic pain medicines have undesired side effects, such as tolerance and physical dependence, and do not fully alleviate the pain. The mechanisms of neuropathic pain are still not fully understood. Injury causes inflammation and immune responses and changed expression and activity of receptors and ion channels in peripheral nerve terminals. Additionally, neuroinflammation is a known factor in the development and maintenance of neuropathic pain. During neuropathic pain development, the C-C motif chemokine receptor 2 (CCR2) acts as an important signaling mediator. Traditional plant treatments have been used throughout the world for treating diseases. We and others have identified food-derived compounds that alleviate neuropathic pain. Here, we review the natural compounds for neuropathic pain relief, their mechanisms of action, and the potential benefits of natural compounds with antagonistic effects on GPCRs, especially those containing CCR2, for neuropathic pain treatment.

Mechanical Diagnosis and Therapy has similar effects on pain and disability as ‘wait and see’ and other approaches in people with neck pain: a systematic review

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Hiroshi Takasaki

2014-06-01

Full Text Available Questions: In people with neck pain, does Mechanical Diagnosis and Therapy (MDT reduce pain and disability more than ‘wait and see’? Does MDT reduce pain and disability more than other interventions? Are any differences in effect clinically important? Design: Systematic review of randomised trials with meta-analysis. Participants: People with neck pain. Intervention: MDT. Outcome measures: Pain intensity and disability due to neck pain in the short (< 3 months, intermediate (< 1 year and long term (≥ 1 year. Results: Five trials were included. Most comparisons demonstrated mean differences in effect that favoured MDT over wait-and-see controls or other interventions, although most were statistically non-significant. For pain, all comparisons had a 95% confidence interval (CI with lower limits that were less than 20 on a scale of 0 to 100, which suggests that the difference may not be clinically important. For disability, even the upper limits of the 95% CI were below this threshold, confirming that the differences are not clinically important. In all of the trials, some or all of the treating therapists did not have the highest level of MDT training. Conclusion: The additional benefit of MDT compared with the wait-and-see approach or other therapeutic approaches may not be clinically important in terms of pain intensity and is not clinically important in terms of disability. However, these estimates of the effect of MDT may reflect suboptimal training of the treating therapists. Further research could improve the precision of the estimates and assess whether the extent of training in MDT influences its effect. [Takasaki H, May S (2014 Mechanical Diagnosis and Therapy has similar effects on pain and disability as ‘wait and see’ and other approaches in people with neck pain: a systematic review. Journal of Physiotherapy 60: 78–84].

Translational pain research: evaluating analgesic effect in experimental visceral pain models

DEFF Research Database (Denmark)

Olesen, Anne Estrup; Andresen, Trine; Christrup, Lona Louring

2009-01-01

Deep visceral pain is frequent and presents major challenges in pain management, since its pathophysiology is still poorly understood. One way to optimize treatment of visceral pain is to improve knowledge of the mechanisms behind the pain and the mode of action of analgesic substances. This can ...... studies and clinical condition in patients suffering from visceral pain, and thus constitute the missing link in translational pain research.......Deep visceral pain is frequent and presents major challenges in pain management, since its pathophysiology is still poorly understood. One way to optimize treatment of visceral pain is to improve knowledge of the mechanisms behind the pain and the mode of action of analgesic substances. This can...... facilitate minimizing the gap between knowledge gained in animal and human clinical studies. Combining experimental pain studies and pharmacokinetic studies can improve understanding of the pharmacokinetic-pharmacodynamic relationship of analgesics and, thus, provide valuable insight into optimal clinical...

Thyroid hormone modulates the development of cholinergic terminal fields in the rat forebrain: relation to nerve growth factor receptor.

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Oh, J D; Butcher, L L; Woolf, N J

1991-04-24

Hyperthyroidism, induced in rat pups by the daily intraperitoneal administration of 1 microgram/g body weight triiodothyronine, facilitated the development of ChAT fiber plexuses in brain regions innervated by basal forebrain cholinergic neurons, leading to an earlier and increased expression of cholinergic markers in those fibers in the cortex, hippocampus and amygdala. A similar enhancement was seen in the caudate-putamen complex. This histochemical profile was correlated with an accelerated appearance of ChAT-positive telencephalic puncta, as well as with a larger total number of cholinergic terminals expressed, which persisted throughout the eight postnatal week, the longest time examined in the present study. Hypothyroidism was produced in rat pups by adding 0.5% propylthiouracil to the dams' diet beginning the day after birth. This dietary manipulation resulted in the diminished expression of ChAT in forebrain fibers and terminals. Hypothyroid treatment also reduced the quantity of ChAT puncta present during postnatal weeks 2 and 3, and, from week 4 and continuing through week 6, the number of ChAT-positive terminals in the telencephalic regions examined was actually less than the amount extant during the former developmental epoch. Immunostaining for nerve growth factor receptor (NGF-R), which is associated almost exclusively with ChAT-positive somata and fibers in the basal forebrain, demonstrated a different time course of postnatal development. Forebrain fibers and terminals demonstrating NGF-R were maximally visualized 1 week postnatally, a time at which these same neuronal elements evinced minimal ChAT-like immunopositivity. Thereafter and correlated with increased immunoreactivity for ChAT, fine details of NGF-R stained fibers were observed less frequently. Although propylthiouracil administration decreased NGF-R immunodensity, no alteration in the development of that receptor was observed as a function of triiodothyronine treatment. Cholinergic

Cytoskeletal Regulation Dominates Temperature-Sensitive Proteomic Changes of Hibernation in Forebrain of 13-Lined Ground Squirrels

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Hindle, Allyson G.; Martin, Sandra L.

2013-01-01

13-lined ground squirrels, Ictidomys tridecemlineatus, are obligate hibernators that transition annually between summer homeothermy and winter heterothermy – wherein they exploit episodic torpor bouts. Despite cerebral ischemia during torpor and rapid reperfusion during arousal, hibernator brains resist damage and the animals emerge neurologically intact each spring. We hypothesized that protein changes in the brain underlie winter neuroprotection. To identify candidate proteins, we applied a sensitive 2D gel electrophoresis method to quantify protein differences among forebrain extracts prepared from ground squirrels in two summer, four winter and fall transition states. Proteins that differed among groups were identified using LC-MS/MS. Only 84 protein spots varied significantly among the defined states of hibernation. Protein changes in the forebrain proteome fell largely into two reciprocal patterns with a strong body temperature dependence. The importance of body temperature was tested in animals from the fall; these fall animals use torpor sporadically with body temperatures mirroring ambient temperatures between 4 and 21°C as they navigate the transition between summer homeothermy and winter heterothermy. Unlike cold-torpid fall ground squirrels, warm-torpid individuals strongly resembled the homeotherms, indicating that the changes observed in torpid hibernators are defined by body temperature, not torpor per se. Metabolic enzymes were largely unchanged despite varied metabolic activity across annual and torpor-arousal cycles. Instead, the majority of the observed changes were cytoskeletal proteins and their regulators. While cytoskeletal structural proteins tended to differ seasonally, i.e., between summer homeothermy and winter heterothermy, their regulatory proteins were more strongly affected by body temperature. Changes in the abundance of various isoforms of the microtubule assembly and disassembly regulatory proteins dihydropyrimidinase

Cytoskeletal regulation dominates temperature-sensitive proteomic changes of hibernation in forebrain of 13-lined ground squirrels.

Directory of Open Access Journals (Sweden)

Allyson G Hindle

Full Text Available 13-lined ground squirrels, Ictidomys tridecemlineatus, are obligate hibernators that transition annually between summer homeothermy and winter heterothermy - wherein they exploit episodic torpor bouts. Despite cerebral ischemia during torpor and rapid reperfusion during arousal, hibernator brains resist damage and the animals emerge neurologically intact each spring. We hypothesized that protein changes in the brain underlie winter neuroprotection. To identify candidate proteins, we applied a sensitive 2D gel electrophoresis method to quantify protein differences among forebrain extracts prepared from ground squirrels in two summer, four winter and fall transition states. Proteins that differed among groups were identified using LC-MS/MS. Only 84 protein spots varied significantly among the defined states of hibernation. Protein changes in the forebrain proteome fell largely into two reciprocal patterns with a strong body temperature dependence. The importance of body temperature was tested in animals from the fall; these fall animals use torpor sporadically with body temperatures mirroring ambient temperatures between 4 and 21°C as they navigate the transition between summer homeothermy and winter heterothermy. Unlike cold-torpid fall ground squirrels, warm-torpid individuals strongly resembled the homeotherms, indicating that the changes observed in torpid hibernators are defined by body temperature, not torpor per se. Metabolic enzymes were largely unchanged despite varied metabolic activity across annual and torpor-arousal cycles. Instead, the majority of the observed changes were cytoskeletal proteins and their regulators. While cytoskeletal structural proteins tended to differ seasonally, i.e., between summer homeothermy and winter heterothermy, their regulatory proteins were more strongly affected by body temperature. Changes in the abundance of various isoforms of the microtubule assembly and disassembly regulatory proteins

Differences in pain processing between patients with chronic low back pain, recurrent low back pain and fibromyalgia

OpenAIRE

Goubert, Dorien; Danneels, Lieven; Graven-Nielsen, Thomas; Descheemaeker, Filip; Coppieters, Iris; Meeus, Mira

2017-01-01

Background: The impairment in musculoskeletal structures in patients with low back pain (LBP) is often disproportionate to their complaint. Therefore, the need arises for exploration of alternative mechanisms contributing to the origin and maintenance of non-specific LBP. The recent focus has been on central nervous system phenomena in LBP and the pathophysiological mechanisms underlying the various symptoms and characteristics of chronic pain. Knowledge concerning changes in pain processing ...

Surgical treatment for central pain after stroke based on the neural mechanism

International Nuclear Information System (INIS)

Hirato, Masafumi; Takahashi, Akio; Watanabe, Katsushige; Kazama, Ken; Yoshimoto, Yuhei

2008-01-01

Previous neurophysiological and neuroimaging studies have suggested that functional changes might occur in the sensory thalamus, associated with reorganization of the thalamocortical system, in cases with central pain after stroke (thalamic pain). It might cause the misconduction of the sensory signal or a hyperactive response to peripheral natural stimulation on the thalamus, resulting in it playing an important roles in the genesis of central pain. Hyperactivity in the cerebral cortex adjacent to the central sulcus on the side ipsilateral to a cerebrovascular disease (CVD) lesion also might relate to central pain. We performed various kinds of surgical treatments in 29 cases with central pain after stroke based on the neural mechanism deserbed above. Epidural spinal cord stimulation was effective in 4 out of 7 cases with localized pain on the distal part of the leg and arm. We achieved pain control in these cases showing definite somatosensory evoked potential (SEP) originating in the sensory cortex before surgery. Stereotactic (Vim-Vcpc) thalamotomy with the aid of depth microrecording was effective in 4 out of 7 cases with diffuse pain. In good responders, we could find responses to natural peripheral stimulation and seldom encountered irregular burst discharges in the sensory thalamus during the operation. Preoperative positron emission tomography (PET) studies also revealed an increase of regional cerebral blood flow (rCBF) in the sensory cortex ipsilateral to the thalamic CVD lesion during contralateral thumb brushing. Gamma knife treatment was effective in 5 out of 7 cases after stereotactic thalamotomy. It became stable in 3 out of these 5 cases. Each case was treated with a maximum dose of 120-150 Gy using a 4 mm collimator. Precentral electrical cortical stimulation was performed in 8 cases. Sufficient pain relief was achieved in 3 out of 6 cases in which we could implant an importable pulse generator (IPG). In one of these cases, we found definite

Experimental tooth clenching. A model for studying mechanisms of muscle pain.

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Dawson, Andreas

2013-01-01

The overall goal of this thesis was to broaden knowledge of pain mechanisms in myofascial temporomandibular disorders (M-TMD). The specific aims were to: Develop a quality assessment tool for experimental bruxism studies (study I). Investigate proprioceptive allodynia after experimental tooth clenching exercises (study II). Evaluate the release of serotonin (5-HT), glutamate, pyruvate, and lactate in healthy subjects (study III) and in patients with M-TMD (study IV), after experimental tooth clenching exercises. In (I), tool development comprised 5 steps: (i) preliminary decisions, (ii) item generation, (iii) face-validity assessment, (iv) reliability and discriminative validity testing, and (v) instrument refinement. After preliminary decisions and a literature review, a list of 52 items to be considered for inclusion in the tool was generated. Eleven experts were invited to participate on the Delphi panel, of which 10 agreed. After four Delphi rounds, 8 items remained and were included in the Quality Assessment Tool for Experimental Bruxism Studies (Qu-ATEBS). Inter-observer reliability was acceptable (k = 0.77), and discriminative validity high (phi coefficient 0.79; P < 0.01). During refinement, 1 item was removed; the final tool comprised 7 items. In (II), 16 healthy females participated in three 60-min sessions, each with 24- and 48-h follow-ups. Participants were randomly assigned to a repetitive experimental tooth clenching task with a clenching level of 10%, 20%, or 40% of maximal voluntary clenching force (MVCF). Pain intensity, fatigue, perceived intensity of vibration (PIV), perceived discomfort (PD), and pressure pain threshold (PPT) were measured throughout. A significant increase in pain intensity and fatigue but not in PD was observed over time. A significant increase in PIV was only observed at 40 min, and PPT decreased significantly over time at 50 and 60 min compared to baseline. In (III), 30 healthy subjects (16 females, and 14 males

Control of cerebral cortical blood flow by stimulation of basal forebrain cholinergic areas in mice.

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Hotta, Harumi; Uchida, Sae; Kagitani, Fusako; Maruyama, Naoki

2011-05-01

We examined whether activity of the nucleus basalis of Meynert (NBM) regulates regional cerebral cortical blood flow (rCBF) in mice, using laser speckle and laser Doppler flowmetry. In anesthetized mice, unilateral focal stimulation, either electrical or chemical, of the NBM increased rCBF of the ipsilateral cerebral cortex in the frontal, parietal and occipital lobes, independent of changes in systemic blood pressure. Most of vasodilative responses to low intensity stimuli (2 times threshold intensity: 2T) were abolished by atropine (a muscarinic cholinergic blocker), whereas responses to higher intensity stimuli (3T) were abolished by atropine and mecamylamine (a nicotinic cholinergic blocker). Blood flow changes were largest when the tip of the electrode was located within the area containing cholinergic neurons shown by choline acetyltransferase-immunocytochemistry. These results suggest that cholinergic projections from basal forebrain neurons in mice cause vasodilation in the ipsilateral cerebral cortex by a combination of muscarinic and nicotinic mechanisms, as previously found in rats and cats.

Pain-related guilt in low back pain.

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Serbic, Danijela; Pincus, Tamar

2014-12-01

Identifying mechanisms that mediate recovery is imperative to improve outcomes in low back pain (LBP). Qualitative studies suggest that guilt may be such a mechanism, but research on this concept is scarce, and reliable instruments to measure pain-related guilt are not available. We addressed this gap by developing and testing a Pain-related Guilt Scale (PGS) for people with LBP. Two samples of participants with LBP completed the scale and provided data on rates of depression, anxiety, pain intensity, and disability. Three factors were identified using exploratory factor analysis (n=137): "Social guilt," (4 items) relating to letting down family and friends; "Managing condition/pain guilt," (5 items) relating to failing to overcome and control pain; and "Verification of pain guilt," (3 items) relating to the absence of objective evidence and diagnosis. This factor structure was confirmed using confirmatory factor analysis (n=288), demonstrating an adequate to good fit with the data (AGFI=0.913, RMSEA=0.061). The PGS subscales positively correlated with depression, anxiety, pain intensity, and disability. After controlling for depression and anxiety the majority of relationships between the PGS subscales and disability and pain intensity remained significant, suggesting that guilt shared unique variance with disability and pain intensity independent of depression and anxiety. High levels of guilt were reported by over 40% of participants. The findings suggest that pain-related guilt is common and is associated with clinical outcomes. Prospective research is needed to examine the role of guilt as a predictor, moderator, and mediator of patients' outcomes.

Stress-induced changes in the expression of the clock protein PERIOD1 in the rat limbic forebrain and hypothalamus: role of stress type, time of day, and predictability.

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Sherin Al-Safadi

Full Text Available Stressful events can disrupt circadian rhythms in mammals but mechanisms underlying this disruption remain largely unknown. One hypothesis is that stress alters circadian protein expression in the forebrain, leading to functional dysregulation of the brain circadian network and consequent disruption of circadian physiological and behavioral rhythms. Here we characterized the effects of several different stressors on the expression of the core clock protein, PER1 and the activity marker, FOS in select forebrain and hypothalamic nuclei in rats. We found that acute exposure to processive stressors, restraint and forced swim, elevated PER1 and FOS expression in the paraventricular and dorsomedial hypothalamic nuclei and piriform cortex but suppressed PER1 and FOS levels exclusively in the central nucleus of the amygdala (CEAl and oval nucleus of the bed nucleus of the stria terminalis (BNSTov. Conversely, systemic stressors, interleukin-1β and 2-Deoxy-D-glucose, increased PER1 and FOS levels in all regions studied, including the CEAl and BNSTov. PER1 levels in the suprachiasmatic nucleus (SCN, the master pacemaker, were unaffected by any of the stress manipulations. The effect of stress on PER1 and FOS was modulated by time of day and, in the case of daily restraint, by predictability. These results demonstrate that the expression of PER1 in the forebrain is modulated by stress, consistent with the hypothesis that PER1 serves as a link between stress and the brain circadian network. Furthermore, the results show that the mechanisms that control PER1 and FOS expression in CEAl and BNSTov are uniquely sensitive to differences in the type of stressor. Finally, the finding that the effect of stress on PER1 parallels its effect on FOS supports the idea that Per1 functions as an immediate-early gene. Our observations point to a novel role for PER1 as a key player in the interface between stress and circadian rhythms.

Shp2 in Forebrain Neurons Regulates Synaptic Plasticity, Locomotion, and Memory Formation in Mice

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Kusakari, Shinya; Saitow, Fumihito; Ago, Yukio; Shibasaki, Koji; Sato-Hashimoto, Miho; Matsuzaki, Yasunori; Kotani, Takenori; Murata, Yoji; Hirai, Hirokazu; Matsuda, Toshio; Suzuki, Hidenori

2015-01-01

Shp2 (Src homology 2 domain-containing protein tyrosine phosphatase 2) regulates neural cell differentiation. It is also expressed in postmitotic neurons, however, and mutations of Shp2 are associated with clinical syndromes characterized by mental retardation. Here we show that conditional-knockout (cKO) mice lacking Shp2 specifically in postmitotic forebrain neurons manifest abnormal behavior, including hyperactivity. Novelty-induced expression of immediate-early genes and activation of extracellular-signal-regulated kinase (Erk) were attenuated in the cerebral cortex and hippocampus of Shp2 cKO mice, suggestive of reduced neuronal activity. In contrast, ablation of Shp2 enhanced high-K+-induced Erk activation in both cultured cortical neurons and synaptosomes, whereas it inhibited that induced by brain-derived growth factor in cultured neurons. Posttetanic potentiation and paired-pulse facilitation were attenuated and enhanced, respectively, in hippocampal slices from Shp2 cKO mice. The mutant mice also manifested transient impairment of memory formation in the Morris water maze. Our data suggest that Shp2 contributes to regulation of Erk activation and synaptic plasticity in postmitotic forebrain neurons and thereby controls locomotor activity and memory formation. PMID:25713104

Fluid mechanics in dentinal microtubules provides mechanistic insights into the difference between hot and cold dental pain.

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Lin, Min; Luo, Zheng Yuan; Bai, Bo Feng; Xu, Feng; Lu, Tian Jian

2011-03-23

Dental thermal pain is a significant health problem in daily life and dentistry. There is a long-standing question regarding the phenomenon that cold stimulation evokes sharper and more shooting pain sensations than hot stimulation. This phenomenon, however, outlives the well-known hydrodynamic theory used to explain dental thermal pain mechanism. Here, we present a mathematical model based on the hypothesis that hot or cold stimulation-induced different directions of dentinal fluid flow and the corresponding odontoblast movements in dentinal microtubules contribute to different dental pain responses. We coupled a computational fluid dynamics model, describing the fluid mechanics in dentinal microtubules, with a modified Hodgkin-Huxley model, describing the discharge behavior of intradental neuron. The simulated results agreed well with existing experimental measurements. We thence demonstrated theoretically that intradental mechano-sensitive nociceptors are not "equally sensitive" to inward (into the pulp) and outward (away from the pulp) fluid flows, providing mechanistic insights into the difference between hot and cold dental pain. The model developed here could enable better diagnosis in endodontics which requires an understanding of pulpal histology, neurology and physiology, as well as their dynamic response to the thermal stimulation used in dental practices.

Ketogenic Diets and Pain

OpenAIRE

Masino, Susan A.; Ruskin, David N.

2013-01-01

Ketogenic diets are well-established as a successful anticonvulsant therapy. Based on overlap between mechanisms postulated to underlie pain and inflammation, and mechanisms postulated to underlie therapeutic effects of ketogenic diets, recent studies have explored the ability for ketogenic diets to reduce pain. Here we review clinical and basic research thus far exploring the impact of a ketogenic diet on thermal pain, inflammation, and neuropathic pain.

Forebrain-Specific Loss of BMPRII in Mice Reduces Anxiety and Increases Object Exploration

OpenAIRE

McBrayer, Zofeyah L.; Dimova, Jiva; Pisansky, Marc T.; Sun, Mu; Beppu, Hideyuki; Gewirtz, Jonathan C.; O’Connor, Michael B.

2015-01-01

To investigate the role of Bone Morphogenic Protein Receptor Type II (BMPRII) in learning, memory, and exploratory behavior in mice, a tissue-specific knockout of BMPRII in the post-natal hippocampus and forebrain was generated. We found that BMPRII mutant mice had normal spatial learning and memory in the Morris water maze, but showed significantly reduced swimming speeds with increased floating behavior. Further analysis using the Porsolt Swim Test to investigate behavioral despair did not ...

Do pain-associated contexts increase pain sensitivity? An investigation using virtual reality.

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Harvie, Daniel S; Sterling, Michele; Smith, Ashley D

2018-04-30

Pain is not a linear result of nociception, but is dependent on multisensory inputs, psychological factors, and prior experience. Since nociceptive models appear insufficient to explain chronic pain, understanding non-nociceptive contributors is imperative. Several recent models propose that cues associatively linked to painful events might acquire the capacity to augment, or even cause, pain. This experiment aimed to determine whether contexts associated with pain, could modulate mechanical pain thresholds and pain intensity. Forty-eight healthy participants underwent a contextual conditioning procedure, where three neutral virtual reality contexts were paired with either unpredictable noxious stimulation, unpredictable vibrotactile stimulation, or no stimulation. Following the conditioning procedure, mechanical pain thresholds and pain evoked by a test stimulus were examined in each context. In the test phase, the effect of expectancy was equalised across conditions by informing participants when thresholds and painful stimuli would be presented. Contrary to our hypothesis, scenes that were associated with noxious stimulation did not increase mechanical sensitivity (p=0.08), or increase pain intensity (p=0.46). However, an interaction with sex highlighted the possibility that pain-associated contexts may alter pain sensitivity in females but not males (p=0.03). Overall, our data does not support the idea that pain-associated contexts can alter pain sensitivity in healthy asymptomatic individuals. That an effect was shown in females highlights the possibility that some subgroups may be susceptible to such an effect, although the magnitude of the effect may lack real-world significance. If pain-associated cues prove to have a relevant pain augmenting effect, in some subgroups, procedures aimed at extinguishing pain-related associations may have therapeutic potential.

Operant conditioning of enhanced pain sensitivity by heat-pain titration.

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Becker, Susanne; Kleinböhl, Dieter; Klossika, Iris; Hölzl, Rupert

2008-11-15

Operant conditioning mechanisms have been demonstrated to be important in the development of chronic pain. Most experimental studies have investigated the operant modulation of verbal pain reports with extrinsic reinforcement, such as verbal reinforcement. Whether this reflects actual changes in the subjective experience of the nociceptive stimulus remained unclear. This study replicates and extends our previous demonstration that enhanced pain sensitivity to prolonged heat-pain stimulation could be learned in healthy participants through intrinsic reinforcement (contingent changes in nociceptive input) independent of verbal pain reports. In addition, we examine whether different magnitudes of reinforcement differentially enhance pain sensitivity using an operant heat-pain titration paradigm. It is based on the previously developed non-verbal behavioral discrimination task for the assessment of sensitization, which uses discriminative down- or up-regulation of stimulus temperatures in response to changes in subjective intensity. In operant heat-pain titration, this discriminative behavior and not verbal pain report was contingently reinforced or punished by acute decreases or increases in heat-pain intensity. The magnitude of reinforcement was varied between three groups: low (N1=13), medium (N2=11) and high reinforcement (N3=12). Continuous reinforcement was applied to acquire and train the operant behavior, followed by partial reinforcement to analyze the underlying learning mechanisms. Results demonstrated that sensitization to prolonged heat-pain stimulation was enhanced by operant learning within 1h. The extent of sensitization was directly dependent on the received magnitude of reinforcement. Thus, operant learning mechanisms based on intrinsic reinforcement may provide an explanation for the gradual development of sustained hypersensitivity during pain that is becoming chronic.

Effects of short-term hormonal replacement on learning and on basal forebrain ChAT and TrkA content in ovariectomized rats.

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Espinosa-Raya, Judith; Plata-Cruz, Noemí; Neri-Gómez, Teresa; Camacho-Arroyo, Ignacio; Picazo, Ofir

2011-02-23

It has been proposed that sex steroid hormones improve performance in some cognitive tasks by regulating the basal forebrain cholinergic function. However, the molecular basis of such influence still remains unknown. Current study analyzed the performance of ovariectomized rats in an autoshaping learning task after a short-term treatment with 17β-estradiol (E2: 4 and 40μg/kg) and/or progesterone (P4: 4mg/kg). These results were correlated with basal forebrain choline acetyltransferase (ChAT) and TrkA protein content. The high dose of E2 enhanced both acquisition in the autoshaping task and the content of ChAT and TrkA. P4 treatment increased ChAT and TrkA content without affecting performance of rats in the autoshaping learning task. Interestingly, the continuous and simultaneous administration of E2 plus P4 did not significantly modify behavioral and biochemical evaluated parameters. These results address the influence of both E2 and P4 on cholinergic and TrkA activity and suggest that the effects of ovarian hormones on cognitive performance involve basal forebrain cholinergic neurons. Copyright © 2010 Elsevier B.V. All rights reserved.

Reliability of four experimental mechanical pain tests in children

DEFF Research Database (Denmark)

Søe, Ann-Britt Langager; Thomsen, Lise L; Tornoe, Birte

2013-01-01

In order to study pain in children, it is necessary to determine whether pain measurement tools used in adults are reliable measurements in children. The aim of this study was to explore the intrasession reliability of pressure pain thresholds (PPT) in healthy children. Furthermore, the aim was a...... was also to study the intersession reliability of the following four tests: (1) Total Tenderness Score; (2) PPT; (3) Visual Analog Scale score at suprapressure pain threshold; and (4) area under the curve (stimulus-response functions for pressure versus pain).......In order to study pain in children, it is necessary to determine whether pain measurement tools used in adults are reliable measurements in children. The aim of this study was to explore the intrasession reliability of pressure pain thresholds (PPT) in healthy children. Furthermore, the aim...

Work and neck pain: a prospective study of psychological, social, and mechanical risk factors.

Science.gov (United States)

Christensen, Jan Olav; Knardahl, Stein

2010-10-01

To determine the impact of occupational psychological/social and mechanical factors on neck pain, a prospective cohort study with a follow-up period of 2 years was conducted with a sample of Norwegian employees. The following designs were tested: (i) cross-sectional analyses at baseline (n=4569) and follow-up (n=4122), (ii) prospective analyses with baseline predictors, (iii) prospective analyses with average exposure over time [(T1+T2)/2] as predictor, and (iv) prospective analyses with measures of change in exposure from T1 to T2 as predictors. A total of 2419 employees responded to both the baseline and follow-up questionnaire. Data were analyzed using ordinal logistic regression. After adjustment for age, sex, neck pain at T1, and other exposure factors that had been estimated to be confounders, the most consistent risk factors were role conflict (highest OR 2.97, 99% CI: 1.29-6.74) and working with arms raised to or above shoulder level (highest OR 1.37, 99% CI: 1.05-1.78). The most consistent protective factors were empowering leadership (lowest OR 0.53, 99% CI: 0.35-0.81) and decision control (lowest OR 0.60, 99% CI: 0.36-1.00). Hence, psychological and social factors are important precursors of neck pain, along with mechanical factors. Although traditional factors such as quantitative demands and decision control play a part in the etiology of neck pain at work, in this study several new factors emerged as more important. Copyright © 2010 International Association for the Study of Pain. Published by Elsevier B.V. All rights reserved.

Potential mechanisms supporting the value of motor cortex stimulation to treat chronic pain syndromes

Directory of Open Access Journals (Sweden)

Marcos Fabio DosSantos

2016-02-01

Full Text Available Throughout the first years of the twenty-first century, neurotechnologies such as motor cortex stimulation (MCS, transcranial magnetic stimulation (TMS and transcranial direct current stimulation (tDCS have attracted scientific attention and been considered as potential tools to centrally modulate chronic pain, especially for those conditions more difficult to manage and refractory to all types of available pharmacological therapies. Interestingly, although the role of the motor cortex in pain has not been fully clarified, it is one of the cortical areas most commonly targeted by invasive and non-invasive neuromodulation technologies. Recent studies have provided significant advances concerning the establishment of the clinical effectiveness of primary motor cortex stimulation to treat different chronic pain syndromes. Concurrently, the neuromechanisms related to each method of primary motor cortex (M1 modulation have been unveiled. In this respect, the most consistent scientific evidence originates from MCS studies, which indicate the activation of top-down controls driven by M1 stimulation. This concept has also been applied to explain M1-TMS mechanisms. Nevertheless, activation of remote areas in the brain, including cortical and subcortical structures, has been reported with both invasive and non-invasive methods and the participation of major neurotransmitters (e.g. glutamate, GABA and serotonin as well as the release of endogenous opioids has been demonstrated. In this critical review, the putative mechanisms underlying the use of motor cortex stimulation to provide relief from chronic migraine and other types of chronic pain are discussed. Emphasis is placed on the most recent scientific evidence obtained from chronic pain research studies involving MCS and non-invasive neuromodulation methods (e.g. tDCS and TMS, which are analyzed comparatively.

Potential Mechanisms Supporting the Value of Motor Cortex Stimulation to Treat Chronic Pain Syndromes.

Science.gov (United States)

DosSantos, Marcos F; Ferreira, Natália; Toback, Rebecca L; Carvalho, Antônio C; DaSilva, Alexandre F

2016-01-01

Throughout the first years of the twenty-first century, neurotechnologies such as motor cortex stimulation (MCS), transcranial magnetic stimulation (TMS), and transcranial direct current stimulation (tDCS) have attracted scientific attention and been considered as potential tools to centrally modulate chronic pain, especially for those conditions more difficult to manage and refractory to all types of available pharmacological therapies. Interestingly, although the role of the motor cortex in pain has not been fully clarified, it is one of the cortical areas most commonly targeted by invasive and non-invasive neuromodulation technologies. Recent studies have provided significant advances concerning the establishment of the clinical effectiveness of primary MCS to treat different chronic pain syndromes. Concurrently, the neuromechanisms related to each method of primary motor cortex (M1) modulation have been unveiled. In this respect, the most consistent scientific evidence originates from MCS studies, which indicate the activation of top-down controls driven by M1 stimulation. This concept has also been applied to explain M1-TMS mechanisms. Nevertheless, activation of remote areas in the brain, including cortical and subcortical structures, has been reported with both invasive and non-invasive methods and the participation of major neurotransmitters (e.g., glutamate, GABA, and serotonin) as well as the release of endogenous opioids has been demonstrated. In this critical review, the putative mechanisms underlying the use of MCS to provide relief from chronic migraine and other types of chronic pain are discussed. Emphasis is placed on the most recent scientific evidence obtained from chronic pain research studies involving MCS and non-invasive neuromodulation methods (e.g., tDCS and TMS), which are analyzed comparatively.

Analysis of deep tissue hypersensitivity to pressure pain in professional pianists with insidious mechanical neck pain

Science.gov (United States)

2011-01-01

Background The aim of this study was to investigate whether pressure pain hyperalgesia is a feature of professional pianists suffering from neck pain as their main playing-related musculoskeletal disorder. Methods Twenty-three active expert pianists, 6 males and 17 females (age: 36 ± 12 years) with insidious neck pain and 23 pianists, 9 males and 14 females (age: 38 ± 10 years) without neck pain the previous year were recruited. A numerical pain rate scale, Neck Disability Index, hand size and pressure pain thresholds (PPT) were assessed bilaterally over the C5-C6 zygapophyseal joint, deltoid muscle, the second metacarpal and the tibialis anterior muscle in a blinded design. Results The results showed that PPT levels were significantly decreased bilaterally over the second metacarpal and tibialis anterior muscles (P 0.10), in pianists with neck pain as compared to healthy pianists. Pianists with neck pain had a smaller (P neck pain (mean: 188. 6 ± 13.1). PPT over the tibialis anterior muscles was negatively correlated with the intensity of neck pain. Conclusions Our findings revealed pressure pain hypersensitivity over distant non-symptomatic distant points but not over the symptomatic areas in pianists suffering from neck pain. In addition, pianists with neck pain also had smaller hand size than those without neck pain. Future studies are needed to further determine the relevance of these findings in the clinical course of neck pain as playing-related musculoskeletal disorder in professional pianists. PMID:22111912

Drinking by amphibious fish: convergent evolution of thirst mechanisms during vertebrate terrestrialization.

Science.gov (United States)

Katayama, Yukitoshi; Sakamoto, Tatsuya; Saito, Kazuhiro; Tsuchimochi, Hirotsugu; Kaiya, Hiroyuki; Watanabe, Taro; Pearson, James T; Takei, Yoshio

2018-01-12

Thirst aroused in the forebrain by angiotensin II (AngII) or buccal drying motivates terrestrial vertebrates to search for water, whereas aquatic fish can drink surrounding water only by reflex swallowing generated in the hindbrain. Indeed, AngII induces drinking through the hindbrain even after removal of the whole forebrain in aquatic fish. Here we show that AngII induces thirst also in the amphibious mudskipper goby without direct action on the forebrain, but through buccal drying. Intracerebroventricular injection of AngII motivated mudskippers to move into water and drink as with tetrapods. However, AngII primarily increased immunoreactive c-Fos at the hindbrain swallowing center where AngII receptors were expressed, as in other ray-finned fish, and such direct action on the forebrain was not found. Behavioural analyses showed that loss of buccal water on land by AngII-induced swallowing, by piercing holes in the opercula, or by water-absorptive gel placed in the cavity motivated mudskippers to move to water for refilling. Since sensory detection of water at the bucco-pharyngeal cavity like 'dry mouth' has recently been noted to regulate thirst in mammals, similar mechanisms seem to have evolved in distantly related species in order to solve osmoregulatory problems during terrestrialization.

Long-lasting novelty-induced neuronal reverberation during slow-wave sleep in multiple forebrain areas.

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Sidarta Ribeiro

2004-01-01

Full Text Available The discovery of experience-dependent brain reactivation during both slow-wave (SW and rapid eye-movement (REM sleep led to the notion that the consolidation of recently acquired memory traces requires neural replay during sleep. To date, however, several observations continue to undermine this hypothesis. To address some of these objections, we investigated the effects of a transient novel experience on the long-term evolution of ongoing neuronal activity in the rat forebrain. We observed that spatiotemporal patterns of neuronal ensemble activity originally produced by the tactile exploration of novel objects recurred for up to 48 h in the cerebral cortex, hippocampus, putamen, and thalamus. This novelty-induced recurrence was characterized by low but significant correlations values. Nearly identical results were found for neuronal activity sampled when animals were moving between objects without touching them. In contrast, negligible recurrence was observed for neuronal patterns obtained when animals explored a familiar environment. While the reverberation of past patterns of neuronal activity was strongest during SW sleep, waking was correlated with a decrease of neuronal reverberation. REM sleep showed more variable results across animals. In contrast with data from hippocampal place cells, we found no evidence of time compression or expansion of neuronal reverberation in any of the sampled forebrain areas. Our results indicate that persistent experience-dependent neuronal reverberation is a general property of multiple forebrain structures. It does not consist of an exact replay of previous activity, but instead it defines a mild and consistent bias towards salient neural ensemble firing patterns. These results are compatible with a slow and progressive process of memory consolidation, reflecting novelty-related neuronal ensemble relationships that seem to be context- rather than stimulus-specific. Based on our current and previous results

Ketogenic Diets and Pain

Science.gov (United States)

Masino, Susan A.; Ruskin, David N.

2014-01-01

Ketogenic diets are well-established as a successful anticonvulsant therapy. Based on overlap between mechanisms postulated to underlie pain and inflammation, and mechanisms postulated to underlie therapeutic effects of ketogenic diets, recent studies have explored the ability for ketogenic diets to reduce pain. Here we review clinical and basic research thus far exploring the impact of a ketogenic diet on thermal pain, inflammation, and neuropathic pain. PMID:23680946

Experimental human pain models in gastro-esophageal reflux disease and unexplained chest pain

Institute of Scientific and Technical Information of China (English)

Asbj(φ)rn Mohr Drewes; Lars Arendt-Nielsen; Peter Funch-Jensen; Hans Gregersen

2006-01-01

Methods related to experimental human pain research aim at activating different nociceptors, evoke pain from different organs and activate specific pathways and mechanisms. The different possibilities for using mechanical, electrical, thermal and chemical methods in visceral pain research are discussed with emphasis of combinations (e.g., the multimodal approach). The methods have been used widely in assessment of pain mechanisms in the esophagus and have contributed to our understanding of the symptoms reported in these patients. Hence abnormal activation and plastic changes of central pain pathways seem to play a major role in the symptoms in some patients with gastro-esophageal reflux disease and in patients with functional chest pain of esophageal origin. These findings may lead to an alternative approach for treatment in patients that does not respond to conventional medical or surgical therapy.

Pain and the alpha-sleep anomaly: a mechanism of sleep disruption in facioscapulohumeral muscular dystrophy.

Science.gov (United States)

Della Marca, Giacomo; Frusciante, Roberto; Vollono, Catello; Iannaccone, Elisabetta; Dittoni, Serena; Losurdo, Anna; Testani, Elisa; Gnoni, Valentina; Colicchio, Salvatore; Di Blasi, Chiara; Erra, Carmen; Mazza, Salvatore; Ricci, Enzo

2013-04-01

To measure the presence of the alpha-sleep anomaly in facioscapulohumeral muscular dystrophy (FSHD) and to evaluate the association between the sleep electroencephalogram (EEG) pattern and the presence of musculoskeletal pain. Cross-sectional study. Sleep laboratory. Fifty-five consecutive adult FSHD patients, 26 women and 29 men, age 49.6 ± 15.1 years (range 18-76). Questionnaires and polysomnography. Patients were asked to indicate if in the 3 months before the sleep study they presented persisting or recurring musculoskeletal pain. Patients who reported pain were asked to fill in the Italian version of the Brief Pain Inventory and the McGill Pain questionnaire, and a 101-point visual analog scale (VAS) for pain intensity. Polysomnographic recordings were performed. EEG was analyzed by means of Fast Fourier Transform. Four power spectra bands (δ 0-4 Hz, θ 4-8 Hz, α 8-14 Hz, β 14-32 Hz) were computed. Sleep macrostructure parameters and alpha/delta EEG power ratio during non rapid eye movement (NREM) sleep were compared between patients with and without pain. Forty-two patients in our sample reported chronic pain. VAS mean score was 55.2 ± 23.8 (range 10-100), pain rating index score was 13.8 ± 10.2, and present pain intensity was 2.5 ± 0.8. The statistical analysis documented an increased occurrence of the alpha and beta rhythms during NREM sleep in FSHD patients with pain. Significant correlations were observed between the alpha/delta power ratio during NREM sleep and pain measures. Chronic musculoskeletal pain is frequent in FSHD patients, and it represents a major mechanism of sleep disruption. Wiley Periodicals, Inc.

Analysis of deep tissue hypersensitivity to pressure pain in professional pianists with insidious mechanical neck pain

Directory of Open Access Journals (Sweden)

Linari-Melfi Marcela

2011-11-01

Full Text Available Abstract Background The aim of this study was to investigate whether pressure pain hyperalgesia is a feature of professional pianists suffering from neck pain as their main playing-related musculoskeletal disorder. Methods Twenty-three active expert pianists, 6 males and 17 females (age: 36 ± 12 years with insidious neck pain and 23 pianists, 9 males and 14 females (age: 38 ± 10 years without neck pain the previous year were recruited. A numerical pain rate scale, Neck Disability Index, hand size and pressure pain thresholds (PPT were assessed bilaterally over the C5-C6 zygapophyseal joint, deltoid muscle, the second metacarpal and the tibialis anterior muscle in a blinded design. Results The results showed that PPT levels were significantly decreased bilaterally over the second metacarpal and tibialis anterior muscles (P 0.10, in pianists with neck pain as compared to healthy pianists. Pianists with neck pain had a smaller (P Conclusions Our findings revealed pressure pain hypersensitivity over distant non-symptomatic distant points but not over the symptomatic areas in pianists suffering from neck pain. In addition, pianists with neck pain also had smaller hand size than those without neck pain. Future studies are needed to further determine the relevance of these findings in the clinical course of neck pain as playing-related musculoskeletal disorder in professional pianists.

The ACTTION-American Pain Society Pain Taxonomy (AAPT): an evidence-based and multidimensional approach to classifying chronic pain conditions.

Science.gov (United States)

Fillingim, Roger B; Bruehl, Stephen; Dworkin, Robert H; Dworkin, Samuel F; Loeser, John D; Turk, Dennis C; Widerstrom-Noga, Eva; Arnold, Lesley; Bennett, Robert; Edwards, Robert R; Freeman, Roy; Gewandter, Jennifer; Hertz, Sharon; Hochberg, Marc; Krane, Elliot; Mantyh, Patrick W; Markman, John; Neogi, Tuhina; Ohrbach, Richard; Paice, Judith A; Porreca, Frank; Rappaport, Bob A; Smith, Shannon M; Smith, Thomas J; Sullivan, Mark D; Verne, G Nicholas; Wasan, Ajay D; Wesselmann, Ursula

2014-03-01

Current approaches to classification of chronic pain conditions suffer from the absence of a systematically implemented and evidence-based taxonomy. Moreover, existing diagnostic approaches typically fail to incorporate available knowledge regarding the biopsychosocial mechanisms contributing to pain conditions. To address these gaps, the Analgesic, Anesthetic, and Addiction Clinical Trial Translations Innovations Opportunities and Networks (ACTTION) public-private partnership with the U.S. Food and Drug Administration and the American Pain Society (APS) have joined together to develop an evidence-based chronic pain classification system called the ACTTION-APS Pain Taxonomy. This paper describes the outcome of an ACTTION-APS consensus meeting, at which experts agreed on a structure for this new taxonomy of chronic pain conditions. Several major issues around which discussion revolved are presented and summarized, and the structure of the taxonomy is presented. ACTTION-APS Pain Taxonomy will include the following dimensions: 1) core diagnostic criteria; 2) common features; 3) common medical comorbidities; 4) neurobiological, psychosocial, and functional consequences; and 5) putative neurobiological and psychosocial mechanisms, risk factors, and protective factors. In coming months, expert working groups will apply this taxonomy to clusters of chronic pain conditions, thereby developing a set of diagnostic criteria that have been consistently and systematically implemented across nearly all common chronic pain conditions. It is anticipated that the availability of this evidence-based and mechanistic approach to pain classification will be of substantial benefit to chronic pain research and treatment. The ACTTION-APS Pain Taxonomy is an evidence-based chronic pain classification system designed to classify chronic pain along the following dimensions: 1) core diagnostic criteria; 2) common features; 3) common medical comorbidities; 4) neurobiological, psychosocial

Do Subjects with Whiplash-Associated Disorders Respond Differently in the Short-Term to Manual Therapy and Exercise than Those with Mechanical Neck Pain?

Science.gov (United States)

Castaldo, Matteo; Catena, Antonella; Chiarotto, Alessandro; Fernández-de-Las-Peñas, César; Arendt-Nielsen, Lars

2017-04-01

To compare the short-term effects of manual therapy and exercise on pain, related disability, range of motion, and pressure pain thresholds between subjects with mechanical neck pain and whiplash-associated disorders. Twenty-two subjects with mechanical neck pain and 28 with whiplash-associated disorders participated. Clinical and physical outcomes including neck pain intensity, neck-related disability, and pain area, as well as cervical range of motion and pressure pain thresholds over the upper trapezius and tibialis anterior muscles, were obtained at baseline and after the intervention by a blinded assessor. Each subject received six sessions of manual therapy and specific neck exercises. Mixed-model repeated measures analyses of covariance (ANCOVAs) were used for the analyses. Subjects with whiplash-associated disorders exhibited higher neck-related disability ( P  = 0.021), larger pain area ( P  = 0.003), and lower pressure pain thresholds in the tibialis anterior muscle ( P  = 0.009) than those with mechanical neck pain. The adjusted ANCOVA revealed no between-group differences for any outcome (all P  > 0.15). A significant main effect of time was demonstrated for clinical outcomes and cervical range of motion with both groups experiencing similar improvements (all P   0.222). The current clinical trial found that subjects with mechanical neck pain and whiplash-associated disorders exhibited similar clinical and neurophysiological responses after a multimodal physical therapy intervention, suggesting that although greater signs of central sensitization are present in subjects with whiplash-associated disorders, this does not alter the response in the short term to manual therapy and exercises. © 2016 American Academy of Pain Medicine. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com

Screening for pain-persistence and pain-avoidance patterns in fibromyalgia.

NARCIS (Netherlands)

Koulil, S. van; Kraaimaat, F.W.; Lankveld, W.G.J.M. van; Helmond, T. van; Vedder, A.; Hoorn, H. van; Cats, H.; Riel, P.L.C.M. van; Evers, A.W.M.

2008-01-01

BACKGROUND: The heterogeneity of patients regarding pain-related cognitive-behavioral mechanisms, such as pain-avoidance and pain-persistence patterns, has been proposed to underlie varying treatment outcomes in patients with fibromyalgia (FM). PURPOSE: To investigate the validity of a screening

Distinct roles of basal forebrain cholinergic neurons in spatial and object recognition memory

OpenAIRE

Kana Okada; Kayo Nishizawa; Tomoko Kobayashi; Shogo Sakata; Kazuto Kobayashi

2015-01-01

Recognition memory requires processing of various types of information such as objects and locations. Impairment in recognition memory is a prominent feature of amnesia and a symptom of Alzheimer?s disease (AD). Basal forebrain cholinergic neurons contain two major groups, one localized in the medial septum (MS)/vertical diagonal band of Broca (vDB), and the other in the nucleus basalis magnocellularis (NBM). The roles of these cell groups in recognition memory have been debated, and it remai...

Abdominal pain in Irritable Bowel Syndrome: a review of putative psychological, neural and neuro-immune mechanisms.

Science.gov (United States)

Elsenbruch, Sigrid

2011-03-01

Chronic abdominal pain is a common symptom of great clinical significance in several areas of medicine. In many cases no organic cause can be established resulting in the classification as functional gastrointestinal disorder. Irritable Bowel Syndrome (IBS) is the most common of these conditions and is considered an important public health problem because it can be disabling and constitutes a major social and economic burden given the lack of effective treatments. IBS aetiology is most likely multi-factorial involving biological, psychological and social factors. Visceral hyperalgesia (or hypersensitivity) and visceral hypervigilance, which could be mediated by peripheral, spinal, and/or central pathways, constitute key concepts in current research on pathophysiological mechanisms of visceral hyperalgesia. The role of central nervous system mechanisms along the "brain-gut axis" is increasingly appreciated, owing to accumulating evidence from brain imaging studies that neural processing of visceral stimuli is altered in IBS together with long-standing knowledge regarding the contribution of stress and negative emotions to symptom frequency and severity. At the same time, there is also growing evidence suggesting that peripheral immune mechanisms and disturbed neuro-immune communication could play a role in the pathophysiology of visceral hyperalgesia. This review presents recent advances in research on the pathophysiology of visceral hyperalgesia in IBS, with a focus on the role of stress and anxiety in central and peripheral response to visceral pain stimuli. Together, these findings support that in addition to lower pain thresholds displayed by a significant proportion of patients, the evaluation of pain appears to be altered in IBS. This may be attributable to affective disturbances, negative emotions in anticipation of or during visceral stimulation, and altered pain-related expectations and learning processes. Disturbed "top-down" emotional and cognitive pain

Altering gender role expectations: effects on pain tolerance, pain threshold, and pain ratings.

Science.gov (United States)

Robinson, Michael E; Gagnon, Christine M; Riley, Joseph L; Price, Donald D

2003-06-01

The literature demonstrating sex differences in pain is sizable. Most explanations for these differences have focused on biologic mechanisms, and only a few studies have examined social learning. The purpose of this study was to examine the contribution of gender-role stereotypes to sex differences in pain. This study used experimental manipulation of gender-role expectations for men and women. One hundred twenty students participated in the cold pressor task. Before the pain task, participants were given 1 of 3 instructional sets: no expectation, 30-second performance expectation, or a 90-second performance expectation. Pain ratings, threshold, and tolerance were recorded. Significant sex differences in the "no expectation" condition for pain tolerance (t = 2.32, df = 38, P differ in their pain tolerance, pain threshold, or pain ratings. This is the first empirical study to show that manipulation of expectations alters sex differences in laboratory pain.

Experimental human pain models in gastro-esophageal reflux disease and unexplained chest pain

Science.gov (United States)

Drewes, Asbjørn Mohr; Arendt-Nielsen, Lars; Funch-Jensen, Peter; Gregersen, Hans

2006-01-01

Methods related to experimental human pain research aim at activating different nociceptors, evoke pain from different organs and activate specific pathways and mechanisms. The different possibilities for using mechanical, electrical, thermal and chemical methods in visceral pain research are discussed with emphasis of combinations (e.g., the multimodal approach). The methods have been used widely in assessment of pain mechanisms in the esophagus and have contributed to our understanding of the symptoms reported in these patients. Hence abnormal activation and plastic changes of central pain pathways seem to play a major role in the symptoms in some patients with gastro-esophageal reflux disease and in patients with functional chest pain of esophageal origin. These findings may lead to an alternative approach for treatment in patients that does not respond to conventional medical or surgical therapy. PMID:16718803

Long-term effects of cholinergic basal forebrain lesions on neuropeptide Y and somatostatin immunoreactivity in rat neocortex

NARCIS (Netherlands)

Gaykema, R.P.A.; Compaan, J.C.; Nyakas, C.; Horvath, E.; Luiten, P.G.M.

1989-01-01

The effect of cholinergic basal forebrain lesions on immunoreactivity to somatostatin (SOM-i) and neuropeptide-Y (NPY-i) was investigated in the rat parietal cortex, 16-18 months after multiple bilateral ibotenic acid injections in the nucleus basalis complex. As a result of the lesion, the

Elevated interleukin-8 enhances prefrontal synaptic transmission in mice with persistent inflammatory pain

Directory of Open Access Journals (Sweden)

Cui Guang-bin

2012-02-01

Full Text Available Abstract Background Interleukin-8 (IL-8 is known for its roles in inflammation and plays critical roles in the development of pain. Its expression increases in the brain after peripheral inflammation. Prefrontal cortex, including the anterior cingulate cortex (ACC, is a forebrain structure known for its roles in pain transmission and modulation. Painful stimuli potentiate the prefrontal synaptic transmission, however, little is known about the expression of IL-8 and its role in the enhanced ACC synaptic transmission in animals with persistent inflammatory pain. Findings In the present study, we examined IL-8 expression in the ACC, somatosensory cortex (SSC, and the dorsal horn of lumbar spinal cord following hind-paw administration of complete Freund's adjuvant (CFA in mice and its effects on the ACC synaptic transmission. Quantification of IL-8 at protein level (by ELISA revealed enhanced expression in the ACC and spinal cord during the chronic phases of CFA-induced peripheral inflammation. In vitro whole-cell patch-clamp recordings revealed that IL-8 significantly enhanced synaptic transmission through increased probability of neurotransmitter release in the ACC slice. ACC local infusion of repertaxin, a non-competitive allosteric blocker of IL-8 receptors, notably prolonged the paw withdrawal latency to thermal radian heat stimuli bilaterally in mice. Conclusions Our findings suggest that up-regulation of IL-8 in the ACC partly attributable to the enhanced prefrontal synaptic transmission in the mice with persistent inflammatory pain.

Mental Health Comorbidities in Pediatric Chronic Pain: A Narrative Review of Epidemiology, Models, Neurobiological Mechanisms and Treatment

Directory of Open Access Journals (Sweden)

Jillian Vinall

2016-12-01

Full Text Available Chronic pain during childhood and adolescence can lead to persistent pain problems and mental health disorders into adulthood. Posttraumatic stress disorders and depressive and anxiety disorders are mental health conditions that co-occur at high rates in both adolescent and adult samples, and are linked to heightened impairment and disability. Comorbid chronic pain and psychopathology has been explained by the presence of shared neurobiology and mutually maintaining cognitive-affective and behavioral factors that lead to the development and/or maintenance of both conditions. Particularly within the pediatric chronic pain population, these factors are embedded within the broader context of the parent–child relationship. In this review, we will explore the epidemiology of, and current working models explaining, these comorbidities. Particular emphasis will be made on shared neurobiological mechanisms, given that the majority of previous research to date has centered on cognitive, affective, and behavioral mechanisms. Parental contributions to co-occurring chronic pain and psychopathology in childhood and adolescence will be discussed. Moreover, we will review current treatment recommendations and future directions for both research and practice. We argue that the integration of biological and behavioral approaches will be critical to sufficiently address why these comorbidities exist and how they can best be targeted in treatment.

Defects in GPI biosynthesis perturb Cripto signaling during forebrain development in two new mouse models of holoprosencephaly

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David M. McKean

2012-07-01

Holoprosencephaly is the most common forebrain defect in humans. We describe two novel mouse mutants that display a holoprosencephaly-like phenotype. Both mutations disrupt genes in the glycerophosphatidyl inositol (GPI biosynthesis pathway: gonzo disrupts Pign and beaker disrupts Pgap1. GPI anchors normally target and anchor a diverse group of proteins to lipid raft domains. Mechanistically we show that GPI anchored proteins are mislocalized in GPI biosynthesis mutants. Disruption of the GPI-anchored protein Cripto (mouse and TDGF1 (human ortholog have been shown to result in holoprosencephaly, leading to our hypothesis that Cripto is the key GPI anchored protein whose altered function results in an HPE-like phenotype. Cripto is an obligate Nodal co-factor involved in TGFβ signaling, and we show that TGFβ signaling is reduced both in vitro and in vivo. This work demonstrates the importance of the GPI anchor in normal forebrain development and suggests that GPI biosynthesis genes should be screened for association with human holoprosencephaly.

A COMPARATIVE STUDY TO FIND OUT THE EFFECTIVENESS BETWEEN CORE STABILIZATION VS MCKENZIE EXERCISES IN THE TREATMENT OF PATIENTS WITH MECHANICAL LOW BACK PAIN

Directory of Open Access Journals (Sweden)

Abhijit Dutta

2015-10-01

Full Text Available Background: Mechanical Low back pain is a leading cause of disability. It occurs in similar proportions in all cultures, interferes with quality of life and work performance. Both male and female populations are affected; however, there is a tendency towards a higher incidence in male patients. Mechanical low back pain is associated with pain and clinical instability in lumbar motion segments. Exercises play an important part in the rehabilitation of low back pain. The aim of this study was to compare the effectiveness between Core stabilization vs McKenzie exercises in the treatment of patients with mechanical low back pain. Methods: 30 patients were selected between the age groups of 20 yrs to 50 yrs and having a past history of low back pain for one month. 15 patients were allotted to each group of experiment. Group I was given Core stabilization exercises and Group II with McKenzie exercises. Interferential therapy was a common treatment for both the groups. Evaluations of the subjects were done using the Revised Oswestry Disability Index and Dynamic Endurance tests. Results: Data analysis revealed statistically significant difference between both the groups (p<0.05 and proved that Core stabilization exercises is more effective than McKenzie exercises in mechanical low back pain. Conclusion: This study shows that core stabilization exercises possess a greater potential over McKenzie exercises in treating Mechanical Low back pain patients.

Do Australian Football players have sensitive groins? Players with current groin pain exhibit mechanical hyperalgesia of the adductor tendon.

Science.gov (United States)

Drew, Michael K; Lovell, Gregory; Palsson, Thorvaldur S; Chiarelli, Pauline E; Osmotherly, Peter G

2016-10-01

This is the first study to evaluate the mechanical sensitivity, clinical classifications and prevalence of groin pain in Australian football players. Case-control. Professional (n=66) and semi-professional (n=9) Australian football players with and without current or previous groin injuries were recruited. Diagnoses were mapped to the Doha Agreement taxonomy. Point and career prevalence of groin pain was calculated. Pressure pain thresholds (PPTs) were assessed at regional and distant sites using handheld pressure algometry across four sites bilaterally (adductor longus tendon, pubic bone, rectus femoris, tibialis anterior muscle). To assess the relationship between current groin pain and fixed effects of hyperalgesia of each site and a history of groin pain, a mixed-effect logistic regression model was utilised. Receiver Operator Characteristic (ROC) curve were determined for the model. Point prevalence of groin pain in the preseason was 21.9% with a career prevalence of 44.8%. Adductor-related groin pain was the most prevalent classification in the pre-season period. Hyperalgesia was observed in the adductor longus tendon site in athletes with current groin pain (OR=16.27, 95% CI 1.86 to 142.02). The ROC area under the curve of the regression model was fair (AUC=0.76, 95% CI 0.54 to 0.83). Prevalence data indicates that groin pain is a larger issue than published incidence rates imply. Adductor-related groin pain is the most common diagnosis in pre-season in this population. This study has shown that hyperalgesia exists in Australian football players experiencing groin pain indicating the value of assessing mechanical pain sensitivity as a component of the clinical assessment. Copyright © 2016 Sports Medicine Australia. Published by Elsevier Ltd. All rights reserved.

Chronic post-thoracotomy pain: a critical review of pathogenic mechanisms and strategies for prevention

DEFF Research Database (Denmark)

Wildgaard, Kim; Ravn, Jesper; Kehlet, Henrik

2009-01-01

Chronic pain complaints after thoracic surgery represent a significant clinical problem in 25-60% of patients. Results from thoracic and other surgical procedures suggest multiple pathogenic mechanisms that include pre-, intra-, and postoperative factors. This review attempts to analyse the metho...

The impact of experiential avoidance on the relations between illness representations, pain catastrophising and pain interference in chronic pain.

Science.gov (United States)

Karademas, Evangelos C; Karekla, Maria; Flouri, Magdalini; Vasiliou, Vasilis S; Kasinopoulos, Orestis; Papacostas, Savvas S

2017-12-01

The aim of this study was to examine the effects of experiential avoidance (EA) on the indirect relationship of chronic pain patients' illness representations to pain interference, through pain catastrophising Design and main outcome measure: The sample consisted of 162 patients diagnosed with an arthritis-related or a musculoskeletal disorder. The effects of EA on the pathway between illness representations, pain catastrophising and pain interference were examined with PROCESS, a computational tool for SPSS Results: After controlling for patient and illness-related variables and pain severity, the 'illness representations-pain catastrophising-pain interference' pathway was interrupted at the higher levels of EA. The reason was that, at the high levels of EA, either the relation of illness representations to pain catastrophising or the relation of pain catastrophising to pain interference was not statistically significant. The findings indicate that EA is not a generalised negative response to highly aversive conditions, at least as far as the factors examined in this study are concerned. EA may rather reflect a coping reaction, the impact of which depends on its specific interactions with the other aspects of the self-regulation mechanism. At least in chronic pain, EA should become the focus of potential intervention only when its interaction with the illness-related self-regulation mechanism results in negative outcomes.

The amygdala and basal forebrain as a pathway for motivationally guided attention.

Science.gov (United States)

Peck, Christopher J; Salzman, C Daniel

2014-10-08

Visual stimuli associated with rewards attract spatial attention. Neurophysiological mechanisms that mediate this process must register both the motivational significance and location of visual stimuli. Recent neurophysiological evidence indicates that the amygdala encodes information about both of these parameters. Furthermore, the firing rate of amygdala neurons predicts the allocation of spatial attention. One neural pathway through which the amygdala might influence attention involves the intimate and bidirectional connections between the amygdala and basal forebrain (BF), a brain area long implicated in attention. Neurons in the rhesus monkey amygdala and BF were therefore recorded simultaneously while subjects performed a detection task in which the stimulus-reward associations of visual stimuli modulated spatial attention. Neurons in BF were spatially selective for reward-predictive stimuli, much like the amygdala. The onset of reward-predictive signals in each brain area suggested different routes of processing for reward-predictive stimuli appearing in the ipsilateral and contralateral fields. Moreover, neurons in the amygdala, but not BF, tracked trial-to-trial fluctuations in spatial attention. These results suggest that the amygdala and BF could play distinct yet inter-related roles in influencing attention elicited by reward-predictive stimuli. Copyright © 2014 the authors 0270-6474/14/3413757-11$15.00/0.

Zic-Proteins Are Repressors of Dopaminergic Forebrain Fate in Mice and C. elegans.

Science.gov (United States)

Tiveron, Marie-Catherine; Beclin, Christophe; Murgan, Sabrina; Wild, Stefan; Angelova, Alexandra; Marc, Julie; Coré, Nathalie; de Chevigny, Antoine; Herrera, Eloisa; Bosio, Andreas; Bertrand, Vincent; Cremer, Harold

2017-11-01

In the postnatal forebrain regionalized neural stem cells along the ventricular walls produce olfactory bulb (OB) interneurons with varying neurotransmitter phenotypes and positions. To understand the molecular basis of this region-specific variability we analyzed gene expression in the postnatal dorsal and lateral lineages in mice of both sexes from stem cells to neurons. We show that both lineages maintain transcription factor signatures of their embryonic site of origin, the pallium and subpallium. However, additional factors, including Zic1 and Zic2, are postnatally expressed in the dorsal stem cell compartment and maintained in the lineage that generates calretinin-positive GABAergic neurons for the OB. Functionally, we show that Zic1 and Zic2 induce the generation of calretinin-positive neurons while suppressing dopaminergic fate in the postnatal dorsal lineage. We investigated the evolutionary conservation of the dopaminergic repressor function of Zic proteins and show that it is already present in C. elegans SIGNIFICANCE STATEMENT The vertebrate brain generates thousands of different neuron types. In this work we investigate the molecular mechanisms underlying this variability. Using a genomics approach we identify the transcription factor signatures of defined neural stem cells and neuron populations. Based thereon we show that two related transcription factors, Zic1 and Zic2, are essential to control the balance between two defined neuron types in the postnatal brain. We show that this mechanism is conserved in evolutionary very distant species. Copyright © 2017 the authors 0270-6474/17/3710611-13$15.00/0.

Basal forebrain motivational salience signal enhances cortical processing and decision speed

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Sylvina M Raver

2015-10-01

Full Text Available The basal forebrain (BF contains major projections to the cerebral cortex, and plays a well-documented role in arousal, attention, decision-making, and in modulating cortical activity. BF neuronal degeneration is an early event in Alzheimer’s disease and dementias, and occurs in normal cognitive aging. While the BF is best known for its population of cortically projecting cholinergic neurons, the region is anatomically and neurochemically diverse, and also contains prominent populations of non-cholinergic projection neurons. In recent years, increasing attention has been dedicated to these non-cholinergic BF neurons in order to better understand how non-cholinergic BF circuits control cortical processing and behavioral performance. In this review, we focus on a unique population of putative non-cholinergic BF neurons that encodes the motivational salience of stimuli with a robust ensemble bursting response. We review recent studies that describe the specific physiological and functional characteristics of these BF salience-encoding neurons in behaving animals. These studies support the unifying hypothesis whereby BF salience-encoding neurons act as a gain modulation mechanism of the decision-making process to enhance cortical processing of behaviorally relevant stimuli, and thereby facilitate faster and more precise behavioral responses. This function of BF salience-encoding neurons represents a critical component in determining which incoming stimuli warrant an animal’s attention, and is therefore a fundamental and early requirement of behavioral flexibility.

A positron emission tomography study of wind-up pain in chronic postherniotomy pain

DEFF Research Database (Denmark)

Kupers, Ron; Lonsdale, Markus Georg; Aasvang, Eske Kvanner

2011-01-01

-induced wind-up pain in neuropathic pain patients. We therefore used positron emission tomography (PET) to investigate the cerebral response pattern of mechanical wind-up pain in a homogenous group of 10 neuropathic pain patients with long-standing postherniotomy pain in the groin area. Patients were scanned...

Ablation of CaV2.1 Voltage-Gated Ca2+ Channels in Mouse Forebrain Generates Multiple Cognitive Impairments

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Mallmann, Robert Theodor; Elgueta, Claudio; Sleman, Faten; Castonguay, Jan; Wilmes, Thomas; van den Maagdenberg, Arn; Klugbauer, Norbert

2013-01-01

Voltage-gated CaV2.1 (P/Q-type) Ca2+ channels located at the presynaptic membrane are known to control a multitude of Ca2+-dependent cellular processes such as neurotransmitter release and synaptic plasticity. Our knowledge about their contributions to complex cognitive functions, however, is restricted by the limited adequacy of existing transgenic CaV2.1 mouse models. Global CaV2.1 knock-out mice lacking the α1 subunit Cacna1a gene product exhibit early postnatal lethality which makes them unsuitable to analyse the relevance of CaV2.1 Ca2+ channels for complex behaviour in adult mice. Consequently we established a forebrain specific CaV2.1 knock-out model by crossing mice with a floxed Cacna1a gene with mice expressing Cre-recombinase under the control of the NEX promoter. This novel mouse model enabled us to investigate the contribution of CaV2.1 to complex cognitive functions, particularly learning and memory. Electrophysiological analysis allowed us to test the specificity of our conditional knock-out model and revealed an impaired synaptic transmission at hippocampal glutamatergic synapses. At the behavioural level, the forebrain-specific CaV2.1 knock-out resulted in deficits in spatial learning and reference memory, reduced recognition memory, increased exploratory behaviour and a strong attenuation of circadian rhythmicity. In summary, we present a novel conditional CaV2.1 knock-out model that is most suitable for analysing the in vivo functions of CaV2.1 in the adult murine forebrain. PMID:24205277

Salvinorin A preserves cerebral pial artery autoregulation after forebrain ischemia via the PI3K/AKT/cGMP pathway

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H.P. Dong

2018-03-01

Full Text Available This study aimed to investigate the protective effect of salvinorin A on the cerebral pial artery after forebrain ischemia and explore related mechanisms. Thirty Sprague-Dawley rats received forebrain ischemia for 10 min. The dilation responses of the cerebral pial artery to hypercapnia and hypotension were assessed in rats before and 1 h after ischemia. The ischemia reperfusion (IR control group received DMSO (1 µL/kg immediately after ischemia. Two different doses of salvinorin A (10 and 20 µg/kg were administered following the onset of reperfusion. The 5th, 6th, and 7th groups received salvinorin A (20 µg/kg and LY294002 (10 µM, L-NAME (10 μM, or norbinaltorphimine (norBIN, 1 μM after ischemia. The levels of cGMP in the cerebrospinal fluid (CSF were also measured. The phosphorylation of AKT (p-AKT was measured in the cerebral cortex by western blot at 24 h post-ischemia. Cell necrosis and apoptosis were examined by hematoxylin-eosin staining (HE and TUNEL staining, respectively. The motor function of the rats was evaluated at 1, 2, and 5 days post-ischemia. The dilation responses of the cerebral pial artery were significantly impaired after ischemia and were preserved by salvinorin A treatment. In addition, salvinorin A significantly increased the levels of cGMP and p-AKT, suppressed cell necrosis and apoptosis of the cerebral cortex and improved the motor function of the rats. These effects were abolished by LY294002, L-NAME, and norBIN. Salvinorin A preserved cerebral pial artery autoregulation in response to hypercapnia and hypotension via the PI3K/AKT/cGMP pathway.

Pharmacologic management of neuropathic pain.

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Gordon, Debra B; Love, Georgette

2004-12-01

The mechanisms underlying the pathogenesis of neuropathic pain are complex but are gradually coming to light. Agents that have been found effective in a variety of neuropathic pain conditions include drugs that act to modulate (a) sodium or calcium channels, (b) N-methyl-D-aspartate receptors, (c) norepinephrine or serotonin reuptake, (d) opioid receptors, and (e) other cellular processes. Clinical trials have primarily evaluated these treatments for postherpetic neuralgia and painful diabetic neuropathy, the two most common types of neuropathic pain. Nonetheless, the identification of effective treatment regimens remains challenging, often because multiple mechanisms may be operating in a given patient giving rise to the same symptom. Alternatively, a single mechanism may be responsible for multiple symptoms. Currently available diagnostic tools are inadequate to determine the best treatment using a mechanism-based model. Clinically, drug treatment of neuropathic pain is often a matter of treatment trials. This article presents a summary of available clinical information on first-line and lesser-known treatments for neuropathic pain.

Pain relief with lidocaine 5% patch in localized peripheral neuropathic pain in relation to pain phenotype

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Torgaard Demant, Dyveke; Lund, Karen; Finnerup, Nanna B

2015-01-01

In neuropathic pain with irritable nociceptor phenotype, up-regulation of sodium channels on nociceptors is supposed to be an important pain mechanism that may be targeted by topical sodium channel blockade. This randomised, double-blind, phenotype-panel, cross-over study with 4-week treatment pe...... had an effect on peripheral neuropathic pain, and it may be most efficacious in patients with irritable nociceptor phenotype. The lack of significant phenotype differences may be caused by too low statistical power.......In neuropathic pain with irritable nociceptor phenotype, up-regulation of sodium channels on nociceptors is supposed to be an important pain mechanism that may be targeted by topical sodium channel blockade. This randomised, double-blind, phenotype-panel, cross-over study with 4-week treatment...... periods of lidocaine 5% patch and placebo was performed to search for phenotype differences in effect. The primary efficacy measure was the total pain intensity on an 11-point numeric rating scale (NRS), and the primary objective was to compare the effect of lidocaine in patients with and without...

Back pain in space and post-flight spine injury: Mechanisms and countermeasure development

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Sayson, Jojo V.; Lotz, Jeffrey; Parazynski, Scott; Hargens, Alan R.

2013-05-01

During spaceflight many astronauts experience moderate to severe lumbar pain and deconditioning of paraspinal muscles. There is also a significant incidence of herniated nucleus pulposus (HNP) in astronauts post-flight being most prevalent in cervical discs. Relief of in-flight lumbar back pain is facilitated by assuming a knee-to-chest position. The pathogenesis of lumbar back pain during spaceflight is most likely discogenic and somatic referred (from the sinuvertebral nerves) due to supra-physiologic swelling of the lumbar intervertebral discs (IVDs) due to removal of gravitational compressive loads in microgravity. The knee-to-chest position may reduce lumbar back pain by redistributing stresses through compressive loading to the IVDs, possibly reducing disc volume by fluid outflow across IVD endplates. IVD stress redistribution may reduce Type IV mechanoreceptor nerve impulse propagation in the annulus fibrosus and vertebral endplate resulting in centrally mediated pain inhibition during spinal flexion. Countermeasures for lumbar back pain may include in-flight use of: (1) an axial compression harness to prevent excessive IVD expansion and spinal column elongation; (2) the use of an adjustable pulley exercise developed to prevent atrophy of spine muscle stabilisers; and (3) other exercises that provide Earth-like annular stress with low-load repetitive active spine rotation movements. The overall objective of these countermeasures is to promote IVD health and to prevent degenerative changes that may lead to HNPs post-flight. In response to "NASA's Critical Path Roadmap Risks and Questions" regarding disc injury and higher incidence of HNPs after space flight (Integrated Research Plan Gap-B4), future studies will incorporate pre- and post-flight imaging of International Space Station long-duration crew members to investigate mechanisms of lumbar back pain as well as degeneration and damage to spinal structures. Quantitative results on morphological, biochemical

Pronociceptive pain modulation in patients with painful chemotherapy-induced polyneuropathy.

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Nahman-Averbuch, Hadas; Yarnitsky, David; Granovsky, Yelena; Sprecher, Elliot; Steiner, Mariana; Tzuk-Shina, Tzahala; Pud, Dorit

2011-08-01

Several chemotherapy agents induce polyneuropathy that is painful for some patients, but not for others. We assumed that these differences might be attributable to varying patterns of pain modulation. The aim of the present study was to evaluate pain modulation in such patients. Twenty-seven patients with chemotherapy-induced polyneuropathy were tested for detection thresholds (cold, warm, and mechanical) in both the forearm and foot, as well as for heat pain threshold, mechanical temporal summation (TS), and conditioned pain modulation (CPM; also known as the diffuse noxious inhibitory control-like effect), which were tested in the upper limbs. Positive correlations were found between clinical pain levels and both TS (r=0.52, P=0.005) and CPM (r=0.40, P=0.050) for all patients. In addition, higher TS was associated with less efficient CPM (r=0.56, P=0.004). The group of patients with painful polyneuropathy (n=12) showed a significantly higher warm detection threshold in the foot (P=0.03), higher TS (P<0.01), and less efficient CPM (P=0.03) in comparison to the group with nonpainful polyneuropathy. The painfulness of polyneuropathy is associated with a "pronociceptive" modulation pattern, which may be primary to the development of pain. The higher warm sensory thresholds in the painful polyneuropathy group suggest that the severity of polyneuropathy may be another factor in determining its painfulness. Copyright © 2011 U.S. Cancer Pain Relief Committee. Published by Elsevier Inc. All rights reserved.

Mast cell deficiency attenuates acupuncture analgesia for mechanical pain using c-kit gene mutant rats

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Cui X

2018-03-01

Full Text Available Xiang Cui,1,2,* Kun Liu,1,* Dandan Xu,1,3 Youyou Zhang,1,4 Xun He,1 Hao Liu,1,5 Xinyan Gao,1 Bing Zhu1 1Department of Physiology, Institute of Acupuncture and Moxibustion, China Academy of Chinese Medical Sciences, Beijing, China; 2College of Acupuncture and Orthopedics, Hubei University of Chinese Medicine, Wuhan, China; 3Classic TCM Department, The Affiliated Hospital of Shandong University of TCM, Jinan, China; 4Acupuncture and Massage Department, Hangzhou Qihuang Traditional Chinese Medicine Clinic, Hangzhou, China; 5TCM and Rehabilitation Department, The Third Hospital of Ulanchap, Ulanchap, China *These authors contributed equally to this work Background: Acupuncture therapy plays a pivotal role in pain relief, and increasing evidence demonstrates that mast cells (MCs may mediate acupuncture analgesia. The present study aims to investigate the role of MCs in acupuncture analgesia using c-kit gene mutant–induced MC-deficient rats. Materials and methods: WsRC-Ws/Ws rats and their wild-type (WT littermates (WsRC-+/+ were used. The number of MCs in skin of ST36 area was compared in two rats after immunofluorescence labeling. Mechanical withdrawal latency (MWL, mechanical withdrawal threshold (MWT, and thermal withdrawal latency (TWL were measured on bilateral plantar for pain threshold evaluation before and after each stimulus. Acupuncture- and moxibustion-like stimuli (43°C, 46°C heat, 1 mA electroacupuncture [EA], 3 mA EA, and manual acupuncture [MA] were applied randomly on different days. Results: Fewer MCs were observed in the skin of ST36 in mutant rats compared to WT rats (P<0.001. For pain thresholds, MWL and MWT were higher in WsRC-Ws/Ws compared to WsRC-+/+ on bilateral paws (P<0.05, but TWL was not different between the two rats (P>0.05. Bilateral MWL and MWT in WsRC-+/+ rats increased significantly after each stimulus compared to baseline (P<0.01, P<0.001. In WsRC-Ws/Ws rats, only noxious stimuli could produce antinociceptive

Cerebral interactions of pain and reward and their relevance for chronic pain.

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Becker, Susanne; Gandhi, Wiebke; Schweinhardt, Petra

2012-06-29

Pain and reward are opponent, interacting processes. Such interactions are enabled by neuroanatomical and neurochemical overlaps of brain systems that process pain and reward. Cerebral processing of hedonic ('liking') and motivational ('wanting') aspects of reward can be separated: the orbitofrontal cortex and opioids play an important role for the hedonic experience, and the ventral striatum and dopamine predominantly process motivation for reward. Supported by neuroimaging studies, we present here the hypothesis that the orbitofrontal cortex and opioids are responsible for pain modulation by hedonic experience, while the ventral striatum and dopamine mediate motivational effects on pain. A rewarding stimulus that appears to be particularly important in the context of pain is pain relief. Further, reward, including pain relief, leads to operant learning, which can affect pain sensitivity. Indirect evidence points at brain mechanisms that might underlie pain relief as a reward and related operant learning but studies are scarce. Investigating the cerebral systems underlying pain-reward interactions as well as related operant learning holds the potential of better understanding mechanisms that contribute to the development and maintenance of chronic pain, as detailed in the last section of this review. Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.

The recognition and evaluation of patterns of compensatory injury in patients with mechanical hip pain.

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Hammoud, Sommer; Bedi, Asheesh; Voos, James E; Mauro, Craig S; Kelly, Bryan T

2014-03-01

In active individuals with femoroacetabular impingement (FAI), the resultant reduction in functional range of motion leads to high impaction loads at terminal ranges. These increased forces result in compensatory effects on bony and soft tissue structures within the hip joint and hemipelvis. An algorithm is useful in evaluating athletes with pre-arthritic, mechanical hip pain and associated compensatory disorders. A literature search was performed by a review of PubMed articles published from 1976 to 2013. Level 4. Increased stresses across the bony hemipelvis result when athletes with FAI attempt to achieve supraphysiologic, terminal ranges of motion (ROM) through the hip joint required for athletic competition. This can manifest as pain within the pubic joint (osteitis pubis), sacroiliac joint, and lumbosacral spine. Subclinical posterior hip instability may result when attempts to increase hip flexion and internal rotation are not compensated for by increased motion through the hemipelvis. Prominence of the anterior inferior iliac spine (AIIS) at the level of the acetabular rim can result in impingement of the anterior hip joint capsule or iliocapsularis muscle origin against the femoral head-neck junction, resulting in a distinct form of mechanical hip impingement (AIIS subspine impingement). Iliopsoas impingement (IPI) has also been described as an etiology for anterior hip pain. IPI results in a typical 3-o'clock labral tear as well as an inflamed capsule in close proximity to the overlying iliopsoas tendon. Injury in athletic pubalgia occurs during high-energy twisting activities in which abnormal hip ROM and resultant pelvic motion lead to shearing across the pubic symphysis. Failure to recognize and address concomitant compensatory injury patterns associated with intra-articular hip pathology can result in significant disability and persistent symptoms in athletes with pre-arthritic, mechanical hip pain. B.

Mechanisms of disease: mechanism-based classification of neuropathic pain - a critical analysis

DEFF Research Database (Denmark)

Finnerup, Nanna Brix; Jensen, Troels Staehelin

2006-01-01

Classification of neuropathic pain according to etiology or localization has clear limitations. The discovery of specific molecular and cellular events following experimental nerve injury has raised the possibility of classifying neuropathic pain on the basis of the underlying neurobiological...

Transcriptional Profiling of Cholinergic Neurons From Basal Forebrain Identifies Changes in Expression of Genes Between Sleep and Wake.

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Nikonova, Elena V; Gilliland, Jason DA; Tanis, Keith Q; Podtelezhnikov, Alexei A; Rigby, Alison M; Galante, Raymond J; Finney, Eva M; Stone, David J; Renger, John J; Pack, Allan I; Winrow, Christopher J

2017-06-01

To assess differences in gene expression in cholinergic basal forebrain cells between sleeping and sleep-deprived mice sacrificed at the same time of day. Tg(ChAT-eGFP)86Gsat mice expressing enhanced green fluorescent protein (eGFP) under control of the choline acetyltransferase (Chat) promoter were utilized to guide laser capture of cholinergic cells in basal forebrain. Messenger RNA expression levels in these cells were profiled using microarrays. Gene expression in eGFP(+) neurons was compared (1) to that in eGFP(-) neurons and to adjacent white matter, (2) between 7:00 am (lights on) and 7:00 pm (lights off), (3) between sleep-deprived and sleeping animals at 0, 3, 6, and 9 hours from lights on. There was a marked enrichment of ChAT and other markers of cholinergic neurons in eGFP(+) cells. Comparison of gene expression in these eGFP(+) neurons between 7:00 am and 7:00 pm revealed expected differences in the expression of clock genes (Arntl2, Per1, Per2, Dbp, Nr1d1) as well as mGluR3. Comparison of expression between spontaneous sleep and sleep-deprived groups sacrificed at the same time of day revealed a number of transcripts (n = 55) that had higher expression in sleep deprivation compared to sleep. Genes upregulated in sleep deprivation predominantly were from the protein folding pathway (25 transcripts, including chaperones). Among 42 transcripts upregulated in sleep was the cold-inducible RNA-binding protein. Cholinergic cell signatures were characterized. Whether the identified genes are changing as a consequence of differences in behavioral state or as part of the molecular regulatory mechanism remains to be determined. © Sleep Research Society 2017. Published by Oxford University Press on behalf of the Sleep Research Society. All rights reserved. For permissions, please e-mail journals.permissions@oup.com.

Dual role for DOCK7 in tangential migration of interneuron precursors in the postnatal forebrain.

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Nakamuta, Shinichi; Yang, Yu-Ting; Wang, Chia-Lin; Gallo, Nicholas B; Yu, Jia-Ray; Tai, Yilin; Van Aelst, Linda

2017-12-04

Throughout life, stem cells in the ventricular-subventricular zone generate neuroblasts that migrate via the rostral migratory stream (RMS) to the olfactory bulb, where they differentiate into local interneurons. Although progress has been made toward identifying extracellular factors that guide the migration of these cells, little is known about the intracellular mechanisms that govern the dynamic reshaping of the neuroblasts' morphology required for their migration along the RMS. In this study, we identify DOCK7, a member of the DOCK180-family, as a molecule essential for tangential neuroblast migration in the postnatal mouse forebrain. DOCK7 regulates the migration of these cells by controlling both leading process (LP) extension and somal translocation via distinct pathways. It controls LP stability/growth via a Rac-dependent pathway, likely by modulating microtubule networks while also regulating F-actin remodeling at the cell rear to promote somal translocation via a previously unrecognized myosin phosphatase-RhoA-interacting protein-dependent pathway. The coordinated action of both pathways is required to ensure efficient neuroblast migration along the RMS. © 2017 Nakamuta et al.

Spinal cord stimulation of dorsal columns in a rat model of neuropathic pain: evidence for a segmental spinal mechanism of pain relief.

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Smits, H; van Kleef, M; Joosten, E A

2012-01-01

Although spinal cord stimulation (SCS) of the dorsal columns is an established method for treating chronic neuropathic pain, patients still suffer from a substantial level of pain. From a clinical perspective it is known that the location of the SCS is of pivotal importance, thereby suggesting a segmental spinal mode of action. However, experimental studies suggest that SCS acts also through the modulation of supraspinal mechanisms, which might suggest that the location is unimportant. Here we investigated the effect of the rostrocaudal location of SCS stimulation and the effectiveness of pain relief in a rat model of chronic neuropathic pain. Adult male rats (n=45) were submitted to a partial ligation of the sciatic nerve. The majority of animals developed tactile hypersensitivity in the nerve lesioned paw. All allodynic rats were submitted to SCS (n=33) for 30 minutes (f=50 Hz; pulse width 0.2 ms). In one group (n=16) the electrodes were located at the level where the injured sciatic nerve afferents enter the spinal cord (T13), and in a second group (n=17) the electrodes were positioned at more rostral levels (T11) as verified by X-ray. A repositioning experiment of electrodes from T12 to T13 was performed in 2 animals. Our data demonstrate that SCS of the dorsal columns at the level where the injured fibers enter the spinal cord dorsal horn result in a much better pain-relieving effect than SCS at more rostral levels. From this we conclude that SCS in treatment of neuropathic pain acts through a segmental spinal site of action. Copyright © 2011 International Association for the Study of Pain. Published by Elsevier B.V. All rights reserved.

Progranulin contributes to endogenous mechanisms of pain defense after nerve injury in mice.

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Lim, Hee-Young; Albuquerque, Boris; Häussler, Annett; Myrczek, Thekla; Ding, Aihao; Tegeder, Irmgard

2012-04-01

Progranulin haploinsufficiency is associated with frontotemporal dementia in humans. Deficiency of progranulin led to exaggerated inflammation and premature aging in mice. The role of progranulin in adaptations to nerve injury and neuropathic pain are still unknown. Here we found that progranulin is up-regulated after injury of the sciatic nerve in the mouse ipsilateral dorsal root ganglia and spinal cord, most prominently in the microglia surrounding injured motor neurons. Progranulin knockdown by continuous intrathecal spinal delivery of small interfering RNA after sciatic nerve injury intensified neuropathic pain-like behaviour and delayed the recovery of motor functions. Compared to wild-type mice, progranulin-deficient mice developed more intense nociceptive hypersensitivity after nerve injury. The differences escalated with aging. Knockdown of progranulin reduced the survival of dissociated primary neurons and neurite outgrowth, whereas addition of recombinant progranulin rescued primary dorsal root ganglia neurons from cell death induced by nerve growth factor withdrawal. Thus, up-regulation of progranulin after neuronal injury may reduce neuropathic pain and help motor function recovery, at least in part, by promoting survival of injured neurons and supporting regrowth. A deficiency in this mechanism may increase the risk for injury-associated chronic pain. © 2011 The Authors Journal of Cellular and Molecular Medicine © 2011 Foundation for Cellular and Molecular Medicine/Blackwell Publishing Ltd.

Spinal high-mobility group box 1 contributes to mechanical allodynia in a rat model of bone cancer pain

International Nuclear Information System (INIS)

Tong, Wei; Wang, Wei; Huang, Jing; Ren, Ning; Wu, Sheng-Xi; Li, Yong-Qi

2010-01-01

Mechanisms underlying bone cancer-induced pain are largely unknown. Previous studies indicate that neuroinflammation in the spinal dorsal horn is especially involved. Being first reported as a nonhistone chromosomal protein, high-mobility group box 1 (HMGB1) is now implicated as a mediator of inflammation. We hypothesized that HMGB1 could trigger the release of cytokines in the spinal dorsal horn and contribute to bone cancer pain. To test this hypothesis, we first built a bone cancer pain model induced by intratibal injection of Walker 256 mammary gland carcinoma cells. The structural damage to the tibia was monitored by radiological analysis. The mechanical allodynia was measured and the expression of spinal HMGB1 and IL-1β was evaluated. We observed that inoculation of cancer cells, but not heat-killed cells, induced progressive bone destruction from 9 d to 21 d post inoculation. Behavioral tests demonstrated that the significant nociceptive response in the cancer cells-injected rats emerged on day 9 and this kind of mechanical allodynia lasted at least 21 d following inoculation. Tumor cells inoculation significantly increased HMGB1 expression in the spinal dorsal horn, while intrathecal injecting a neutralizing antibody against HMGB1 showed an effective and reliable anti-allodynia effect with a dose-dependent manner. IL-1β was significantly increased in caner pain rats while intrathecally administration of anti-HMGB1 could decrease IL-1β. Together with previous reports, we predict that bone cancer induces HMGB1 production, enhancing spinal IL-1β expression and thus modulating spinal excitatory synaptic transmission and pain response.

Efficient in vivo electroporation of the postnatal rodent forebrain.

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Camille Boutin

Full Text Available Functional gene analysis in vivo represents still a major challenge in biomedical research. Here we present a new method for the efficient introduction of nucleic acids into the postnatal mouse forebrain. We show that intraventricular injection of DNA followed by electroporation induces strong expression of transgenes in radial glia, neuronal precursors and neurons of the olfactory system. We present two proof-of-principle experiments to validate our approach. First, we show that expression of a human isoform of the neural cell adhesion molecule (hNCAM-140 in radial glia cells induces their differentiation into cells showing a neural precursor phenotype. Second, we demonstrate that p21 acts as a cell cycle inhibitor for postnatal neural stem cells. This approach will represent an important tool for future studies of postnatal neurogenesis and of neural development in general.

Chronic Lateral Epicondylalgia Does Not Exhibit Mechanical Pain Modulation in Response to Noxious Conditioning Heat Stimulus.

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Lim, Edwin Choon Wyn; Sterling, Michele; Vicenzino, Bill

2017-10-01

The impaired attenuation of pain by the application of a noxious conditioning stimulus at a segmentally distinct site, known as conditioned pain modulation (CPM), has been implicated in clinical pain states. Chronic lateral epicondylalgia (LE), which is characterized by lower pressure pain thresholds (PPTs) at sites remote to the affected elbow and spinal cord hyperexcitability, is a clinical pain state that might plausibly involve less efficacious CPM. This study aimed to determine whether LE exhibits a less efficacious CPM compared with that in pain-free controls. Results: Twenty participants with LE, aged 50.7 years (SD=7.05) and who had their condition for 10.2 months (range: 2 to 80 mo), were matched by age and sex to 22 pain-free participants. All participants indicated their PPT over the lateral epicondyle(s) before and during a conditioning noxious heat stimulus that was applied over the calf. A CPM score was calculated as the difference between the PPT before and during the heat pain-conditioning stimulus expressed as a percentage of PPT before the heat pain-conditioning stimulus. The condition (LE vs. control) by side (affected vs. unaffected) analysis of variance revealed a significant condition effect (P=0.001), but not side effect (P=0.192) or side-by-condition interaction effect (P=0.951). Follow-up tests for the effect of condition revealed a mean deficit in CPM of -24.5% (95% confidence interval, -38.0 to -11.0) in LE compared with that in pain-free participants. The results that suggest an impaired ability to modulate pain might be associated with the previously observed spinal cord hyperexcitability and the mechanical hyperalgesia that characterizes LE.

Central adaptation of pain perception in response to rehabilitation of musculoskeletal pain

DEFF Research Database (Denmark)

Andersen, Lars L; Andersen, Christoffer H; Sundstrup, Emil

2012-01-01

Understanding the mechanisms of long-standing musculoskeletal pain and adaptations in response to physical rehabilitation is important for developing optimal treatment strategies. The influence of central adaptations of pain perception in response to rehabilitation of musculoskeletal pain remains...

Transgenic up-regulation of alpha-CaMKII in forebrain leads to increased anxiety-like behaviors and aggression

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Hasegawa Shunsuke

2009-03-01

Full Text Available Abstract Background Previous studies have demonstrated essential roles for alpha-calcium/calmodulin-dependent protein kinase II (alpha-CaMKII in learning, memory and long-term potentiation (LTP. However, previous studies have also shown that alpha-CaMKII (+/- heterozygous knockout mice display a dramatic decrease in anxiety-like and fearful behaviors, and an increase in defensive aggression. These findings indicated that alpha-CaMKII is important not only for learning and memory but also for emotional behaviors. In this study, to understand the roles of alpha-CaMKII in emotional behavior, we generated transgenic mice overexpressing alpha-CaMKII in the forebrain and analyzed their behavioral phenotypes. Results We generated transgenic mice overexpressing alpha-CaMKII in the forebrain under the control of the alpha-CaMKII promoter. In contrast to alpha-CaMKII (+/- heterozygous knockout mice, alpha-CaMKII overexpressing mice display an increase in anxiety-like behaviors in open field, elevated zero maze, light-dark transition and social interaction tests, and a decrease in locomotor activity in their home cages and novel environments; these phenotypes were the opposite to those observed in alpha-CaMKII (+/- heterozygous knockout mice. In addition, similarly with alpha-CaMKII (+/- heterozygous knockout mice, alpha-CaMKII overexpressing mice display an increase in aggression. However, in contrast to the increase in defensive aggression observed in alpha-CaMKII (+/- heterozygous knockout mice, alpha-CaMKII overexpressing mice display an increase in offensive aggression. Conclusion Up-regulation of alpha-CaMKII expression in the forebrain leads to an increase in anxiety-like behaviors and offensive aggression. From the comparisons with previous findings, we suggest that the expression levels of alpha-CaMKII are associated with the state of emotion; the expression level of alpha-CaMKII positively correlates with the anxiety state and strongly affects

Antinociceptive effects of fisetin against diabetic neuropathic pain in mice: Engagement of antioxidant mechanisms and spinal GABAA receptors.

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Zhao, Xin; Li, Xin-Lin; Liu, Xin; Wang, Chuang; Zhou, Dong-Sheng; Ma, Qing; Zhou, Wen-Hua; Hu, Zhen-Yu

2015-12-01

Peripheral painful neuropathy is one of the most common complications in diabetes and necessitates improved treatment. Fisetin, a naturally occurring flavonoid, has been reported to exert antidepressant-like effect in previous studies. As antidepressant drugs are employed clinically to treat neuropathic pain, this work aimed to investigate whether fisetin possess beneficial effect on diabetic neuropathic pain and explore the mechanism(s). We subjected mice to diabetes by a single intraperitoneal (i.p.) injection of streptozotocin (200mg/kg), and von Frey test or Hargreaves test was used to assess mechanical allodynia or thermal hyperalgesia, respectively. Chronic treatment of diabetic mice with fisetin not only ameliorated the established symptoms of thermal hyperalgesia and mechanical allodynia, but also arrested the development of neuropathic pain when given at low doses. Although chronic fisetin administration did not impact on the symptom of hyperglycemia in diabetic mice, it reduced exacerbated oxidative stress in tissues of spinal cord, dorsal root ganglion (DRG) and sciatic verve. Furthermore, the analgesic actions of fisetin were abolished by repetitive co-treatment with the reactive oxygen species (ROS) donor tert-butyl hydroperoxide (t-BOOH), but potentiated by the ROS scavenger phenyl-N-tert-butylnitrone (PBN). Finally, acute blockade of spinal GABAA receptors by bicuculline totally counteracted such fisetin analgesia. These findings indicate that chronic fisetin treatment can delay or correct neuropathic hyperalgesia and allodynia in mice with type 1 diabetes. Mechanistically, the present fisetin analgesia may be associated with its antioxidant activity, and spinal GABAA receptors are likely rendered as downstream targets. Copyright © 2015 Elsevier Ltd. All rights reserved.

The basal forebrain cholinergic system in aging and dementia : Rescuing cholinergic neurons from neurotoxic amyloid-beta 42 with memantine

NARCIS (Netherlands)

Nyakas, Csaba; Granic, Ivica; Halmy, Laszlo G.; Banerjee, Pradeep; Luiten, Paul G. M.

2011-01-01

The dysfunction and loss of basal forebrain cholinergic neurons and their cortical projections are among the earliest pathological events in the pathogenesis of Alzheimer's disease (AD). The evidence pointing to cholinergic impairments come from studies that report a decline in the activity of

A preliminary study comparing the use of cervical/upper thoracic mobilization and manipulation for individuals with mechanical neck pain.

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Griswold, David; Learman, Ken; O'Halloran, Bryan; Cleland, Josh

2015-05-01

Neck pain is routinely managed using manual therapy (MT) to the cervical and thoracic spines. While both mobilizations and manipulations to these areas have been shown to reduce neck pain, increase cervical range of motion, and reduce disability, the most effective option remains elusive. The purpose of this preliminary trial was to compare the pragmatic use of cervical and thoracic mobilizations vs. manipulation for mechanical neck pain. This trial included 20 patients with mechanical neck pain. Each patient was randomized to receive either mobilization or manipulation to both the cervical and thoracic spines during their plan of care. Within-group analyses were made with Wilcoxon signed-rank tests and between-group analyses were made with Mann-Whitney U. There were no between-group differences for any of the dependent variables including cervical active range of motion (CAROM) (P = 0.18), deep cervical flexion (DCF) endurance (P = 0.06), numerical pain rating scale (NPRS) (P = 0.26), the neck disability index (NDI, P = 0.33), patient-specific functional scale (PSFS, P = 0.20), or the global rating of change (GROC) scale (P = 0.94). Within-group results were significant for all outcome variables (Ppain.

Neuropathic pain mechanisms in patients with chronic sports injuries: a diagnostic model useful in sports medicine?

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van Wilgen, Cornelis P; Keizer, Doeke

2011-01-01

The pathophysiology of chronic sports injuries such as overuse or tendinopathy remains largely unknown. With this exploratory study, we aim to detect signs of sensitization of the nervous system. Sensitization is an indication of the involvement of neuropathic mechanisms in patients with chronic sports injuries. Sensory descriptors were assessed by means of a neuropathic pain questionnaire (DN4-interview) and by three methods of sensory testing. The test results were integrated in a scoring system. Patients were recruited from an outpatient clinic of a University Medical Centre and at primary care physical therapy practices. Fifteen athletes with a unilateral chronic sports injury were included. All subjects filled out the seven-items of the DN4-interview to assess sensory descriptors. Next, the presence of brush-evoked allodynia was assessed and pain thresholds with Von Frey monofilaments and a pressure algometer were measured in all patients to determine signs of sensitization. Based on the scoring system, in 4 out of 15 patients (27%) the presence of sensitization could be detected. In two other patients, signs of hypoalgesia were observed. The involvement of sensitization as an explanation for the pain in chronic sports injuries is credible in a considerable proportion of patients. With respect to treatment, the establishment of such neuropathic pain mechanisms is of clinical significance. Wiley Periodicals, Inc.

Migraine, vertigo and migrainous vertigo: Links between vestibular and pain mechanisms.

Science.gov (United States)

Balaban, Carey D

2011-01-01

This review develops the hypothesis that co-morbid balance disorders and migraine can be understood as additive effects of processing afferent vestibular and pain information in pre-parabrachial and pre-thalamic pathways, that have consequences on cortical mechanisms influencing perception, interoception and affect. There are remarkable parallel neurochemical phenotypes for inner ear and trigeminal ganglion cells and these afferent channels appear to converge in shared central pathways for vestibular and nociceptive information processing. These pathways share expression of receptors targeted by anti-migraine drugs. New evidence is also presented regarding the distribution of serotonin receptors in the planum semilunatum of the primate cristae ampullaris, which may indicate involvement of inner ear ionic homeostatic mechanisms in audiovestibular symptoms that can accompany migraine.

Human psychophysics and rodent spinal neurones exhibit peripheral and central mechanisms of inflammatory pain in the UVB and UVB heat rekindling models.

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O'Neill, Jessica; Sikandar, Shafaq; McMahon, Stephen B; Dickenson, Anthony H

2015-09-01

Translational research is key to bridging the gaps between preclinical findings and the patients, and a translational model of inflammatory pain will ideally induce both peripheral and central sensitisation, more effectively mimicking clinical pathophysiology in some chronic inflammatory conditions. We conducted a parallel investigation of two models of inflammatory pain, using ultraviolet B (UVB) irradiation alone and UVB irradiation with heat rekindling. We used rodent electrophysiology and human quantitative sensory testing to characterise nociceptive processing in the peripheral and central nervous systems in both models. In both species, UVB irradiation produces peripheral sensitisation measured as augmented evoked activity of rat dorsal horn neurones and increased perceptual responses of human subjects to mechanical and thermal stimuli. In both species, UVB with heat rekindling produces central sensitisation. UVB irradiation alone and UVB with heat rekindling are translational models of inflammation that produce peripheral and central sensitisation, respectively. The predictive value of laboratory models for human pain processing is crucial for improving translational research. The discrepancy between peripheral and central mechanisms of pain is an important consideration for drug targets, and here we describe two models of inflammatory pain that involve ultraviolet B (UVB) irradiation, which can employ peripheral and central sensitisation to produce mechanical and thermal hyperalgesia in rats and humans. We use electrophysiology in rats to measure the mechanically- and thermally-evoked activity of rat spinal neurones and quantitative sensory testing to assess human psychophysical responses to mechanical and thermal stimulation in a model of UVB irradiation and in a model of UVB irradiation with heat rekindling. Our results demonstrate peripheral sensitisation in both species driven by UVB irradiation, with a clear mechanical and thermal hypersensitivity of

Pain Intensity Moderates the Relationship Between Age and Pain Interference in Chronic Orofacial Pain Patients.

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Boggero, Ian A; Geiger, Paul J; Segerstrom, Suzanne C; Carlson, Charles R

2015-01-01

BACKGROUND/STUDY CONTEXT: Chronic pain is associated with increased interference in daily functioning that becomes more pronounced as pain intensity increases. Based on previous research showing that older adults maintain well-being in the face of pain as well as or better than their younger counterparts, the current study examined the interaction of age and pain intensity on interference in a sample of chronic orofacial pain patients. Data were obtained from the records of 508 chronic orofacial pain patients being seen for an initial evaluation from 2008 to 2012. Collected data included age (range: 18-78) and self-reported measures of pain intensity and pain interference. Bivariate correlations and regression models were used to assess for statistical interactions. Regression analyses revealed that pain intensity positively predicted pain interference (R(2) = .35, B = 10.40, SE = 0.62, t(507) = 16.70, p theories, including socioemotional selectivity theory, which posits that as people age, they become more motivated to maximize positive emotions and minimize negative ones. The results highlight the importance of studying the mechanisms older adults use to successfully cope with pain.

Probing the Effects and Mechanisms of Electroacupuncture at Ipsilateral or Contralateral ST36-ST37 Acupoints on CFA-induced Inflammatory Pain.

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Lu, Kung-Wen; Hsu, Chao-Kuei; Hsieh, Ching-Liang; Yang, Jun; Lin, Yi-Wen

2016-02-24

Transient receptor potential vanilloid 1 (TRPV1) and associated signaling pathways have been reported to be increased in inflammatory pain signaling. There are accumulating evidences surrounding the therapeutic effect of electroacupuncture (EA). EA can reliably attenuate the increase of TRPV1 in mouse inflammatory pain models with unclear signaling mechanisms. Moreover, the difference in the clinical therapeutic effects between using the contralateral and ipsilateral acupoints has been rarely studied. We found that inflammatory pain, which was induced by injecting the complete Freund's adjuvant (CFA), (2.14 ± 0.1, p CFA injection; this expression can be further attenuated significantly in EA treatment. TRPV1 and associated signaling pathways can be prevented in TRPV1 knockout mice, suggesting that TRPV1 knockout mice are resistant to inflammatory pain. Through this study, we have increased the understanding of the mechanism that both ipsilateral and contralateral EA might alter TRPV1 and associated signaling pathways to reduce inflammatory pain.

Preoperative pain mechanisms assessed by cuff algometry are associated with chronic postoperative pain relief after total knee replacement.

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Petersen, Kristian Kjær; Graven-Nielsen, Thomas; Simonsen, Ole; Laursen, Mogens Berg; Arendt-Nielsen, Lars

2016-07-01

Chronic postoperative pain after total knee replacement (TKR) in knee osteoarthritis (KOA) implies clinical challenges. Widespread hyperalgesia, facilitated temporal summation of pain (TSP), and impaired conditioned pain modulation (CPM) have been found in painful KOA. This exploratory study investigated postoperative pain relief 12 months after TKR in 4 subgroups of patients preoperatively profiled by mechanistic quantitative sensory testing. In 103 patients with KOA, pressure pain detection threshold (PDT) and tolerance thresholds (PTT) were assessed at the lower leg using cuff algometry. Temporal summation of pain was measured as an increase in pain intensity scores during 10 repeated (2 seconds intervals) painful cuff stimuli. Conditioned pain modulation was calculated as the relative increase in PDT during painful conditioning stimulation. The grand averages of TSP and CPM were calculated and values below or above were used for subgrouping: facilitated TSP/impaired CPM (group A, N = 16), facilitated TSP/normal CPM (group B, N = 15), normal TSP/impaired CPM (group C, N = 44), and normal TSP/normal CPM (group D, N = 28). Clinical VAS pain intensity scores were collected before and 12 months after TKR surgery and the pain relief calculated. Less pain relief was found in group A (52.0% ± 14.0% pain relief) than in group B (81.1% ± 3.5%, P = 0.023) and group C (79.6% ± 4.4%, P = 0.007), but not group D (69.4% ± 7.9%, P = 0.087). Low preoperative PDT was associated with a less postoperative pain relief (R = -0.222, P = 0.034), whereas TSP or CPM alone showed no associations with postoperative pain relief. This explorative study indicated that patients with osteoarthritis with facilitated TSP together with impaired CPM are more vulnerable to experience less pain relief after TKR.

[Pathophysiology and treatment of orofacial pain.

Science.gov (United States)

Shinoda, Masamichi; Noma, Noboru

"Pain" is one of body defense mechanisms and crucial for the life support. However, orofacial pain such as myofascial pain syndrome, burning mouth syndrome and trigeminal neuralgia plays no part in body defense mechanisms and requires therapeutic intervention. Recent studies have indicated that plastic changes in the activities of trigeminal neurons, satellite glial cells in trigeminal ganglion, secondary neurons, microglia and astrocytes in trigeminal spinal subnucleus following orofacial inflammation and trigeminal nerve injury are responsible for orofacial pain mechanisms. Clinically, it is well known that the etiologic differential diagnosis which consists of careful history-taking and physical examination is essential for therapeutic decision in patients with orofacial pain. This report outlines the current knowledge on the pathophysiology, diagnosis, treatment of orofacial pain.

Basal forebrain projections to the lateral habenula modulate aggression reward.

Science.gov (United States)

Golden, Sam A; Heshmati, Mitra; Flanigan, Meghan; Christoffel, Daniel J; Guise, Kevin; Pfau, Madeline L; Aleyasin, Hossein; Menard, Caroline; Zhang, Hongxing; Hodes, Georgia E; Bregman, Dana; Khibnik, Lena; Tai, Jonathan; Rebusi, Nicole; Krawitz, Brian; Chaudhury, Dipesh; Walsh, Jessica J; Han, Ming-Hu; Shapiro, Matt L; Russo, Scott J

2016-06-30

Maladaptive aggressive behaviour is associated with a number of neuropsychiatric disorders and is thought to result partly from the inappropriate activation of brain reward systems in response to aggressive or violent social stimuli. Nuclei within the ventromedial hypothalamus, extended amygdala and limbic circuits are known to encode initiation of aggression; however, little is known about the neural mechanisms that directly modulate the motivational component of aggressive behaviour. Here we established a mouse model to measure the valence of aggressive inter-male social interaction with a smaller subordinate intruder as reinforcement for the development of conditioned place preference (CPP). Aggressors develop a CPP, whereas non-aggressors develop a conditioned place aversion to the intruder-paired context. Furthermore, we identify a functional GABAergic projection from the basal forebrain (BF) to the lateral habenula (lHb) that bi-directionally controls the valence of aggressive interactions. Circuit-specific silencing of GABAergic BF-lHb terminals of aggressors with halorhodopsin (NpHR3.0) increases lHb neuronal firing and abolishes CPP to the intruder-paired context. Activation of GABAergic BF-lHb terminals of non-aggressors with channelrhodopsin (ChR2) decreases lHb neuronal firing and promotes CPP to the intruder-paired context. Finally, we show that altering inhibitory transmission at BF-lHb terminals does not control the initiation of aggressive behaviour. These results demonstrate that the BF-lHb circuit has a critical role in regulating the valence of inter-male aggressive behaviour and provide novel mechanistic insight into the neural circuits modulating aggression reward processing.

Pre-operative pain and sensory function in groin hernia

DEFF Research Database (Denmark)

Aasvang, Eske K; Hansen, Jeanette B; Kehlet, Henrik

2009-01-01

(rho=-0.413, p=0.049), indicating a paradoxical association between level of mechanical pain threshold and magnitude of spontaneous pain. No other sensory modality was significantly correlated to pain intensity. New/increased pain during repetitive pinprick stimulation (wind-up) was seen in 3 patients...... mechanism. AIMS: To investigate the correlation between pre-operative pain intensity and sensory functions in the groin hernia area. METHODS: Patients with unilateral groin hernia were examined preoperatively by quantitative sensory testing (thermal, mechanical, and pressure [detection and pain thresholds...... pain is not related to findings of hyperalgesia or other changes in sensory function that may support pain-induced pre-operative neuroplasticity as a pathogenic mechanism for the development of persistent postherniotomy pain....

Pain and neuroplasticity

Directory of Open Access Journals (Sweden)

Sabine Sator-Katzenschlager, MD.

2014-07-01

However, the cerebral processing of hyperalgesia and allodynia is still controversially discussed. In recent years, neuroimaging methods (functional magnetic resonance imaging, fMRI; magnetoencephalography, MEG; positron emission tomography, PET have provided new insightsinto the aberrant cerebral processing of neuropathic pain. Thepresent paper reviews different cerebral mechanisms contributing to chronicity processes in neuropathic pain syndromes. These mechanisms include reorganisation of cortical somatotopic maps in sensory or motor areas (highly relevant for phantom limb pain and CRPS, increased activity in primary nociceptive areas, recruitment of new cortical areas usually not activated by nociceptive stimuli and aberrant activity in brain areas normally involved in descending inhibitory pain networks. Moreover, there is evidence from PET studies for changes of excitatory and inhibitory transmitter systems. Finally, advanced methods of structural brain imaging (voxel-based morphometry, VBM show significant structural changes suggesting that chronic pain syndromes may be associated with neurodegeneration.

Comparison of burrowing and stimuli-evoked pain behaviors as end-points in rat models of inflammatory pain and peripheral neuropathic pain

Directory of Open Access Journals (Sweden)

Arjun eMuralidharan

2016-05-01

Full Text Available Establishment and validation of ethologically-relevant, non-evoked behavioral end-points as surrogate measures of spontaneous pain in rodent pain models has been proposed as a means to improve preclinical to clinical research translation in the pain field. Here, we compared the utility of burrowing behavior with hypersensitivity to applied mechanical stimuli for pain assessment in rat models of chronic inflammatory and peripheral neuropathic pain. Briefly, groups of male Sprague-Dawley rats were habituated to the burrowing environment and trained over a 5-day period. Rats that burrowed ≤450g of gravel on any two days of the individual training phase were excluded from the study. The remaining rats received either a unilateral intraplantar injection of Freund’s complete adjuvant (FCA or saline, or underwent unilateral chronic constriction injury (CCI of the sciatic nerve- or sham-surgery. Baseline burrowing behavior and evoked pain behaviors were assessed prior to model induction, and twice-weekly until study completion on day 14. For FCA- and CCI-rats, but not the corresponding groups of sham-rats, evoked mechanical hypersensitivity developed in a temporal manner in the ipsilateral hindpaws. Although burrowing behavior also decreased in a temporal manner for both FCA- and CCI-rats, there was considerable inter-animal variability. By contrast, mechanical hyperalgesia and mechanical allodynia in the ipsilateral hindpaws of FCA- and CCI-rats respectively, exhibited minimal inter-animal variability. Our data collectively show that burrowing behavior is altered in rodent models of chronic inflammatory pain and peripheral neuropathic pain. However, large group sizes are needed to ensure studies are adequately powered due to considerable inter-animal variability.

Pain, emotion, headache.

Science.gov (United States)

Bussone, Gennaro; Grazzi, Licia; Panerai, Alberto E

2012-10-01

Pain has been considered as part of a defensive strategy whose specific role is to signal an immediate active danger to the organism. This definition fits well for acute pain. It does not work well, however, for chronic pain that is maintained even in absence of an ongoing, active threat. Currently, acute and chronic pain are considered to be separate conditions. What follows is a review of the different theories about pain and its history. Different hypotheses regarding pain mechanisms are illustrated. New data emerging from scientific research on chronic pain (migraine in particular) involving innovative imaging techniques are reported and discussed. © 2012 American Headache Society.

Pain in patients with chronic fatigue syndrome: time for specific pain treatment?

NARCIS (Netherlands)

Nijs, J.; Crombez, G.; Meeus, M.; Knoop, H.; Damme, S.V.; Cauwenbergh, V.; Bleijenberg, G.

2012-01-01

BACKGROUND: Besides chronic fatigue, patients with chronic fatigue syndrome (CFS) have debilitating widespread pain. Yet pain from CFS is often ignored by clinicians and researchers. OBJECTIVES: To examine whether pain is a unique feature of CFS, or does it share the same underlying mechanisms as

Effects of a Pain Catastrophizing Induction on Sensory Testing in Women with Chronic Low Back Pain: A Pilot Study

Directory of Open Access Journals (Sweden)

Chloe J. Taub

2017-01-01

Full Text Available Pain catastrophizing, a pattern of negative cognitive-emotional responses to actual or anticipated pain, maintains chronic pain and undermines response to treatments. Currently, precisely how pain catastrophizing influences pain processing is not well understood. In experimental settings, pain catastrophizing has been associated with amplified pain processing. This study sought to clarify pain processing mechanisms via experimental induction of pain catastrophizing. Forty women with chronic low back pain were assigned in blocks to an experimental condition, either a psychologist-led 10-minute pain catastrophizing induction or a control (10-minute rest period. All participants underwent a baseline round of several quantitative sensory testing (QST tasks, followed by the pain catastrophizing induction or the rest period, and then a second round of the same QST tasks. The catastrophizing induction appeared to increase state pain catastrophizing levels. Changes in QST pain were detected for two of the QST tasks administered, weighted pin pain and mechanical allodynia. Although there is a need to replicate our preliminary results with a larger sample, study findings suggest a potential relationship between induced pain catastrophizing and central sensitization of pain. Clarification of the mechanisms through which catastrophizing affects pain modulatory systems may yield useful clinical insights into the treatment of chronic pain.

Effects of a Pain Catastrophizing Induction on Sensory Testing in Women with Chronic Low Back Pain: A Pilot Study.

Science.gov (United States)

Taub, Chloe J; Sturgeon, John A; Johnson, Kevin A; Mackey, Sean C; Darnall, Beth D

2017-01-01

Pain catastrophizing, a pattern of negative cognitive-emotional responses to actual or anticipated pain, maintains chronic pain and undermines response to treatments. Currently, precisely how pain catastrophizing influences pain processing is not well understood. In experimental settings, pain catastrophizing has been associated with amplified pain processing. This study sought to clarify pain processing mechanisms via experimental induction of pain catastrophizing. Forty women with chronic low back pain were assigned in blocks to an experimental condition, either a psychologist-led 10-minute pain catastrophizing induction or a control (10-minute rest period). All participants underwent a baseline round of several quantitative sensory testing (QST) tasks, followed by the pain catastrophizing induction or the rest period, and then a second round of the same QST tasks. The catastrophizing induction appeared to increase state pain catastrophizing levels. Changes in QST pain were detected for two of the QST tasks administered, weighted pin pain and mechanical allodynia. Although there is a need to replicate our preliminary results with a larger sample, study findings suggest a potential relationship between induced pain catastrophizing and central sensitization of pain. Clarification of the mechanisms through which catastrophizing affects pain modulatory systems may yield useful clinical insights into the treatment of chronic pain.

Effects of a Pain Catastrophizing Induction on Sensory Testing in Women with Chronic Low Back Pain: A Pilot Study

Science.gov (United States)

Sturgeon, John A.; Johnson, Kevin A.

2017-01-01

Pain catastrophizing, a pattern of negative cognitive-emotional responses to actual or anticipated pain, maintains chronic pain and undermines response to treatments. Currently, precisely how pain catastrophizing influences pain processing is not well understood. In experimental settings, pain catastrophizing has been associated with amplified pain processing. This study sought to clarify pain processing mechanisms via experimental induction of pain catastrophizing. Forty women with chronic low back pain were assigned in blocks to an experimental condition, either a psychologist-led 10-minute pain catastrophizing induction or a control (10-minute rest period). All participants underwent a baseline round of several quantitative sensory testing (QST) tasks, followed by the pain catastrophizing induction or the rest period, and then a second round of the same QST tasks. The catastrophizing induction appeared to increase state pain catastrophizing levels. Changes in QST pain were detected for two of the QST tasks administered, weighted pin pain and mechanical allodynia. Although there is a need to replicate our preliminary results with a larger sample, study findings suggest a potential relationship between induced pain catastrophizing and central sensitization of pain. Clarification of the mechanisms through which catastrophizing affects pain modulatory systems may yield useful clinical insights into the treatment of chronic pain. PMID:28348505

Evaluation of reward from pain relief

Science.gov (United States)

Navratilova, Edita; Xie, Jennifer Yanhua; King, Tamara; Porreca, Frank

2014-01-01

The human experience of pain is multidimensional and comprises sensory, affective, and cognitive dimensions. Preclinical assessment of pain has been largely focused on the sensory features that contribute to nociception. The affective (aversive) qualities of pain are clinically significant but have received relatively less mechanistic investigation in preclinical models. Recently, operant behaviors such as conditioned place preference, avoidance, escape from noxious stimulus, and analgesic drug self-administration have been used in rodents to evaluate affective aspects of pain. An important advance of such operant behaviors is that these approaches may allow the detection and mechanistic investigation of spontaneous neuropathic or ongoing inflammatory/nociceptive (i.e., nonevoked) pain that is otherwise difficult to assess in nonverbal animals. Operant measures may allow the identification of mechanisms that contribute differentially to reflexive hypersensitivity or to pain affect and may inform the decision to progress novel mechanisms to clinical trials for pain therapy. Additionally, operant behaviors may allow investigation of the poorly understood mechanisms and neural circuits underlying motivational aspects of pain and the reward of pain relief. PMID:23496247

Effects of vicarious pain on self-pain perception: investigating the role of awareness

Science.gov (United States)

Terrighena, Esslin L; Lu, Ge; Yuen, Wai Ping; Lee, Tatia MC; Keuper, Kati

2017-01-01

The observation of pain in others may enhance or reduce self-pain, yet the boundary conditions and factors that determine the direction of such effects are poorly understood. The current study set out to show that visual stimulus awareness plays a crucial role in determining whether vicarious pain primarily activates behavioral defense systems that enhance pain sensitivity and stimulate withdrawal or appetitive systems that attenuate pain sensitivity and stimulate approach. We employed a mixed factorial design with the between-subject factors exposure time (subliminal vs optimal) and vicarious pain (pain vs no pain images), and the within-subject factor session (baseline vs trial) to investigate how visual awareness of vicarious pain images affects subsequent self-pain in the cold-pressor test. Self-pain tolerance, intensity and unpleasantness were evaluated in a sample of 77 healthy participants. Results revealed significant interactions of exposure time and vicarious pain in all three dependent measures. In the presence of visual awareness (optimal condition), vicarious pain compared to no-pain elicited overall enhanced self-pain sensitivity, indexed by reduced pain tolerance and enhanced ratings of pain intensity and unpleasantness. Conversely, in the absence of visual awareness (subliminal condition), vicarious pain evoked decreased self-pain intensity and unpleasantness while pain tolerance remained unaffected. These findings suggest that the activation of defense mechanisms by vicarious pain depends on relatively elaborate cognitive processes, while – strikingly – the appetitive system is activated in highly automatic manner independent from stimulus awareness. Such mechanisms may have evolved to facilitate empathic, protective approach responses toward suffering individuals, ensuring survival of the protective social group. PMID:28831270

Orofacial complex regional pain syndrome: pathophysiologic mechanisms and functional MRI.

Science.gov (United States)

Lee, Yeon-Hee; Lee, Kyung Mi; Kim, Hyug-Gi; Kang, Soo-Kyung; Auh, Q-Schick; Hong, Jyung-Pyo; Chun, Yang-Hyun

2017-08-01

Complex regional pain syndrome (CRPS) is one of the most challenging chronic pain conditions and is characterized by burning pain, allodynia, hyperalgesia, autonomic changes, trophic changes, edema, and functional loss involving mainly the extremities. Until recently, very few reports have been published concerning CRPS involving the orofacial area. We report on a 50-year-old female patient who presented with unbearable pain in all of her teeth and hypersensitivity of the facial skin. She also reported intractable pain in both extremities accompanied by temperature changes and orofacial pain that increased when the other pains were aggravated. In the case of CRPS with trigeminal neuropathic pain, protocols for proper diagnosis and prompt treatment have yet to be established in academia or in the clinical field. We performed functional magnetic resonance imaging for a thorough analysis of the cortical representation of the affected orofacial area immediately before and immediately after isolated light stimulus of the affected hand and foot and concluded that CRPS can be correlated with trigeminal neuropathy in the orofacial area. Furthermore, the patient was treated with carbamazepine administration and stellate ganglion block, which can result in a rapid improvement of pain in the trigeminal region. Copyright © 2017 Elsevier Inc. All rights reserved.

EFFECTIVENESS OF MUSCLE STRETCHING IN OCCUPATION RELATED CHRONIC MECHANICAL LOW BACK PAIN IN COMMUNITY NURSES –A SINGLE BLIND STUDY

OpenAIRE

Khwairakpam Zhimina Devi; Sai Kumar. N; Vinod Babu. K; V.R. Ayyappan

2014-01-01

Background and Objective: Stretching of Lower Back Muscle, Hamstring and Tensor Fasciae Latae have an immediate effect on Chronic Lower Back Pain. Hence the purpose is to find the short term effect of stretching of Lower Back Muscle, Hamstring and Tensor Fasciae Latae on intensity of low back pain, flexibility and functional disability in occupation related Chronic Mechanical Low Back Pain in Community Nurses. Method: Single blind experimental study design, 40 subjects with Chronic mechani...

Spinal pain

International Nuclear Information System (INIS)

Izzo, R.; Popolizio, T.; D’Aprile, P.; Muto, M.

2015-01-01

Highlights: • Purpose of this review is to address the current concepts on the pathophysiology of discogenic, radicular, facet and dysfunctional spinal pain, focusing on the role of the imaging in the diagnostic setting, to potentially address a correct approach also to minimally invasive interventional techniques. • Special attention will be given to the discogenic pain, actually considered as the most frequent cause of chronic low back pain. • The correct distinction between referred pain and radicular pain contributes to give a more correct approach to spinal pain. • The pathogenesis of chronic pain renders this pain a true pathology requiring a specific management. - Abstract: The spinal pain, and expecially the low back pain (LBP), represents the second cause for a medical consultation in primary care setting and a leading cause of disability worldwide [1]. LBP is more often idiopathic. It has as most frequent cause the internal disc disruption (IDD) and is referred to as discogenic pain. IDD refers to annular fissures, disc collapse and mechanical failure, with no significant modification of external disc shape, with or without endplates changes. IDD is described as a separate clinical entity in respect to disc herniation, segmental instability and degenerative disc desease (DDD). The radicular pain has as most frequent causes a disc herniation and a canal stenosis. Both discogenic and radicular pain also have either a mechanical and an inflammatory genesis. For to be richly innervated, facet joints can be a direct source of pain, while for their degenerative changes cause compression of nerve roots in lateral recesses and in the neural foramina. Degenerative instability is a common and often misdiagnosed cause of axial and radicular pain, being also a frequent indication for surgery. Acute pain tends to extinguish along with its cause, but the setting of complex processes of peripheral and central sensitization may influence its evolution in chronic

Spinal pain

Energy Technology Data Exchange (ETDEWEB)

Izzo, R., E-mail: roberto1766@interfree.it [Neuroradiology Department, A. Cardarelli Hospital, Naples (Italy); Popolizio, T., E-mail: t.popolizio1@gmail.com [Radiology Department, Casa Sollievo della Sofferenza Hospital, San Giovanni Rotondo (Fg) (Italy); D’Aprile, P., E-mail: paoladaprile@yahoo.it [Neuroradiology Department, San Paolo Hospital, Bari (Italy); Muto, M., E-mail: mutomar@tiscali.it [Neuroradiology Department, A. Cardarelli Hospital, Napoli (Italy)

2015-05-15

Highlights: • Purpose of this review is to address the current concepts on the pathophysiology of discogenic, radicular, facet and dysfunctional spinal pain, focusing on the role of the imaging in the diagnostic setting, to potentially address a correct approach also to minimally invasive interventional techniques. • Special attention will be given to the discogenic pain, actually considered as the most frequent cause of chronic low back pain. • The correct distinction between referred pain and radicular pain contributes to give a more correct approach to spinal pain. • The pathogenesis of chronic pain renders this pain a true pathology requiring a specific management. - Abstract: The spinal pain, and expecially the low back pain (LBP), represents the second cause for a medical consultation in primary care setting and a leading cause of disability worldwide [1]. LBP is more often idiopathic. It has as most frequent cause the internal disc disruption (IDD) and is referred to as discogenic pain. IDD refers to annular fissures, disc collapse and mechanical failure, with no significant modification of external disc shape, with or without endplates changes. IDD is described as a separate clinical entity in respect to disc herniation, segmental instability and degenerative disc desease (DDD). The radicular pain has as most frequent causes a disc herniation and a canal stenosis. Both discogenic and radicular pain also have either a mechanical and an inflammatory genesis. For to be richly innervated, facet joints can be a direct source of pain, while for their degenerative changes cause compression of nerve roots in lateral recesses and in the neural foramina. Degenerative instability is a common and often misdiagnosed cause of axial and radicular pain, being also a frequent indication for surgery. Acute pain tends to extinguish along with its cause, but the setting of complex processes of peripheral and central sensitization may influence its evolution in chronic

Cancer Pain Physiology

DEFF Research Database (Denmark)

Falk, Sarah; Bannister, Kirsty; Dickenson, Anthony

2014-01-01

Mechanisms of inflammatory and neuropathic pains have been elucidated and translated to patient care by the use of animal models of these pain states. Cancer pain has lagged behind since early animal models of cancer-induced bone pain were based on the systemic injection of carcinoma cells....... This precluded systematic investigation of specific neuronal and pharmacological alterations that occur in cancer-induced bone pain. In 1999, Schwei et al. described a murine model of cancer-induced bone pain that paralleled the clinical condition in terms of pain development and bone destruction, confined...... to the mouse femur. This model prompted related approaches and we can now state that cancer pain may include elements of inflammatory and neuropathic pains but also unique changes in sensory processing. Cancer induced bone pain results in progressive bone destruction, elevated osteoclast activity...

The ACTTION–APS–AAPM Pain Taxonomy (AAAPT) Multidimensional Approach to Classifying Acute Pain Conditions

Science.gov (United States)

Kent, Michael L.; Tighe, Patrick J.; Belfer, Inna; Brennan, Timothy J.; Bruehl, Stephen; Brummett, Chad M.; Buckenmaier, Chester C.; Buvanendran, Asokumar; Cohen, Robert I.; Desjardins, Paul; Edwards, David; Fillingim, Roger; Gewandter, Jennifer; Gordon, Debra B.; Hurley, Robert W.; Kehlet, Henrik; Loeser, John D.; Mackey, Sean; McLean, Samuel A.; Polomano, Rosemary; Rahman, Siamak; Raja, Srinivasa; Rowbotham, Michael; Suresh, Santhanam; Schachtel, Bernard; Schreiber, Kristin; Schumacher, Mark; Stacey, Brett; Stanos, Steven; Todd, Knox; Turk, Dennis C.; Weisman, Steven J.; Wu, Christopher; Carr, Daniel B.; Dworkin, Robert H.; Terman, Gregory

2017-01-01

Objective. With the increasing societal awareness of the prevalence and impact of acute pain, there is a need to develop an acute pain classification system that both reflects contemporary mechanistic insights and helps guide future research and treatment. Existing classifications of acute pain conditions are limiting, with a predominant focus on the sensory experience (e.g., pain intensity) and pharmacologic consumption. Consequently, there is a need to more broadly characterize and classify the multidimensional experience of acute pain. Setting. Consensus report following expert panel involving the Analgesic, Anesthetic, and Addiction Clinical Trial Translations, Innovations, Opportunities, and Networks (ACTTION), American Pain Society (APS), and American Academy of Pain Medicine (AAPM). Methods. As a complement to a taxonomy recently developed for chronic pain, the ACTTION public-private partnership with the US Food and Drug Administration, the APS, and the AAPM convened a consensus meeting of experts to develop an acute pain taxonomy using prevailing evidence. Key issues pertaining to the distinct nature of acute pain are presented followed by the agreed-upon taxonomy. The ACTTION-APS-AAPM Acute Pain Taxonomy will include the following dimensions: 1) core criteria, 2) common features, 3) modulating factors, 4) impact/functional consequences, and 5) putative pathophysiologic pain mechanisms. Future efforts will consist of working groups utilizing this taxonomy to develop diagnostic criteria for a comprehensive set of acute pain conditions. Perspective. The ACTTION-APS-AAPM Acute Pain Taxonomy (AAAPT) is a multidimensional acute pain classification system designed to classify acute pain along the following dimensions: 1) core criteria, 2) common features, 3) modulating factors, 4) impact/functional consequences, and 5) putative pathophysiologic pain mechanisms. Conclusions. Significant numbers of patients still suffer from significant acute pain

The ACTTION-APS-AAPM Pain Taxonomy (AAAPT) Multidimensional Approach to Classifying Acute Pain Conditions.

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Kent, Michael L; Tighe, Patrick J; Belfer, Inna; Brennan, Timothy J; Bruehl, Stephen; Brummett, Chad M; Buckenmaier, Chester C; Buvanendran, Asokumar; Cohen, Robert I; Desjardins, Paul; Edwards, David; Fillingim, Roger; Gewandter, Jennifer; Gordon, Debra B; Hurley, Robert W; Kehlet, Henrik; Loeser, John D; Mackey, Sean; McLean, Samuel A; Polomano, Rosemary; Rahman, Siamak; Raja, Srinivasa; Rowbotham, Michael; Suresh, Santhanam; Schachtel, Bernard; Schreiber, Kristin; Schumacher, Mark; Stacey, Brett; Stanos, Steven; Todd, Knox; Turk, Dennis C; Weisman, Steven J; Wu, Christopher; Carr, Daniel B; Dworkin, Robert H; Terman, Gregory

2017-05-01

With the increasing societal awareness of the prevalence and impact of acute pain, there is a need to develop an acute pain classification system that both reflects contemporary mechanistic insights and helps guide future research and treatment. Existing classifications of acute pain conditions are limiting, with a predominant focus on the sensory experience (eg, pain intensity) and pharmacologic consumption. Consequently, there is a need to more broadly characterize and classify the multidimensional experience of acute pain. Consensus report following expert panel involving the Analgesic, Anesthetic, and Addiction Clinical Trial Translations, Innovations, Opportunities, and Networks (ACTTION), American Pain Society (APS), and American Academy of Pain Medicine (AAPM). As a complement to a taxonomy recently developed for chronic pain, the ACTTION public-private partnership with the US Food and Drug Administration, the APS, and the AAPM convened a consensus meeting of experts to develop an acute pain taxonomy using prevailing evidence. Key issues pertaining to the distinct nature of acute pain are presented followed by the agreed-upon taxonomy. The ACTTION-APS-AAPM Acute Pain Taxonomy will include the following dimensions: 1) core criteria, 2) common features, 3) modulating factors, 4) impact/functional consequences, and 5) putative pathophysiologic pain mechanisms. Future efforts will consist of working groups utilizing this taxonomy to develop diagnostic criteria for a comprehensive set of acute pain conditions. The ACTTION-APS-AAPM Acute Pain Taxonomy (AAAPT) is a multidimensional acute pain classification system designed to classify acute pain along the following dimensions: 1) core criteria, 2) common features, 3) modulating factors, 4) impact/functional consequences, and 5) putative pathophysiologic pain mechanisms. Significant numbers of patients still suffer from significant acute pain, despite the advent of modern multimodal analgesic strategies

EFFECTS OF CORE STABILIZATION PROGRAM AND CONVENTIONAL EXERCISES IN THE MANAGEMENT OF PATIENTS WITH CHRONIC MECHANICAL LOW BACK PAIN

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Suresh Babu Reddy .A

2015-04-01

Full Text Available Background: Conventional back care exercises are advocated to treat the pain and to strengthen the involved muscles. There will be possibility of the pain getting recurred due to disproportionate balance and stability in the muscles. The core stabilization is major trend in rehabilitation, it aims at improving stability during functional activities, balance, flexibility, strength training and effectively manage the pain as well. Objective: To find the efficacy of the concept of core stabilization when compared to conventional back care exercises in patients with chronic mechanical low back pain. Methods: Forty patients with chronic Mechanical Low back pain were selected through purposive sampling and were randomly assigned into control group who received conventional back exercises and SWD (n=20, experimental group who received core stabilization and SWD (n=20. Both the groups received SWD, along with conventional back exercises for one group and core stabilization for the other group three days a week for 6 weeks. The treatment outcome was assessed using visual analogue scale, Rolland Morris Disability Questionnaire and Lumbar range of motion using goniometer. Results: After a 6 weeks training period the core stabilization group scored significantly higher than the conventional group for VAS (p=0.05 RMDQ (p=0.05 whereas ROM improved higher in conventional group (p=0.05. Conclusion: After the treatment sessions Core stabilization group registered a significant improvement when compared to conventional back care exercises in improving function and in relieving pain.

Reliability of four experimental mechanical pain tests in children

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Soee AL

2013-02-01

Full Text Available Ann-Britt L Soee,1 Lise L Thomsen,2 Birte Tornoe,1,3 Liselotte Skov11Department of Pediatrics, Children’s Headache Clinic, Copenhagen University Hospital Herlev, Copenhagen, Denmark; 2Department of Neuropediatrics, Juliane Marie Centre, Copenhagen University Hospital Rigshospitalet, København Ø, Denmark; 3Department of Physiotherapy, Medical Department O, Copenhagen University Hospital Herlev, Herlev, DenmarkPurpose: In order to study pain in children, it is necessary to determine whether pain measurement tools used in adults are reliable measurements in children. The aim of this study was to explore the intrasession reliability of pressure pain thresholds (PPT in healthy children. Furthermore, the aim was also to study the intersession reliability of the following four tests: (1 Total Tenderness Score; (2 PPT; (3 Visual Analog Scale score at suprapressure pain threshold; and (4 area under the curve (stimulus–response functions for pressure versus pain.Participants and methods: Twenty-five healthy school children, 8–14 years of age, participated. Test 2, PPT, was repeated three times at 2 minute intervals on the same day to estimate PPT intrasession reliability using Cronbach’s alpha. Tests 1–4 were repeated after median 21 (interquartile range 10.5–22 days, and Pearson’s correlation coefficient was used to describe the intersession reliability.Results: The PPT test was precise and reliable (Cronbach’s alpha ≥ 0.92. All tests showed a good to excellent correlation between days (intersessions r = 0.66–0.81. There were no indications of significant systematic differences found in any of the four tests between days.Conclusion: All tests seemed to be reliable measurements in pain evaluation in healthy children aged 8–14 years. Given the small sample size, this conclusion needs to be confirmed in future studies.Keywords: repeatability, intraindividual reliability, pressure pain threshold, pain measurement, algometer

The different effects of over-expressing murine NMDA receptor 2B subunit in the forebrain on conditioned taste aversion.

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Li, Shijia; Gu, Yiran; Meng, Bo; Mei, Bing; Li, Fei

2010-09-10

The glutamate transmission system and the N-methyl-D-aspartate receptor (NMDA-R), in particular its 2B subunit (NR2B), have been reported to be possibly related to taste memory as a result of treatment with NMDA antagonists and agonists. In order to further study the role of the NR2B subunit in gustation memory, we applied four different taste aversive tasks to observe the behavior of a transgenic mice model in which the NR2B subunit was specifically over-expressed in the forebrain. We found that in both short- and long-term conditioned taste aversion (CTA) experiments, mice with forebrain expression of the NR2B transgene (Tg) showed significantly enhanced CTA 2 days after training. However, both the Tg and the wild-type (Wt) mice shared the same level of aversive memory on the 30th day after training. In both fast and slow extinction experiments, Tg mice maintained a higher CTA memory than that of control mice in most extinction trials. The third experiment, which involved testing the memory for familiar taste, demonstrated that NR2B augmentation had no benefit on the latent inhibition (LI) of CTA. In addition, the last experiment (two-taste LI) showed a suppression of enhanced CTA in Tg mice when the mice were exposed to both novel and familiar tastes. These data suggested that forebrain NR2B over-expression had different effects on gustatory learning and memory. The transgenic animals were only sensitive to novel but not familiar tastes, and up-regulation of NR2B resulted in enhanced CTA function for only a short period of time. 2010 Elsevier B.V. All rights reserved.

Ablation of cdk4 and cdk6 affects proliferation of basal progenitor cells in the developing dorsal and ventral forebrain.

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Grison, Alice; Gaiser, Carine; Bieder, Andrea; Baranek, Constanze; Atanasoski, Suzana

2018-03-23

Little is known about the molecular players driving proliferation of neural progenitor cells (NPCs) during embryonic mouse development. Here, we demonstrate that proliferation of NPCs in the developing forebrain depends on a particular combination of cell cycle regulators. We have analyzed the requirements for members of the cyclin-dependent kinase (cdk) family using cdk-deficient mice. In the absence of either cdk4 or cdk6, which are both regulators of the G1 phase of the cell cycle, we found no significant effects on the proliferation rate of cortical progenitor cells. However, concomitant loss of cdk4 and cdk6 led to a drastic decrease in the proliferation rate of NPCs, specifically the basal progenitor cells of both the dorsal and ventral forebrain at embryonic day 13.5 (E13.5). Moreover, basal progenitors in the forebrain of Cdk4;Cdk6 double mutant mice exhibited altered cell cycle characteristics. Cdk4;cdk6 deficiency led to an increase in cell cycle length and cell cycle exit of mutant basal progenitor cells in comparison to controls. In contrast, concomitant ablation of cdk2 and cdk6 had no effect on the proliferation of NCPs. Together, our data demonstrate that the expansion of the basal progenitor pool in the developing telencephalon is dependent on the presence of distinct combinations of cdk molecules. Our results provide further evidence for differences in the regulation of proliferation between apical and basal progenitors during cortical development. © 2018 Wiley Periodicals, Inc. Develop Neurobiol, 2018. © 2018 Wiley Periodicals, Inc.

Ablation of Ca(V)2.1 voltage-gated Ca²⁺ channels in mouse forebrain generates multiple cognitive impairments.

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Mallmann, Robert Theodor; Elgueta, Claudio; Sleman, Faten; Castonguay, Jan; Wilmes, Thomas; van den Maagdenberg, Arn; Klugbauer, Norbert

2013-01-01

Voltage-gated Ca(V)2.1 (P/Q-type) Ca²⁺ channels located at the presynaptic membrane are known to control a multitude of Ca²⁺-dependent cellular processes such as neurotransmitter release and synaptic plasticity. Our knowledge about their contributions to complex cognitive functions, however, is restricted by the limited adequacy of existing transgenic Ca(V)2.1 mouse models. Global Ca(V)2.1 knock-out mice lacking the α1 subunit Cacna1a gene product exhibit early postnatal lethality which makes them unsuitable to analyse the relevance of Ca(V)2.1 Ca²⁺ channels for complex behaviour in adult mice. Consequently we established a forebrain specific Ca(V)2.1 knock-out model by crossing mice with a floxed Cacna1a gene with mice expressing Cre-recombinase under the control of the NEX promoter. This novel mouse model enabled us to investigate the contribution of Ca(V)2.1 to complex cognitive functions, particularly learning and memory. Electrophysiological analysis allowed us to test the specificity of our conditional knock-out model and revealed an impaired synaptic transmission at hippocampal glutamatergic synapses. At the behavioural level, the forebrain-specific Ca(V)2.1 knock-out resulted in deficits in spatial learning and reference memory, reduced recognition memory, increased exploratory behaviour and a strong attenuation of circadian rhythmicity. In summary, we present a novel conditional Ca(V)2.1 knock-out model that is most suitable for analysing the in vivo functions of Ca(V)2.1 in the adult murine forebrain.

A Simple fMRI Compatible Robotic Stimulator to Study the Neural Mechanisms of Touch and Pain.

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Riillo, F; Bagnato, C; Allievi, A G; Takagi, A; Fabrizi, L; Saggio, G; Arichi, T; Burdet, E

2016-08-01

This paper presents a simple device for the investigation of the human somatosensory system with functional magnetic imaging (fMRI). PC-controlled pneumatic actuation is employed to produce innocuous or noxious mechanical stimulation of the skin. Stimulation patterns are synchronized with fMRI and other relevant physiological measurements like electroencephalographic activity and vital physiological parameters. The system allows adjustable regulation of stimulation parameters and provides consistent patterns of stimulation. A validation experiment demonstrates that the system safely and reliably identifies clusters of functional activity in brain regions involved in the processing of pain. This new device is inexpensive, portable, easy-to-assemble and customizable to suit different experimental requirements. It provides robust and consistent somatosensory stimulation, which is of crucial importance to investigating the mechanisms of pain and its strong connection with the sense of touch.

Mechanisms of placebo analgesia: A dual-process model informed by insights from cross-species comparisons.

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Schafer, Scott M; Geuter, Stephan; Wager, Tor D

2018-01-01

Placebo treatments are pharmacologically inert, but are known to alleviate symptoms across a variety of clinical conditions. Associative learning and cognitive expectations both play important roles in placebo responses, however we are just beginning to understand how interactions between these processes lead to powerful effects. Here, we review the psychological principles underlying placebo effects and our current understanding of their brain bases, focusing on studies demonstrating both the importance of cognitive expectations and those that demonstrate expectancy-independent associative learning. To account for both forms of placebo analgesia, we propose a dual-process model in which flexible, contextually driven cognitive schemas and attributions guide associative learning processes that produce stable, long-term placebo effects. According to this model, the placebo-induction paradigms with the most powerful effects are those that combine reinforcement (e.g., the experience of reduced pain after placebo treatment) with suggestions and context cues that disambiguate learning by attributing perceived benefit to the placebo. Using this model as a conceptual scaffold, we review and compare neurobiological systems identified in both human studies of placebo analgesia and behavioral pain modulation in rodents. We identify substantial overlap between the circuits involved in human placebo analgesia and those that mediate multiple forms of context-based modulation of pain behavior in rodents, including forebrain-brainstem pathways and opioid and cannabinoid systems in particular. This overlap suggests that placebo effects are part of a set of adaptive mechanisms for shaping nociceptive signaling based on its information value and anticipated optimal response in a given behavioral context. Copyright © 2017 Elsevier Ltd. All rights reserved.

The Input-Output Relationship of the Cholinergic Basal Forebrain

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Matthew R. Gielow

2017-02-01

Full Text Available Basal forebrain cholinergic neurons influence cortical state, plasticity, learning, and attention. They collectively innervate the entire cerebral cortex, differentially controlling acetylcholine efflux across different cortical areas and timescales. Such control might be achieved by differential inputs driving separable cholinergic outputs, although no input-output relationship on a brain-wide level has ever been demonstrated. Here, we identify input neurons to cholinergic cells projecting to specific cortical regions by infecting cholinergic axon terminals with a monosynaptically restricted viral tracer. This approach revealed several circuit motifs, such as central amygdala neurons synapsing onto basolateral amygdala-projecting cholinergic neurons or strong somatosensory cortical input to motor cortex-projecting cholinergic neurons. The presence of input cells in the parasympathetic midbrain nuclei contacting frontally projecting cholinergic neurons suggest that the network regulating the inner eye muscles are additionally regulating cortical state via acetylcholine efflux. This dataset enables future circuit-level experiments to identify drivers of known cortical cholinergic functions.

13. Sacroiliac joint pain

NARCIS (Netherlands)

Vanelderen, P.; Szadek, K.M.; Cohen, S.P.; Witte, J.; Lataster, A.; Patijn, J.; Mekhail, N.; van Kleef, M.; van Zundert, J.

2010-01-01

The sacroiliac joint accounts for approximately 16% to 30% of cases of chronic mechanical low back pain. Pain originating in the sacroiliac joint is predominantly perceived in the gluteal region, although pain is often referred into the lower and upper lumbar region, groin, abdomen, and/ or lower

PHYSIOLOGICAL MECHANISMS OF POLARIZED LIGHT INFLUENCE ON PAIN

OpenAIRE

S. О. Gulyar; Z. А. Tamarova

2016-01-01

There are presented experimental evidences of BIOPTRON device polarized light influence on the acupuncture points and pain locus. It is proved that PILER-light can induce analgesia which depends on the choice of the application zone, exposure and nature of pain (tonic, acute or visceral). Analgesic response has systemic character and is accompanied by participation of opioidergic nociceptive system

Differences in Pain Processing Between Patients with Chronic Low Back Pain, Recurrent Low Back Pain, and Fibromyalgia.

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Goubert, Dorien; Danneels, Lieven; Graven-Nielsen, Thomas; Descheemaeker, Filip; Meeus, Mira

2017-05-01

The impairment in musculoskeletal structures in patients with low back pain (LBP) is often disproportionate to their complaint. Therefore, the need arises for exploration of alternative mechanisms contributing to the origin and maintenance of non-specific LBP. The recent focus has been on central nervous system phenomena in LBP and the pathophysiological mechanisms underlying the various symptoms and characteristics of chronic pain. Knowledge concerning changes in pain processing in LBP remains ambiguous, partly due to the diversity in the LBP population. The purpose of this study is to compare quantitative sensory assessment in different groups of LBP patients with regard to chronicity. Recurrent low back pain (RLBP), mild chronic low back pain (CLBP), and severe CLBP are compared on the one hand with healthy controls (HC), and on the other hand with fibromyalgia (FM) patients, in which abnormal pain processing has previously been reported. Cross-sectional study. Department of Rehabilitation Sciences, Ghent University, Belgium. Twenty-three RLBP, 15 mild CLBP, 16 severe CLBP, 26 FM, and 21 HC participated in this study. Quantitative sensory testing was conducted by manual pressure algometry and computer-controlled cuff algometry. A manual algometer was used to evaluate hyperalgesia as well as temporal summation of pain and a cuff algometer was used to evaluate deep tissue hyperalgesia, the efficacy of the conditioned pain modulation and spatial summation of pain. Pressure pain thresholds by manual algometry were significantly lower in FM compared to HC, RLBP, and severe CLBP. Temporal summation of pain was significantly higher in FM compared to HC and RLBP. Pain tolerance thresholds assessed by cuff algometry were significantly lower in FM compared to HC and RLBP and also in severe CLBP compared to RLBP. No significant differences between groups were found for spatial summation or conditioned pain modulation. No psychosocial issues were taken into account for this

Bilateral widespread mechanical pain sensitivity in carpal tunnel syndrome: evidence of central processing in unilateral neuropathy.

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Fernández-de-las-Peñas, César; de la Llave-Rincón, Ana Isabel; Fernández-Carnero, Josué; Cuadrado, María Luz; Arendt-Nielsen, Lars; Pareja, Juan A

2009-06-01

The aim of this study was to investigate whether bilateral widespread pressure hypersensitivity exists in patients with unilateral carpal tunnel syndrome. A total of 20 females with carpal tunnel syndrome (aged 22-60 years), and 20 healthy matched females (aged 21-60 years old) were recruited. Pressure pain thresholds were assessed bilaterally over median, ulnar, and radial nerve trunks, the C5-C6 zygapophyseal joint, the carpal tunnel and the tibialis anterior muscle in a blinded design. The results showed that pressure pain threshold levels were significantly decreased bilaterally over the median, ulnar, and radial nerve trunks, the carpal tunnel, the C5-C6 zygapophyseal joint, and the tibialis anterior muscle in patients with unilateral carpal tunnel syndrome as compared to healthy controls (all, P < 0.001). Pressure pain threshold was negatively correlated to both hand pain intensity and duration of symptoms (all, P < 0.001). Our findings revealed bilateral widespread pressure hypersensitivity in subjects with carpal tunnel syndrome, which suggest that widespread central sensitization is involved in patients with unilateral carpal tunnel syndrome. The generalized decrease in pressure pain thresholds associated with pain intensity and duration of symptoms supports a role of the peripheral drive to initiate and maintain central sensitization. Nevertheless, both central and peripheral sensitization mechanisms are probably involved at the same time in carpal tunnel syndrome.

Intervertebral Foramen Injection of Ozone Relieves Mechanical Allodynia and Enhances Analgesic Effect of Gabapentin in Animal Model of Neuropathic Pain.

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Luo, Wen-Jun; Yang, Fan; Yang, Fei; Sun, Wei; Zheng, Wei; Wang, Xiao-Liang; Wu, Fang-Fang; Wang, Jiang-Lin; Wang, Jia-Shuang; Guan, Su-Min; Chen, Jun

2017-07-01

In a 5-year follow-up study in a hospital in southern China, it was shown that intervertebral foramen (IVF) injection of ozone at the involved segmental levels could significantly alleviate paroxysmal spontaneous pain and mechanical allodynia in patients with chronic, intractable postherpetic neuralgia (PHN) and improve the quality of life. However, so far no proof-of-concept studies in animals have been available. This study was designed to investigate whether IVF ozone has an analgesic effect on animal models of neuropathic and inflammatory pain. Experimental trial in rats. Institute for Biomedical Sciences of Pain. By IVF injection, a volume of 50 µl containing 30 µg/mL ozone-oxygen mixture or 50 µl air was carried out on male Sprague-Dawley rats of naïve, inflammatory pain states produced by injections of either bee venom or complete Freud's adjuvant, and neuropathic pain state produced by spared nerve injury, respectively. The effects of IVF ozone on pain-related behaviors were evaluated for 2 weeks or one month. Then combined use of gabapentin (100 mg/1 kg body weight) with IVF ozone was evaluated in rats with neuropathic pain by intraperitoneal administration 5 days after the ozone treatment. Finally, the analgesic effects of another 4 drugs, AMD3100 (a CXCR4 antagonist), A-803467 (a selective Nav1.8 blocker), rapamycin (the mTOR inhibitor), and MGCD0103 (a selective histone deacetylase inhibitor) were evaluated for long term through IVF injection, respectively. (1) IVF injection of ozone at L4-5 was only effective in suppression of mechanical allodynia in rats with neuropathic pain but not with inflammatory pain; (2) the analgesic effects of IVF ozone lasted much longer (> 14 days) than other selective molecular target drugs (bee venom, complete Freud's adjuvant.

Bilateral widespread mechanical pain hypersensitivity as sign of central sensitization in patients with cluster headache.

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Fernández-de-Las-Peñas, César; Ortega-Santiago, Ricardo; Cuadrado, María L; López-de-Silanes, Carlos; Pareja, Juan A

2011-03-01

To investigate bilateral widespread pressure pain hyperalgesia in deep tissues over symptomatic (trigemino-cervical) and nonsymptomatic (distant pain-free) regions in patients with cluster headache (CH). Central sensitization is claimed to play a relevant role in CH. No study has previously searched for widespread pressure hyperalgesia in deep tissues over both symptomatic (trigemino-cervical) and nonsymptomatic (distant pain-free) regions in patients with CH. Sixteen men (mean age: 43 ± 11 years) with CH in a remission phase and 16 matched controls were recruited. Pressure pain thresholds (PPTs) were bilaterally measured over the supra-orbital (V1), infra-orbital (V2), mental (V3), median (C5), radial (C6), and ulnar (C7) nerves, C5-C6 zygapophyseal joint, mastoid process, and tibialis anterior muscle by an assessor blinded to the subjects' condition. The results showed that PPT levels were significantly decreased bilaterally in patients with CH as compared with healthy controls (all sites, P < .001). A greater degree of sensitization over the mastoid process (P < .001) and a lower degree of sensitization over the tibialis anterior muscle (P < .01) was found. Our findings revealed bilateral widespread pressure pain hypersensitivity in patients with CH confirming the presence of central sensitization mechanisms in this headache condition. © 2010 American Headache Society.

Neuroinflammatory contributions to pain after SCI: roles for central glial mechanisms and nociceptor-mediated host defense.

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Walters, Edgar T

2014-08-01

Neuropathic pain after spinal cord injury (SCI) is common, often intractable, and can be severely debilitating. A number of mechanisms have been proposed for this pain, which are discussed briefly, along with methods for revealing SCI pain in animal models, such as the recently applied conditioned place preference test. During the last decade, studies of animal models have shown that both central neuroinflammation and behavioral hypersensitivity (indirect reflex measures of pain) persist chronically after SCI. Interventions that reduce neuroinflammation have been found to ameliorate pain-related behavior, such as treatment with agents that inhibit the activation states of microglia and/or astroglia (including IL-10, minocycline, etanercept, propentofylline, ibudilast, licofelone, SP600125, carbenoxolone). Reversal of pain-related behavior has also been shown with disruption by an inhibitor (CR8) and/or genetic deletion of cell cycle-related proteins, deletion of a truncated receptor (trkB.T1) for brain-derived neurotrophic factor (BDNF), or reduction by antisense knockdown or an inhibitor (AMG9810) of the activity of channels (TRPV1 or Nav1.8) important for electrical activity in primary nociceptors. Nociceptor activity is known to drive central neuroinflammation in peripheral injury models, and nociceptors appear to be an integral component of host defense. Thus, emerging results suggest that spinal and systemic effects of SCI can activate nociceptor-mediated host defense responses that interact via neuroinflammatory signaling with complex central consequences of SCI to drive chronic pain. This broader view of SCI-induced neuroinflammation suggests new targets, and additional complications, for efforts to develop effective treatments for neuropathic SCI pain. Copyright © 2014 Elsevier Inc. All rights reserved.

PHYSIOLOGICAL MECHANISMS OF POLARIZED LIGHT INFLUENCE ON PAIN

Directory of Open Access Journals (Sweden)

S. О. Gulyar

2016-06-01

Full Text Available There are presented experimental evidences of BIOPTRON device polarized light influence on the acupuncture points and pain locus. It is proved that PILER-light can induce analgesia which depends on the choice of the application zone, exposure and nature of pain (tonic, acute or visceral. Analgesic response has systemic character and is accompanied by participation of opioidergic nociceptive system

Directed differentiation of basal forebrain cholinergic neurons from human pluripotent stem cells.

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Hu, Yao; Qu, Zhuang-Yin; Cao, Shi-Ying; Li, Qi; Ma, Lixiang; Krencik, Robert; Xu, Min; Liu, Yan

2016-06-15

Basal forebrain cholinergic neurons (BFCNs) play critical roles in learning, memory and cognition. Dysfunction or degeneration of BFCNs may connect to neuropathology, such as Alzheimer's disease, Down's syndrome and dementia. Generation of functional BFCNs may contribute to the studies of cell-based therapy and pathogenesis that is related to learning and memory deficits. Here we describe a detail method for robust generation of BFCNs from human embryonic stem cells (hESCs) and human induced pluripotent stem cells (hiPSCs). In this method, BFCN progenitors are patterned from hESC or hiPSC-derived primitive neuroepithelial cells, with the treatment of sonic hedgehog (SHH) or combination with its agonist Purmorphamine, and by co-culturing with human astrocytes. At day 20, ∼90% hPSC-derived progenitors expressed NKX2.1, which is a transcriptional marker for MGE. Moreover, around 40% of NKX2.1+ cells co-expressed OLIG2 and ∼15% of NKX2.1+ cells co-expressed ISLET1, which are ventral markers. At day 35, ∼40% neurons robustly express ChAT, most of which are co-labeled with NKX2.1, ISLET1 and FOXG1, indicating the basal forebrain-like identity. At day 45, these neurons express mature neuronal markers MAP2, Synapsin, and VAChT. In this method, undefined conditions including genetic modification or cell-sorting are avoided. As a choice, feeder free conditions are used to avoid ingredients of animal origin. Moreover, Purmorphamine can be substituted for SHH to induce ventral progenitors effectively and economically. We provide an efficient method to generate BFCNs from multiple hPSC lines, which offers the potential application for disease modeling and pharmacological studies. Copyright © 2016 Elsevier B.V. All rights reserved.

A comparative behavioural study of mechanical hypersensitivity in 2 pain models in rats and humans.

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Reitz, Marie-Céline; Hrncic, Dragan; Treede, Rolf-Detlef; Caspani, Ombretta

2016-06-01

The assessment of pain sensitivity in humans has been standardized using quantitative sensory testing, whereas in animals mostly paw withdrawal thresholds to diverse stimuli are measured. This study directly compares tests used in quantitative sensory testing (pinpricks, pressure algometer) with tests used in animal studies (electronic von Frey test: evF), which we applied to the dorsal hind limbs of humans after high frequency stimulation and rats after tibial nerve transection. Both experimental models induce profound mechanical hypersensitivity. At baseline, humans and rats showed a similar sensitivity to evF with 0.2 mm diameter tips, but significant differences for other test stimuli (all P pain models (P pain sensitivity, but probe size and shape should be standardized. Hypersensitivity to blunt pressure-the leading positive sensory sign after peripheral nerve injury in humans-is a novel finding in the tibial nerve transection model. By testing outside the primary zone of nerve damage (rat) or activation (humans), our methods likely involve effects of central sensitization in both species.

Cortical stimulation and neuropathic pain

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Cristiane Cagnoni Ramos

2015-05-01

Full Text Available This paper is a review of physiological and behavioral data on motor cortex stimulation (MCS and its role in persistent neuropathic pain. MCS has been widely used in clinical medicine as a tool for the management of pain that does not respond satisfactorily to any kind of conventional analgesia. Some important mechanisms involved in nociceptive modulation still remains unclear. The aim of this study was to describe the mechanisms involved in neuropathic pain and introduce the effectiveness of electrical stimulation of the motor cortex used in the treatment of this disease. The ascending pain pathways are activated by peripheral receptors, in which there is the transduction of a chemical, physical or mechanical stimulus as a nerve impulse, where this impulse is transmitted to the dorsal horn of the spinal cord, which connects with second-order neurons and ascends to different locations in the central nervous system where the stimulus is perceived as pain. Because MCS has been proved to modulate this pathway in the motor cortex, it has been studied to mimic its effects in clinical practice and improve the treatments used for chronic pain. MCS has gained much attention in recent years due to its action in reversing chronic neuropathic pain, this being more effective than electrical stimulation at different locations and related pain nuclei.

Stress-Induced Chronic Visceral Pain of Gastrointestinal Origin

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Beverley Greenwood-Van Meerveld

2017-11-01

Full Text Available Visceral pain is generally poorly localized and characterized by hypersensitivity to a stimulus such as organ distension. In concert with chronic visceral pain, there is a high comorbidity with stress-related psychiatric disorders including anxiety and depression. The mechanisms linking visceral pain with these overlapping comorbidities remain to be elucidated. Evidence suggests that long term stress facilitates pain perception and sensitizes pain pathways, leading to a feed-forward cycle promoting chronic visceral pain disorders such as irritable bowel syndrome (IBS. Early life stress (ELS is a risk-factor for the development of IBS, however the mechanisms responsible for the persistent effects of ELS on visceral perception in adulthood remain incompletely understood. In rodent models, stress in adult animals induced by restraint and water avoidance has been employed to investigate the mechanisms of stress-induce pain. ELS models such as maternal separation, limited nesting, or odor-shock conditioning, which attempt to model early childhood experiences such as neglect, poverty, or an abusive caregiver, can produce chronic, sexually dimorphic increases in visceral sensitivity in adulthood. Chronic visceral pain is a classic example of gene × environment interaction which results from maladaptive changes in neuronal circuitry leading to neuroplasticity and aberrant neuronal activity-induced signaling. One potential mechanism underlying the persistent effects of stress on visceral sensitivity could be epigenetic modulation of gene expression. While there are relatively few studies examining epigenetically mediated mechanisms involved in visceral nociception, stress-induced visceral pain has been linked to alterations in DNA methylation and histone acetylation patterns within the brain, leading to increased expression of pro-nociceptive neurotransmitters. This review will discuss the potential neuronal pathways and mechanisms responsible for

Stress-Induced Chronic Visceral Pain of Gastrointestinal Origin

Science.gov (United States)

Greenwood-Van Meerveld, Beverley; Johnson, Anthony C.

2017-01-01

Visceral pain is generally poorly localized and characterized by hypersensitivity to a stimulus such as organ distension. In concert with chronic visceral pain, there is a high comorbidity with stress-related psychiatric disorders including anxiety and depression. The mechanisms linking visceral pain with these overlapping comorbidities remain to be elucidated. Evidence suggests that long term stress facilitates pain perception and sensitizes pain pathways, leading to a feed-forward cycle promoting chronic visceral pain disorders such as irritable bowel syndrome (IBS). Early life stress (ELS) is a risk-factor for the development of IBS, however the mechanisms responsible for the persistent effects of ELS on visceral perception in adulthood remain incompletely understood. In rodent models, stress in adult animals induced by restraint and water avoidance has been employed to investigate the mechanisms of stress-induce pain. ELS models such as maternal separation, limited nesting, or odor-shock conditioning, which attempt to model early childhood experiences such as neglect, poverty, or an abusive caregiver, can produce chronic, sexually dimorphic increases in visceral sensitivity in adulthood. Chronic visceral pain is a classic example of gene × environment interaction which results from maladaptive changes in neuronal circuitry leading to neuroplasticity and aberrant neuronal activity-induced signaling. One potential mechanism underlying the persistent effects of stress on visceral sensitivity could be epigenetic modulation of gene expression. While there are relatively few studies examining epigenetically mediated mechanisms involved in visceral nociception, stress-induced visceral pain has been linked to alterations in DNA methylation and histone acetylation patterns within the brain, leading to increased expression of pro-nociceptive neurotransmitters. This review will discuss the potential neuronal pathways and mechanisms responsible for stress

Pain management : Internationally a nursing responsibility

OpenAIRE

Petrini, Marcia, A

1999-01-01

Pain management by nurses internationally has increased with the awareness of the importance of relief from pain in the healing process. Studies of the physiological mechanisms of pain and the impact on healing havepromoted the recognition for pain relief

Mechanisms of low back pain: a guide for diagnosis and therapy

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Allegri, Massimo; Montella, Silvana; Salici, Fabiana; Valente, Adriana; Marchesini, Maurizio; Compagnone, Christian; Baciarello, Marco; Manferdini, Maria Elena; Fanelli, Guido

2016-01-01

Chronic low back pain (CLBP) is a chronic pain syndrome in the lower back region, lasting for at least 3 months. CLBP represents the second leading cause of disability worldwide being a major welfare and economic problem. The prevalence of CLBP in adults has increased more than 100% in the last decade and continues to increase dramatically in the aging population, affecting both men and women in all ethnic groups, with a significant impact on functional capacity and occupational activities. It can also be influenced by psychological factors, such as stress, depression and/or anxiety. Given this complexity, the diagnostic evaluation of patients with CLBP can be very challenging and requires complex clinical decision-making. Answering the question “what is the pain generator” among the several structures potentially involved in CLBP is a key factor in the management of these patients, since a mis-diagnosis can generate therapeutical mistakes. Traditionally, the notion that the etiology of 80% to 90% of LBP cases is unknown has been mistaken perpetuated across decades. In most cases, low back pain can be attributed to specific pain generator, with its own characteristics and with different therapeutical opportunity. Here we discuss about radicular pain, facet Joint pain, sacro-iliac pain, pain related to lumbar stenosis, discogenic pain. Our article aims to offer to the clinicians a simple guidance to identify pain generators in a safer and faster way, relying a correct diagnosis and further therapeutical approach. PMID:27408698

Extensibility of the hamstrings is best explained by mechanical components of muscle contraction, not behavioral measures in individuals with chronic low back pain.

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Marshall, Paul W M; Mannion, Jamie; Murphy, Bernadette A

2009-08-01

To examine the relationship between hamstring extensibility by use of the instrumented straight leg raise; mechanical components of muscle contraction, including muscle recruitment, passive torque measures of tissue stiffness, and eccentric strength; and self-reported measures of pain and disability. Cross-sectional study. University laboratory. Twenty-one individuals with chronic nonspecific axial lower back pain and 15 healthy control subjects. Instrumented straight leg raise, concentric and eccentric hamstring strength, self-reported measures of pain, disability, fear avoidance, general health and well-being Objective measures included hamstring extensibility, hamstring muscle stiffness, absolute and relative concentric/eccentric strength, concentric/eccentric strength ratios. Self-reported measures included Oswestry disability index, visual analog pain scale, fear avoidance beliefs, and general health and well being. Patients with lower back pain had lower range of motion, greater changes in muscle stiffness, and impaired concentric-to-eccentric strength levels. Stepwise regression identified measures of stiffness as significantly predicting hamstring extensibility (adjusted r(2) = 0.58, F = 23.76, P hamstrings also was associated with greater hamstring extensibility. Decreased extensibility of the hamstrings was associated with increased passive stiffness during the common range of motion (20 to 50 degrees ). Impaired stretch tolerance is associated with actual mechanical restriction, not behavioral measures indicating increased pain or fear-avoidant behavior. With no relationship to actual disability and contradictory findings in the literature for the relationship of the hamstrings to the mechanics of the low back, it is unclear whether decreased hamstring extensibility should be targeted in rehabilitation programs for axial lower back pain.

Ablation of Ca(V2.1 voltage-gated Ca²⁺ channels in mouse forebrain generates multiple cognitive impairments.

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Robert Theodor Mallmann

Full Text Available Voltage-gated Ca(V2.1 (P/Q-type Ca²⁺ channels located at the presynaptic membrane are known to control a multitude of Ca²⁺-dependent cellular processes such as neurotransmitter release and synaptic plasticity. Our knowledge about their contributions to complex cognitive functions, however, is restricted by the limited adequacy of existing transgenic Ca(V2.1 mouse models. Global Ca(V2.1 knock-out mice lacking the α1 subunit Cacna1a gene product exhibit early postnatal lethality which makes them unsuitable to analyse the relevance of Ca(V2.1 Ca²⁺ channels for complex behaviour in adult mice. Consequently we established a forebrain specific Ca(V2.1 knock-out model by crossing mice with a floxed Cacna1a gene with mice expressing Cre-recombinase under the control of the NEX promoter. This novel mouse model enabled us to investigate the contribution of Ca(V2.1 to complex cognitive functions, particularly learning and memory. Electrophysiological analysis allowed us to test the specificity of our conditional knock-out model and revealed an impaired synaptic transmission at hippocampal glutamatergic synapses. At the behavioural level, the forebrain-specific Ca(V2.1 knock-out resulted in deficits in spatial learning and reference memory, reduced recognition memory, increased exploratory behaviour and a strong attenuation of circadian rhythmicity. In summary, we present a novel conditional Ca(V2.1 knock-out model that is most suitable for analysing the in vivo functions of Ca(V2.1 in the adult murine forebrain.

[Effect of Medicated-catgut Embedding at "Changqiang" (GV 1) on Mechanical Pain Threshold and P 38 MAPK Expression in Spinal Cord Tissue in Anus Incisional Pain Rats].

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Shu, Tao; Zhang, Shi-Ti; Yan, Feng; Ke, Yu-Pei; Wang, Jun

2017-10-25

To observe the effect of medicated-catgut embedding at "Changqiang"(GV 1) on regional pain reaction and expression of p 38 MAPK in the dorsal horn of spinal cord in anus incisional pain rats, so as to explore its analgesic mechanism. Forty male SD rats were randomly divided into control, model, GV 1-embedding and sham acupoint embedding groups ( n =10 rats in each group). The anus incisional pain model was established by making a radial incision (about 10 mm length) at the left lithotomy position of the anus with a surgical knife, and the mechanical pain threshold (PT) was measured by using a Von Frey before and 4, 8, 12, 24 h after operation. The medicated-catgut (about 12.5 mm length/kg body weight) was implanted in the subcutaneous tissue of GV 1 region. The immunoactivity of p 38 MAPK was determined by immunohistochemistry. Compared with the control group, the mechanical PTs were significantly decreased 4, 8, 12 and 24 h after operation both at the site of incision and about 15 mm proximal to the site of incision in the model group ( P <0.05), and the immunoactivity of phosphorylated (p)-p 38 MAPK in the superficial layer of dorsal horns of lumbar spinal cord was significantly increased(24 h)after operation( P <0.05). Compared with the model group, the PTs were significantly increased 8, 12 and 24 h after operation at the site of incision, and 12 h and 24 h at the site about 15 mm proximal to the incision region ( P <0.05), and the immunoactivity level of p-p 38 MAPK was significantly down-regulated in the GV 1-embedding group ( P <0.05). No significant changes were found in the PT and p-p 38 MAPK immunoactivity levels in the sham acupoint embedding group ( P <0.05). Medicated-catgut embedding at "Changqiang"(GV 1) has an analgesic effect in anus incisional pain model rats, which may be related to its effect in down-regulating the expression of p 38 MAPK in the dorsal horn of lumbar spinal cord.

Transforaminal epidural steroid injections influence Mechanical Diagnosis and Therapy (MDT) pain response classification in candidates for lumbar herniated disc surgery.

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van Helvoirt, Hans; Apeldoorn, Adri T; Knol, Dirk L; Arts, Mark P; Kamper, Steven J; van Tulder, Maurits W; Ostelo, Raymond W

2016-04-27

Prospective cohort study. Although lumbar radiculopathy is regarded as a specific diagnosis, the most effective treatment strategy is unclear. Commonly used treatments include transforaminal epidural steroid injections (TESIs) and Mechanical Diagnosis & Therapy (MDT), but no studies have investigated the effectiveness of this combination. MDT differentiates pain centralization (C) from non-centralization (NC), which indicates good vs. poor prognostic validity respectively. The main aims were 1) to determine changes in Mechanical Diagnosis and Therapy (MDT) pain response classifications after transforaminal epidural steroid injections (TESIs) in candidates for lumbar herniated disc surgery and 2) to evaluate differences in short and long term outcomes for patients with different pain response classifications. Candidates for lumbar herniated disc surgery were assessed with a MDT protocol and their pain response classified as centralizing or peripheralizing. For this study,only patients were eligible who showed a peripheralizing pain response at intake. All patients then received TESIs and were reassessed and classified using the MDT protocol, into groups according to pain response (resolved, centralizing, peripheralizing with less pain and peripheralising with severe pain). After receiving targeted treatment based on pain response after TESIs, ranging from advice, MDT or surgery, follow-up assessments were completed at discharge and at 12 months. The primary outcomes were disability (Roland-Morris Disability Questionnaire [RMDQ] for Sciatica), pain severity in leg (visual analogue scale [VAS], 0-100) and global perceived effect (GPE). Linear mixed-models were used to determine between-groups differences in outcome. A total of 77 patients with lumbar disc herniation and peripheralizing symptoms were included. Patients received an average of 2 (SD 0.7) TESIs. After TESIs, 17 patients (22%) were classified as peripheralizing with continuing severe pain.These patients

An Evolutionarily Conserved Network Mediates Development of the zona limitans intrathalamica, a Sonic Hedgehog-Secreting Caudal Forebrain Signaling Center

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Elena Sena

2016-10-01

Full Text Available Recent studies revealed new insights into the development of a unique caudal forebrain-signaling center: the zona limitans intrathalamica (zli. The zli is the last brain signaling center to form and the first forebrain compartment to be established. It is the only part of the dorsal neural tube expressing the morphogen Sonic Hedgehog (Shh whose activity participates in the survival, growth and patterning of neuronal progenitor subpopulations within the thalamic complex. Here, we review the gene regulatory network of transcription factors and cis-regulatory elements that underlies formation of a shh-expressing delimitated domain in the anterior brain. We discuss evidence that this network predates the origin of chordates. We highlight the contribution of Shh, Wnt and Notch signaling to zli development and discuss implications for the fact that the morphogen Shh relies on primary cilia for signal transduction. The network that underlies zli development also contributes to thalamus induction, and to its patterning once the zli has been set up. We present an overview of the brain malformations possibly associated with developmental defects in this gene regulatory network (GRN.

[The pain-emotion: Advocating pain as an emotion].

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Fonseca Das Neves, J; Sule, N; Serra, E

2017-12-01

Pain is a common experience, both physical and emotional. However we often feel powerless with our patients suffering pain. This paper aims to give a new heuristic and psychological understanding of pain. According to new theories, recent researches as well as different points of view, we form an analogy between pain and emotion. Throughout historical considerations pain has always been perceived through theories and beliefs, changing its definition. This is also the case for emotion. Could they be two ways of expressing a single phenomenon? First, we must clarify the definition of emotion. In past, emotion was considered as a multiple-conditioned notion. To be considered as an emotion the pain had to fill numerous features, which differ according to the scientific opinions. The emotion may be considered as a physical expression or perceived only as the consequences of a real emotion, i.e., the subjective feeling. We propose as a way of thinking that emotion brings together these two concepts. We support a flexible vision of emotion. To investigate the field of the emotion different mental steps may be thought of: we should conceive of the emotion as a stimulus, as an emotional evaluation and as a tendency to action, which becomes an emotional response. These steps are colored by subjective feelings. It can be summarized in three levels: the situation decoding (1), the response organization (2) and the effectiveness of the response (3). Second pain can be considered as a complex notion involving personal and subjective feelings. We can use multidimensional patterns and consider emotion with its multiple features: the generating mechanisms, the pain perception, the pain behavior and the environment. Each stage can be divided in different ways. Hence pain treatment could be approached as an emotional treatment. Indeed, we can make a link between generating mechanisms and emotion situation decoding, between pain perception and emotion situation decoding and response

Social learning pathways in the relation between parental chronic pain and daily pain severity and functional impairment in adolescents with functional abdominal pain.

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Stone, Amanda L; Bruehl, Stephen; Smith, Craig A; Garber, Judy; Walker, Lynn S

2017-10-06

Having a parent with chronic pain (CP) may confer greater risk for persistence of CP from childhood into young adulthood. Social learning, such as parental modeling and reinforcement, represents one plausible mechanism for the transmission of risk for CP from parents to offspring. Based on a 7-day pain diary in 154 pediatric patients with functional abdominal CP, we tested a model in which parental CP predicted adolescents' daily average CP severity and functional impairment (distal outcomes) via parental modeling of pain behaviors and parental reinforcement of adolescent's pain behaviors (mediators) and adolescents' cognitive appraisals of pain threat (proximal outcome representing adolescents' encoding of parents' behaviors). Results indicated significant indirect pathways from parental CP status to adolescent average daily pain severity (b = 0.18, SE = 0.08, 95% CI: 0.04, 0.31, p = 0.03) and functional impairment (b = 0.08, SE = 0.04, 95% CI: 0.02, 0.15, p = 0.03) over the 7-day diary period via adolescents' observations of parent pain behaviors and adolescent pain threat appraisal. The indirect pathway through parental reinforcing responses to adolescents' pain did not reach significance for either adolescent pain severity or functional impairment. Identifying mechanisms of increased risk for pain and functional impairment in children of parents with CP ultimately could lead to targeted interventions aimed at improving functioning and quality of life in families with chronic pain. Parental modeling of pain behaviors represents a potentially promising target for family based interventions to ameliorate pediatric chronic pain.

Temporal summation of pain as a prospective predictor of clinical pain severity in adults aged 45 years and above with knee osteoarthritis: ethnic differences

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Goodin, Burel R.; Bulls, Hailey W.; Herbert, Matthew S.; Schmidt, Jessica; King, Christopher D.; Glover, Toni L.; Sotolongo, Adriana; Sibille, Kimberly T.; Cruz-Almeida, Yenisel; Staud, Roland; Fessler, Barri J.; Redden, David T.; Bradley, Laurence A.; Fillingim, Roger B.

2014-01-01

Objective Enhanced pain facilitation is reportedly an important contributor to the clinical pain experiences of individuals with knee osteoarthritis (OA). Ethnic differences in the prevalence and severity of knee OA in addition to associated pain are also well documented. Temporal summation (TS) of pain is a widely applicable quantitative sensory testing method that invokes neural mechanisms related to pain facilitatory processes. This study tested whether TS of pain, an index of pain facilitation, differentially predicts the clinical pain experiences of African Americans and non-Hispanic Whites with symptomatic knee OA. Methods A total of 225 study participants underwent assessment of TS of mechanical and heat pain stimuli applied to their most symptomatic knee and their ipsilateral hand (mechanical) or forearm (heat). Using telephone-based surveys, participants subsequently reported their average and worst clinical pain severity across four consecutive weeks following assessment of TS. Results In predicting future clinical pain, ethnicity interacted with TS of mechanical pain (but not heat pain), such that TS of mechanical pain at the knee significantly predicted greater clinical ratings of average (b = .02, p = .016) and worst (b = .02, p = .044) clinical pain for non-Hispanic Whites but not African Americans (p’s > .30). Conclusions These results reveal the importance of considering ethnicity when examining pain facilitation and the clinical pain of individuals with symptomatic knee OA. The results of this study are discussed in terms of ethnic differences in the predictors of clinical pain experiences among African Americans and non-Hispanic Whites with knee OA. PMID:24804882

Genetic ablation of Dicer in adult forebrain neurons results in abnormal tau hyperphosphorylation and neurodegeneration

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Hébert, Sébastien S; Papadopoulou, Aikaterini S; Smith, Pascal

2010-01-01

, particularly in the adult brain, remain poorly defined. Here we show that the absence of Dicer in the adult forebrain is accompanied by a mixed neurodegenerative phenotype. Although neuronal loss is observed in the hippocampus, cellular shrinkage is predominant in the cortex. Interestingly, neuronal...... degeneration coincides with the hyperphosphorylation of endogenous tau at several epitopes previously associated with neurofibrillary pathology. Transcriptome analysis of enzymes involved in tau phosphorylation identified ERK1 as one of the candidate kinases responsible for this event in vivo. We further...

Menopause affects pain depending on pain type and characteristics.

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Meriggiola, Maria Cristina; Nanni, Michela; Bachiocco, Valeria; Vodo, Stellina; Aloisi, Anna M

2012-05-01

Women are more affected than men by many chronic pain conditions, suggesting the effect of sex-related mechanisms in their occurrence. The role of gonadal hormones has been studied but with contrasting results depending on the pain syndrome, reproductive status, and hormone considered. The aim of the present study was to evaluate the pain changes related to the menopausal transition period. In this observational study, postmenopausal women were asked to evaluate the presence of pain in their life during the premenopausal and postmenopausal periods and its modification with menopause. One hundred one women were enrolled and completed questionnaires on their sociodemographic status, pain characteristics, and evolution. The most common pain syndromes were headache (38%), osteoarticular pain (31%), and cervical/lumbar pain (21%). Pain was present before menopause in 66 women, ceased with menopause in 17, and started after menopause in 18. Data were used for cluster analysis, which allowed the division of participants into four groups. In the first, all women experienced headaches that disappeared or improved with menopause. The second group included osteoarticular pain; the pain improved in half of these women and remained stable in the other half. The third group had cervical/lumbar pain, which disappeared or improved with menopause in all. The fourth group presented different kinds of moderate pain, which worsened in all. The present study provides preliminary data suggesting that menopause can affect pain depending on the painful condition experienced by the woman. This underlines the different interactions of menopause-related events with body structures involved in pain.

Visceral pain originating from the upper urinary tract

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Pedersen, Katja Venborg; Drewes, Asbjørn Mohr; Frimodt-Møller, Poul Christian

2010-01-01

Pain originating from the upper urinary tract is a common problem and stone colic is one of the most intense pain conditions that can be experienced in the clinic. The pain is difficult to alleviate and often leads to medical attention. In humans, pain mechanisms of the upper urinary tract pain...... are still poorly understood, which often leads to a trial and error approach in clinical pain management. Pain from the upper urinary tract seems to have all the characteristics of pure visceral pain, including referred pain with or without hyperalgesia/trophic changes in somatic tissues and viscero......-visceral hyperalgesia. However, further studies are needed to better understand these visceral pain mechanisms with regard to optimising pain management. This review gives an introduction to visceral pain in general and upper urinary tract pain in particular, with special reference to pain pathways and pharmacological...

Hypersensitivity to mechanical and intra-articular electrical stimuli in persons with painful temporomandibular joints

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Ayesh, Emad; Jensen, Troels Staehelin; Svensson, P

2007-01-01

This study tested whether persons with TMJ arthralgia have a modality-specific and site-specific hypersensitivity to somatosensory stimuli assessed by quantitative sensory tests (QST). Forty-three healthy persons and 20 with TMJ arthralgia participated. The QST consisted of: sensory and pain dete...... of sensitization of the TMJs as well as central nociceptive pathways. QST may facilitate a mechanism-based classification of temporomandibular disorders. Udgivelsesdato: 2007-Dec...

Manual and Instrument Applied Cervical Manipulation for Mechanical Neck Pain: A Randomized Controlled Trial.

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Gorrell, Lindsay M; Beath, Kenneth; Engel, Roger M

2016-06-01

The purpose of this study was to compare the effects of 2 different cervical manipulation techniques for mechanical neck pain (MNP). Participants with MNP of at least 1 month's duration (n = 65) were randomly allocated to 3 groups: (1) stretching (control), (2) stretching plus manually applied manipulation (MAM), and (3) stretching plus instrument-applied manipulation (IAM). MAM consisted of a single high-velocity, low-amplitude cervical chiropractic manipulation, whereas IAM involved the application of a single cervical manipulation using an (Activator IV) adjusting instrument. Preintervention and postintervention measurements were taken of all outcomes measures. Pain was the primary outcome and was measured using visual analogue scale and pressure pain thresholds. Secondary outcomes included cervical range of motion, hand grip-strength, and wrist blood pressure. Follow-up subjective pain scores were obtained via telephone text message 7 days postintervention. Subjective pain scores decreased at 7-day follow-up in the MAM group compared with control (P = .015). Cervical rotation bilaterally (ipsilateral: P = .002; contralateral: P = .015) and lateral flexion on the contralateral side to manipulation (P = .001) increased following MAM. Hand grip-strength on the contralateral side to manipulation (P = .013) increased following IAM. No moderate or severe adverse events were reported. Mild adverse events were reported on 6 occasions (control, 4; MAM, 1; IAM, 1). This study demonstrates that a single cervical manipulation is capable of producing immediate and short-term benefits for MNP. The study also demonstrates that not all manipulative techniques have the same effect and that the differences may be mediated by neurological or biomechanical factors inherent to each technique. Copyright © 2016. Published by Elsevier Inc.

The mechanism of neurofeedback training for treatment of central neuropathic pain in paraplegia: a pilot study.

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Hassan, Muhammad Abul; Fraser, Matthew; Conway, Bernard A; Allan, David B; Vuckovic, Aleksandra

2015-10-13

Central neuropathic pain has a prevalence of 40% in patients with spinal cord injury. Electroencephalography (EEG) studies showed that this type of pain has identifiable signatures, that could potentially be targeted by a neuromodulation therapy. The aim of the study was to investigate the putative mechanism of neurofeedback training on central neuropathic pain and its underlying brain signatures in patients with chronic paraplegia. Patients' EEG activity was modulated from the sensory-motor cortex, electrode location C3/Cz/C4/P4 in up to 40 training sessions Results. Six out of seven patients reported immediate reduction of pain during neurofeedback training. Best results were achieved with suppressing Ɵ and higher β (20-30 Hz) power and reinforcing α power at C4. Four patients reported clinically significant long-term reduction of pain (>30%) which lasted at least a month beyond the therapy. EEG during neurofeedback revealed a wide spread modulation of power in all three frequency bands accompanied with changes in the coherence most notable in the beta band. The standardized low resolution electromagnetic tomography analysis of EEG before and after neurofeedback therapy showed the statistically significant reduction of power in beta frequency band in all tested patients. Areas with reduced power included the Dorsolateral Prefrontal Cortex, the Anterior Cingulate Cortex and the Insular Cortex. Neurofeedback training produces both immediate and longer term reduction of central neuropathic pain that is accompanied with a measurable short and long term modulation of cortical activity. Controlled trials are required to confirm the efficacy of this neurofeedback protocol on treatment of pain. The study is a registered UKCRN clinical trial Nr 9824.

Pragmatically Applied Cervical and Thoracic Nonthrust Manipulation Versus Thrust Manipulation for Patients With Mechanical Neck Pain: A Multicenter Randomized Clinical Trial.

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Griswold, David; Learman, Ken; Kolber, Morey J; O'Halloran, Bryan; Cleland, Joshua A

2018-03-01

Study Design Randomized clinical trial. Background The comparative effectiveness between nonthrust manipulation (NTM) and thrust manipulation (TM) for mechanical neck pain has been investigated, with inconsistent results. Objective To compare the clinical effectiveness of concordant cervical and thoracic NTM and TM for patients with mechanical neck pain. Methods The Neck Disability Index (NDI) was the primary outcome. Secondary outcomes included the Patient-Specific Functional Scale (PSFS), numeric pain-rating scale (NPRS), deep cervical flexion endurance (DCF), global rating of change (GROC), number of visits, and duration of care. The covariate was clinical equipoise for intervention. Outcomes were collected at baseline, visit 2, and discharge. Patients were randomly assigned to receive either NTM or TM directed at the cervical and thoracic spines. Techniques and dosages were selected pragmatically and applied to the most symptomatic level. Two-way mixed-model analyses of covariance were used to assess clinical outcomes at 3 time points. Analyses of covariance were used to assess between-group differences for the GROC, number of visits, and duration of care at discharge. Results One hundred three patients were included in the analyses (NTM, n = 55 and TM, n = 48). The between-group analyses revealed no differences in outcomes on the NDI (P = .67), PSFS (P = .26), NPRS (P = .25), DCF (P = .98), GROC (P = .77), number of visits (P = .21), and duration of care (P = .61) for patients with mechanical neck pain who received either NTM or TM. Conclusion NTM and TM produce equivalent outcomes for patients with mechanical neck pain. The trial was registered with ClinicalTrials.gov (NCT02619500). Level of Evidence Therapy, level 1b. J Orthop Sports Phys Ther 2018;48(3):137-145. Epub 6 Feb 2018. doi:10.2519/jospt.2018.7738.

Managing neuropathic pain in dogs

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Sarah A Moore

2016-02-01

Full Text Available Disorders of the somatosensory system such as neuropathic pain are common in people with chronic neurologic and musculoskeletal diseases, yet these conditions remain an underappreciated morbidity in our veterinary patients. This is likely because assessment of neuropathic pain in people relies heavily on self-reporting, something our veterinary patients are not able to do. The development of neuropathic pain is a complex phenomenon, and concepts related to it are frequently not addressed in the standard veterinary medical curriculum such that veterinarians may not recognize this as a potential problem in patients. The goals of this review are to discuss basic concepts in the pathophysiology of neuropathic pain, provide definitions for common clinical terms used in association with the condition, and discuss available medical treatment options for dogs with neuropathic pain. The development of neuropathic pain involves key mechanisms such as ectopic afferent nerve activity, peripheral sensitization, central sensitization, impaired inhibitory modulation, and activation of microglia. Treatments aimed at reducing neuropathic pain are targeted at one or more of these mechanisms. Several drugs are commonly used in the veterinary clinical setting to treat neuropathic pain. These include gabapentin, pregabalin, amantadine, and amitriptyline. Proposed mechanisms of action for each drug, and known pharmacokinetic profiles in dogs are discussed. Strong evidence exists in the human literature for the utility of most of these treatments, but clinical veterinary-specific literature is currently limited. Future studies should focus on objective methods to document neuropathic pain and monitor response to therapy in our veterinary patients.

Cortical stimulation and neuropathic pain

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Cristiane Cagnoni Ramos

2015-02-01

Full Text Available http://dx.doi.org/10.5007/2175-7925.2015v28n2p1 This paper is a review of physiological and behavioral data on motor cortex stimulation (MCS and its role in persistent neuropathic pain. MCS has been widely used in clinical medicine as a tool for the management of pain that does not respond satisfactorily to any kind of conventional analgesia. Some important mechanisms involved in nociceptive modulation still remains unclear. The aim of this study was to describe the mechanisms involved in neuropathic pain and introduce the effectiveness of electrical stimulation of the motor cortex used in the treatment of this disease. The ascending pain pathways are activated by peripheral receptors, in which there is the transduction of a chemical, physical or mechanical stimulus as a nerve impulse, where this impulse is transmitted to the dorsal horn of the spinal cord, which connects with second-order neurons and ascends to different locations in the central nervous system where the stimulus is perceived as pain. Because MCS has been proved to modulate this pathway in the motor cortex, it has been studied to mimic its effects in clinical practice and improve the treatments used for chronic pain. MCS has gained much attention in recent years due to its action in reversing chronic neuropathic pain, this being more effective than electrical stimulation at different locations and related pain nuclei.

Effects of vicarious pain on self-pain perception: investigating the role of awareness

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Terrighena EL

2017-07-01

findings suggest that the activation of defense mechanisms by vicarious pain depends on relatively elaborate cognitive processes, while – strikingly – the appetitive system is activated in highly automatic manner independent from stimulus awareness. Such mechanisms may have evolved to facilitate empathic, protective approach responses toward suffering individuals, ensuring survival of the protective social group. Keywords: observation of pain, approach, defense, pain tolerance

Effect of Estradiol on Neurotrophin Receptors in Basal Forebrain Cholinergic Neurons: Relevance for Alzheimer's Disease.

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Kwakowsky, Andrea; Milne, Michael R; Waldvogel, Henry J; Faull, Richard L

2016-12-17

The basal forebrain is home to the largest population of cholinergic neurons in the brain. These neurons are involved in a number of cognitive functions including attention, learning and memory. Basal forebrain cholinergic neurons (BFCNs) are particularly vulnerable in a number of neurological diseases with the most notable being Alzheimer's disease, with evidence for a link between decreasing cholinergic markers and the degree of cognitive impairment. The neurotrophin growth factor system is present on these BFCNs and has been shown to promote survival and differentiation on these neurons. Clinical and animal model studies have demonstrated the neuroprotective effects of 17β-estradiol (E2) on neurodegeneration in BFCNs. It is believed that E2 interacts with neurotrophin signaling on cholinergic neurons to mediate these beneficial effects. Evidence presented in our recent study confirms that altering the levels of circulating E2 levels via ovariectomy and E2 replacement significantly affects the expression of the neurotrophin receptors on BFCN. However, we also showed that E2 differentially regulates neurotrophin receptor expression on BFCNs with effects depending on neurotrophin receptor type and neuroanatomical location. In this review, we aim to survey the current literature to understand the influence of E2 on the neurotrophin system, and the receptors and signaling pathways it mediates on BFCN. In addition, we summarize the physiological and pathophysiological significance of E2 actions on the neurotrophin system in BFCN, especially focusing on changes related to Alzheimer's disease.

Internal and external factors affecting the development of neuropathic pain in rodents. Is it all about pain?

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Vissers, K; De Jongh, R; Hoffmann, V; Heylen, R; Crul, B; Meert, T

2003-12-01

It is important to know the factors that will influence animal models of neuropathic pain. A good reproducibility and predictability in different strains of animals for a given test increases the clinical relevance and possible targeting. An obligatory requirement for enabling comparisons of results of different origin is a meticulous definition of the specific sensitivities of a model for neuropathic pain and a description of the test conditions. Factors influencing neuropathic pain behavior can be subdivided in external and internal factors. The most important external factors are; timing of the measurement of pain after induction of neuropathy, circadian rhythms, seasonal influences, air humidity, influence of order of testing, diet, social variables, housing and manipulation, cage density, sexual activity, external stress factors, and influences of the experimenter. The internal factors are related to the type of animal, its genetic background, gender, age, and the presence of homeostatic adaptation mechanisms to specific situations or stress. In practice, the behavioral presentations to pain depend on the combination of genetic and environmental factors such as accepted social behavior. It also depends on the use of genetic manipulation of the animals such as in transgenic animals. These make the interpretation of data even more difficult. Differences of pain behavior between in- and outbred animals will be better understood by using modern analysis techniques. Substrains of animals with a high likelihood for developing neuropathic pain make the unraveling of specific pathophysiological mechanisms possible. Concerning the effect of stress on pain, it is important to differentiate between external and internal stress such as social coping behavior. The individual dealing with this stress is species sensitive, and depends on the genotype and the social learning. In the future, histo-immunological and genetic analysis will highlight similarities of the different

Perspectives in Pancreatic Pain

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A. S. Salim

1997-01-01

Full Text Available This review describes some of the mechanisms which are thought to be important in the causation of pain in chronic pancreatitis. Both medical and surgical techniques for treating this pain are described.

An improved behavioural assay demonstrates that ultrasound vocalizations constitute a reliable indicator of chronic cancer pain and neuropathic pain

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Selvaraj Deepitha

2010-03-01

Full Text Available Abstract Background On-going pain is one of the most debilitating symptoms associated with a variety of chronic pain disorders. An understanding of mechanisms underlying on-going pain, i.e. stimulus-independent pain has been hampered so far by a lack of behavioural parameters which enable studying it in experimental animals. Ultrasound vocalizations (USVs have been proposed to correlate with pain evoked by an acute activation of nociceptors. However, literature on the utility of USVs as an indicator of chronic pain is very controversial. A majority of these inconsistencies arise from parameters confounding behavioural experiments, which include novelty, fear and stress due to restrain, amongst others. Results We have developed an improved assay which overcomes these confounding factors and enables studying USVs in freely moving mice repetitively over several weeks. Using this improved assay, we report here that USVs increase significantly in mice with bone metastases-induced cancer pain or neuropathic pain for several weeks, in comparison to sham-treated mice. Importantly, analgesic drugs which are known to alleviate tumour pain or neuropathic pain in human patients significantly reduce USVs as well as mechanical allodynia in corresponding mouse models. Conclusions We show that studying USVs and mechanical allodynia in the same cohort of mice enables comparing the temporal progression of on-going pain (i.e. stimulus-independent pain and stimulus-evoked pain in these clinically highly-relevant forms of chronic pain.

Effects of a Pain Catastrophizing Induction on Sensory Testing in Women with Chronic Low Back Pain: A Pilot Study

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Taub, Chloe J.; Sturgeon, John A.; Johnson, Kevin A.; Mackey, Sean C.; Darnall, Beth D.

2017-01-01

Pain catastrophizing, a pattern of negative cognitive-emotional responses to actual or anticipated pain, maintains chronic pain and undermines response to treatments. Currently, precisely how pain catastrophizing influences pain processing is not well understood. In experimental settings, pain catastrophizing has been associated with amplified pain processing. This study sought to clarify pain processing mechanisms via experimental induction of pain catastrophizing. Forty women with chronic l...

Pain without nociceptors?

DEFF Research Database (Denmark)

Minett, Michael S; Falk, Sarah; Santana-Varela, Sonia

2014-01-01

Nav1.7, a peripheral neuron voltage-gated sodium channel, is essential for pain and olfaction in mice and humans. We examined the role of Nav1.7 as well as Nav1.3, Nav1.8, and Nav1.9 in different mouse models of chronic pain. Constriction-injury-dependent neuropathic pain is abolished when Nav1.......7 is deleted in sensory neurons, unlike nerve-transection-related pain, which requires the deletion of Nav1.7 in sensory and sympathetic neurons for pain relief. Sympathetic sprouting that develops in parallel with nerve-transection pain depends on the presence of Nav1.7 in sympathetic neurons. Mechanical...... and cold allodynia required distinct sets of neurons and different repertoires of sodium channels depending on the nerve injury model. Surprisingly, pain induced by the chemotherapeutic agent oxaliplatin and cancer-induced bone pain do not require the presence of Nav1.7 sodium channels or Nav1.8-positive...

Slow brushing reduces heat pain in humans.

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Liljencrantz, J; Strigo, I; Ellingsen, D M; Krämer, H H; Lundblad, L C; Nagi, S S; Leknes, S; Olausson, H

2017-08-01

C-tactile (CT) afferents are unmyelinated low-threshold mechanoreceptors optimized for signalling affective, gentle touch. In three separate psychophysical experiments, we examined the contribution of CT afferents to pain modulation. In total, 44 healthy volunteers experienced heat pain and CT optimal (slow brushing) and CT sub-optimal (fast brushing or vibration) stimuli. Three different experimental paradigms were used: Concurrent application of heat pain and tactile (slow brushing or vibration) stimulation; Slow brushing, applied for variable duration and intervals, preceding heat pain; Slow versus fast brushing preceding heat pain. Slow brushing was effective in reducing pain, whereas fast brushing or vibration was not. The reduction in pain was significant not only when the CT optimal touch was applied simultaneously with the painful stimulus but also when the two stimuli were separated in time. For subsequent stimulation, the pain reduction was more pronounced for a shorter time interval between brushing and pain. Likewise, the effect was more robust when pain was preceded by a longer duration of brush stimulation. Strong CT-related pain reduction was associated with low anxiety and high calmness scores obtained by a state anxiety questionnaire. Slow brushing - optimal for CT activation - is effective in reducing pain from cutaneous heating. The precise mechanisms for the pain relief are as yet unknown but possible mechanisms include inhibition of nociceptive projection neurons at the level of the dorsal horn as well as analgesia through cortical mechanisms. Slow brushing stimuli - optimal for activation of C-tactile fibres - can reduce pain from cutaneous heating. No such effect was seen with fast brushing or vibration. These observations indicate the role of C-tactile fibres in pain modulation. © 2017 European Pain Federation - EFIC®.

Effect of cervical vs. thoracic spinal manipulation on peripheral neural features and grip strength in subjects with chronic mechanical neck pain: a randomized controlled trial.

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Bautista-Aguirre, Francisco; Oliva-Pascual-Vaca, Ángel; Heredia-Rizo, Alberto M; Boscá-Gandía, Juan J; Ricard, François; Rodriguez-Blanco, Cleofás

2017-06-01

Cervical and thoracic spinal manipulative therapy has shown positive impact for relief of pain and improve function in non-specific mechanical neck pain. Several attempts have been made to compare their effectiveness although previous studies lacked a control group, assessed acute neck pain or combined thrust and non-thrust techniques. To compare the immediate effects of cervical and thoracic spinal thrust manipulations on mechanosensitivity of upper limb nerve trunks and grip strength in patients with chronic non-specific mechanical neck pain. Randomized, single-blinded, controlled clinical trial. Private physiotherapy clinical consultancy. Eighty-eight subjects (32.09±6.05 years; 72.7% females) suffering neck pain (grades I or II) of at least 12 weeks of duration. Participants were distributed into three groups: 1) cervical group (N.=28); 2) thoracic group (N.=30); and 3) control group (N.=30). One treatment session consisting of applying a high-velocity low-amplitude spinal thrust technique over the lower cervical spine (C7) or the upper thoracic spine (T3) was performed, while the control group received a sham-manual contact. Measurements were taken at baseline and after intervention of the pressure pain threshold over the median, ulnar and radial nerves. Secondary measures included assessing free-pain grip strength with a hydraulic dynamometer. No statistically significant differences were observed when comparing between-groups in any of the outcome measures (P>0.05). Those who received thrust techniques, regardless of the manipulated area, reported an immediate increase in mechanosensitivity over the radial (both sides) and left ulnar nerve trunks (Ppain perception over the radial nerve also improved (P≤0.025). Low-cervical and upper-thoracic thrust manipulation is no more effective than placebo to induce immediate changes on mechanosensitivity of upper limb nerve trunks and grip strength in patients with chronic non-specific mechanical neck pain. A single

Articular dysfunction patterns in patients with mechanical neck pain: a clinical algorithm to guide specific mobilization and manipulation techniques.

Science.gov (United States)

Dewitte, Vincent; Beernaert, Axel; Vanthillo, Bart; Barbe, Tom; Danneels, Lieven; Cagnie, Barbara

2014-02-01

In view of a didactical approach for teaching cervical mobilization and manipulation techniques to students as well as their use in daily practice, it is mandatory to acquire sound clinical reasoning to optimally apply advanced technical skills. The aim of this Masterclass is to present a clinical algorithm to guide (novice) therapists in their clinical reasoning to identify patients who are likely to respond to mobilization and/or manipulation. The presented clinical reasoning process is situated within the context of pain mechanisms and is narrowed to and applicable in patients with a dominant input pain mechanism. Based on key features in subjective and clinical examination, patients with mechanical nociceptive pain probably arising from articular structures can be categorized into specific articular dysfunction patterns. Pending on these patterns, specific mobilization and manipulation techniques are warranted. The proposed patterns are illustrated in 3 case studies. This clinical algorithm is the corollary of empirical expertise and is complemented by in-depth discussions and knowledge exchange with international colleagues. Consequently, it is intended that a carefully targeted approach contributes to an increase in specificity and safety in the use of cervical mobilizations and manipulation techniques as valuable adjuncts to other manual therapy modalities. Copyright © 2013 Elsevier Ltd. All rights reserved.

Hopes for the Future of Pain Control.

Science.gov (United States)

Bannister, Kirsty; Kucharczyk, Mateusz; Dickenson, Anthony H

2017-12-01

Here we aim to present an accessible review of the pharmacological targets for pain management, and succinctly discuss the newest trends in pain therapy. A key task for current pain pharmacotherapy is the identification of receptors and channels orchestrating nociception. Notwithstanding peripheral alterations in the receptors and channels following pathophysiological events, the modulatory mechanisms in the central nervous system are also fundamental to the regulation of pain perception. Bridging preclinical and clinical studies of peripheral and central components of pain modulation, we present the different types of pain and relate these to pharmacological interventions. We firstly highlight the roles of several peripheral nociceptors, such as NGF, CGRP, sodium channels, and TRP-family channels that may become novel targets for therapies. In the central nervous system, the roles of calcium channels and gabapentinoids as well as NMDA receptors in generating excitability are covered including ideas on central sensitization. We then turn to central modulatory systems and discuss opioids and monoamines. We aim to explain the importance of central sensitization and the dialogue of the spinal circuits with the brain descending modulatory controls before discussing a mechanism-based effectiveness of antidepressants in pain therapy and their potential to modulate the descending controls. Emphasizing the roles of conditioned pain modulation and its animal's equivalent, diffuse noxious inhibitory controls, we discuss these unique descending modulations as a potential tool for understanding mechanisms in patients suffering from pain. Mechanism-based therapy is the key to picking the correct treatments and recent clinical studies using sensory symptoms of patients as surrogates for underlying mechanisms can be used to subgroup patients and reveal actions of drugs that may be lost when studying heterogenous groups of patients. Key advances in the understanding of basic pain

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

OpenAIRE

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

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 hypersensit...

Pre-operative pain and sensory function in groin hernia

DEFF Research Database (Denmark)

Aasvang, Eske K; Hansen, Jeanette B; Kehlet, Henrik

2009-01-01

BACKGROUND: Although persistent postherniotomy occurs in 5-10% of patients, pathogenic mechanisms remain debatable. Since pre-operative pain has been demonstrated to be a risk factor for persistent postherniotomy pain, pre-operative alterations in nociceptive function may be a potential pathogenic...... mechanism. AIMS: To investigate the correlation between pre-operative pain intensity and sensory functions in the groin hernia area. METHODS: Patients with unilateral groin hernia were examined preoperatively by quantitative sensory testing (thermal, mechanical, and pressure [detection and pain thresholds...... (7%), all whom experienced no pain or pain less than weekly. Only cool detection thresholds were significantly lower between the hernia vs. contralateral side (poperative groin hernia...

The autism-associated MET receptor tyrosine kinase engages early neuronal growth mechanism and controls glutamatergic circuits development in the forebrain.

Science.gov (United States)

Peng, Y; Lu, Z; Li, G; Piechowicz, M; Anderson, M; Uddin, Y; Wu, J; Qiu, S

2016-07-01

The human MET gene imparts a replicated risk for autism spectrum disorder (ASD), and is implicated in the structural and functional integrity of brain. MET encodes a receptor tyrosine kinase, MET, which has a pleiotropic role in embryogenesis and modifies a large number of neurodevelopmental events. Very little is known, however, on how MET signaling engages distinct cellular events to collectively affect brain development in ASD-relevant disease domains. Here, we show that MET protein expression is dynamically regulated and compartmentalized in developing neurons. MET is heavily expressed in neuronal growth cones at early developmental stages and its activation engages small GTPase Cdc42 to promote neuronal growth, dendritic arborization and spine formation. Genetic ablation of MET signaling in mouse dorsal pallium leads to altered neuronal morphology indicative of early functional maturation. In contrast, prolonged activation of MET represses the formation and functional maturation of glutamatergic synapses. Moreover, manipulating MET signaling levels in vivo in the developing prefrontal projection neurons disrupts the local circuit connectivity made onto these neurons. Therefore, normal time-delimited MET signaling is critical in regulating the timing of neuronal growth, glutamatergic synapse maturation and cortical circuit function. Dysregulated MET signaling may lead to pathological changes in forebrain maturation and connectivity, and thus contribute to the emergence of neurological symptoms associated with ASD.

Osteoarthritis: the genesis of pain.

Science.gov (United States)

Fu, Kai; Robbins, Sarah R; McDougall, Jason J

2018-05-01

OA is a painful joint disease that predominantly affects the elderly. Pain is the primary symptom of OA, and it can present as either intermittent or constant. OA pain mechanisms are complex and have only recently been determined. Both peripheral and central processes are involved in creating the OA pain experience, making targeted therapy problematic. Nociceptive, inflammatory and neuropathic pains are all known to occur in OA, but to varying degrees in a patient- and time-specific manner. A better understanding of these multifactorial components of OA pain will lead to the development of more effective and safer pain treatments.

Whole-Brain Monosynaptic Afferent Inputs to Basal Forebrain Cholinergic System

Directory of Open Access Journals (Sweden)

Rongfeng Hu

2016-10-01

Full Text Available The basal forebrain cholinergic system (BFCS robustly modulates many important behaviors, such as arousal, attention, learning and memory, through heavy projections to cortex and hippocampus. However, the presynaptic partners governing BFCS activity still remain poorly understood. Here, we utilized a recently developed rabies virus-based cell-type-specific retrograde tracing system to map the whole-brain afferent inputs of the BFCS. We found that the BFCS receives inputs from multiple cortical areas, such as orbital frontal cortex, motor cortex, and insular cortex, and that the BFCS also receives dense inputs from several subcortical nuclei related to motivation and stress, including lateral septum (LS, central amygdala (CeA, paraventricular nucleus of hypothalamus (PVH, dorsal raphe (DRN and parabrachial nucleus (PBN. Interestingly, we found that the BFCS receives inputs from the olfactory areas and the entorhinal-hippocampal system. These results greatly expand our knowledge about the connectivity of the mouse BFCS and provided important preliminary indications for future exploration of circuit function.

Pain measurement in mechanically ventilated patients after cardiac surgery : comparison of the Behavioral Pain Scale (BPS) and the Critical-Care Pain Observation Tool (CPOT)

NARCIS (Netherlands)

Rijkenberg, Saskia; Stilma, Willemke; Bosman, Robert J; van der Meer, Nardo J; van der Voort, Peter H J

OBJECTIVES: The Behavioral Pain Scale (BPS) and Critical-Care Pain Observation Tool (CPOT) are behavioral pain assessment tools for sedated and unconscious critically ill patients. The aim of this study was to compare the reliability, internal consistency, and discriminant validation of the BPS and

Current advances in orthodontic pain

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Long, Hu; Wang, Yan; Jian, Fan; Liao, Li-Na; Yang, Xin; Lai, Wen-Li

2016-01-01

Orthodontic pain is an inflammatory pain that is initiated by orthodontic force-induced vascular occlusion followed by a cascade of inflammatory responses, including vascular changes, the recruitment of inflammatory and immune cells, and the release of neurogenic and pro-inflammatory mediators. Ultimately, endogenous analgesic mechanisms check the inflammatory response and the sensation of pain subsides. The orthodontic pain signal, once received by periodontal sensory endings, reaches the sensory cortex for pain perception through three-order neurons: the trigeminal neuron at the trigeminal ganglia, the trigeminal nucleus caudalis at the medulla oblongata and the ventroposterior nucleus at the thalamus. Many brain areas participate in the emotion, cognition and memory of orthodontic pain, including the insular cortex, amygdala, hippocampus, locus coeruleus and hypothalamus. A built-in analgesic neural pathway—periaqueductal grey and dorsal raphe—has an important role in alleviating orthodontic pain. Currently, several treatment modalities have been applied for the relief of orthodontic pain, including pharmacological, mechanical and behavioural approaches and low-level laser therapy. The effectiveness of nonsteroidal anti-inflammatory drugs for pain relief has been validated, but its effects on tooth movement are controversial. However, more studies are needed to verify the effectiveness of other modalities. Furthermore, gene therapy is a novel, viable and promising modality for alleviating orthodontic pain in the future. PMID:27341389

Differentiation of Forebrain and Hippocampal Dopamine 1-Class Receptors, D1R and D5R, in Spatial Learning and Memory

Science.gov (United States)

Sariñana, Joshua; Tonegawa, Susumu

2017-01-01

Activation of prefrontal cortical (PFC), striatal, and hippocampal dopamine 1-class receptors (D1R and D5R) is necessary for normal spatial information processing. Yet the precise role of the D1R versus the D5R in the aforementioned structures, and their specific contribution to the water-maze spatial learning task remains unknown. D1R- and D5R- specific in situ hybridization probes showed that forebrain restricted D1R and D5R KO mice (F-D1R/D5R KO) displayed D1R mRNA deletion in the medial (m)PFC, dorsal and ventral striatum, and the dentate gyrus (DG) of the hippocampus. D5R mRNA deletion was limited to the mPFC, the CA1 and DG hippocampal subregions. F-D1R/D5R KO mice were given water-maze training and displayed subtle spatial latency differences between genotypes and spatial memory deficits during both regular and reversal training. To differentiate forebrain D1R from D5R activation, forebrain restricted D1R KO (F-D1R KO) and D5R KO (F-D5R KO) mice were trained on the water-maze task. F-D1R KO animals exhibited escape latency deficits throughout regular and reversal training as well as spatial memory deficits during reversal training. F-D1R KO mice also showed perseverative behavior during the reversal spatial memory probe test. In contrast, F-D5R KO animals did not present observable deficits on the water-maze task. Because F-D1R KO mice showed water-maze deficits we tested the necessity of hippocampal D1R activation for spatial learning and memory. We trained DG restricted D1R KO (DG-D1R KO) mice on the water-maze task. DG-D1R KO mice did not present detectable spatial memory deficit, but did show subtle deficits during specific days of training. Our data provides evidence that forebrain D5R activation plays a unique role in spatial learning and memory in conjunction with D1R activation. Moreover, these data suggest that mPFC and striatal, but not DG D1R activation are essential for spatial learning and memory. PMID:26174222

Finite element simulation of the mechanism of laser ultrasound induced pain weapon

Science.gov (United States)

Zhou, Bo; Zhan, Ren Jun; Shan, Ning

2018-03-01

The Laser-Ultrasonic technique uses laser energy to generate ultrasound waves in various solids. In normal conditions, this technique is used to inspect large structures without destruction, but in military use, we hope get this destruction. Nociceptors in Human skin can feel cold, heat, mechanical and other stimuli, when the stimulus exceeds a certain threshold will produce pain. Based on this principle, a laser induced pain weapon may be made. The generated ultrasound wave form is affected by features of laser pulse. The results obtained from the finite element model of laser generated ultrasound are presented in terms of temperature and displacement. At first step, the transient temperature field can be precisely calculated by using the finite element method. Then, laser generated surface acoustic wave forms are calculated by coupling the temperature distribution. Displacement is used to represent the mechanical action of skin caused by laser ultrasound. Results from numerical simulation are compared with other references; the accuracy of the method is proved accordingly. The results of simulation in the given conditions demonstrate that the stresses generated by pulse laser in human skin model were about -8 and +4 MPa. According to the results of simulation, the max and min stress are both emerged in the range of 0 600 um, that is exactly the location of myelinated Aδ and unmyelinated C nociceptor. The value of stress is can be adjusted by chose suitable parameters of laser. The study provides a possibility for developing a new non-lethal weapon to control riots or crowd.