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Sample records for nociceptive neurons innervate

  1. Contrasting phenotypes of putative proprioceptive and nociceptive trigeminal neurons innervating jaw muscle in rat

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    Connor Mark

    2005-10-01

    Full Text Available Abstract Background Despite the clinical significance of muscle pain, and the extensive investigation of the properties of muscle afferent fibers, there has been little study of the ion channels on sensory neurons that innervate muscle. In this study, we have fluorescently tagged sensory neurons that innervate the masseter muscle, which is unique because cell bodies for its muscle spindles are in a brainstem nucleus (mesencephalic nucleus of the 5th cranial nerve, MeV while all its other sensory afferents are in the trigeminal ganglion (TG. We examine the hypothesis that certain molecules proposed to be used selectively by nociceptors fail to express on muscle spindles afferents but appear on other afferents from the same muscle. Results MeV muscle afferents perfectly fit expectations of cells with a non-nociceptive sensory modality: Opiates failed to inhibit calcium channel currents (ICa in 90% of MeV neurons, although ICa were inhibited by GABAB receptor activation. All MeV afferents had brief (1 msec action potentials driven solely by tetrodotoxin (TTX-sensitive Na channels and no MeV afferent expressed either of three ion channels (TRPV1, P2X3, and ASIC3 thought to be transducers for nociceptive stimuli, although they did express other ATP and acid-sensing channels. Trigeminal masseter afferents were much more diverse. Virtually all of them expressed at least one, and often several, of the three putative nociceptive transducer channels, but the mix varied from cell to cell. Calcium currents in 80% of the neurons were measurably inhibited by μ-opioids, but the extent of inhibition varied greatly. Almost all TG masseter afferents expressed some TTX-insensitive sodium currents, but the amount compared to TTX sensitive sodium current varied, as did the duration of action potentials. Conclusion Most masseter muscle afferents that are not muscle spindle afferents express molecules that are considered characteristic of nociceptors, but these

  2. Visceral sensory neurons that innervate both uterus and colon express nociceptive TRPv1 and P2X3 receptors in rats.

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    Chaban, Victor V

    2008-01-01

    In women, clinical studies suggest that functional pain syndromes such as irritable bowel syndrome, interstitial cystitis, and fibromyalgia, are co-morbid with endometriosis, chronic pelvic pain, and others diseases. One of the possible explanations for this phenomenon is visceral cross-sensitization in which increased nociceptive input from inflamed reproductive system organs sensitize neurons that receive convergent input from an unaffected visceral organ to the same dorsal root ganglion (DRG). The purpose of this study was to determine whether primary sensory neurons that innervate both visceral organs--the uterus and the colon--express nociceptive ATP-sensitive purinergic (P2X3) and capsaicin-sensitive vanilloid (TRPV1) receptors. To test this hypothesis, cell bodies of colonic and uterine DRG were retrogradely labeled with fluorescent tracer dyes micro-injected into the colon/rectum and uterus of rats. Ganglia were harvested, cryo-protected, and cut in 20-microm slices for fluorescent microscopy to identify positively stained cells. Up to 5% neurons were colon-specific or uterus-specific, and 10%-15% of labeled DRG neurons innervate both viscera in the lumbosacral neurons (L1-S3 levels). We found that viscerally labeled DRGs express nociceptive P2X3 and TRPV1 receptors. Our results suggest a novel form of visceral sensory integration in the DRG that may underlie co-morbidity of many functional pain syndromes.

  3. Nociceptive neurons detect cytokines in arthritis

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    Schaible, Hans-Georg

    2014-01-01

    Proinflammatory cytokines are major mediators in the pathogenesis of diseases of joints such as rheumatoid arthritis and osteoarthritis. This review emphasizes that proinflammatory cytokines such as tumor necrosis factor-alpha, interleukin-1beta, interleukin-6 and interleukin-17 are also mediators of pain by directly acting on the nociceptive system. Proportions of nociceptive sensory neurons express receptors for these cytokines, and the application of cytokines rapidly changes the excitabil...

  4. Orexin neurons receive glycinergic innervations.

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    Mari Hondo

    Full Text Available Glycine, a nonessential amino-acid that acts as an inhibitory neurotransmitter in the central nervous system, is currently used as a dietary supplement to improve the quality of sleep, but its mechanism of action is poorly understood. We confirmed the effects of glycine on sleep/wakefulness behavior in mice when administered peripherally. Glycine administration increased non-rapid eye movement (NREM sleep time and decreased the amount and mean episode duration of wakefulness when administered in the dark period. Since peripheral administration of glycine induced fragmentation of sleep/wakefulness states, which is a characteristic of orexin deficiency, we examined the effects of glycine on orexin neurons. The number of Fos-positive orexin neurons markedly decreased after intraperitoneal administration of glycine to mice. To examine whether glycine acts directly on orexin neurons, we examined the effects of glycine on orexin neurons by patch-clamp electrophysiology. Glycine directly induced hyperpolarization and cessation of firing of orexin neurons. These responses were inhibited by a specific glycine receptor antagonist, strychnine. Triple-labeling immunofluorescent analysis showed close apposition of glycine transporter 2 (GlyT2-immunoreactive glycinergic fibers onto orexin-immunoreactive neurons. Immunoelectron microscopic analysis revealed that GlyT2-immunoreactive terminals made symmetrical synaptic contacts with somata and dendrites of orexin neurons. Double-labeling immunoelectron microscopy demonstrated that glycine receptor alpha subunits were localized in the postsynaptic membrane of symmetrical inhibitory synapses on orexin neurons. Considering the importance of glycinergic regulation during REM sleep, our observations suggest that glycine injection might affect the activity of orexin neurons, and that glycinergic inhibition of orexin neurons might play a role in physiological sleep regulation.

  5. Modulatory Mechanism of Nociceptive Neuronal Activity by Dietary Constituent Resveratrol

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    Mamoru Takeda

    2016-10-01

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

  6. ZBTB20 regulates nociception and pain sensation by modulating TRP channel expression in nociceptive sensory neurons.

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    Ren, An-Jing; Wang, Kai; Zhang, Huan; Liu, Anjun; Ma, Xianhua; Liang, Qing; Cao, Dongmei; Wood, John N; He, David Z; Ding, Yu-Qiang; Yuan, Wen-Jun; Xie, Zhifang; Zhang, Weiping J

    2014-11-05

    In mammals, pain sensation is initiated by the detection of noxious stimuli through specialized transduction ion channels and receptors in nociceptive sensory neurons. Transient receptor potential (TRP) channels are the key sensory transducers that confer nociceptors distinct sensory modalities. However, the regulatory mechanisms about their expression are poorly defined. Here we show that the zinc-finger protein ZBTB20 regulates TRP channels expression in nociceptors. ZBTB20 is highly expressed in nociceptive sensory neurons of dorsal root ganglia. Disruption of ZBTB20 in nociceptors led to a marked decrease in the expression levels of TRPV1, TRPA1 and TRPM8 and the response of calcium flux and whole-cell currents evoked by their respective specific agonists. Phenotypically, the mice lacking ZBTB20 specifically in nociceptors showed a defect in nociception and pain sensation in response to thermal, mechanical and inflammatory stimulation. Our findings point to ZBTB20 as a critical regulator of nociception and pain sensation by modulating TRP channels expression in nociceptors.

  7. P2X receptors mediate ATP-induced primary nociceptive neurone activation.

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    Bland-Ward, P A; Humphrey, P P

    2000-07-01

    ATP-gated P2X ion-channel receptors are localised throughout the mammalian nervous system and have been identified on neurones which participate in conduction of nociceptive information from the periphery to, and within, the CNS. This article briefly reviews recently published research describing the role that ATP and P2X receptors may play in pain perception, highlighting the importance of the P2X(3) receptor in this process. The P2X(3) receptor subunit is almost exclusively expressed on a subset of small and medium diameter sensory neurones innervating cutaneous and visceral tissue. Activation of P2X receptors present on the peripheral terminals of primary afferents results in neuronal depolarisation and, in conscious animals, leads to the manifestation of acute nociceptive behaviour. Recent animal studies have also shown that P2X(3) receptor expression is increased in sensory ganglia following acute neuronal injury, hinting that similar plasticity in the expression of this receptor subtype could underlie the mechanisms involved in a range of conditions characterised by sensory hypersensitivity in man. It is apparent from the evidence available that functional antagonists at specific P2X receptor subtypes could represent an important class of novel analgesic agents.

  8. Morphological properties of nociceptive and non-nociceptive neurons in primary somatic cerebral cortex (SI) of cat

    Institute of Scientific and Technical Information of China (English)

    2000-01-01

    With the techniques of intracellular recording and labelling, we investigated pain sensation and modulation of the somatic cortical cortex at the neuron's level. After observing the evoked potentials from stimulating the saphenous nerves (SN) of 654 neurons in SI area of the cats, we labelled 30 of the neurons with Neurobiotin to preserve the distribution and the morphologic characteristics of the neurons in the cortex. Based on the tridimensional reconstruction in addition to the eletrophysiological functions, we found clear morphological distinctions between nociceptive and non-nociceptive neurons (P<0.01). This result provided new experimental material to illustrate the function of nociceptive neurons in somatosensory cortex (SI) and presented further evidence to support the "specificity theory" of pain sensation in terms of morphology.

  9. Changes in Aβ non-nociceptive primary sensory neurons in a rat model of osteoarthritis pain

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    Henry James L

    2010-07-01

    Full Text Available Abstract Background Pain is a major debilitating factor in osteoarthritis (OA, yet few mechanism-based therapies are available. To address the need to understand underlying mechanisms the aim of the present study was to determine changes in sensory neurons in an animal model of OA pain. Results The model displayed typical osteoarthritis pathology characterized by cartilage degeneration in the knee joint and also manifested knee pathophysiology (edema and increased vasculature permeability of the joint and altered nociception of the affected limb (hind paw tenderness and knee articulation-evoked reduction in the tail flick latency. Neurons included in this report innervated regions throughout the entire hind limb. Aβ-fiber low threshold mechanoreceptors exhibited a slowing of the dynamics of action potential (AP genesis, including wider AP duration and slower maximum rising rate, and muscle spindle neurons were the most affected subgroup. Only minor AP configuration changes were observed in either C- or Aδ-fiber nociceptors. Conclusion Thus, at one month after induction of the OA model Aβ-fiber low threshold mechanoreceptors but not C- or Aδ-fiber nociceptors had undergone changes in electrophysiological properties. If these changes reflect a change in functional role of these neurons in primary afferent sensory processing, then Aβ-fiber non-nociceptive primary sensory neurons may be involved in the pathogenesis of OA pain. Further, it is important to point out that the patterns of the changes we observed are consistent with observations in models of peripheral neuropathy but not models of peripheral inflammation.

  10. The Specification and Maturation of Nociceptive Neurons from Human Embryonic Stem Cells.

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    Boisvert, Erin M; Engle, Sandra J; Hallowell, Shawn E; Liu, Ping; Wang, Zhao-Wen; Li, Xue-Jun

    2015-11-19

    Nociceptive neurons play an essential role in pain sensation by transmitting painful stimuli to the central nervous system. However, investigations of nociceptive neuron biology have been hampered by the lack of accessibility of human nociceptive neurons. Here, we describe a system for efficiently guiding human embryonic stem cells into nociceptive neurons by first inducing these cells to the neural lineage. Subsequent addition of retinoic acid and BMP4 at specific time points and concentrations yielded a high population of neural crest progenitor cells (AP2α(+), P75(+)), which further differentiated into nociceptive neurons (TRKA(+), Nav1.7(+), P2X3(+)). The overexpression of Neurogenin 1 (Neurog1) promoted the neurons to express genes related to sensory neurons (Peripherin, TrkA) and to further mature into TRPV1(+) nociceptive neurons. Importantly, the overexpression of Neurog1 increased the response of these neurons to capsaicin stimulation, a hallmark of mature functional nociceptive neurons. Taken together, this study reveals the important role that Neurog1 plays in generating functional human nociceptive neurons.

  11. Egr3 dependent sympathetic target tissue innervation in the absence of neuron death.

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    Lin Li

    Full Text Available Nerve Growth Factor (NGF is a target tissue derived neurotrophin required for normal sympathetic neuron survival and target tissue innervation. NGF signaling regulates gene expression in sympathetic neurons, which in turn mediates critical aspects of neuron survival, axon extension and terminal axon branching during sympathetic nervous system (SNS development. Egr3 is a transcription factor regulated by NGF signaling in sympathetic neurons that is essential for normal SNS development. Germline Egr3-deficient mice have physiologic dysautonomia characterized by apoptotic sympathetic neuron death and abnormal innervation to many target tissues. The extent to which sympathetic innervation abnormalities in the absence of Egr3 is caused by altered innervation or by neuron death during development is unknown. Using Bax-deficient mice to abrogate apoptotic sympathetic neuron death in vivo, we show that Egr3 has an essential role in target tissue innervation in the absence of neuron death. Sympathetic target tissue innervation is abnormal in many target tissues in the absence of neuron death, and like NGF, Egr3 also appears to effect target tissue innervation heterogeneously. In some tissues, such as heart, spleen, bowel, kidney, pineal gland and the eye, Egr3 is essential for normal innervation, whereas in other tissues such as lung, stomach, pancreas and liver, Egr3 appears to have little role in innervation. Moreover, in salivary glands and heart, two tissues where Egr3 has an essential role in sympathetic innervation, NGF and NT-3 are expressed normally in the absence of Egr3 indicating that abnormal target tissue innervation is not due to deregulation of these neurotrophins in target tissues. Taken together, these results clearly demonstrate a role for Egr3 in mediating sympathetic target tissue innervation that is independent of neuron survival or neurotrophin deregulation.

  12. Divergent Modulation of Nociception by Glutamatergic and GABAergic Neuronal Subpopulations in the Periaqueductal Gray

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    Grajales-Reyes, Jose G.; Copits, Bryan A.; O’Brien, Daniel E.; Trigg, Sarah L.; Gomez, Adrian M.

    2017-01-01

    Abstract The ventrolateral periaqueductal gray (vlPAG) constitutes a major descending pain modulatory system and is a crucial site for opioid-induced analgesia. A number of previous studies have demonstrated that glutamate and GABA play critical opposing roles in nociceptive processing in the vlPAG. It has been suggested that glutamatergic neurotransmission exerts antinociceptive effects, whereas GABAergic neurotransmission exert pronociceptive effects on pain transmission, through descending pathways. The inability to exclusively manipulate subpopulations of neurons in the PAG has prevented direct testing of this hypothesis. Here, we demonstrate the different contributions of genetically defined glutamatergic and GABAergic vlPAG neurons in nociceptive processing by employing cell type-specific chemogenetic approaches in mice. Global chemogenetic manipulation of vlPAG neuronal activity suggests that vlPAG neural circuits exert tonic suppression of nociception, consistent with previous pharmacological and electrophysiological studies. However, selective modulation of GABAergic or glutamatergic neurons demonstrates an inverse regulation of nociceptive behaviors by these cell populations. Selective chemogenetic activation of glutamatergic neurons, or inhibition of GABAergic neurons, in vlPAG suppresses nociception. In contrast, inhibition of glutamatergic neurons, or activation of GABAergic neurons, in vlPAG facilitates nociception. Our findings provide direct experimental support for a model in which excitatory and inhibitory neurons in the PAG bidirectionally modulate nociception. PMID:28374016

  13. Inflammation in the uterus induces phosphorylated extracellular signal-regulated kinase and substance P immunoreactivity in dorsal root ganglia neurons innervating both uterus and colon in rats.

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    Li, Jichang; Micevych, Paul; McDonald, John; Rapkin, Andrea; Chaban, Victor

    2008-09-01

    In women, clinical studies suggest that pain syndromes such as irritable bowel syndrome and interstitial cystitis, which are associated with visceral hyperalgesia, are often comorbid with endometriosis and chronic pelvic pain. One of the possible explanations for this phenomenon is viscerovisceral cross-sensitization, in which increased nociceptive input from an inflamed pelvic organ sensitizes neurons that receive convergent input to the same dorsal root ganglion (DRG) from an unaffected visceral organ. Nociception induces up-regulation of cellular mechanisms such as phosphorylated extracellular signal-regulated kinase (pERK) and substance P (SP), neurotransmitters associated with induced pain sensation. The purpose of this study was to determine, in a rodent model, whether uterine inflammation increased the number of pERK- and SP-positive neurons that received input from both the uterus and the colon. Cell bodies of colonic and uterine DRG were retrogradely labeled with fluorescent tracer dyes microinjected into the colon/rectum and into the uterus. Ganglia were harvested for fluorescent microscopy to identify positively stained neurons. Approximately 6% of neurons were colon specific and 10% uterus specific. Among these uterus- or colon-specific neurons, up to 3-5% of DRG neurons in the lumbosacral neurons (L1-S3 levels) received input from both visceral organs. Uterine inflammation increased the number of pERK- and SP-immunoreactive DRG neurons innervating specifically colon, or innervating specifically uterus, and those innervating both organs. These results suggest that a localized inflammation activates primary visceral afferents, regardless of whether they innervate the affected organ. This visceral sensory integration in the DRG may underlie the observed comorbidity of female pelvic pain syndromes.

  14. Dissociation of Thermal Nociception and Epidermal Innervation in Streptozotocin-Diabetic Mice

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    Beiswenger, Kristina K; Calcutt, Nigel A; Mizisin, Andrew P

    2008-01-01

    The quantification of epidermal innervation, which consists primarily of heat-sensitive C-fibers, is emerging as a tool for diagnosing and staging diabetic neuropathy. However, the relationship between changes in heat sensitivity and changes in epidermal innervation has not yet been adequately explored. Therefore, we assessed epidermal nerve fiber density and thermal withdrawal latency in the hind paw of Swiss Webster mice after two and four weeks of streptozotocin-induced diabetes. Thermal hypoalgesia developed after only two weeks of diabetes, but a measurable reduction in PGP9.5-immunoreactive epidermal nerve fiber density did not appear until four weeks. These data suggest that impaired epidermal nociceptor function contributes to early diabetes-induced thermal hypoalgesia prior to the loss of peripheral terminals. PMID:18619518

  15. Changes in Activity of the Same Thalamic Neurons to Repeated Nociception in Behaving Mice.

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    Huh, Yeowool; Cho, Jeiwon

    2015-01-01

    The sensory thalamus has been reported to play a key role in central pain sensory modulation and processing, but its response to repeated nociception at thalamic level is not well known. Current study investigated thalamic response to repeated nociception by recording and comparing the activity of the same thalamic neuron during the 1st and 2nd formalin injection induced nociception, with a week interval between injections, in awake and behaving mice. Behaviorally, the 2nd injection induced greater nociceptive responses than the 1st. Thalamic activity mirrored these behavioral changes with greater firing rate during the 2nd injection. Analysis of tonic and burst firing, characteristic firing pattern of thalamic neurons, revealed that tonic firing activity was potentiated while burst firing activity was not significantly changed by the 2nd injection relative to the 1st. Likewise, burst firing property changes, which has been consistently associated with different phases of nociception, were not induced by the 2nd injection. Overall, data suggest that repeated nociception potentiated responsiveness of thalamic neurons and confirmed that tonic firing transmits nociceptive signals.

  16. Localization of sympathetic postganglionic neurons innervating mesenteric artery and vein in rats.

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    Hsieh, N K; Liu, J C; Chen, H I

    2000-04-12

    Physiological and histochemical studies have demonstrated the control and innervation of sympathetic nerves to the artery and vein vessels of splanchnic circulation. In our laboratory, we first used the technique of retrograde transport of horseradish peroxidase to identify the origin of sympathetic neurons innervating the mesenteric vein. In this study, double fluorescence staining technique was used for a simultaneous localization of the sympathetic postganglionic neurons supplying the mesenteric artery and vein in rats. First-order branches of mesenteric artery (A) and vein (V) in the vicinity of ileo-cecal junction were isolated for application of fluorescent dyes (Fast Blue, FB and Diamidino Yellow, DY). The application of FB and DY on A and V was alternated in the next animal to minimize the difference in dye uptake. The animal was allowed to recover for 6-7 days assuring a complete uptake of FB and DY into the cytoplasm and nucleus, respectively. The number of FB, DY and double staining neurons in the prevertebral and paravertebral ganglia were counted under a fluorescent microscope after animal fixation and serial frozen section (30 microm) of the sympathetic ganglia. Our study revealed the following findings: (1) Distribution of the fluorescence-staining neurons in the sympathetic ganglia was as follows: right celiac ganglion (39%), superior mesenteric ganglion (30%), left celiac ganglion (26%), inferior mesenteric ganglion (1%) and paravertebral ganglia (4%). (2) Double staining neurons that dually innervate A and V amounted to 54% of total staining neurons. There were 41% neurons singly innervating A and 5% innervating V. (3) The ratio of neurons supplying the A and V ranged from 1.41 to 1.75 (average 1.61). (4) There was no distinct topographical distribution with respect to the neuron location innervating A and V. The distribution of neurons appeared in a scattering pattern.

  17. Nociceptive sensory neurons drive interleukin-23-mediated psoriasiform skin inflammation.

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    Riol-Blanco, Lorena; Ordovas-Montanes, Jose; Perro, Mario; Naval, Elena; Thiriot, Aude; Alvarez, David; Paust, Silke; Wood, John N; von Andrian, Ulrich H

    2014-06-05

    The skin has a dual function as a barrier and a sensory interface between the body and the environment. To protect against invading pathogens, the skin harbours specialized immune cells, including dermal dendritic cells (DDCs) and interleukin (IL)-17-producing γδ T (γδT17) cells, the aberrant activation of which by IL-23 can provoke psoriasis-like inflammation. The skin is also innervated by a meshwork of peripheral nerves consisting of relatively sparse autonomic and abundant sensory fibres. Interactions between the autonomic nervous system and immune cells in lymphoid organs are known to contribute to systemic immunity, but how peripheral nerves regulate cutaneous immune responses remains unclear. We exposed the skin of mice to imiquimod, which induces IL-23-dependent psoriasis-like inflammation. Here we show that a subset of sensory neurons expressing the ion channels TRPV1 and Nav1.8 is essential to drive this inflammatory response. Imaging of intact skin revealed that a large fraction of DDCs, the principal source of IL-23, is in close contact with these nociceptors. Upon selective pharmacological or genetic ablation of nociceptors, DDCs failed to produce IL-23 in imiquimod-exposed skin. Consequently, the local production of IL-23-dependent inflammatory cytokines by dermal γδT17 cells and the subsequent recruitment of inflammatory cells to the skin were markedly reduced. Intradermal injection of IL-23 bypassed the requirement for nociceptor communication with DDCs and restored the inflammatory response. These findings indicate that TRPV1(+)Nav1.8(+) nociceptors, by interacting with DDCs, regulate the IL-23/IL-17 pathway and control cutaneous immune responses.

  18. Nociceptive Sensory Neurons Drive Interleukin-23 Mediated Psoriasiform Skin Inflammation

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    Riol-Blanco, Lorena; Ordovas-Montanes, Jose; Perro, Mario; Naval, Elena; Thiriot, Aude; Alvarez, David; Wood, John N.; von Andrian, Ulrich H.

    2014-01-01

    The skin has a dual function as a barrier and a sensory interface between the body and the environment. To protect against invading pathogens, the skin harbors specialized immune cells, including dermal dendritic cells (DDCs) and interleukin (IL)-17 producing γδ T cells (γδT17), whose aberrant activation by IL-23 can provoke psoriasis-like inflammation1–4. The skin is also innervated by a meshwork of peripheral nerves consisting of relatively sparse autonomic and abundant sensory fibers. Interactions between the autonomic nervous system and immune cells in lymphoid organs are known to contribute to systemic immunity, but how peripheral nerves regulate cutaneous immune responses remains unclear5,6. Here, we have exposed the skin of mice to imiquimod (IMQ), which induces IL-23 dependent psoriasis-like inflammation7,8. We show that a subset of sensory neurons expressing the ion channels TRPV1 and NaV1.8 is essential to drive this inflammatory response. Imaging of intact skin revealed that a large fraction of DDCs, the principal source of IL-23, is in close contact with these nociceptors. Upon selective pharmacological or genetic ablation of nociceptors9–11, DDCs failed to produce IL-23 in IMQ exposed skin. Consequently, the local production of IL-23 dependent inflammatory cytokines by dermal γδT17 cells and the subsequent recruitment of inflammatory cells to the skin were dramatically reduced. Intradermal injection of IL-23 bypassed the requirement for nociceptor communication with DDCs and restored the inflammatory response12. These findings indicate that TRPV1+NaV1.8+ nociceptors, by interacting with DDCs, regulate the IL-23/IL-17 pathway and control cutaneous immune responses. PMID:24759321

  19. Dense and overlapping innervation of pyramidal neurons by neocortical chandelier cells

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    Inan, Melis; Blázquez-Llorca, Lidia; Merchán-Perez, Angel; Anderson, Stewart A.; DeFelipe, Javier; Yuste, Rafael

    2013-01-01

    Chandelier (or axo-axonic) cells are a distinct group of GABAergic interneurons that innervate the axon initial segments of pyramidal cells and thus could have an important role controlling the activity of cortical circuits. To understand their connectivity we labeled upper layers chandelier cells (ChCs) from mouse neocortex with a genetic strategy and studied how their axons contact local populations of pyramidal neurons, using immunohistochemical detection of axon initial segments. We studied ChCs located in the border of layers 1 and 2 from primary somatosensory cortex and find that practically all ChC axon terminals contact axon initial segments with an average of 3–5 boutons per cartridge. By measuring the number of putative synapses in initial segments we estimate that each pyramidal neuron is innervated, on average, by at least 4 ChCs. Additionally, each individual ChC contacts 35–50% of pyramidal neurons within its axonal arbor, with pockets of high innervation density. Finally, we find that ChC axons seems to have a conserved innervation pattern at different postnatal ages (P18–90), with only relatively small lateral expansions of their arbor and increases in the total number of their cartridges during the developmental period analyzed. We conclude that ChCs innervate neighboring pyramidal neurons in a dense and overlapping manner, an innervation pattern which could enable ChCs exert a widespread influence on their local circuits. PMID:23365230

  20. Acid-sensing ion channels in trigeminal ganglion neurons innervating the orofacial region contribute to orofacial inflammatory pain.

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    Fu, Hui; Fang, Peng; Zhou, Hai-Yun; Zhou, Jun; Yu, Xiao-Wei; Ni, Ming; Zheng, Jie-Yan; Jin, You; Chen, Jian-Guo; Wang, Fang; Hu, Zhuang-Li

    2016-02-01

    Orofacial pain is a common clinical symptom that is accompanied by tooth pain, migraine and gingivitis. Accumulating evidence suggests that acid-sensing ion channels (ASICs), especially ASIC3, can profoundly affect the physiological properties of nociception in peripheral sensory neurons. The aim of this study is to examine the contribution of ASICs in trigeminal ganglion (TG) neurons to orofacial inflammatory pain. A Western blot (WB), immunofluorescence assay of labelled trigeminal ganglion neurons, orofacial formalin test, cell preparation and electrophysiological experiments are performed. This study demonstrated that ASIC1, ASIC2a and ASIC3 are highly expressed in TG neurons innervating the orofacial region of rats. The amplitude of ASIC currents in these neurons increased 119.72% (for ASIC1-like current) and 230.59% (for ASIC3-like current) in the formalin-induced orofacial inflammatory pain model. In addition, WB and immunofluorescence assay demonstrated a significantly augmented expression of ASICs in orofacial TG neurons during orofacial inflammation compared with the control group. The relative protein density of ASIC1, ASIC2a and ASIC3 also increased 58.82 ± 8.92%, 45.30 ± 11.42% and 55.32 ± 14.71%, respectively, compared with the control group. Furthermore, pharmacological blockade of ASICs and genetic deletion of ASIC1 attenuated the inflammation response. These findings indicate that peripheral inflammation can induce the upregulation of ASICs in TG neurons, causing orofacial inflammatory pain. Additionally, the specific inhibitor of ASICs may have a significant analgesic effect on orofacial inflammatory pain.

  1. Ion Channel Photoswitch Reveals Crosstalk between Intact and Injured Nociceptive Neurons after Nerve Injury

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    Herold, Christian

    2015-01-01

    The development of novel techniques utilizing the advantages of light has created an optical revolution for neuroscience research. Controlling and probing neuronal function with light has provided unprecedented insights by being able to manipulate many neurons simultaneously in intact circuits and living organisms.In my dissertation research, I used novel optical methods to probe the cellular permeability of sensory neuron populations. Primary nociceptive afferents detect, modulate and integr...

  2. Relative number and distribution of murine hypothalamic proopiomelanocortin neurons innervating distinct target sites.

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    Connie M King

    Full Text Available Proopiomelanocortin (POMC neurons send projections widely throughout the brain consistent with their role in regulating numerous homeostatic processes and mediating analgesia and reward. Recent data suggest that POMC neurons located in the rostral and caudal extents of the arcuate nucleus of the hypothalamus may mediate selective actions, however it is not clear if POMC neurons in these regions of the arcuate nucleus innervate specific target sites. In the present study, fluorescent microspheres and cholera toxin B were used to retrogradely label POMC neurons in POMC-DsRed transgenic mice. The number and location of POMC cells projecting to the supraoptic nucleus, periaqueductal gray, ventral tegmental area, paraventricular nucleus, lateral hypothalamic nucleus, amygdala and the dosal vagal complex was determined. Tracer injected unilaterally labeled POMC neurons in both sides of the arcuate nucleus. While the total number of retrogradely labeled cells in the arcuate nucleus varied by injection site, less than 10% of POMC neurons were labeled with tracer injected into any target area. Limited target sites appear to be preferentially innervated by POMC neurons that reside in the rostral or caudal extremes of the arcuate nucleus, whereas the majority of target sites are innervated by diffusely distributed POMC neurons. The modest number of cells projecting to each target site indicates that relatively few POMC neurons may mediate potent and specific physiologic responses and therefore disturbed signaling in a very few POMC neurons may have significant consequences.

  3. Relative number and distribution of murine hypothalamic proopiomelanocortin neurons innervating distinct target sites.

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    King, Connie M; Hentges, Shane T

    2011-01-01

    Proopiomelanocortin (POMC) neurons send projections widely throughout the brain consistent with their role in regulating numerous homeostatic processes and mediating analgesia and reward. Recent data suggest that POMC neurons located in the rostral and caudal extents of the arcuate nucleus of the hypothalamus may mediate selective actions, however it is not clear if POMC neurons in these regions of the arcuate nucleus innervate specific target sites. In the present study, fluorescent microspheres and cholera toxin B were used to retrogradely label POMC neurons in POMC-DsRed transgenic mice. The number and location of POMC cells projecting to the supraoptic nucleus, periaqueductal gray, ventral tegmental area, paraventricular nucleus, lateral hypothalamic nucleus, amygdala and the dosal vagal complex was determined. Tracer injected unilaterally labeled POMC neurons in both sides of the arcuate nucleus. While the total number of retrogradely labeled cells in the arcuate nucleus varied by injection site, less than 10% of POMC neurons were labeled with tracer injected into any target area. Limited target sites appear to be preferentially innervated by POMC neurons that reside in the rostral or caudal extremes of the arcuate nucleus, whereas the majority of target sites are innervated by diffusely distributed POMC neurons. The modest number of cells projecting to each target site indicates that relatively few POMC neurons may mediate potent and specific physiologic responses and therefore disturbed signaling in a very few POMC neurons may have significant consequences.

  4. Midbrain dopamine neurons associated with reward processing innervate the neurogenic subventricular zone.

    Science.gov (United States)

    Lennington, Jessica B; Pope, Sara; Goodheart, Anna E; Drozdowicz, Linda; Daniels, Stephen B; Salamone, John D; Conover, Joanne C

    2011-09-14

    Coordinated regulation of the adult neurogenic subventricular zone (SVZ) is accomplished by a myriad of intrinsic and extrinsic factors. The neurotransmitter dopamine is one regulatory molecule implicated in SVZ function. Nigrostriatal and ventral tegmental area (VTA) midbrain dopamine neurons innervate regions adjacent to the SVZ, and dopamine synapses are found on SVZ cells. Cell division within the SVZ is decreased in humans with Parkinson's disease and in animal models of Parkinson's disease following exposure to toxins that selectively remove nigrostriatal neurons, suggesting that dopamine is critical for SVZ function and nigrostriatal neurons are the main suppliers of SVZ dopamine. However, when we examined the aphakia mouse, which is deficient in nigrostriatal neurons, we found no detrimental effect to SVZ proliferation or organization. Instead, dopamine innervation of the SVZ tracked to neurons at the ventrolateral boundary of the VTA. This same dopaminergic neuron population also innervated the SVZ of control mice. Characterization of these neurons revealed expression of proteins indicative of VTA neurons. Furthermore, exposure to the neurotoxin MPTP depleted neurons in the ventrolateral VTA and resulted in decreased SVZ proliferation. Together, these results reveal that dopamine signaling in the SVZ originates from a population of midbrain neurons more typically associated with motivational and reward processing.

  5. Interaction and regulatory functions of μ- and δ-opioid receptors in nociceptive afferent neurons

    Institute of Scientific and Technical Information of China (English)

    Xu Zhang; Lan Bao

    2012-01-01

    μ-opioid receptor (MOR) agonists such as morphine are powerful analgesics used for pain therapy.However,the use of these drugs is limited by their side-effects,which include antinociceptive tolerance and dependence.Earlier studies reported that MOR analgesic tolerance is reduced by blockade of δ-opioid receptors (DORs) that interact with MORs.Recent studies show that the MOR/DOR interaction in nociceptive afferent neurons in the dorsal root ganglion may contribute to morphine analgesic tolerance.Further analysis of the mechanisms for regulating the trafficking of receptors,ion channels and signaling molecules in nociceptive afferent neurons would help to understand the nociceptive mechanisms and improve pain therapy.

  6. Morphology of parasympathetic neurons innervating rat lingual salivary glands.

    Science.gov (United States)

    Kim, Miwon; Chiego, Daniel J; Bradley, Robert M

    2004-03-31

    Saliva is essential for taste function and not only does saliva influence taste reception, but also taste perception initiates salivation. As a first step in investigating circuits involved in gustatory-salivary reflexes, we have studied the morphology of the rat inferior salivatory nucleus (ISN), which contains parasympathetic secretomotor neurons that control the parotid and lingual (von Ebner) salivary glands. By applying the fluorescent label Fluorogold to the cut end of the glossopharyngeal nerve, the neurons supplying only the lingual salivary glands were labeled. Confocal microscopy and three-dimensional reconstruction were used to analyze the labeled neurons in the horizontal plane to determine their morphological characteristics. Additional neurons were studied in the coronal plane to determine the influence of the plane of section on neuron morphology. Reconstructions indicated that inferior salivatory neurons extend in a rostral-caudal distribution just adjacent to the medial border of the nucleus of the solitary tract (NST). There is considerable morphological variability among neurons, with neurons having up to 6 primary dendrites and 17 dendritic segments that extend a maximum of 834 microm from the soma. However, although ISN neurons vary in the size and complexity of their dendritic trees, distributions of all measures of neuron morphology are unimodal, indicating that distinct groups of neurons are not revealed based on these measures. There is, however, variability in the orientation pattern of the dendritic trees that is not represented in either the population or mean measures. Individual neurons can be categorized with either mediolateral, rostro-caudal or no apparent preferred orientation. Comparisons of neurons in rostral, intermediate or caudal third of the ISN revealed regional differences in neuron morphology; neurons in the caudal third have significantly longer dendrites than those in the intermediate or rostral third. Thus, while ISN

  7. Nociceptive Sensory Neurons Drive Interleukin-23 Mediated Psoriasiform Skin Inflammation

    OpenAIRE

    Riol-Blanco, Lorena; Ordovas-Montanes, Jose; Perro, Mario; Naval, Elena; Thiriot, Aude; Alvarez, David; Wood, John N.; von Andrian, Ulrich H.

    2014-01-01

    The skin has a dual function as a barrier and a sensory interface between the body and the environment. To protect against invading pathogens, the skin harbors specialized immune cells, including dermal dendritic cells (DDCs) and interleukin (IL)-17 producing γδ T cells (γδT17), whose aberrant activation by IL-23 can provoke psoriasis-like inflammation1–4. The skin is also innervated by a meshwork of peripheral nerves consisting of relatively sparse autonomic and abundant sensory fibers. Inte...

  8. Nociceptive Sensory Neurons Drive Interleukin-23 Mediated Psoriasiform Skin Inflammation

    OpenAIRE

    Riol-Blanco, Lorena; Ordovas-Montanes, Jose; Perro, Mario; Naval, Elena; Thiriot, Aude; Alvarez, David; Wood, John N.; von Andrian, Ulrich H.

    2014-01-01

    The skin has a dual function as a barrier and a sensory interface between the body and the environment. To protect against invading pathogens, the skin harbors specialized immune cells, including dermal dendritic cells (DDCs) and interleukin (IL)-17 producing γδ T cells (γδT17), whose aberrant activation by IL-23 can provoke psoriasis-like inflammation 1–4 . The skin is also innervated by a meshwork of peripheral nerves consisting of relatively sparse autonomic and abundant sensory fibers. In...

  9. Nociceptive input from the rat thoracolumbar fascia to lumbar dorsal horn neurones.

    Science.gov (United States)

    Hoheisel, Ulrich; Taguchi, Toru; Treede, Rolf-Detlef; Mense, Siegfried

    2011-09-01

    In anaesthetised rats, systematic electrophysiological recordings from dorsal horn neurones in spinal segments Th13-L5 were made to obtain information about the spinal nociceptive processing from the lumbar thoracolumbar fascia. Six to fourteen percent of the neurones in the spinal segments Th13-L2 had nociceptive input from the thoracolumbar fascia in naïve animals, no neurones responsive to input from the lumbar fascia were found in segments L3-L5. The segmental location of the receptive fields in the fascia was shifted 2-4 segments caudally relative to the spinal segment recorded from. Most neurones were convergent in that they received additional input from other deep somatic tissues in the low back (87%) and from the skin in the abdominal wall or the proximal leg (50%). The proportion of neurones responsive to input from the thoracolumbar fascia rose significantly from 4% to 15% (Pfascia in normal animals - responded to fascia input in animals with inflamed muscle. The data suggest that the nociceptive input from the thoracolumbar fascia contributes to the pain in low back pain patients.

  10. The same dorsal root ganglion neurons innervate uterus and colon in the rat.

    Science.gov (United States)

    Chaban, Victor; Christensen, Amy; Wakamatsu, Micah; McDonald, Michelle; Rapkin, Andrea; McDonald, John; Micevych, Paul

    2007-02-12

    The purpose of this study was to determine whether primary sensory neurons that innervate the uterus receive convergent input from the colon. To test this, in the rat, cell bodies of colonic and uterine dorsal root ganglia were retrogradely labeled with fluorescent tracer dyes microinjected into the colon/rectum and bilaterally into the uterine horns. Ganglia were harvested, cryoprotected and cut into 20 microm slices to identify positively stained cells for fluorescent microscopy. Up to 5% of neurons were colon-specific or uterus-specific, and 10-15% of labeled ganglion neurons innervate both viscera in the L1, L2, L6 and S1-S3 levels. These results suggest a novel form of visceral sensory integration in the dorsal root ganglion that may underlie comorbidity of many functional pain syndromes.

  11. Cholecystokinin (CCK)-expressing neurons in the suprachiasmatic nucleus: innervation, light responsiveness and entrainment in CCK-deficient mice

    DEFF Research Database (Denmark)

    Hannibal, Jens; Hundahl, Christian; Fahrenkrug, Jan

    2010-01-01

    , CCK-containing processes make synaptic contacts with both groups of neurons and some CCK cell bodies were innervated by VIPergic neurons. The CCK neurons received no direct input from the three major pathways to the SCN, and the CCK neurons were not light-responsive as evaluated by induction of c...

  12. Phorbol Ester Modulation of Ca2+ Channels Mediates Nociceptive Transmission in Dorsal Horn Neurones

    Directory of Open Access Journals (Sweden)

    Gary J. Stephens

    2013-05-01

    Full Text Available Phorbol esters are analogues of diacylglycerol which activate C1 domain proteins, such as protein kinase C (PKC. Phorbol ester/PKC pathways have been proposed as potential therapeutic targets for chronic pain states, potentially by phosphorylating proteins involved in nociception, such as voltage-dependent Ca2+ channels (VDCCs. In this brief report, we investigate the potential involvement of CaV2 VDCC subtypes in functional effects of the phorbol ester, phorbol 12-myristate 13-acetate (PMA on nociceptive transmission in the spinal cord. Effects of PMA and of selective pharmacological blockers of CaV2 VDCC subtypes on nociceptive transmission at laminae II dorsal horn neurones were examined in mouse spinal cord slices. Experiments were extended to CaV2.3(−/− mice to complement pharmacological studies. PMA increased the mean frequency of spontaneous postsynaptic currents (sPSCs in dorsal horn neurones, without an effect on event amplitude or half-width. sPSC frequency was reduced by selective VDCC blockers, w-agatoxin-IVA (AgTX; CaV2.1, w-conotoxin-GVIA (CTX; CaV2.2 or SNX-482 (CaV2.3. PMA effects were attenuated in the presence of each VDCC blocker and, also, in CaV2.3(−/− mice. These initial data demonstrate that PMA increases nociceptive transmission at dorsal horn neurones via actions on different CaV2 subtypes suggesting potential anti-nociceptive targets in this system.

  13. Localization of the autonomic, somatic and sensory neurons innervating the cranial tibial muscle of the pig.

    Science.gov (United States)

    Botti, Maddalena; Gazza, Ferdinando; Ragionieri, Luisa; Minelli, Luisa Bo; Panu, Rino

    2011-01-01

    The location of sympathetic, somatic and sensory neurons projecting to the cranial tibial muscle of the pig hindlimb was studied with the neuronal non-transynaptic tracer Fast Blue. Additionally, the number and the size of these neurons were determinated. The Fast blue, randomly applied to the cranial tibial muscle belly of 3 pigs, labelled sympathetic neurons in the ipsilateral L5-S3 and contralateral S1 sympathetic trunk ganglia and in the prevertebral caudal mesenteric ganglia of both sides. The somatic motoneurons were identified in the ipsilateral ventral horn of the S1 segment of spinal cord, while the sensory neurons were located in the ipsilateral L7-S1 spinal ganglia. The diameter of the multipolar sympathetic neurons oscillated between 26 and 46 microm in the sympathetic trunk ganglia and between 18 and 42 microm in the caudal mesenteric ganglia. The size of the multipolar spinal motoneurons oscillated between 33 and 102 microm. The size of the pseudounipolar sensory neurons oscillated between 23 and 67 microm. In all ganglia, the labelled neurons were localized at random and did not show a somatotopic distribution. Our results document a conspicuous autonomic innervation projecting to the "classic" skeletal cranial tibial muscle. Probably this innervation is destined to the muscle vessels.

  14. Somatotopic organization of lumbar muscle-innervating neurons in the ventral horn of the rat spinal cord.

    Science.gov (United States)

    Takahashi, Yuzuru; Ohtori, Seiji; Takahashi, Kazuhisa

    2010-04-01

    The ventral horn of the rat spinal cord was investigated with respect to the somatotopic organization of the motor neurons that innervate the lumbar muscles. Neurotracer 1,1'-dioctadecyl-3,3,3',3'-tetramethylindocarbocyanine perchlorate (DiI) was applied to specific sites in lumbar muscles. Spinal cord segments at L1 through L4 levels were cut into 40-mum serial transverse sections. Labeled neurons were located in the ventromedial nucleus (VM) and lateromedial nucleus (LM) nuclei of Rexed's lamina IX. Motor neurons innervating the m. interspinales lumborum and m. multifidus were without exception present in the VM, whereas all motor neurons innervating the m. rectus abdominis were present in the LM. Forty percent of motor neurons innervating the m. quadratus lumborum were present in the VM and the other 60% were in the LM. Although most of the motor neurons innervating the m. psoas major were present in the LM, a few labeled neurons existed in the VM. These results suggest that the border zone demarcating the areas of innervation of the dorsal and ventral rami of spinal nerves crosses the m. quadratus lumborum.

  15. Optogenetic Demonstration of Functional Innervation of Mouse Colon by Neurons Derived From Transplanted Neural Cells.

    Science.gov (United States)

    Stamp, Lincon A; Gwynne, Rachel M; Foong, Jaime P P; Lomax, Alan E; Hao, Marlene M; Kaplan, David I; Reid, Christopher A; Petrou, Steven; Allen, Andrew M; Bornstein, Joel C; Young, Heather M

    2017-05-01

    Cell therapy offers the potential to treat gastrointestinal motility disorders caused by diseased or absent enteric neurons. We examined whether neurons generated from transplanted enteric neural cells provide a functional innervation of bowel smooth muscle in mice. Enteric neural cells expressing the light-sensitive ion channel, channelrhodopsin, were isolated from the fetal or postnatal mouse bowel and transplanted into the distal colon of 3- to 4-week-old wild-type recipient mice. Intracellular electrophysiological recordings of responses to light stimulation of the transplanted cells were made from colonic smooth muscle cells in recipient mice. Electrical stimulation of endogenous enteric neurons was used as a control. The axons of graft-derived neurons formed a plexus in the circular muscle layer. Selective stimulation of graft-derived cells by light resulted in excitatory and inhibitory junction potentials, the electrical events underlying contraction and relaxation, respectively, in colonic muscle cells. Graft-derived excitatory and inhibitory motor neurons released the same neurotransmitters as endogenous motor neurons-acetylcholine and a combination of adenosine triphosphate and nitric oxide, respectively. Graft-derived neurons also included interneurons that provided synaptic inputs to motor neurons, but the pharmacologic properties of interneurons varied with the age of the donors from which enteric neural cells were obtained. Enteric neural cells transplanted into the bowel give rise to multiple functional types of neurons that integrate and provide a functional innervation of the smooth muscle of the bowel wall. Circuits composed of both motor neurons and interneurons were established, but the age at which cells are isolated influences the neurotransmitter phenotype of interneurons that are generated. Copyright © 2017 AGA Institute. Published by Elsevier Inc. All rights reserved.

  16. Development of cardiac parasympathetic neurons, glial cells, and regional cholinergic innervation of the mouse heart.

    Science.gov (United States)

    Fregoso, S P; Hoover, D B

    2012-09-27

    Very little is known about the development of cardiac parasympathetic ganglia and cholinergic innervation of the mouse heart. Accordingly, we evaluated the growth of cholinergic neurons and nerve fibers in mouse hearts from embryonic day 18.5 (E18.5) through postnatal day 21(P21). Cholinergic perikarya and varicose nerve fibers were identified in paraffin sections immunostained for the vesicular acetylcholine transporter (VAChT). Satellite cells and Schwann cells in adjacent sections were identified by immunostaining for S100β calcium binding protein (S100) and brain-fatty acid binding protein (B-FABP). We found that cardiac ganglia had formed in close association to the atria and cholinergic innervation of the atrioventricular junction had already begun by E18.5. However, most cholinergic innervation of the heart, including the sinoatrial node, developed postnatally (P0.5-P21) along with a doubling of the cross-sectional area of cholinergic perikarya. Satellite cells were present throughout neonatal cardiac ganglia and expressed primarily B-FABP. As they became more mature at P21, satellite cells stained strongly for both B-FABP and S100. Satellite cells appeared to surround most cardiac parasympathetic neurons, even in neonatal hearts. Mature Schwann cells, identified by morphology and strong staining for S100, were already present at E18.5 in atrial regions that receive cholinergic innervation at later developmental times. The abundance and distribution of S100-positive Schwann cells increased postnatally along with nerve density. While S100 staining of cardiac Schwann cells was maintained in P21 and older mice, Schwann cells did not show B-FABP staining at these times. Parallel development of satellite cells and cholinergic perikarya in the cardiac ganglia and the increase in abundance of Schwann cells and varicose cholinergic nerve fibers in the atria suggest that neuronal-glial interactions could be important for development of the parasympathetic nervous

  17. Immortalized human dorsal root ganglion cells differentiate into neurons with nociceptive properties.

    Science.gov (United States)

    Raymon, H K; Thode, S; Zhou, J; Friedman, G C; Pardinas, J R; Barrere, C; Johnson, R M; Sah, D W

    1999-07-01

    A renewable source of human sensory neurons would greatly facilitate basic research and drug development. We had established previously conditionally immortalized human CNS cell lines that can differentiate into functional neurons (). We report here the development of an immortalized human dorsal root ganglion (DRG) clonal cell line, HD10.6, with a tetracycline-regulatable v-myc oncogene. In the proliferative condition, HD10.6 cells have a doubling time of 1.2 d and exhibit a neuronal precursor morphology. After differentiation of clone HD10.6 for 7 d in the presence of tetracycline, v-myc expression was suppressed, and >50% of the cells exhibited typical neuronal morphology, stained positively for neuronal cytoskeletal markers, and fired action potentials in response to current injection. Furthermore, this cell line was fate-restricted to a neuronal phenotype; even in culture conditions that promote Schwann cell or smooth muscle differentiation of neural crest stem cells, HD10.6 differentiated exclusively into neurons. Moreover, differentiated HD10.6 cells expressed sensory neuron-associated transcription factors and exhibited capsaicin sensitivity. Taken together, these data indicate that we have established an immortalized human DRG cell line that can differentiate into sensory neurons with nociceptive properties. The cell line HD10.6 represents the first example of a human sensory neuronal line and will be valuable for basic research, as well as for the discovery of novel drug targets and clinical candidates.

  18. Eight different types of dopaminergic neurons innervate the Drosophila mushroom body neuropil: anatomical and physiological heterogeneity

    Directory of Open Access Journals (Sweden)

    Zhengmei Mao

    2009-07-01

    Full Text Available We examined tyrosine hydroxylase (TH-GAL4 expression and anti-TH immunoreactivity in the Drosophila protocerebrum and characterized single cell clones of the TH-GAL4 neurons. Eight clusters of putative dopaminergic neurons were characterized. Neurons in three of the clusters project to the mushroom body neuropil: PAM neurons project to the medial portion of the horizontal lobes; PPL1 neurons project to the vertical lobes, the junction area, the heel and distal peduncle; and PPL2ab neurons project to the calyx. Five types of PPL1 neurons were discovered that innervate different zones of the mushroom body lobes. Functional imaging experiments showed that the dopaminergic processes in four of the zones differ in response properties to odor, electric shock, or following the pairing of odor and electric shock. These results indicate that distinct dopaminergic neurons define separate zones of the mushroom body lobes and are probably involved in different functions. Differences in functional response properties of these neurons suggest that they are involved in different behavioral processes.

  19. Ascending projections of nociceptive neurons from trigeminal subnucleus caudalis: A population approach.

    Science.gov (United States)

    Saito, Hiroto; Katagiri, Ayano; Okada, Shinji; Mikuzuki, Lou; Kubo, Asako; Suzuki, Tatsuro; Ohara, Kinuyo; Lee, Jun; Gionhaku, Nobuhito; Iinuma, Toshimitsu; Bereiter, David A; Iwata, Koichi

    2017-07-01

    Second-order neurons in trigeminal subnucleus caudalis (Vc) and upper cervical spinal cord (C1) are critical for craniofacial pain processing and project rostrally to terminate in: ventral posteromedial thalamic nucleus (VPM), medial thalamic nuclei (MTN) and parabrachial nuclei (PBN). The contribution of each region to trigeminal nociception was assessed by the number of phosphorylated extracellular signal-regulated kinase-immunoreactive (pERK-IR) neurons co-labeled with fluorogold (FG). The phenotype of pERK-IR neurons was further defined by the expression of neurokinin 1 receptor (NK1). The retrograde tracer FG was injected into VPM, MTN or PBN of the right hemisphere and after seven days, capsaicin was injected into the left upper lip in male rats. Nearly all pERK-IR neurons were found in superficial laminae of Vc-C1 ipsilateral to the capsaicin injection. Nearly all VPM and MTN FG-labeled neurons in Vc-C1 were found contralateral to the injection site, whereas FG-labeled neurons were found bilaterally after PBN injection. The percentage of FG-pERK-NK1-IR neurons was significantly greater (>10%) for PBN projection neurons than for VPM and MTN projection neurons (NK1-IR VPM projection neurons were found mainly in the middle-Vc, while pERK-NK1-immunoreactive MTN or PBN projection neurons were found in the middle-Vc and caudal Vc-C1. These results suggest that a significant percentage of capsaicin-responsive neurons in superficial laminae of Vc-C1 project directly to PBN, while neurons that project to VPM and MTN are subject to greater modulation by pERK-IR local interneurons. Furthermore, the rostrocaudal distribution differences of FG-pERK-NK1-IR neurons in Vc-C1 may reflect functional differences between these projection areas regarding craniofacial pain. Copyright © 2017 Elsevier Inc. All rights reserved.

  20. Muscles innervated by a single motor neuron exhibit divergent synaptic properties on multiple time scales.

    Science.gov (United States)

    Blitz, Dawn M; Pritchard, Amy E; Latimer, John K; Wakefield, Andrew T

    2017-01-19

    Adaptive changes in the output of neural circuits underlying rhythmic behaviors are relayed to muscles via motor neuron activity. Pre- and postsynaptic properties of neuromuscular junctions can impact the transformation from motor neuron activity to muscle response. Further, synaptic plasticity occurring on the time scale of inter-spike intervals can differ between multiple muscles innervated by the same motor neuron. In rhythmic behaviors, motor neuron bursts can elicit additional synaptic plasticity. However, it is unknown if plasticity regulated by the longer time scale of inter-burst intervals also differs between synapses from the same neuron, and whether any such distinctions occur across a physiological activity range. To address these issues, we measured electrical responses in muscles innervated by a chewing circuit neuron, the lateral gastric (LG) motor neuron, in a well-characterized small motor system, the stomatogastric nervous system (STNS) of the Jonah crab, Cancer borealis In vitro and in vivo, sensory, hormonal and modulatory inputs elicit LG bursting consisting of inter-spike intervals of 50-250 ms and inter-burst intervals of 2-24 s. Muscles expressed similar facilitation measured with paired stimuli except at the shortest inter-spike interval. However distinct decay time constants resulted in differences in temporal summation. In response to bursting activity, augmentation occurred to different extents and saturated at different inter-burst intervals in the three muscles. Further, augmentation interacted with facilitation, resulting in distinct intra-burst facilitation between muscles. Thus, responses of multiple target muscles diverge across a physiological activity range due to distinct synaptic properties sensitive to multiple time scales.

  1. THE PARABRACHIAL NUCLEUS IS A CRITICAL LINK IN THE TRANSMISSION OF SHORT LATENCY NOCICEPTIVE INFORMATION TO MIDBRAIN DOPAMINERGIC NEURONS

    NARCIS (Netherlands)

    Coizet, V.; Dommett, E. J.; Klop, E. M.; Redgrave, P.; Overton, P. G.

    2010-01-01

    Many dopaminergic neurons exhibit a short-latency response to noxious stimuli, the source of which is unknown. Here we report that the nociceptive-recipient parabrachial nucleus appears to be a critical link in the transmission of pain related information to dopaminergic neurons. Injections of retro

  2. THE PARABRACHIAL NUCLEUS IS A CRITICAL LINK IN THE TRANSMISSION OF SHORT LATENCY NOCICEPTIVE INFORMATION TO MIDBRAIN DOPAMINERGIC NEURONS

    NARCIS (Netherlands)

    Coizet, V.; Dommett, E. J.; Klop, E. M.; Redgrave, P.; Overton, P. G.

    2010-01-01

    Many dopaminergic neurons exhibit a short-latency response to noxious stimuli, the source of which is unknown. Here we report that the nociceptive-recipient parabrachial nucleus appears to be a critical link in the transmission of pain related information to dopaminergic neurons. Injections of

  3. Protease activated receptors 1 and 4 sensitize TRPV1 in nociceptive neurones

    Directory of Open Access Journals (Sweden)

    Magherini Pier C

    2010-09-01

    Full Text Available Abstract Protease-activated receptors (PAR1-4 are activated by proteases released by cell damage or blood clotting, and are known to be involved in promoting pain and hyperalgesia. Previous studies have shown that PAR2 receptors enhance activation of TRPV1 but the role of other PARs is less clear. In this paper we investigate the expression and function of the PAR1, 3 and 4 thrombin-activated receptors in sensory neurones. Immunocytochemistry and in situ hybridization show that PAR1 and PAR4 are expressed in 10 - 15% of neurons, distributed across all size classes. Thrombin or a specific PAR1 or PAR4 activating peptide (PAR1/4-AP caused functional effects characteristic of activation of the PLCβ/PKC pathway: intracellular calcium release, sensitisation of TRPV1, and translocation of the epsilon isoform of PKC (PKCε to the neuronal cell membrane. Sensitisation of TRPV1 was significantly reduced by PKC inhibitors. Neurons responding to thrombin or PAR1-AP were either small nociceptive neurones of the peptidergic subclass, or larger neurones which expressed markers for myelinated fibres. Sequential application of PAR1-AP and PAR4-AP showed that PAR4 is expressed in a subset of the PAR1-expressing neurons. Calcium responses to PAR2-AP were by contrast seen in a distinct population of small IB4+ nociceptive neurones. PAR3 appears to be non-functional in sensory neurones. In a skin-nerve preparation the release of the neuropeptide CGRP by heat was potentiated by PAR1-AP. Culture with nerve growth factor (NGF increased the proportion of thrombin-responsive neurons in the IB4- population, while glial-derived neurotropic factor (GDNF and neurturin upregulated the proportion of thrombin-responsive neurons in the IB4+ population. We conclude that PAR1 and PAR4 are functionally expressed in large myelinated fibre neurons, and are also expressed in small nociceptors of the peptidergic subclass, where they are able to potentiate TRPV1 activity.

  4. Network dynamics in nociceptive pathways assessed by the neuronal avalanche model

    Directory of Open Access Journals (Sweden)

    Wu José

    2012-04-01

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

  5. Pericellular innervation of neurons expressing abnormally hyperphosphorylated tau in the hippocampal formation of Alzheimer's disease patients

    Directory of Open Access Journals (Sweden)

    Lidia Blazquez-Llorca

    2010-06-01

    Full Text Available Neurofibrillary tangles (NFT represent one of the main neuropathological features in the cerebral cortex associated with Alzheimer’s disease (AD. This neurofibrillary lesion involves the accumulation of abnormally hyperphosphorylated or abnormally phosphorylated microtubule-associated protein tau into paired helical filaments (PHF-tau within neurons. We have used immunocytochemical techniques and confocal microscopy reconstructions to examine the distribution of PHF-tau-immunoreactive (ir cells, and their perisomatic GABAergic and glutamatergic innervations in the hippocampal formation and adjacent cortex of AD patients. Furthermore, correlative light and electron microscopy was employed to examine these neurons and the perisomatic synapses. We observed two patterns of staining in PHF-tau-ir neurons, pattern I (without NFT and pattern II (with NFT, the distribution of which varies according to the cortical layer and area. Furthermore, the distribution of both GABAergic and glutamatergic terminals around the soma and proximal processes of PHF-tau-ir neurons does not seem to be altered as it is indistinguishable from both control cases and from adjacent neurons that did not contain PHF-tau. At the electron microscope level, a normal looking neuropil with typical symmetric and asymmetric synapses was observed around PHF-tau-ir neurons. These observations suggest that the synaptic connectivity around the perisomatic region of these PHF-tau-ir neurons was apparently unaltered.

  6. Selective depression of nociceptive responses of dorsal horn neurones by SNC 80 in a perfused hindquarter preparation of adult mouse.

    Science.gov (United States)

    Cao, C Q; Hong, Y G; Dray, A; Perkins, M N

    2001-01-01

    Detailed electrophysiological characterisation of spinal opioid receptors in the mouse has been limited due to various technical difficulties. In this study, extracellular single unit recordings were made from dorsal horn neurones in a perfused spinal cord with attached trunk-hindquarter to investigate the role of delta-opioid receptor in mediating nociceptive and non-nociceptive transmission in mouse. Noxious electrical shock, pinch and heat stimuli evoked a mean response of 20.8+/-2.5 (n=10, PSNC 80) was perfused for 8-10 min, these evoked nociceptive responses were reversibly depressed. SNC 80 (2 microM) depressed the nociceptive responses evoked by electrical shock, pinch and heat by 74.0+/-13.7% (n=8, PSNC 80 was 92.6+/-6.8% (n=3). SNC 80 at 5 microM also completely abolished the wind-up and/or hypersensitivity (n=5). The depressant effects of SNC 80 on the nociceptive responses were completely blocked by 10 microM naloxone (n=5) and 3 microM 17-(cyclopropylmethyl)-6,7-dehydro-4,5 alpha-epoxy-14 beta-ethoxy-5 beta-methylindolo [2',3':6',7'] morphinan-3-ol hydrochloride (HS 378, n=8), a novel highly selective delta-opioid receptor antagonist. Interestingly, HS 378 (3 microM) itself potentiated the background activity and evoked responses to pinch and heat by 151.8+/-38.4% (PSNC 80 at a dose of up to 10 microM (n=5). These data demonstrate that delta-opioid receptor modulate nociceptive, but not non-nociceptive, transmission in spinal dorsal horn neurones of the adult mouse. The potentiation of neuronal activity by HS 378 may reflect an autoregulatory role of the endogenous delta-opioid in nociceptive transmission in mouse.

  7. Distinct requirements for TrkB and TrkC signaling in target innervation by sensory neurons

    Science.gov (United States)

    Postigo, Antonio; Calella, Anna Maria; Fritzsch, Bernd; Knipper, Marlies; Katz, David; Eilers, Andreas; Schimmang, Thomas; Lewin, Gary R.; Klein, Rudiger; Minichiello, Liliana

    2002-01-01

    Signaling by brain-derived neurotrophic factor (BDNF) via the TrkB receptor, or by neurotrophin-3 (NT3) through the TrkC receptor support distinct populations of sensory neurons. The intracellular signaling pathways activated by Trk (tyrosine kinase) receptors, which in vivo promote neuronal survival and target innervation, are not well understood. Using mice with TrkB or TrkC receptors lacking the docking site for Shc adaptors (trkB(shc/shc) and trkC(shc/shc) mice), we show that TrkB and TrkC promote survival of sensory neurons mainly through Shc site-independent pathways, suggesting that these receptors use similar pathways to prevent apoptosis. In contrast, the regulation of target innervation appears different: in trkB(shc/shc) mice neurons lose target innervation, whereas in trkC(shc/shc) mice the surviving TrkC-dependent neurons maintain target innervation and function. Biochemical analysis indicates that phosphorylation at the Shc site positively regulates autophosphorylation of TrkB, but not of TrkC. Our findings show that although TrkB and TrkC signals mediating survival are largely similar, TrkB and TrkC signals required for maintenance of target innervation in vivo are regulated by distinct mechanisms.

  8. Tremorgenesis: a new conceptual scheme using reciprocally innervated circuit of neurons

    Directory of Open Access Journals (Sweden)

    Manto Mario

    2008-11-01

    Full Text Available Abstract Neural circuits controlling fast movements are inherently unsteady as a result of their reciprocal innervation. This instability is enhanced by increased membrane excitability. Recent studies indicate that the loss of external inhibition is an important factor in the pathogenesis of several tremor disorders such as essential tremor, cerebellar kinetic tremor or parkinsonian tremor. Shaikh and colleagues propose a new conceptual scheme to analyze tremor disorders. Oscillations are simulated by changing the intrinsic membrane properties of burst neurons. The authors use a model neuron of Hodgkin-Huxley type with added hyperpolarization activated cation current (Ih, low threshold calcium current (It, and GABA/glycine mediated chloride currents. Post-inhibitory rebound is taken into account. The model includes a reciprocally innervated circuit of neurons projecting to pairs of agonist and antagonist muscles. A set of four burst neurons has been simulated: inhibitory agonist, inhibitory antagonist, excitatory agonist, and excitatory antagonist. The model fits well with the known anatomical organization of neural circuits for limb movements in premotor/motor areas, and, interestingly, this model does not require any structural modification in the anatomical organization or connectivity of the constituent neurons. The authors simulate essential tremor when Ih is increased. Membrane excitability is augmented by up-regulating Ih and It. A high level of congruence with the recordings made in patients exhibiting essential tremor is reached. These simulations support the hypothesis that increased membrane excitability in potentially unsteady circuits generate oscillations mimicking tremor disorders encountered in daily practice. This new approach opens new perspectives for both the understanding and the treatment of neurological tremor. It provides the rationale for decreasing membrane excitability by acting on a normal ion channel in a context of

  9. Tremorgenesis: a new conceptual scheme using reciprocally innervated circuit of neurons.

    Science.gov (United States)

    Manto, Mario

    2008-11-26

    Neural circuits controlling fast movements are inherently unsteady as a result of their reciprocal innervation. This instability is enhanced by increased membrane excitability. Recent studies indicate that the loss of external inhibition is an important factor in the pathogenesis of several tremor disorders such as essential tremor, cerebellar kinetic tremor or parkinsonian tremor. Shaikh and colleagues propose a new conceptual scheme to analyze tremor disorders. Oscillations are simulated by changing the intrinsic membrane properties of burst neurons. The authors use a model neuron of Hodgkin-Huxley type with added hyperpolarization activated cation current (Ih), low threshold calcium current (It), and GABA/glycine mediated chloride currents. Post-inhibitory rebound is taken into account. The model includes a reciprocally innervated circuit of neurons projecting to pairs of agonist and antagonist muscles. A set of four burst neurons has been simulated: inhibitory agonist, inhibitory antagonist, excitatory agonist, and excitatory antagonist. The model fits well with the known anatomical organization of neural circuits for limb movements in premotor/motor areas, and, interestingly, this model does not require any structural modification in the anatomical organization or connectivity of the constituent neurons. The authors simulate essential tremor when Ih is increased. Membrane excitability is augmented by up-regulating Ih and It. A high level of congruence with the recordings made in patients exhibiting essential tremor is reached. These simulations support the hypothesis that increased membrane excitability in potentially unsteady circuits generate oscillations mimicking tremor disorders encountered in daily practice. This new approach opens new perspectives for both the understanding and the treatment of neurological tremor. It provides the rationale for decreasing membrane excitability by acting on a normal ion channel in a context of impaired external

  10. TRPM8 function and expression in vagal sensory neurons and afferent nerves innervating guinea pig esophagus.

    Science.gov (United States)

    Yu, Xiaoyun; Hu, Youtian; Ru, Fei; Kollarik, Marian; Undem, Bradley J; Yu, Shaoyong

    2015-03-15

    Sensory transduction in esophageal afferents requires specific ion channels and receptors. TRPM8 is a new member of the transient receptor potential (TRP) channel family and participates in cold- and menthol-induced sensory transduction, but its role in visceral sensory transduction is still less clear. This study aims to determine TRPM8 function and expression in esophageal vagal afferent subtypes. TRPM8 agonist WS-12-induced responses were first determined in nodose and jugular neurons by calcium imaging and then investigated by whole cell patch-clamp recordings in Dil-labeled esophageal nodose and jugular neurons. Extracellular single-unit recordings were performed in nodose and jugular C fiber neurons using ex vivo esophageal-vagal preparations with intact nerve endings in the esophagus. TRPM8 mRNA expression was determined by single neuron RT-PCR in Dil-labeled esophageal nodose and jugular neurons. The TRPM8 agonist WS-12 elicited calcium influx in a subpopulation of jugular but not nodose neurons. WS-12 activated outwardly rectifying currents in esophageal Dil-labeled jugular but not nodose neurons in a dose-dependent manner, which could be inhibited by the TRPM8 inhibitor AMTB. WS-12 selectively evoked action potential discharges in esophageal jugular but not nodose C fibers. Consistently, TRPM8 transcripts were highly expressed in esophageal Dil-labeled TRPV1-positive jugular neurons. In summary, the present study demonstrated a preferential expression and function of TRPM8 in esophageal vagal jugular but not nodose neurons and C fiber subtypes. This provides a distinctive role of TRPM8 in esophageal sensory transduction and may lead to a better understanding of the mechanisms of esophageal sensation and nociception.

  11. Local administration of resveratrol inhibits excitability of nociceptive wide-dynamic range neurons in rat trigeminal spinal nucleus caudalis.

    Science.gov (United States)

    Shimazu, Yoshihito; Shibuya, Eri; Takehana, Shiori; Sekiguchi, Kenta; Oshima, Katsuo; Kamata, Hiroaki; Karibe, Hiroyuki; Takeda, Mamoru

    2016-06-01

    Although we recently reported that intravenous administration of resveratrol suppresses trigeminal nociception, the precise peripheral effect of resveratrol on nociceptive and non-nociceptive mechanical stimulation-induced trigeminal neuron activity in vivo remains to be determined. The aim of the present study was to investigate whether local subcutaneous administration of resveratrol attenuates mechanical stimulation-induced excitability of trigeminal spinal nucleus caudalis (SpVc) neuron activity in rats, in vivo. Extracellular single-unit recordings were made of SpVc wide-dynamic range (WDR) neuron activity in response to orofacial mechanical stimulation in pentobarbital-anesthetized rats. Neurons responded to non-noxious and noxious mechanical stimulation applied to the orofacial skin. Local subcutaneous administration of resveratrol (1-10mM) into the orofacial skin dose dependently and significantly reduced the mean number of SpVc WDR neurons firing in response to both non-noxious and noxious mechanical stimuli, with the maximal inhibition of discharge frequency in response to both stimuli being seen within 5min. These inhibitory effects were no longer evident after approximately 20min. The mean magnitude of inhibition by resveratrol (10mM) of SpVc neuron discharge frequency was almost equal to that of the local anesthetic 1% lidocaine (37mM). These results suggest that local injection of resveratrol into the peripheral receptive field suppresses the excitability of SpVc neurons, possibly via inhibition of Na(+) channels in the nociceptive nerve terminals of trigeminal ganglion neurons. Therefore, local subcutaneous administration of resveratrol may provide relief of trigeminal nociceptive pain, without side effects, thus contributing to the suite of complementary and alternative medicines used as local anesthetic agents.

  12. Innervation by a GABAergic neuron depresses spontaneous release in glutamatergic neurons and unveils the clamping phenotype of synaptotagmin-1.

    Science.gov (United States)

    Wierda, Keimpe D B; Sørensen, Jakob B

    2014-02-01

    The role of spontaneously occurring release events in glutamatergic and GABAergic neurons and their regulation is intensely debated. To study the interdependence of glutamatergic and GABAergic spontaneous release, we compared reciprocally connected "mixed" glutamatergic/GABAergic neuronal pairs from mice cultured on astrocyte islands with "homotypic" glutamatergic or GABAergic pairs and autaptic neurons. We measured mEPSC and mIPSC frequencies simultaneously from both neurons. Neuronal pairs formed both interneuronal synaptic and autaptic connections indiscriminately. We find that whereas mEPSC and mIPSC frequencies did not deviate between autaptic and synaptic connections, the frequency of mEPSCs in mixed pairs was strongly depressed compared with either autaptic neurons or glutamatergic pairs. Simultaneous imaging of synapses, or comparison to evoked release amplitudes, showed that this decrease was not caused by fewer active synapses. The mEPSC frequency was negatively correlated with the mIPSC frequency, indicating interdependence. Moreover, the reduction in mEPSC frequency was abolished when established pairs were exposed to bicuculline for 3 d, but not by long-term incubation with tetrodotoxin, indicating that spontaneous GABA release downregulates mEPSC frequency. Further investigations showed that knockout of synaptotagmin-1 did not affect mEPSC frequencies in either glutamatergic autaptic neurons or in glutamatergic pairs. However, in mixed glutamatergic/GABAergic pairs, mEPSC frequencies were increased by a factor of four in the synaptotagmin-1-null neurons, which is in line with data obtained from mixed cultures. The effect persisted after incubation with BAPTA-AM. We conclude that spontaneous GABA release exerts control over mEPSC release, and GABAergic innervation of glutamatergic neurons unveils the unclamping phenotype of the synaptotagmin-1-null neurons.

  13. Convergent nociceptive input to spinal dorsal horn neurons after peripheral nerve injury.

    Science.gov (United States)

    Terayama, Ryuji; Kishimoto, Noriko; Yamamoto, Yuya; Maruhama, Kotaro; Tsuchiya, Hiroki; Mizutani, Masahide; Iida, Seiji; Sugimoto, Tomosada

    2015-03-01

    The number of c-Fos protein-like immunoreactive (c-Fos-IR) neurons in the spinal dorsal horn evoked by noxious stimulation was previously shown to be increased following peripheral nerve injury, and this increase was proposed to reflect the neuropathic pain state. The aim of this study was to investigate whether anomalous convergent primary afferent input to spinal dorsal horn neurons contributed to nerve injury-induced c-Fos hyperinducibility. Double immunofluorescence labeling for c-Fos and phosphorylated extracellular signal-regulated kinase (p-ERK) was performed to detect convergent synaptic input from different branches of the sciatic nerve after injury to the tibial nerve. c-Fos expression and the phosphorylation of ERK were induced by noxious heat stimulation of the hindpaw and also by electrical stimulation (ES) of the injured tibial nerve, respectively. The number of c-Fos-IR neurons was significantly decreased 3 days after the injury. However, the number of c-Fos-IR neurons returned to the control level 14 days after the injury. P-ERK immunoreactive (p-ERK-IR) neurons were induced in the central terminal field of the tibial nerve by ES of the tibial nerve. The topographic distribution pattern and number of such p-ERK-IR neurons remained unchanged after the nerve injury. The time course of changes in the number of double-labeled neurons, that presumably received convergent primary afferent input, showed a pattern similar to that of c-Fos-IR neurons after the injury. These results indicate that convergent primary nociceptive input through neighboring intact nerves may contribute to c-Fos hyperinducibility in the spinal dorsal horn.

  14. Increased innervation of forebrain targets by midbrain dopaminergic neurons in the absence of FGF-2.

    Science.gov (United States)

    Rumpel, R; Baron, O; Ratzka, A; Schröder, M-L; Hohmann, M; Effenberg, A; Claus, P; Grothe, C

    2016-02-09

    Fibroblast growth factors (FGFs) regulate development and maintenance, and reduce vulnerability of neurons. FGF-2 is essential for survival of midbrain dopaminergic (DA) neurons and is responsible for their dysplasia and disease-related degeneration. We previously reported that FGF-2 is involved in adequate forebrain (FB) target innervation by these neurons in an organotypic co-culture model. It remains unclear, how this ex-vivo phenotype relates to the in vivo situation, and which FGF-related signaling pathway is involved in this process. Here, we demonstrate that lack of FGF-2 results in an increased volume of the striatal target area in mice. We further add evidence that the low molecular weight (LMW) FGF-2 isoform is responsible for this phenotype, as this isoform is predominantly expressed in the embryonic ventral midbrain (VM) as well as in postnatal striatum (STR) and known to act via canonical transmembrane FGF receptor (FGFR) activation. Additionally, we confirm that the phenotype with an enlarged FB-target area by DA neurons can be mimicked in an ex-vivo explant model by inhibiting the canonical FGFR signaling, which resulted in decreased extracellular signal-regulated kinase (ERK) activation, while AKT activation remained unchanged.

  15. TMC-1 Mediates Alkaline Sensation in C. elegans through Nociceptive Neurons.

    Science.gov (United States)

    Wang, Xiang; Li, Guang; Liu, Jie; Liu, Jianfeng; Xu, X Z Shawn

    2016-07-06

    Noxious pH triggers pungent taste and nocifensive behavior. While the mechanisms underlying acidic pH sensation have been extensively characterized, little is known about how animals sense alkaline pH in the environment. TMC genes encode a family of evolutionarily conserved membrane proteins whose functions are largely unknown. Here, we characterize C. elegans TMC-1, which was suggested to form a Na(+)-sensitive channel mediating salt chemosensation. Interestingly, we find that TMC-1 is required for worms to avoid noxious alkaline environment. Alkaline pH evokes an inward current in nociceptive neurons, which is primarily mediated by TMC-1 and to a lesser extent by the TRP channel OSM-9. However, unlike OSM-9, which is sensitive to both acidic and alkaline pH, TMC-1 is only required for alkali-activated current, revealing a specificity for alkaline sensation. Ectopic expression of TMC-1 confers alkaline sensitivity to alkali-insensitive cells. Our results identify an unexpected role for TMCs in alkaline sensation and nociception.

  16. KCNQ channels in nociceptive cold-sensing trigeminal ganglion neurons as therapeutic targets for treating orofacial cold hyperalgesia.

    Science.gov (United States)

    Abd-Elsayed, Alaa A; Ikeda, Ryo; Jia, Zhanfeng; Ling, Jennifer; Zuo, Xiaozhuo; Li, Min; Gu, Jianguo G

    2015-07-31

    Hyperexcitability of nociceptive afferent fibers is an underlying mechanism of neuropathic pain and ion channels involved in neuronal excitability are potentially therapeutic targets. KCNQ channels, a subfamily of voltage-gated K(+) channels mediating M-currents, play a key role in neuronal excitability. It is unknown whether KCNQ channels are involved in the excitability of nociceptive cold-sensing trigeminal afferent fibers and if so, whether they are therapeutic targets for orofacial cold hyperalgesia, an intractable trigeminal neuropathic pain. Patch-clamp recording technique was used to study M-currents and neuronal excitability of cold-sensing trigeminal ganglion neurons. Orofacial operant behavioral assessment was performed in animals with trigeminal neuropathic pain induced by oxaliplatin or by infraorbital nerve chronic constrictive injury. We showed that KCNQ channels were expressed on and mediated M-currents in rat nociceptive cold-sensing trigeminal ganglion (TG) neurons. The channels were involved in setting both resting membrane potentials and rheobase for firing action potentials in these cold-sensing TG neurons. Inhibition of KCNQ channels by linopirdine significantly decreased resting membrane potentials and the rheobase of these TG neurons. Linopirdine directly induced orofacial cold hyperalgesia when the KCNQ inhibitor was subcutaneously injected into rat orofacial regions. On the other hand, retigabine, a KCNQ channel potentiator, suppressed the excitability of nociceptive cold-sensing TG neurons. We further determined whether KCNQ channel could be a therapeutic target for orofacial cold hyperalgesia. Orofacial cold hyperalgesia was induced in rats either by the administration of oxaliplatin or by infraorbital nerve chronic constrictive injury. Using the orofacial operant test, we showed that retigabine dose-dependently alleviated orofacial cold hyperalgesia in both animal models. Taken together, these findings indicate that KCNQ channel plays a

  17. Hypothalamic Vasopressinergic Projections Innervate Central Amygdala GABAergic Neurons: Implications for Anxiety and Stress Coping

    Science.gov (United States)

    Hernández, Vito S.; Hernández, Oscar R.; Perez de la Mora, Miguel; Gómora, María J.; Fuxe, Kjell; Eiden, Lee E.; Zhang, Limei

    2016-01-01

    The arginine-vasopressin (AVP)-containing hypothalamic magnocellular neurosecretory neurons (VPMNNs) are known for their role in hydro-electrolytic balance control via their projections to the neurohypophysis. Recently, projections from these same neurons to hippocampus, habenula and other brain regions in which vasopressin infusion modulates contingent social and emotionally-affected behaviors, have been reported. Here, we present evidence that VPMNN collaterals also project to the amygdaloid complex, and establish synaptic connections with neurons in central amygdala (CeA). The density of AVP innervation in amygdala was substantially increased in adult rats that had experienced neonatal maternal separation (MS), consistent with our previous observations that MS enhances VPMNN number in the paraventricular (PVN) and supraoptic (SON) nuclei of the hypothalamus. In the CeA, V1a AVP receptor mRNA was only observed in GABAergic neurons, demonstrated by complete co-localization of V1a transcripts in neurons expressing Gad1 and Gad2 transcripts in CeA using the RNAscope method. V1b and V2 receptor mRNAs were not detected, using the same method. Water-deprivation (WD) for 24 h, which increased the metabolic activity of VPMNNs, also increased anxiety-like behavior measured using the elevated plus maze (EPM) test, and this effect was mimicked by bilateral microinfusion of AVP into the CeA. Anxious behavior induced by either WD or AVP infusion was reversed by CeA infusion of V1a antagonist. VPMNNs are thus a newly discovered source of CeA inhibitory circuit modulation, through which both early-life and adult stress coping signals are conveyed from the hypothalamus to the amygdala. PMID:27932956

  18. Hypothalamic vasopressinergic projections innervate central amygdala GABAergic neurons: implications for anxiety and stress coping

    Directory of Open Access Journals (Sweden)

    Vito Salvador Hernandez

    2016-11-01

    Full Text Available The arginine-vasopressin (AVP-containing hypothalamic magnocellular neurosecretory neurons (VPMNNs are known for their role in hydro-electrolytic balance control via their projections to neurohypophysis. Recently, projections from these same neurons to hippocampus, habenula, and other brain regions, in which vasopressin infusion modulates contingent social and emotionally-affected behaviors, have been reported. Here, we present evidence that VPMNN collaterals also project to the amygdaloid complex, and establish synaptic connections with neurons in central amygdala (CeA. The density of AVP innervation in amygdala was substantially increased in adult rats that had experienced neonatal maternal separation (MS, consistent with our previous observations that MS enhances VPMNN number in the paraventricular (PVN and supraoptic (SON nuclei of the hypothalamus. In the CeA, V1a AVP receptor mRNA was only observed in GABAergic neurons, demonstrated by complete co-localization of V1a transcripts in neurons expressing Gad1 and Gad2 transcripts in CeA using the RNAscope method. V1b and V2 receptors mRNA were not detected, using the same method. Water-deprivation for 24 hrs, which increased the metabolic activity of VPMNNs, also increased anxiety-like behavior measured using the elevated plus maze test, and this effect was mimicked by bilateral microinfusion of VP into the CeA. Anxious behavior induced by either water deprivation or VP infusion was reversed by CeA infusion of V1a antagonist. VPMNNs are thus a newly discovered source of central amygdala inhibitory circuit modulation, through which both early-life and adult stress coping signals are conveyed from the hypothalamus to the amygdala.

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

    Directory of Open Access Journals (Sweden)

    Yeowool eHuh

    2013-10-01

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

  20. Nociceptive-induced myocardial remote conditioning is mediated by neuronal gamma protein kinase C.

    Science.gov (United States)

    Gross, Eric R; Hsu, Anna K; Urban, Travis J; Mochly-Rosen, Daria; Gross, Garrett J

    2013-09-01

    Deciphering the remote conditioning molecular mechanism may provide targets to develop therapeutics that can broaden the clinical application. To further investigate this, we tested whether two protein kinase C (PKC) isozymes, the ubiquitously expressed epsilon PKC (εPKC) and the neuronal-specific gamma PKC (γPKC), mediate nociceptive-induced remote myocardial conditioning. Male Sprague-Dawley rats were used for both in vivo and ex vivo myocardial ischemia-reperfusion protocols. For the in vivo studies, using a surgical abdominal incision for comparison, applying only to the abdomen either bradykinin or the εPKC activator (ψεRACK) reduced myocardial infarct size (45 ± 1, 44 ± 2 %, respectively, vs. incision: 43 ± 2 %, and control: 63 ± 2 %, P classical PKC isozyme activator (activating α, β, βII, and γ), reduced myocardial injury. Importantly, the classical PKC isozyme activator given to the abdomen in vivo (with an intact nervous system including γPKC) during myocardial ischemia reduced infarct size as effectively as an abdominal incision or ψεRACK (45 ± 1 vs. 45 ± 2 and 47 ± 1 %, respectively). The classical PKC activator-induced protection was also blocked by spinal cord surgical transection. These findings identified potential remote conditioning mimetics, with these strategies effective even during myocardial ischemia. A novel mechanism of nociceptive-induced remote conditioning, involving γPKC, was also identified.

  1. Neuronal mechanisms during repetitive trigemino-nociceptive stimulation in migraine patients.

    Science.gov (United States)

    Aderjan, David; Stankewitz, Anne; May, Arne

    2010-10-01

    Habituation deficits in various sensory modalities have been observed in migraine patients in several experimental designs. The underlying neuronal mechanisms are, however, still unknown. Past studies have used electrophysiological measures and focussed on habituation behaviour during one single session. We were interested in how repeated painful stimulation over several days is processed, perceived and modulated in migraineurs. Fifteen migraine patients and 15 healthy controls were stimulated daily with a 20 min trigeminal pain paradigm for eight consecutive days, using functional MRI performed on days one and eight and one follow-up measurement three months later. The results demonstrate that migraine patients did not differ in behavioural pain ratings compared to the controls at any time. However, functional imaging data revealed a significant difference in several brain areas over time. The activity level in the prefrontal cortex (PFC) and the rostral anterior cingulate cortex (rACC) increased in healthy control subjects from day one to day eight, whereas it decreased in migraine patients. These data suggest that several brain areas known to be involved in endogenous pain control show a completely opposite behaviour in migraine patients compared to healthy controls. These brain networks seem not to be disrupted per se in migraine patients but changed activity over time responding to repetitive nociceptive input. The alteration of pain inhibitory circuits may be the underlying mechanism responsible for the dys-functional neuronal filters of sensory input.

  2. Orientational Recognition and Low-Resistance Passing (LRP) Regulation of Segmental Re-innervation by Central Neurons in Leeches

    Institute of Scientific and Technical Information of China (English)

    张帆; 张人骥

    1994-01-01

    Re-innervation of sensory and motor neurons on a defined area of the body wall was studied in two species of leeches, Whitmania pigra and Hirudo medicinalis, as a model of segmental animals. Following isolation and rotation of a tube of body wall, the mechanical sensory and annular erection (AE) motor neurons re-innervated the body wall, at a rate of approximately 3. 8 -8. 4 μm/h. The patterns of re-innerva-tion by pairs of neurons on each side of a ganglion were bilaterally symmetric. The repairs are synchronous for the sensory and motor neurons which are of different functions but in a same ganglion. The gap junctions are widely spread in leech between neurons and glia cells, as well as among the neurons and glia cells themselves. Therefore, it is proposed that the nervous system repair is regulated by a low-resistance pathway. In the xenotransplantation experiments, neurons recognized target tissues before the immuno-recognition and rejection.

  3. Cholecystokinin (CCK)-expressing neurons in the suprachiasmatic nucleus: innervation, light responsiveness and entrainment in CCK-deficient mice.

    Science.gov (United States)

    Hannibal, Jens; Hundahl, Christian; Fahrenkrug, Jan; Rehfeld, Jens F; Friis-Hansen, Lennart

    2010-09-01

    The suprachiasmatic nucleus (SCN) is the principal pacemaker driving circadian rhythms of physiology and behaviour. Neurons within the SCN express both classical and neuropeptide transmitters which regulate clock functions. Cholecyctokinin (CCK) is a potent neurotransmitter expressed in neurons of the mammalian SCN, but its role in circadian timing is not known. In the present study, CCK was demonstrated in a distinct population of neurons located in the shell region of the SCN and in a few cells in the core region. The CCK neurons did not express vasopressin or vasoactive intestinal peptide. However, CCK-containing processes make synaptic contacts with both groups of neurons and some CCK cell bodies were innervated by VIPergic neurons. The CCK neurons received no direct input from the three major pathways to the SCN, and the CCK neurons were not light-responsive as evaluated by induction of cFOS, and did not express the core clock protein PER1. Accordingly, CCK-deficient mice showed normal entrainment and had similar τ, light-induced phase shift and negative masking behaviour as wild-type animals. In conclusion, CCK signalling seems not to be involved directly in light-induced resetting of the clock or in regulating core clock function. The expression of CCK in a subpopulation of neurons, which do not belonging to either the VIP or AVP cells but which have synaptic contacts to both cell types and reverse innervation of CCK neurons from VIP neurons, suggests that the CCK neurons may act in non-photic regulation within the clock and/or, via CCK projections, mediate clock information to hypothalamic nuclei.

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

    Science.gov (United States)

    Hiranuma, Maya

    2013-03-01

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

  5. Recruitment in a heterogeneous population of motor neurons that innervates the depressor muscle of the crayfish walking leg muscle.

    Science.gov (United States)

    Hill, Andrew A V; Cattaert, Daniel

    2008-02-01

    According to the size principle the fine control of muscle tension depends on the orderly recruitment of motor neurons from a heterogeneous pool. We took advantage of the small number of excitatory motor neurons (about 12) that innervate the depressor muscle of the crayfish walking leg to determine if the size principle applies to this muscle. We found that in accordance with the size principle, when stimulated by proprioceptive input, neurons with small extracellular spikes were recruited before neurons with medium or large spikes. Because only a small fraction of the motor neurons responded strongly enough to sensory input to be recruited in this way, we extended our analysis to all neurons by characterizing properties that have classically been associated with recruitment order such as speed of axonal conduction and extracellular spike amplitude. Through a combination of physiological and anatomical criteria we were able to identify seven classes of excitatory depressor motor neurons. The majority of these classes responded to proprioceptive input with a resistance reflex, while a few responded with an assistance reflex, and yet others did not respond. Our results are in general agreement with the size principle. However, we found qualitative differences between neuronal classes in terms of synaptic input and neuronal structure that would in theory be unnecessary, according to a strict interpretation of the size principle. We speculate that the qualitative heterogeneity observed may be due to the fact that the depressor is a complex muscle, consisting of two muscle bundles that share a single insertion but have multiple origins.

  6. Decreased spontaneous activity and altered evoked nociceptive response of rat thalamic submedius neurons to lumbar vertebra thrust.

    Science.gov (United States)

    Reed, William R; Cranston, Jamie T; Onifer, Stephen M; Little, Joshua W; Sozio, Randall S

    2017-07-07

    The thalamus is a central structure important to modulating and processing all mechanoreceptor input destined for the cortex. A large number of diverse mechanoreceptor endings are stimulated when a high velocity low amplitude thrust is delivered to the lumbar spine during spinal manipulation. The objective of this study was to determine if a lumbar thrust alters spontaneous and/or evoked nociceptive activity in medial thalamic submedius (Sm) neurons. Extracellular recordings were obtained from 94 thalamic Sm neurons in 54 urethane-anesthetized adult Wistar rats. Spontaneous activity was recorded 5 min before and after an L5 control (no thrust) and thrust (85% rat body weight; 100 ms) procedure. In a subset of responsive nociceptive-specific neurons, mean changes in noxious-evoked response (10-s pinch with clip; 795 g) at three sites (tail, contra- and ipsilateral hindpaw) were determined following an L5 thrust. Mean changes in Sm spontaneous activity (60 s bins) and evoked noxious response were compared using a mixed model repeated measures ANOVA with Bonferroni post hoc t tests and paired t tests, respectively. Compared to control, spontaneous Sm activity decreased 180-240 s following the lumbar thrust (p thrust compared to control (p thrust suggest that thalamic submedius neurons may play a role in central pain modulation related to manual therapy intervention.

  7. Cysteine Proteinase-1 and Cut Protein Isoform Control Dendritic Innervation of Two Distinct Sensory Fields by a Single Neuron

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    Gray R. Lyons

    2014-03-01

    Full Text Available Dendrites often exhibit structural changes in response to local inputs. Although mechanisms that pattern and maintain dendritic arbors are becoming clearer, processes regulating regrowth, during context-dependent plasticity or after injury, remain poorly understood. We found that a class of Drosophila sensory neurons, through complete pruning and regeneration, can elaborate two distinct dendritic trees, innervating independent sensory fields. An expression screen identified Cysteine proteinase-1 (Cp1 as a critical regulator of this process. Unlike known ecdysone effectors, Cp1-mutant ddaC neurons pruned larval dendrites normally but failed to regrow adult dendrites. Cp1 expression was upregulated/concentrated in the nucleus during metamorphosis, controlling production of a truncated Cut homeodomain transcription factor. This truncated Cut, but not the full-length protein, allowed Cp1-mutant ddaC neurons to regenerate higher-order adult dendrites. These results identify a molecular pathway needed for dendrite regrowth after pruning, which allows the same neuron to innervate distinct sensory fields.

  8. Influence of a serotonin receptor antagonist, 5-HTP-DP-hex, on spinal and thalamic nociceptive neurons in rats.

    Science.gov (United States)

    Emmers, R; Tamir, H; Wilchek, M

    1987-06-01

    The antinociceptive properties of a new synthetic dipeptide (N-hexanoyl-5-hydroxytryptophyl-5-hydroxytryptophan amide, or 5-HTP-DP-hex) were studied in rats by an electrophysiological method. After an i.p. injection of alpha-chloralose and urethane, the animals were prepared for stereotaxic approach to the nucleus ventralis posterolateralis of the thalamus. With tungsten microelectrodes, individual nociceptive neurons in the nucleus were identified by the sequence of spikes emitted in response to single-pulse stimulation of the sciatic nerve. In addition to the usual short-latency spikes, a nociceptive neuron fired late spikes at regular intervals within 500 ms following each stimulus. When the spikes were accumulated in poststimulus time histograms, the short-latency spikes compiled an intensity-related (I) peak. The late spikes formed modality-related (M) peaks with spacing characteristic of nociception. Intracarotid infusion of 5-HTP-DP-hex (1 mg/kg) elevated the delayed portion of the I peak and the first M peak. This effect was followed in 25 min by suppression of all M peaks. The control record could be reinstated at any time by 5-hydroxytryptophan (3.5 mg/kg), or by natural recovery in 2.5 h. Responses evoked from a thalamic nociceptive neuron by single-pulse stimulation of the spinothalamic tract were modified by 5-HTP-DP-hex in a similar manner, except that no elevation of the activity peaks was observed. As shown previously, elevation of the delayed I peak and M1 indicated an increased input of A-delta and C fibers, respectively. The increased input lowers the response threshold and may represent hyperalgesia. Suppression of the M peaks may result from altered function of the positive feedback loop in the nociceptive system at the thalamic level, and may represent analgesia. Naloxone, methysergide, as well as ketanserin had no significant effect on the response histograms. These findings suggested that 5-HTP-DP-hex, a known serotonin receptor antagonist

  9. Central sensitization of nociceptive neurons in rat medullary dorsal horn involves purinergic P2X7 receptors.

    Science.gov (United States)

    Itoh, K; Chiang, C-Y; Li, Z; Lee, J-C; Dostrovsky, J O; Sessle, B J

    2011-09-29

    Central sensitization is a crucial process underlying the increased neuronal excitability of nociceptive pathways following peripheral tissue injury and inflammation. Our previous findings have suggested that extracellular adenosine 5'-triphosphate (ATP) molecules acting at purinergic receptors located on presynaptic terminals (e.g., P2X2/3, P2X3 subunits) and glial cells are involved in the glutamatergic-dependent central sensitization induced in medullary dorsal horn (MDH) nociceptive neurons by application to the tooth pulp of the inflammatory irritant mustard oil (MO). Since growing evidence indicates that activation of P2X7 receptors located on glia is involved in chronic inflammatory and neuropathic pain, the aim of the present study was to test in vivo for P2X7 receptor involvement in this acute inflammatory pain model. Experiments were carried out in anesthetized Sprague-Dawley male rats. Single unit recordings were made in MDH functionally identified nociceptive neurons for which mechanoreceptive field, mechanical activation threshold and responses to noxious stimuli were tested. We found that continuous intrathecal (i.t.) superfusion over MDH of the potent P2X7 receptor antagonists brilliant blue G and periodated oxidized ATP could each significantly attenuate the MO-induced MDH central sensitization. MDH central sensitization could also be produced by i.t. superfusion of ATP and even more effectively by the P2X7 receptor agonist benzoylbenzoyl ATP. Superfusion of the microglial blocker minocycline abolished the MO-induced MDH central sensitization, consistent with reports that dorsal horn P2X7 receptors are mostly expressed on microglia. In control experiments, superfusion over MDH of vehicle did not produce any significant changes. These novel findings suggest that activation of P2X7 receptors in vivo may be involved in the development of central sensitization in an acute inflammatory pain model.

  10. Serotonergic innervation and serotonin receptor expression of NPY-producing neurons in the rat lateral and basolateral amygdaloid nuclei.

    Science.gov (United States)

    Bonn, M; Schmitt, A; Lesch, K-P; Van Bockstaele, E J; Asan, E

    2013-03-01

    Pharmacobehavioral studies in experimental animals, and imaging studies in humans, indicate that serotonergic transmission in the amygdala plays a key role in emotional processing, especially for anxiety-related stimuli. The lateral and basolateral amygdaloid nuclei receive a dense serotonergic innervation in all species studied to date. We investigated interrelations between serotonergic afferents and neuropeptide Y (NPY)-producing neurons, which are a subpopulation of inhibitory interneurons in the rat lateral and basolateral nuclei with particularly strong anxiolytic properties. Dual light microscopic immunolabeling showed numerous appositions of serotonergic afferents on NPY-immunoreactive somata. Using electron microscopy, direct membrane appositions and synaptic contacts between serotonin-containing axon terminals and NPY-immunoreactive cellular profiles were unequivocally established. Double in situ hybridization documented that more than 50 %, and about 30-40 % of NPY mRNA-producing neurons, co-expressed inhibitory 5-HT1A and excitatory 5-HT2C mRNA receptor subtype mRNA, respectively, in both nuclei with no gender differences. Triple in situ hybridization showed that individual NPY mRNA-producing interneurons co-express both 5-HT1A and 5-HT2C mRNAs. Co-expression of NPY and 5-HT3 mRNA was not observed. The results demonstrate that serotonergic afferents provide substantial innervation of NPY-producing neurons in the rat lateral and basolateral amygdaloid nuclei. Studies of serotonin receptor subtype co-expression indicate a differential impact of the serotonergic innervation on this small, but important, population of anxiolytic interneurons, and provide the basis for future studies of the circuitry underlying serotonergic modulation of emotional stimulus processing in the amygdala.

  11. Cadherin-13 Deficiency Increases Dorsal Raphe 5-HT Neuron Density and Prefrontal Cortex Innervation in the Mouse Brain

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    Andrea Forero

    2017-09-01

    Full Text Available Background: During early prenatal stages of brain development, serotonin (5-HT-specific neurons migrate through somal translocation to form the raphe nuclei and subsequently begin to project to their target regions. The rostral cluster of cells, comprising the median and dorsal raphe (DR, innervates anterior regions of the brain, including the prefrontal cortex. Differential analysis of the mouse 5-HT system transcriptome identified enrichment of cell adhesion molecules in 5-HT neurons of the DR. One of these molecules, cadherin-13 (Cdh13 has been shown to play a role in cell migration, axon pathfinding, and synaptogenesis. This study aimed to investigate the contribution of Cdh13 to the development of the murine brain 5-HT system.Methods: For detection of Cdh13 and components of the 5-HT system at different embryonic developmental stages of the mouse brain, we employed immunofluorescence protocols and imaging techniques, including epifluorescence, confocal and structured illumination microscopy. The consequence of CDH13 loss-of-function mutations on brain 5-HT system development was explored in a mouse model of Cdh13 deficiency.Results: Our data show that in murine embryonic brain Cdh13 is strongly expressed on 5-HT specific neurons of the DR and in radial glial cells (RGCs, which are critically involved in regulation of neuronal migration. We observed that 5-HT neurons are intertwined with these RGCs, suggesting that these neurons undergo RGC-guided migration. Cdh13 is present at points of intersection between these two cell types. Compared to wildtype controls, Cdh13-deficient mice display increased cell densities in the DR at embryonic stages E13.5, E17.5, and adulthood, and higher serotonergic innervation of the prefrontal cortex at E17.5.Conclusion: Our findings provide evidence for a role of CDH13 in the development of the serotonergic system in early embryonic stages. Specifically, we indicate that Cdh13 deficiency affects the cell

  12. Induction of long-term potentiation in single nociceptive dorsal horn neurons is blocked by the CaMKII inhibitor AIP.

    Science.gov (United States)

    Pedersen, Linda Margareth; Lien, Guro Flor; Bollerud, Ingunn; Gjerstad, Johannes

    2005-04-11

    Neuronal events leading to development of long-term potentiation (LTP) in the nociceptive pathways may be a cellular mechanism underlying central hyperalgesia. Here, we examine whether induction of LTP in nociceptive dorsal horn neurons at depths of 80-500 microm from the cord surface can be affected by spinal application of the Ca(2+)/calmodulin-dependent protein kinase II (CaMKII) inhibitor AIP. Extracellular recordings from single neurons in intact urethane anesthetized Sprague-Dawley rats were performed, and the neuronal A-fiber and C-fiber responses after sciatic nerve test pulses were defined according to latencies. A clear LTP of the nociceptive transmission following sciatic nerve high-frequency stimulation (HFS) was observed in single neurons in laminae I-IV of the dorsal horn. The increase in the C-fiber response after HFS was blocked in the presence of 2.0 mM AIP (P fiber response was not affected by 2.0 mM AIP alone or by vehicle. Thus, our data show that the neuronal process leading to the induction of LTP in the dorsal horn induced by HFS is clearly inhibited by the specific CaMKII inhibitor AIP. It is concluded that CaMKII may be important for the induction of LTP in single nociceptive dorsal horn neurons.

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

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    Serena Boccella

    2015-01-01

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

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

    Science.gov (United States)

    Boccella, Serena; Vacca, Valentina; Errico, Francesco; Marinelli, Sara; Squillace, Marta; Di Maio, Anna; Vitucci, Daniela; Palazzo, Enza; De Novellis, Vito; Maione, Sabatino; Pavone, Flaminia; Usiello, Alessandro

    2015-01-01

    D-Aspartate (D-Asp) is a free D-amino acid found in the mammalian brain with a temporal-dependent concentration based on the postnatal expression of its metabolizing enzyme D-aspartate oxidase (DDO). D-Asp acts as an agonist on NMDA receptors (NMDARs). Accordingly, high levels of D-Asp in knockout mice for Ddo gene (Ddo−/−) or in mice treated with D-Asp increase NMDAR-dependent processes. We have here evaluated in Ddo−/− mice the effect of high levels of free D-Asp on the long-term plastic changes along the nociceptive pathway occurring in chronic and acute pain condition. We found that Ddo−/− mice show an increased evoked activity of the nociceptive specific (NS) neurons of the dorsal horn of the spinal cord (L4–L6) and a significant decrease of mechanical and thermal thresholds, as compared to control mice. Moreover, Ddo gene deletion exacerbated the nocifensive responses in the formalin test and slightly reduced pain thresholds in neuropathic mice up to 7 days after chronic constriction injury. These findings suggest that the NMDAR agonist, D-Asp, may play a role in the regulation of NS neuron electrophysiological activity and behavioral responses in physiological and pathological pain conditions. PMID:25629055

  15. Mechanism of pain relief by low-power infrared irradiation: ATP is an IR-target molecule in nociceptive neurons.

    Science.gov (United States)

    Yachnev, Igor L; Plakhova, Vera B; Podzorova, Svetlana A; Shelykh, Tatiana N; Rogachevsky, Ilya V; Krylov, Boris V

    2012-01-01

    Effects of infrared (IR) radiation generated by a low-power CO2-laser on the membrane of cultured dissociated nociceptive neurons of newborn rat spinal ganglia were investigated using the whole-cell patch-clamp method. Low-power IR radiation diminished the voltage sensitivity of activation gating machinery of slow sodium channels (Na(v)1.8). Ouabain known to block both transducer and pumping functions of Na+,K+-ATPase eliminated IR irradiation effects. The molecular mechanism of interaction of CO2-laser radiation with sensory membrane was proposed. The primary event of this interaction is the process of energy absorption by ATP molecules. The transfer of vibrational energy from Na+,K+- ATPase-bound and vibrationally excited ATP molecules to Na+,K+-ATPase activates this enzyme and converts it into a signal transducer. This effect leads to a decrease in the voltage sensitivity of Na(v)1.8 channels. The effect of IR-radiation was elucidated by the combined application of a very sensitive patch-clamp method and an optical facility with a controlled CO2-laser. As a result, the mechanism of interaction of non-thermal low-power IR radiation with the nociceptive neuron membrane is suggested.

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

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    Henry James L

    2009-09-01

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

  17. The potentiating effect of calcitonin gene-related peptide on transient receptor potential vanilloid-1 activity and the electrophysiological responses of rat trigeminal neurons to nociceptive stimuli.

    Science.gov (United States)

    Chatchaisak, Duangthip; Connor, Mark; Srikiatkhachorn, Anan; Chetsawang, Banthit

    2017-02-15

    Growing evidence suggests that calcitonin gene-related peptide (CGRP) participates in trigeminal nociceptive responses. However, the role of CGRP in sensitization or desensitization of nociceptive transduction remains poorly understood. In this study, we sought to further investigate the CGRP-induced up-regulation of transient receptor potential vanilloid-1 (TRPV1) and the responses of trigeminal neurons to nociceptive stimuli. Rat trigeminal ganglion (TG) organ cultures and isolated trigeminal neurons were incubated with CGRP. An increase in TRPV1 levels was observed in CGRP-incubated TG organ cultures. CGRP potentiated capsaicin-induced increase in phosphorylated CaMKII levels in the TG organ cultures. The incubation of the trigeminal neurons with CGRP significantly increased the inward currents in response to capsaicin challenge, and this effect was inhibited by co-incubation with the CGRP receptor antagonist, BIBN4068BS or the inhibitor of protein kinase A, H-89. These findings reveal that CGRP acting on trigeminal neurons may play a significant role in facilitating cellular events that contribute to the peripheral sensitization of the TG in nociceptive transmission.

  18. Sound-sensitive neurons innervate the ventro-lateral protocerebrum of the heliothine moth brain

    DEFF Research Database (Denmark)

    Pfuhl, Gerit; Zhao, Xin Cheng; Ian, Elena

    2014-01-01

    -sensitive neurons in the moth brain. During intracellular recordings from the lateral protocerebrum in the brain of three noctuid moth species, Heliothis virescens, Helicoverpa armigera and Helicoverpa assulta, we found an assembly of neurons responding to transient sound pulses of broad bandwidth. The majority...... of the auditory neurons ascended from the ventral cord and ramified densely within the anterior region of the ventro-lateral protocerebrum. The physiological and morphological characteristics of these auditory neurons were similar. We detected one additional sound-sensitive neuron, a brain interneuron with its...... soma positioned near the calyces of mushroom bodies and with numerous neuronal processes in the ventro-lateral protocerebrum. Mass-staining of ventral-cord neurons supported the assumption that the ventro-lateral region of the moth brain was the main target for the auditory projections ascending from...

  19. Differences in electrophysiological properties of functionally identified nociceptive sensory neurons in an animal model of cancer-induced bone pain

    Science.gov (United States)

    Zhu, Yong Fang; Ungard, Robert; Seidlitz, Eric; Zacal, Natalie; Huizinga, Jan; Henry, James L

    2016-01-01

    Background Bone cancer pain is often severe, yet little is known about mechanisms generating this type of chronic pain. While previous studies have identified functional alterations in peripheral sensory neurons that correlate with bone tumours, none has provided direct evidence correlating behavioural nociceptive responses with properties of sensory neurons in an intact bone cancer model. Results In a rat model of prostate cancer-induced bone pain, we confirmed tactile hypersensitivity using the von Frey test. Subsequently, we recorded intracellularly from dorsal root ganglion neurons in vivo in anesthetized animals. Neurons remained connected to their peripheral receptive terminals and were classified on the basis of action potential properties, responses to dorsal root stimulation, and to mechanical stimulation of the respective peripheral receptive fields. Neurons included C-, Aδ-, and Aβ-fibre nociceptors, identified by their expression of substance P. We suggest that bone tumour may induce phenotypic changes in peripheral nociceptors and that these could contribute to bone cancer pain. Conclusions This work represents a significant technical and conceptual advance in the study of peripheral nociceptor functions in the development of cancer-induced bone pain. This is the first study to report that changes in sensitivity and excitability of dorsal root ganglion primary afferents directly correspond to mechanical allodynia and hyperalgesia behaviours following prostate cancer cell injection into the femur of rats. Furthermore, our unique combination of techniques has allowed us to follow, in a single neuron, mechanical pain-related behaviours, electrophysiological changes in action potential properties, and dorsal root substance P expression. These data provide a more complete understanding of this unique pain state at the cellular level that may allow for future development of mechanism-based treatments for cancer-induced bone pain. PMID:27030711

  20. Separate groups of dopamine neurons innervate caudate head and tail encoding flexible and stable value memories.

    Science.gov (United States)

    Kim, Hyoung F; Ghazizadeh, Ali; Hikosaka, Okihide

    2014-01-01

    Dopamine (DA) neurons are thought to be critical for reward value-based learning by modifying synaptic transmissions in the striatum. Yet, different regions of the striatum seem to guide different kinds of learning. Do DA neurons contribute to the regional differences of the striatum in learning? As a first step to answer this question, we examined whether the head and tail of the caudate nucleus of the monkey (Macaca mulatta) receive inputs from the same or different DA neurons. We chose these caudate regions because we previously showed that caudate head neurons learn values of visual objects quickly and flexibly, whereas caudate tail neurons learn object values slowly but retain them stably. Here we confirmed the functional difference by recording single neuronal activity while the monkey performed the flexible and stable value tasks, and then injected retrograde tracers in the functional domains of caudate head and tail. The projecting dopaminergic neurons were identified using tyrosine hydroxylase immunohistochemistry. We found that two groups of DA neurons in the substantia nigra pars compacta project largely separately to the caudate head and tail. These groups of DA neurons were mostly separated topographically: head-projecting neurons were located in the rostral-ventral-medial region, while tail-projecting neurons were located in the caudal-dorsal-lateral regions of the substantia nigra. Furthermore, they showed different morphological features: tail-projecting neurons were larger and less circular than head-projecting neurons. Our data raise the possibility that different groups of DA neurons selectively guide learning of flexible (short-term) and stable (long-term) memories of object values.

  1. Separate groups of dopamine neurons innervate caudate head and tail encoding flexible and stable value memories

    Directory of Open Access Journals (Sweden)

    Hyoung F Kim

    2014-10-01

    Full Text Available Dopamine neurons are thought to be critical for reward value-based learning by modifying synaptic transmissions in the striatum. Yet, different regions of the striatum seem to guide different kinds of learning. Do dopamine neurons contribute to the regional differences of the striatum in learning? As a first step to answer this question, we examined whether the head and tail of the caudate nucleus of the monkey (Macaca mulatta receive inputs from the same or different dopamine neurons. We chose these caudate regions because we previously showed that caudate head neurons learn values of visual objects quickly and flexibly, whereas caudate tail neurons learn object values slowly but retain them stably. Here we confirmed the functional difference by recording single neuronal activity while the monkey performed the flexible and stable value tasks, and then injected retrograde tracers in the functional domains of caudate head and tail. The projecting dopaminergic neurons were identified using tyrosine hydroxylase immunohistochemistry. We found that two groups of dopamine neurons in the substantia nigra pars compacta project largely separately to the caudate head and tail. These groups of dopamine neurons were mostly separated topographically: head-projecting neurons were located in the rostral-ventral-medial region, while tail-projecting neurons were located in the caudal-dorsal-lateral regions of the substantia nigra. Furthermore, they showed different morphological features: tail-projecting neurons were larger and less circular than head-projecting neurons. Our data raise the possibility that different groups of dopamine neurons selectively guide learning of flexible (short-term and stable (long-term memories of object values.

  2. Effect of spinal manipulation thrust duration on trunk mechanical activation thresholds of nociceptive-specific lateral thalamic neurons.

    Science.gov (United States)

    Reed, William R; Sozio, Randall; Pickar, Joel G; Onifer, Stephen M

    2014-10-01

    The objective of this preliminary study was to determine if high-velocity, low-amplitude spinal manipulation (HVLA-SM) thrust duration alters mechanical trunk activation thresholds of nociceptive-specific (NS) lateral thalamic neurons. Extracellular recordings were obtained from 18 NS neurons located in 2 lateral thalamic nuclei (ventrolateral [n = 12] and posterior [n = 6]) in normal anesthetized Wistar rats. Response thresholds to electronic von Frey anesthesiometer (rigid tip) mechanical trunk stimuli applied in 3 lumbar directions (dorsal-ventral, 45° caudal, and 45° cranial) were determined before and immediately after the delivery of 3 HVLA-SM thrust durations (time control 0, 100, and 400 milliseconds). Mean changes in mechanical trunk activation thresholds were compared using a mixed model analysis of variance. High-velocity, low-amplitude spinal manipulation duration did not significantly alter NS lateral thalamic neurons' mechanical trunk responses to any of the 3 directions tested with the anesthesiometer. This study is the first to examine the effect of HVLA-SM thrust duration on NS lateral thalamic mechanical response thresholds. High-velocity, low-amplitude spinal manipulation thrust duration did not affect mechanical trunk thresholds. Copyright © 2014 National University of Health Sciences. Published by Elsevier Inc. All rights reserved.

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

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    Yulin Dong

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

  4. Sound-sensitive neurons innervate the ventro-lateral protocerebrum of the heliothine moth brain

    DEFF Research Database (Denmark)

    Pfuhl, Gerit; Zhao, Xin Cheng; Ian, Elena

    2014-01-01

    soma positioned near the calyces of mushroom bodies and with numerous neuronal processes in the ventro-lateral protocerebrum. Mass-staining of ventral-cord neurons supported the assumption that the ventro-lateral region of the moth brain was the main target for the auditory projections ascending from...

  5. Phenotypic alterations of neuropeptide Y and calcitonin gene-related peptide-containing neurons innervating the rat temporomandibular joint during carrageenan-induced arthritis

    Science.gov (United States)

    Damico, J.P.; Ervolino, E.; Torres, K.R.; Batagello, D.S.; Cruz-Rizzolo, R.J.; Casatti, C.A.; Bauer, J.A.

    2012-01-01

    The aim of this study was to identify immunoreactive neuropeptide Y (NPY) and calcitonin gene-related peptide (CGRP) neurons in the autonomic and sensory ganglia, specifically neurons that innervate the rat temporomandibular joint (TMJ). A possible variation between the percentages of these neurons in acute and chronic phases of carrageenan-induced arthritis was examined. Retrograde neuronal tracing was combined with indirect immunofluorescence to identify NPY-immunoreactive (NPY-IR) and CGRP- immunoreactive (CGRP-IR) neurons that send nerve fibers to the normal and arthritic temporomandibular joint. In normal joints, NPY-IR neurons constitute 78±3%, 77±6% and 10±4% of double-labeled nucleated neuronal profile originated from the superior cervical, stellate and otic ganglia, respectively. These percentages in the sympathetic ganglia were significantly decreased in acute (58±2% for superior cervical ganglion and 58±8% for stellate ganglion) and chronic (60±2% for superior cervical ganglion and 59±15% for stellate ganglion) phases of arthritis, while in the otic ganglion these percentages were significantly increased to 19±5% and 13±3%, respectively. In the trigeminal ganglion, CGRP-IR neurons innervating the joint significantly increased from 31±3% in normal animals to 54±2% and 49±3% in the acute and chronic phases of arthritis, respectively. It can be concluded that NPY neurons that send nerve fibers to the rat temporomandibular joint are located mainly in the superior cervical, stellate and otic ganglia. Acute and chronic phases of carrageenan-induced arthritis lead to an increase in the percentage of NPY-IR parasympathetic and CGRP-IR sensory neurons and to a decrease in the percentage of NPY-IR sympathetic neurons related to TMJ innervation. PMID:23027347

  6. Phenotypic alterations of neuropeptide Y and calcitonin gene-related peptide-containing neurons innervating the rat temporomandibular joint during carrageenan-induced arthritis

    Directory of Open Access Journals (Sweden)

    J.P. Damico

    2012-10-01

    Full Text Available The aim of this study was to identify immunoreactive neuropeptide Y (NPY and calcitonin gene-related peptide (CGRP neurons in the autonomic and sensory ganglia, specifically neurons that innervate the rat temporomandibular joint (TMJ. A possible variation between the percentages of these neurons in acute and chronic phases of carrageenan-induced arthritis was examined. Retrograde neuronal tracing was combined with indirect immunofluorescence to identify NPY-immunoreactive (NPY-IR and CGRP- immunoreactive (CGRP-IR neurons that send nerve fibers to the normal and arthritic temporomandibular joint. In normal joints, NPY-IR neurons constitute 78±3%, 77±6% and 10±4% of double-labeled nucleated neuronal profile originated from the superior cervical, stellate and otic ganglia, respectively. These percentages in the autonomic ganglia were significantly decreased in acute (58±2% to superior cervical ganglion and 58±8% to stellate ganglion and chronic (60±2% to superior cervical ganglion and 59±15% to stellate ganglion phases of arthritis, while in the otic ganglion these percentages were significantly increased to 19±5% and 13±3%, respectively. In the trigeminal ganglion, CGRP-IR neurons innervating the joint significantly increased from 31±3% in normal animals to 54±2% and 49±3% in the acute and chronic phases of arthritis, respectively. It can be concluded that NPY neurons that send nerve fibers to the rat temporomandibular joint are located mainly in the superior cervical, stellate and otic ganglia. Acute and chronic phases of carrageenan-induced arthritis lead to an increase in the percentage of NPY-IR parasympathetic and CGRP-IR sensory neurons and decrease in the percentage of NPY-IR sympathetic neurons related to TMJ innervation.

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

    Directory of Open Access Journals (Sweden)

    Stéphanie Ventéo

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

  8. Innervation by a GABAergic neuron depresses spontaneous release in glutamatergic neurons and unveils the clamping phenotype of synaptotagmin-1

    DEFF Research Database (Denmark)

    Wierda, Keimpe D B; Sørensen, Jakob Balslev

    2014-01-01

    The role of spontaneously occurring release events in glutamatergic and GABAergic neurons and their regulation is intensely debated. To study the interdependence of glutamatergic and GABAergic spontaneous release, we compared reciprocally connected "mixed" glutamatergic/GABAergic neuronal pairs...... from mice cultured on astrocyte islands with "homotypic" glutamatergic or GABAergic pairs and autaptic neurons. We measured mEPSC and mIPSC frequencies simultaneously from both neurons. Neuronal pairs formed both interneuronal synaptic and autaptic connections indiscriminately. We find that whereas m......EPSC and mIPSC frequencies did not deviate between autaptic and synaptic connections, the frequency of mEPSCs in mixed pairs was strongly depressed compared with either autaptic neurons or glutamatergic pairs. Simultaneous imaging of synapses, or comparison to evoked release amplitudes, showed...

  9. Innervation of ectopic endometrium in a rat model of endometriosis.

    Science.gov (United States)

    Berkley, Karen J; Dmitrieva, Natalia; Curtis, Kathleen S; Papka, Raymond E

    2004-07-27

    Endometriosis (ENDO) is a disorder in which vascularized growths of endometrial tissue occur outside the uterus. Its symptoms include reduced fertility and severe pelvic pain. Mechanisms that maintain the ectopic growths and evoke symptoms are poorly understood. One factor not yet considered is that the ectopic growths develop their own innervation. Here, we tested the hypothesis that the growths develop both an autonomic and a sensory innervation. We used a rat model of surgically induced ENDO whose growths mimic those in women. Furthermore, similar to women with ENDO, such rats exhibit reduced fertility and increased pelvic nociception. The ENDO was induced by autotransplanting, on mesenteric cascade arteries, small pieces of uterus that formed vascularized cysts. The cysts and healthy uterus were harvested from proestrous rats and immunostained using the pan-neuronal marker PGP9.5 and specific markers for calcitonin gene-related peptide (CGRP) (sensory C and A delta fibers), substance P (SP) (sensory C and A delta fibers) and vesicular monoamine transporter (sympathetic fibers). Cysts (like the uterus) were robustly innervated, with many PGP9.5-stained neurites accompanying blood vessels and extending into nearby luminal epithelial layers. CGRP-, SP-, and vesicular monoamine transporter-immunostained neurites also were observed, with CGRP and SP neurites extending the furthest into the cyst lining. These results demonstrate that ectopic endometrial growths develop an autonomic and sensory innervation. This innervation could contribute not only to symptoms associated with ENDO but also to maintenance of the ectopic growths.

  10. Spatial segregation within the sacral parasympathetic nucleus of neurons innervating the bladder or the penis of the rat as revealed by three-dimensional reconstruction.

    Science.gov (United States)

    Banrezes, B; Andrey, P; Maschino, E; Schirar, A; Peytevin, J; Rampin, O; Maurin, Y

    2002-01-01

    The purpose of the present investigations was (1) to examine the spatial organization of preganglionic neurons of the sacral parasympathetic nucleus in the lumbosacral spinal cord of male adult rats and (2) to search, in this nucleus, for a possible segregation of sub-populations of neurons innervating the penis or the bladder, respectively. To estimate their spatial organization, neurons of the sacral parasympathetic nucleus were retrogradely labeled by wheat germ agglutinin coupled to horseradish peroxidase applied to the central end of the sectioned pelvic nerve. The sub-populations of lumbosacral neurons innervating the corpus cavernosum of the penis or the dome of the bladder were identified using transsynaptic retrograde labeling by pseudorabies virus injected into these organs in different rats. In both wheat germ agglutinin-labeled and pseudorabies virus-labeled rats, serial coronal sections were cut through the spinal L5-S1 segments. Labeled neurons were revealed by histochemistry (peroxidase experiments) or immunohistochemistry (pseudorabies virus experiments). By means of a three-dimensional reconstruction software developed in our laboratory, three-dimensional models were calculated from each spinal section image series. They revealed the spatial organization of (i) preganglionic neurons and (ii) neurons innervating the bladder or the penis. The different three-dimensional models were subsequently merged into a single one which revealed the segregation, within the sacral parasympathetic nucleus, of the sub-populations of neurons. Neurons labeled by virus injected into the penis extended predominantly from the rostral part of the L6 segment to the rostral part of the S1 segment while those labeled by bladder injections were distributed predominantly from the caudal part of the L6 segment to the caudal part of the S1 segment. These results support the hypothesis of a viscerotopic organization of sacral neurons providing the spinal control of pelvic organs.

  11. Multiple sensory G proteins in the olfactory, gustatory and nociceptive neurons modulate longevity in Caenorhabditis elegans

    NARCIS (Netherlands)

    H. Lans (Hannes); G. Jansen (Gert)

    2007-01-01

    textabstractThe life span of the nematode Caenorhabditis elegans is under control of sensory signals detected by the amphid neurons. In these neurons, C. elegans expresses at least 13 Galpha subunits and a Ggamma subunit, which are involved in the transduction and modulation of sensory signals. Here

  12. Sensitization of voltage activated calcium channel currents for capsaicin in nociceptive neurons by tumor-necrosis-factor-alpha.

    Science.gov (United States)

    Hagenacker, T; Czeschik, J C; Schäfers, M; Büsselberg, D

    2010-01-15

    It is known that application of tumor-necrosis-factor-alpha (TNF-alpha) sensitizes neuronal calcium channels for heat stimuli in rat models of neuropathic pain. This study examines whether TNF-alpha modulates the capsaicin-induced effects after transient receptor potential vanilloid (TRPV)-1 receptor activation on voltage activated calcium channel currents (I(Ca(V))). TRPV-1 receptors are activated by heat and play an important role in the pathogenesis of thermal hyperalgesia in neuropathic pain syndromes, while voltage activated channels are essential for transmission of neuronal signals. Eliciting I(Ca(V)) in DRG neurons of rats by a depolarization from the resting potential to 0 mV, TNF-alpha (100 ng/ml) reduces I(Ca(V)) by 16.9+/-2.2%, while capsaicin (0.1 microM) decreases currents by 27+/-4.3%. Pre-application of TNF-alpha (100 ng/ml) for 24h results in a sensitization of I(Ca(V)) to capsaicin (0.1 microM) with a reduction of 42.8+/-4.4% mediated by TRPV-1. While L-type (36.6+/-5.2%) and P/Q-type currents (35.6+/-4.1%) are also sensitized by TRPV-1 activation, N-type channel currents are most sensitive (74.5+/-7.3%). The capsaicin-induced shift towards the hyperpolarizing voltage range does not occur when TNF-alpha is applied. Summarizing, TNF-alpha sensitizes nociceptive neurons for capsaicin.

  13. TRESK channel contribution to nociceptive sensory neurons excitability: modulation by nerve injury

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    Serra Jordi

    2011-04-01

    Full Text Available Abstract Background Neuronal hyperexcitability is a crucial phenomenon underlying spontaneous and evoked pain. In invertebrate nociceptors, the S-type leak K+ channel (analogous to TREK-1 in mammals plays a critical role of in determining neuronal excitability following nerve injury. Few data are available on the role of leak K2P channels after peripheral axotomy in mammals. Results Here we describe that rat sciatic nerve axotomy induces hyperexcitability of L4-L5 DRG sensory neurons and decreases TRESK (K2P18.1 expression, a channel with a major contribution to total leak current in DRGs. While the expression of other channels from the same family did not significantly change, injury markers ATF3 and Cacna2d1 were highly upregulated. Similarly, acute sensory neuron dissociation (in vitro axotomy produced marked hyperexcitability and similar total background currents compared with neurons injured in vivo. In addition, the sanshool derivative IBA, which blocked TRESK currents in transfected HEK293 cells and DRGs, increased intracellular calcium in 49% of DRG neurons in culture. Most IBA-responding neurons (71% also responded to the TRPV1 agonist capsaicin, indicating that they were nociceptors. Additional evidence of a biological role of TRESK channels was provided by behavioral evidence of pain (flinching and licking, in vivo electrophysiological evidence of C-nociceptor activation following IBA injection in the rat hindpaw, and increased sensitivity to painful pressure after TRESK knockdown in vivo. Conclusions In summary, our results clearly support an important role of TRESK channels in determining neuronal excitability in specific DRG neurons subpopulations, and show that axonal injury down-regulates TRESK channels, therefore contributing to neuronal hyperexcitability.

  14. Methylglyoxal modification of Nav1.8 facilitates nociceptive neuron firing and causes hyperalgesia in diabetic neuropathy.

    Science.gov (United States)

    Bierhaus, Angelika; Fleming, Thomas; Stoyanov, Stoyan; Leffler, Andreas; Babes, Alexandru; Neacsu, Cristian; Sauer, Susanne K; Eberhardt, Mirjam; Schnölzer, Martina; Lasitschka, Felix; Lasischka, Felix; Neuhuber, Winfried L; Kichko, Tatjana I; Konrade, Ilze; Elvert, Ralf; Mier, Walter; Pirags, Valdis; Lukic, Ivan K; Morcos, Michael; Dehmer, Thomas; Rabbani, Naila; Thornalley, Paul J; Edelstein, Diane; Nau, Carla; Forbes, Josephine; Humpert, Per M; Schwaninger, Markus; Ziegler, Dan; Stern, David M; Cooper, Mark E; Haberkorn, Uwe; Brownlee, Michael; Reeh, Peter W; Nawroth, Peter P

    2012-06-01

    This study establishes a mechanism for metabolic hyperalgesia based on the glycolytic metabolite methylglyoxal. We found that concentrations of plasma methylglyoxal above 600 nM discriminate between diabetes-affected individuals with pain and those without pain. Methylglyoxal depolarizes sensory neurons and induces post-translational modifications of the voltage-gated sodium channel Na(v)1.8, which are associated with increased electrical excitability and facilitated firing of nociceptive neurons, whereas it promotes the slow inactivation of Na(v)1.7. In mice, treatment with methylglyoxal reduces nerve conduction velocity, facilitates neurosecretion of calcitonin gene-related peptide, increases cyclooxygenase-2 (COX-2) expression and evokes thermal and mechanical hyperalgesia. This hyperalgesia is reflected by increased blood flow in brain regions that are involved in pain processing. We also found similar changes in streptozotocin-induced and genetic mouse models of diabetes but not in Na(v)1.8 knockout (Scn10(-/-)) mice. Several strategies that include a methylglyoxal scavenger are effective in reducing methylglyoxal- and diabetes-induced hyperalgesia. This previously undescribed concept of metabolically driven hyperalgesia provides a new basis for the design of therapeutic interventions for painful diabetic neuropathy.

  15. Double labelling immunohistochemical characterization of autonomic sympathetic neurons innervating the sow retractor clitoridis muscle

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    L Ragionieri

    2009-08-01

    Full Text Available Retrograde neuronal tracing and immunohistochemical methods were used to define the neurochemical content of sympathetic neurons projecting to the sow retractor clitoridis muscle (RCM. Differently from the other smooth muscles of genital organs, the RCM is an isolated muscle that is tonically contracted in the rest phase and relaxed in the active phase. This peculiarity makes it an interesting experimental model. The fluorescent tracer fast blue was injected into the RCM of three 50 kg subjects. After a one-week survival period, the ipsilateral paravertebral ganglion S1, that in a preliminary study showed the greatest number of cells projecting to the muscle, was collected from each animal. The co-existence of tyrosine hydroxylase with choline acetyltransferase, neuronal nitric oxide synthase, calcitonin gene-related peptide, leuenkephalin, neuropeptide Y, substance P and vasoactive intestinal polypeptide was studied under a fluorescent microscope on cryostat sections. Tyrosine hydroxylase was present in about 58% of the neurons projecting to the muscle and was found to be co-localized with each of the other tested substances.Within fast blue-labelled cells negative to the adrenergic marker, small populations of neurons singularly containing each of the other enzymatic markers or peptides were also observed. The present study documents the complexity of the neurochemical interactions that regulate the activity of the smooth myocytes of the RCM and their vascular components.

  16. Enhancement of spontaneous and heat-evoked activity in spinal nociceptive neurons by the endovanilloid/endocannabinoid N-arachidonoyldopamine (NADA).

    Science.gov (United States)

    Huang, Susan M; Walker, J Michael

    2006-02-01

    N-arachidonoyldopamine (NADA) is an endogenous molecule found in the nervous system that is capable of acting as a vanilloid agonist via the TRPV1 receptor and as a cannabinoid agonist via the CB1 receptor. Using anesthetized rats, we investigated the neural correlates of behavioral thermal hyperalgesia produced by NADA. Extracellular single cell electrophysiology was conducted to assess the effects of peripheral administration of NADA (i.pl.) on nociceptive neurons in the dorsal horn of the spinal cord. Injection of NADA in the hindpaw caused increased spontaneous discharge of spinal nociceptive neurons compared with injection of vehicle. The neurons also displayed magnified responses to application of thermal stimuli ranging from 34 to 52 degrees C. NADA-induced neural hypersensitivity was dose dependent (EC50 = 1.55 microg) and TRPV1 dependent, as the effect was abolished by co-administration of the TRPV1 antagonist 5'-iodoresiniferatoxin (I-RTX). In contrast, co-administration of the CB1 antagonist SR 141716A did not attenuate this effect. These results suggest that the enhanced responses of spinal nociceptive neurons likely underlie the behavioral thermal hyperalgesia and implicate a possible pain-sensitizing role of endogenous NADA mediated by TRPV1 in the periphery.

  17. "Hybrid" synapses formed by foreign innervation of parasympathetic neurons: a model for selectivity during competitive reinnervation.

    Science.gov (United States)

    Proctor, W; Frenk, S; Taylor, B; Roper, S

    1979-01-01

    Selectivity of synapse formation after nerve regeneration was tested in the parasympathetic cardiac ganglion of frogs (Rana pipiens). First, we tested the ability of somatic motor axons to establish synaptic connections with denervated ganglion cells by implanting the hypoglossus nerve into the vagotomized heart. After several weeks, stimulation of the implanted hypoglossus mediated a parasympathetic-like inhibition of the heart rate, and synaptic responses produced by hypoglossal stimulation were recorded intracellularly in ganglion cells. Light and electron microscopy indicated that implanted hypoglossal nerve terminals contacted parasympathetic ganglion cells only on their axons and not on the cell body (where most vagal synapses are found in control animals). Second, we tested whether regenerating vagal preganglionic axons would complete with foreign (hypoglossal) terminals for innervation of cardiac ganglion cells. We allowed the vagus nerve to regenerate in animals in which the implanted hypoglossus had established functional contacts with the cardiac ganglion. Vagal axons were able to reinnervate the heart and reestablish synaptic connections on the cell bodies of ganglion cells. Furthermore, functional transmission at the foriegn (hypoglossal) terminals disappeared concomitant with vagal reinnervation. Images PMID:315564

  18. Changes in response properties of nociceptive dorsal horn neurons in a murine model of cancer pain

    Institute of Scientific and Technical Information of China (English)

    Donald A. Simone; Sergey G. Khasabov; Darryl T. Hamamoto

    2008-01-01

    Pain associated with cancer that metastasizes to bone is often severe and debilitating. A better understanding of the neural mechanisms that mediate cancer pain is needed for the development of more effective treatments. In this study, we used an established model of cancer pain to characterize changes in response properties of dorsal horn neurons. Fibrosarcoma cells were implanted into and around the calcaneus bone in mice and extracellular electrophysiological recordings were made from wide dynamic range (WDR) and high threshold (HT) dorsal horn neurons. Responses of WDR and HT neurons evoked by mechanical, heat, and cold stimuli applied to the plantar surface of the hind paw were compared between tumor bearing mice and control mice. Mice exhibited hyperalgesia to mechanical and heat stimuli applied to their tumor-bearing hind paw. WDR neurons in tumor-beating mice exhibited an increase in spontaneous activity, and enhanced responses to mechanical, heat, and cold stimuli as compared to controls. Our findings show that sensitization of WDR neurons, but not HT neurons, contributes to tumor-evoked hyperalgesia.

  19. Sensitization of spinal cord nociceptive neurons with a conjugate of substance P and cholera toxin

    Directory of Open Access Journals (Sweden)

    Perez Federico M

    2007-05-01

    Full Text Available Abstract Background Several investigators have coupled toxins to neuropeptides for the purpose of lesioning specific neurons in the central nervous system. By producing deficits in function these toxin conjugates have yielded valuable information about the role of these cells. In an effort to specifically stimulate cells rather than kill them we have conjugated the neuropeptide substance P to the catalytic subunit of cholera toxin (SP-CTA. This conjugate should be taken up selectively by neurokinin receptor expressing neurons resulting in enhanced adenylate cyclase activity and neuronal firing. Results The conjugate SP-CTA stimulates adenylate cyclase in cultured cells that are transfected with either the NK1 or NK2 receptor, but not the NK3 receptor. We further demonstrate that intrathecal injection of SP-CTA in rats induces the phosphorylation of the transcription factor cyclic AMP response element binding protein (CREB and also enhances the expression of the immediate early gene c-Fos. Behaviorally, low doses of SP-CTA (1 μg injected intrathecally produce thermal hyperalgesia. At higher doses (10 μg peripheral sensitivity is suppressed suggesting that descending inhibitory pathways may be activated by the SP-CTA induced sensitization of spinal cord neurons. Conclusion The finding that stimulation of adenylate cyclase in neurokinin receptor expressing neurons in the spinal cord produces thermal hyperalgesia is consistent with the known actions of these neurons. These data demonstrate that cholera toxin can be targeted to specific cell types by coupling the catalytic subunit to a peptide agonist for a g-protein coupled receptor. Furthermore, these results demonstrate that SP-CTA can be used as a tool to study sensitization of central neurons in vivo in the absence of an injury.

  20. Prostaglandin potentiates 5-HT responses in stomach and ileum innervating visceral afferent sensory neurons

    Energy Technology Data Exchange (ETDEWEB)

    Kim, Sojin; Jin, Zhenhua; Lee, Goeun [Department of Physiology, School of Medicine, Kyung Hee University, Seoul 130-701 (Korea, Republic of); Park, Yong Seek; Park, Cheung-Seog [Department of Microbiology, School of Medicine, Kyung Hee University, Seoul 130-701 (Korea, Republic of); Jin, Young-Ho, E-mail: jinyh@khu.ac.kr [Department of Physiology, School of Medicine, Kyung Hee University, Seoul 130-701 (Korea, Republic of)

    2015-01-02

    Highlights: • Prostaglandin E2 (PGE{sub 2}) effect was tested on visceral afferent neurons. • PGE{sub 2} did not evoke response but potentiated serotonin (5-HT) currents up to 167%. • PGE{sub 2}-induced potentiation was blocked by E-prostanoid type 4 receptors antagonist. • PGE{sub 2} effect on 5-HT response was also blocked by protein kinase A inhibitor KT5720. • Thus, PGE{sub 2} modulate visceral afferent neurons via synergistic signaling with 5-HT. - Abstract: Gastrointestinal disorder is a common symptom induced by diverse pathophysiological conditions that include food tolerance, chemotherapy, and irradiation for therapy. Prostaglandin E{sub 2} (PGE{sub 2}) level increase was often reported during gastrointestinal disorder and prostaglandin synthetase inhibitors has been used for ameliorate the symptoms. Exogenous administration of PGE{sub 2} induces gastrointestinal disorder, however, the mechanism of action is not known. Therefore, we tested PGE{sub 2} effect on visceral afferent sensory neurons of the rat. Interestingly, PGE{sub 2} itself did not evoked any response but enhanced serotonin (5-HT)-evoked currents up to 167% of the control level. The augmented 5-HT responses were completely inhibited by a 5-HT type 3 receptor antagonist, ondansetron. The PGE{sub 2}-induced potentiation were blocked by a selective E-prostanoid type4 (EP{sub 4}) receptors antagonist, L-161,982, but type1 and 2 receptor antagonist AH6809 has no effect. A membrane permeable protein kinase A (PKA) inhibitor, KT5720 also inhibited PGE{sub 2} effects. PGE{sub 2} induced 5-HT current augmentation was observed on 15% and 21% of the stomach and ileum projecting neurons, respectively. Current results suggest a synergistic signaling in visceral afferent neurons underlying gastrointestinal disorder involving PGE{sub 2} potentiation of 5-HT currents. Our findings may open a possibility for screen a new type drugs with lower side effects than currently using steroidal prostaglandin

  1. The influence of gender and sex steroids on craniofacial nociception.

    Science.gov (United States)

    Cairns, Brian E

    2007-02-01

    Several pain conditions localized to the craniofacial region show a remarkable sex-related difference in their prevalence. These conditions include temporomandibular disorders and burning mouth syndrome as well as tension-type, migraine, and cluster headaches. The mechanisms that underlie sex-related differences in the prevalence of these craniofacial pain conditions remain obscure and likely involve both physiological and psychosocial factors. In terms of physiological factors relevant to the development of headache, direct evidence of sex-related differences in the properties of dural afferent fibers or durally activated second-order trigeminal sensory neurons has yet to be provided. There is, however, evidence for sex-related differences in the response properties of afferent fibers and second-order trigeminal sensory neurons that convey nociceptive input from other craniofacial tissues associated with sex-related differences in chronic pain conditions, such as those that innervate the masseter muscle and temporomandibular joint. Further, modulation of craniofacial nociceptive input by opioidergic receptor mechanisms appears to be dependent on biological sex. Research into mechanisms that may contribute to sex-related differences in trigeminal nociceptive processing has primarily focused on effect of the female sex hormone estrogen, which appears to alter the excitability of trigeminal afferent fibers and sensory neurons to noxious stimulation of craniofacial tissues. This article discusses current knowledge of potential physiological mechanisms that could contribute to sex-related differences in certain craniofacial pain conditions.

  2. The innervation of rainbow trout (Oncorhynchus mykiss) liver: protein gene product 9.5 and neuronal nitric oxide synthase immunoreactivities.

    Science.gov (United States)

    Esteban, F J; Jiménez, A; Barroso, J B; Pedrosa, J A; del Moral, M L; Rodrigo, J; Peinado, M A

    1998-08-01

    We have explored the innervation of the rainbow trout (O. mykiss) liver using immunohistochemical procedures and light microscopy to detect in situ protein gene product 9.5 and neuronal nitric oxide synthase immunoreactivities (PGP-IR and NOS-IR). The results showed PGP-IR nerve fibres running with the extralobular biliary duct (EBD), hepatic artery (EHA) and portal vein (EPV) that form the hepatic hilum, as well as following the spatial distribution of the intrahepatic blood vessel and biliary channels. These nerve fibres appear as single varicose processes, thin bundles, or thick bundles depending on their diameter and location in the wall of the blood vessel or biliary duct. No PGP-IR fibres were detected in the liver parenchyma. NOS-IR nerve fibres were located only in the vessels and ducts that form the hepatic hilum (EBD, EHA, EPV); in addition, NOS-IR nerve cell bodies were found isolated or forming ganglionated plexuses in the peribiliary fibromuscular tissue of the EBD. No PGP-IR ganglionated plexuses were detected in the EBD. The location of the general (PGP-IR) and nitrergic (nNOS-IR) intrinsic nerves of the trout liver suggest a conserved evolutionary role of the nervous control of hepatic blood flow and hepatobiliary activity.

  3. Entorhinal cortical innervation of parvalbumin-containing neurons (Basket and Chandelier cells) in the rat Ammon's horn.

    Science.gov (United States)

    Kiss, J; Buzsaki, G; Morrow, J S; Glantz, S B; Leranth, C

    1996-01-01

    Physiological data suggest that in the CA1-CA3 hippocampal areas of rats, entorhinal cortical efferents directly influence the activity of interneurons, in addition to pyramidal cells. To verify this hypothesis, the following experiments were performed: 1) light microscopic double-immunostaining for parvalbumin and the anterograde tracer Phaseolus vulgaris-leucoagglutinin injected into the entorhinal cortex; 2) light and electron microscopic analysis of cleaved spectrin-immunostained (i.e., degenerating axons and boutons) hippocampal sections following entorhinal cortex lesion; and 3) an electron microscopic study of parvalbumin-immunostained hippocampal sections after entorhinal cortex lesion. The results demonstrate that in the stratum lacunosum-moleculare of the CA1 and CA3 regions, entorhinal cortical axons form asymmetric synaptic contacts on parvalbumin-containing dendritic shafts. In the stratum lacunosum-moleculare, parvalbumin-immunoreactive dendrites represent processes of GABAergic, inhibitory basket and chandelier cells; these interneurons innervate the perisomatic area and axon initial segments of pyramidal cells, respectively. A feed-forward activation of these neurons by the entorhinal input may explain the strong, short-latency inhibition of pyramidal cells.

  4. Nerve repulsion by the lens and cornea during cornea innervation is dependent on Robo-Slit signaling and diminishes with neuron age.

    Science.gov (United States)

    Schwend, Tyler; Lwigale, Peter Y; Conrad, Gary W

    2012-03-01

    The cornea, the most densely innervated tissue on the surface of the body, becomes innervated in a series of highly coordinated developmental events. During cornea development, chick trigeminal nerve growth cones reach the cornea margin at embryonic day (E)5, where they are initially repelled for days from E5 to E8, instead encircling the corneal periphery in a nerve ring prior to entering on E9. The molecular events coordinating growth cone guidance during cornea development are poorly understood. Here we evaluated a potential role for the Robo-Slit nerve guidance family. We found that Slits 1, 2 and 3 expression in the cornea and lens persisted during all stages of cornea innervation examined. Robo1 expression was developmentally regulated in trigeminal cell bodies, expressed robustly during nerve ring formation (E5-8), then later declining concurrent with projection of growth cones into the cornea. In this study we provide in vivo and in vitro evidence that Robo-Slit signaling guides trigeminal nerves during cornea innervation. Transient, localized inhibition of Robo-Slit signaling, by means of beads loaded with inhibitory Robo-Fc protein implanted into the developing eyefield in vivo, led to disorganized nerve ring formation and premature cornea innervation. Additionally, when trigeminal explants (source of neurons) were oriented adjacent to lens vesicles or corneas (source of repellant molecules) in organotypic tissue culture both lens and cornea tissues strongly repelled E7 trigeminal neurites, except in the presence of inhibitory Robo-Fc protein. In contrast, E10 trigeminal neurites were not as strongly repelled by cornea, and presence of Robo-Slit inhibitory protein had no effect. In full, these findings suggest that nerve repulsion from the lens and cornea during nerve ring formation is mediated by Robo-Slit signaling. Later, a shift in nerve guidance behavior occurs, in part due to molecular changes in trigeminal neurons, including Robo1 downregulation

  5. Locomotor-activated neurons of the cat. II. Noradrenergic innervation and colocalization with NEα 1a or NEα 2b receptors in the thoraco-lumbar spinal cord.

    Science.gov (United States)

    Noga, Brian R; Johnson, Dawn M G; Riesgo, Mirta I; Pinzon, Alberto

    2011-04-01

    Norepinephrine (NE) is a strong modulator and/or activator of spinal locomotor networks. Thus noradrenergic fibers likely contact neurons involved in generating locomotion. The aim of the present study was to investigate the noradrenergic innervation of functionally related, locomotor-activated neurons within the thoraco-lumbar spinal cord. This was accomplished by immunohistochemical colocalization of noradrenergic fibers using dopamine-β-hydroxylase or NEα(1A) and NEα(2B) receptors with cells expressing the c-fos gene activity-dependent marker Fos. Experiments were performed on paralyzed, precollicular-postmamillary decerebrate cats, in which locomotion was induced by electrical stimulation of the mesencephalic locomotor region. The majority of Fos labeled neurons, especially abundant in laminae VII and VIII throughout the thoraco-lumbar (T13-L7) region of locomotor animals, showed close contacts with multiple noradrenergic boutons. A small percentage (10-40%) of Fos neurons in the T7-L7 segments showed colocalization with NEα(1A) receptors. In contrast, NEα(2B) receptor immunoreactivity was observed in 70-90% of Fos cells, with no obvious rostrocaudal gradient. In comparison with results obtained from our previous study on the same animals, a significantly smaller proportion of Fos labeled neurons were innervated by noradrenergic than serotonergic fibers, with significant differences observed for laminae VII and VIII in some segments. In lamina VII of the lumbar segments, the degree of monoaminergic receptor subtype/Fos colocalization examined statistically generally fell into the following order: NEα(2B) = 5-HT(2A) ≥ 5-HT(7) = 5-HT(1A) > NEα(1A). These results suggest that noradrenergic modulation of locomotion involves NEα(1A)/NEα(2B) receptors on noradrenergic-innervated locomotor-activated neurons within laminae VII and VIII of thoraco-lumbar segments. Further study of the functional role of these receptors in locomotion is warranted.

  6. A New Population of Parvocellular Oxytocin Neurons Controlling Magnocellular Neuron Activity and Inflammatory Pain Processing.

    Science.gov (United States)

    Eliava, Marina; Melchior, Meggane; Knobloch-Bollmann, H Sophie; Wahis, Jérôme; da Silva Gouveia, Miriam; Tang, Yan; Ciobanu, Alexandru Cristian; Triana del Rio, Rodrigo; Roth, Lena C; Althammer, Ferdinand; Chavant, Virginie; Goumon, Yannick; Gruber, Tim; Petit-Demoulière, Nathalie; Busnelli, Marta; Chini, Bice; Tan, Linette L; Mitre, Mariela; Froemke, Robert C; Chao, Moses V; Giese, Günter; Sprengel, Rolf; Kuner, Rohini; Poisbeau, Pierrick; Seeburg, Peter H; Stoop, Ron; Charlet, Alexandre; Grinevich, Valery

    2016-03-16

    Oxytocin (OT) is a neuropeptide elaborated by the hypothalamic paraventricular (PVN) and supraoptic (SON) nuclei. Magnocellular OT neurons of these nuclei innervate numerous forebrain regions and release OT into the blood from the posterior pituitary. The PVN also harbors parvocellular OT cells that project to the brainstem and spinal cord, but their function has not been directly assessed. Here, we identified a subset of approximately 30 parvocellular OT neurons, with collateral projections onto magnocellular OT neurons and neurons of deep layers of the spinal cord. Evoked OT release from these OT neurons suppresses nociception and promotes analgesia in an animal model of inflammatory pain. Our findings identify a new population of OT neurons that modulates nociception in a two tier process: (1) directly by release of OT from axons onto sensory spinal cord neurons and inhibiting their activity and (2) indirectly by stimulating OT release from SON neurons into the periphery.

  7. The evolutionary transition to sideways-walking gaits in brachyurans was accompanied by a reduction in the number of motor neurons innervating proximal leg musculature.

    Science.gov (United States)

    Vidal-Gadea, Andrés G; Belanger, Jim H

    2013-11-01

    The forwards-walking portly crab, Libinia emarginata is an ancient brachyuran. Its phylogenetic position and behavioral repertoire make it an excellent candidate to reveal the adaptations, which were required for brachyuran crabs to complete their transition to sideways-walking from their forwards-walking ancestors. Previously we showed that in common with other forwards-walking (but distantly related) crustaceans, L. emarginata relies more heavily on its more numerous proximal musculature to propel itself forward than its sideways-walking closer relatives. We investigated if the proximal musculature of L. emarginata is innervated by a greater number of motor neurons than that of sideways-walking brachyurans. We found the distal musculature of spider crabs is innervated by a highly conserved number of motor neurons. However, innervation of its proximal musculature is more numerous than in closely-related (sideways-walking) species, resembling in number and morphology those described for forwards-walking crustaceans. We propose that transition from forward- to sideways-walking in crustaceans involved a decreased role for the proximal leg in favor of the more distal merus-carpus joint.

  8. Cardiac nociception in rats - Neuronal pathways and the influence of dermal neurostimulation on conveyance to the central nervous system

    NARCIS (Netherlands)

    Albutaihi, IAM; Hautvast, RWM; DeJongste, MJL; Ter Horst, GJ; Staal, MJ

    2003-01-01

    Neurostimulation for refractory angina pectoris is often advocated for its clinical efficacy. However, the recruited pathways to induce electroanalgesia are partially unknown. Therefore, we sought to study the effect of neurostimulation on experimentally induced cardiac nociception, using capsaicin

  9. Expression of the transient receptor potential channels TRPV1, TRPA1 and TRPM8 in mouse trigeminal primary afferent neurons innervating the dura

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    Huang Dongyue

    2012-09-01

    Full Text Available Abstract Background Migraine and other headache disorders affect a large percentage of the population and cause debilitating pain. Activation and sensitization of the trigeminal primary afferent neurons innervating the dura and cerebral vessels is a crucial step in the “headache circuit”. Many dural afferent neurons respond to algesic and inflammatory agents. Given the clear role of the transient receptor potential (TRP family of channels in both sensing chemical stimulants and mediating inflammatory pain, we investigated the expression of TRP channels in dural afferent neurons. Methods We used two fluorescent tracers to retrogradely label dural afferent neurons in adult mice and quantified the abundance of peptidergic and non-peptidergic neuron populations using calcitonin gene-related peptide immunoreactivity (CGRP-ir and isolectin B4 (IB4 binding as markers, respectively. Using immunohistochemistry, we compared the expression of TRPV1 and TRPA1 channels in dural afferent neurons with the expression in total trigeminal ganglion (TG neurons. To examine the distribution of TRPM8 channels, we labeled dural afferent neurons in mice expressing farnesylated enhanced green fluorescent protein (EGFPf from a TRPM8 locus. We used nearest-neighbor measurement to predict the spatial association between dural afferent neurons and neurons expressing TRPA1 or TRPM8 channels in the TG. Results and conclusions We report that the size of dural afferent neurons is significantly larger than that of total TG neurons and facial skin afferents. Approximately 40% of dural afferent neurons exhibit IB4 binding. Surprisingly, the percentage of dural afferent neurons containing CGRP-ir is significantly lower than those of total TG neurons and facial skin afferents. Both TRPV1 and TRPA1 channels are expressed in dural afferent neurons. Furthermore, nearest-neighbor measurement indicates that TRPA1-expressing neurons are clustered around a subset of dural afferent

  10. Expression of the transient receptor potential channels TRPV1, TRPA1 and TRPM8 in mouse trigeminal primary afferent neurons innervating the dura

    Science.gov (United States)

    2012-01-01

    Background Migraine and other headache disorders affect a large percentage of the population and cause debilitating pain. Activation and sensitization of the trigeminal primary afferent neurons innervating the dura and cerebral vessels is a crucial step in the “headache circuit”. Many dural afferent neurons respond to algesic and inflammatory agents. Given the clear role of the transient receptor potential (TRP) family of channels in both sensing chemical stimulants and mediating inflammatory pain, we investigated the expression of TRP channels in dural afferent neurons. Methods We used two fluorescent tracers to retrogradely label dural afferent neurons in adult mice and quantified the abundance of peptidergic and non-peptidergic neuron populations using calcitonin gene-related peptide immunoreactivity (CGRP-ir) and isolectin B4 (IB4) binding as markers, respectively. Using immunohistochemistry, we compared the expression of TRPV1 and TRPA1 channels in dural afferent neurons with the expression in total trigeminal ganglion (TG) neurons. To examine the distribution of TRPM8 channels, we labeled dural afferent neurons in mice expressing farnesylated enhanced green fluorescent protein (EGFPf) from a TRPM8 locus. We used nearest-neighbor measurement to predict the spatial association between dural afferent neurons and neurons expressing TRPA1 or TRPM8 channels in the TG. Results and conclusions We report that the size of dural afferent neurons is significantly larger than that of total TG neurons and facial skin afferents. Approximately 40% of dural afferent neurons exhibit IB4 binding. Surprisingly, the percentage of dural afferent neurons containing CGRP-ir is significantly lower than those of total TG neurons and facial skin afferents. Both TRPV1 and TRPA1 channels are expressed in dural afferent neurons. Furthermore, nearest-neighbor measurement indicates that TRPA1-expressing neurons are clustered around a subset of dural afferent neurons. Interestingly, TRPM

  11. Distinct subclassification of DRG neurons innervating the distal colon and glans penis/distal urethra based on the electrophysiological current signature.

    Science.gov (United States)

    Rau, Kristofer K; Petruska, Jeffrey C; Cooper, Brian Y; Johnson, Richard D

    2014-09-15

    Spinal sensory neurons innervating visceral and mucocutaneous tissues have unique microanatomic distribution, peripheral modality, and physiological, pharmacological, and biophysical characteristics compared with those neurons that innervate muscle and cutaneous tissues. In previous patch-clamp electrophysiological studies, we have demonstrated that small- and medium-diameter dorsal root ganglion (DRG) neurons can be subclassified on the basis of their patterns of voltage-activated currents (VAC). These VAC-based subclasses were highly consistent in their action potential characteristics, responses to algesic compounds, immunocytochemical expression patterns, and responses to thermal stimuli. For this study, we examined the VAC of neurons retrogradely traced from the distal colon and the glans penis/distal urethra in the adult male rat. The afferent population from the distal colon contained at least two previously characterized cell types observed in somatic tissues (types 5 and 8), as well as four novel cell types (types 15, 16, 17, and 18). In the glans penis/distal urethra, two previously described cell types (types 6 and 8) and three novel cell types (types 7, 14, and 15) were identified. Other characteristics, including action potential profiles, responses to algesic compounds (acetylcholine, capsaicin, ATP, and pH 5.0 solution), and neurochemistry (expression of substance P, CGRP, neurofilament, TRPV1, TRPV2, and isolectin B4 binding) were consistent for each VAC-defined subgroup. With identification of distinct DRG cell types that innervate the distal colon and glans penis/distal urethra, future in vitro studies related to the gastrointestinal and urogenital sensory function in normal as well as abnormal/pathological conditions may be benefitted.

  12. Autonomic cardiac innervation

    OpenAIRE

    Hasan, Wohaib

    2013-01-01

    Autonomic cardiac neurons have a common origin in the neural crest but undergo distinct developmental differentiation as they mature toward their adult phenotype. Progenitor cells respond to repulsive cues during migration, followed by differentiation cues from paracrine sources that promote neurochemistry and differentiation. When autonomic axons start to innervate cardiac tissue, neurotrophic factors from vascular tissue are essential for maintenance of neurons before they reach their targe...

  13. The transfection of BDNF to dopamine neurons potentiates the effect of dopamine D3 receptor agonist recovering the striatal innervation, dendritic spines and motor behavior in an aged rat model of Parkinson's disease.

    Science.gov (United States)

    Razgado-Hernandez, Luis F; Espadas-Alvarez, Armando J; Reyna-Velazquez, Patricia; Sierra-Sanchez, Arturo; Anaya-Martinez, Veronica; Jimenez-Estrada, Ismael; Bannon, Michael J; Martinez-Fong, Daniel; Aceves-Ruiz, Jorge

    2015-01-01

    The progressive degeneration of the dopamine neurons of the pars compacta of substantia nigra and the consequent loss of the dopamine innervation of the striatum leads to the impairment of motor behavior in Parkinson's disease. Accordingly, an efficient therapy of the disease should protect and regenerate the dopamine neurons of the substantia nigra and the dopamine innervation of the striatum. Nigral neurons express Brain Derived Neurotropic Factor (BDNF) and dopamine D3 receptors, both of which protect the dopamine neurons. The chronic activation of dopamine D3 receptors by their agonists, in addition, restores, in part, the dopamine innervation of the striatum. Here we explored whether the over-expression of BDNF by dopamine neurons potentiates the effect of the activation of D3 receptors restoring nigrostriatal innervation. Twelve-month old Wistar rats were unilaterally injected with 6-hydroxydopamine into the striatum. Five months later, rats were treated with the D3 agonist 7-hydroxy-N,N-di-n-propy1-2-aminotetralin (7-OH-DPAT) administered i.p. during 4½ months via osmotic pumps and the BDNF gene transfection into nigral cells using the neurotensin-polyplex nanovector (a non-viral transfection) that selectively transfect the dopamine neurons via the high-affinity neurotensin receptor expressed by these neurons. Two months after the withdrawal of 7-OH-DPAT when rats were aged (24 months old), immunohistochemistry assays were made. The over-expression of BDNF in rats receiving the D3 agonist normalized gait and motor coordination; in addition, it eliminated the muscle rigidity produced by the loss of dopamine. The recovery of motor behavior was associated with the recovery of the nigral neurons, the dopamine innervation of the striatum and of the number of dendritic spines of the striatal neurons. Thus, the over-expression of BDNF in dopamine neurons associated with the chronic activation of the D3 receptors appears to be a promising strategy for restoring

  14. Motor cortex-periaqueductal gray-spinal cord neuronal circuitry may involve in modulation of nociception: a virally mediated transsynaptic tracing study in spinally transected transgenic mouse model.

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    Da-Wei Ye

    Full Text Available Several studies have shown that motor cortex stimulation provided pain relief by motor cortex plasticity and activating descending inhibitory pain control systems. Recent evidence indicated that the melanocortin-4 receptor (MC4R in the periaqueductal gray played an important role in neuropathic pain. This study was designed to assess whether MC4R signaling existed in motor cortex-periaqueductal gray-spinal cord neuronal circuitry modulated the activity of sympathetic pathway by a virally mediated transsynaptic tracing study. Pseudorabies virus (PRV-614 was injected into the left gastrocnemius muscle in adult male MC4R-green fluorescent protein (GFP transgenic mice (n = 15. After a survival time of 4-6 days, the mice (n = 5 were randomly assigned to humanely sacrifice, and spinal cords and brains were removed and sectioned, and processed for PRV-614 visualization. Neurons involved in the efferent control of the left gastrocnemius muscle were identified following visualization of PRV-614 retrograde tracing. The neurochemical phenotype of MC4R-GFP-positive neurons was identified using fluorescence immunocytochemical labeling. PRV-614/MC4R-GFP dual labeled neurons were detected in spinal IML, periaqueductal gray and motor cortex. Our findings support the hypothesis that MC4R signaling in motor cortex-periaqueductal gray-spinal cord neural pathway may participate in the modulation of the melanocortin-sympathetic signaling and contribute to the descending modulation of nociceptive transmission, suggesting that MC4R signaling in motor cortex-periaqueductal gray-spinal cord neural pathway may modulate the activity of sympathetic outflow sensitive to nociceptive signals.

  15. Nociception and pain: lessons from optogenetics

    OpenAIRE

    Venetia eZachariou; Fiona eCarr

    2014-01-01

    The process of pain perception begins in the periphery by activation of nociceptors. From here nociceptive signals are conveyed via the dorsal horn of the spinal cord to multiple brain regions, where pain is perceived. Despite great progress in pain research in recent years, many questions remain regarding nociceptive circuitry and behavior, in both acute nociception and chronic pain states. Techniques that allow for selective activation of neuronal subpopulations in vivo can provide a better...

  16. Expression and function of a CP339,818-sensitive K⁺ current in a subpopulation of putative nociceptive neurons from adult mouse trigeminal ganglia.

    Science.gov (United States)

    Sforna, Luigi; D'Adamo, Maria Cristina; Servettini, Ilenio; Guglielmi, Luca; Pessia, Mauro; Franciolini, Fabio; Catacuzzeno, Luigi

    2015-04-01

    Trigeminal ganglion (TG) neurons are functionally and morphologically heterogeneous, and the molecular basis of this heterogeneity is still not fully understood. Here we describe experiments showing that a subpopulation of neurons expresses a delayed-rectifying K(+) current (IDRK) with a characteristically high (nanomolar) sensitivity to the dihydroquinoline CP339,818 (CP). Although submicromolar CP has previously been shown to selectively block Kv1.3 and Kv1.4 channels, the CP-sensitive IDRK found in TG neurons could not be associated with either of these two K(+) channels. It could neither be associated with Kv2.1 channels homomeric or heteromerically associated with the Kv9.2, Kv9.3, or Kv6.4 subunits, whose block by CP, tested using two-electrode voltage-clamp recordings from Xenopus oocytes, resulted in the low micromolar range, nor to the Kv7 subfamily, given the lack of blocking efficacy of 3 μM XE991. Within the group of multiple-firing neurons considered in this study, the CP-sensitive IDRK was preferentially expressed in a subpopulation showing several nociceptive markers, such as small membrane capacitance, sensitivity to capsaicin, and slow afterhyperpolarization (AHP); in these neurons the CP-sensitive IDRK controls the membrane resting potential, the firing frequency, and the AHP duration. A biophysical study of the CP-sensitive IDRK indicated the presence of two kinetically distinct components: a fast deactivating component having a relatively depolarized steady-state inactivation (IDRKf) and a slow deactivating component with a more hyperpolarized V1/2 for steady-state inactivation (IDRKs). Copyright © 2015 the American Physiological Society.

  17. Ultrastructural characterization of the mesostriatal dopamine innervation in mice, including two mouse lines of conditional VGLUT2 knockout in dopamine neurons.

    Science.gov (United States)

    Bérubé-Carrière, Noémie; Guay, Ginette; Fortin, Guillaume M; Kullander, Klas; Olson, Lars; Wallén-Mackenzie, Åsa; Trudeau, Louis-Eric; Descarries, Laurent

    2012-02-01

    Despite the increasing use of genetically modified mice to investigate the dopamine (DA) system, little is known about the ultrastructural features of the striatal DA innervation in the mouse. This issue is particularly relevant in view of recent evidence for expression of the vesicular glutamate transporter 2 (VGLUT2) by a subset of mesencephalic DA neurons in mouse as well as rat. We used immuno-electron microscopy to characterize tyrosine hydroxylase (TH)-labeled terminals in the core and shell of nucleus accumbens and the neostriatum of two mouse lines in which the Vglut2 gene was selectively disrupted in DA neurons (cKO), their control littermates, and C57BL/6/J wild-type mice, aged P15 or adult. The three regions were also examined in cKO mice and their controls of both ages after dual TH-VGLUT2 immunolabeling. Irrespective of the region, age and genotype, the TH-immunoreactive varicosities appeared similar in size, vesicular content, percentage with mitochondria, and exceedingly low frequency of synaptic membrane specialization. No dually labeled axon terminals were found at either age in control or in cKO mice. Unless TH and VGLUT2 are segregated in different axon terminals of the same neurons, these results favor the view that the glutamatergic cophenotype of mesencephalic DA neurons is more important during the early development of these neurons than for the establishment of their scarce synaptic connectivity. They also suggest that, in mouse even more than rat, the mesostriatal DA system operates mainly through non-targeted release of DA, diffuse transmission and the maintenance of an ambient DA level.

  18. Coexpression of neuropeptide Y and vasoactive intestinal polypeptide in pelvic plexus neurones innervating the uterus and cervix in the rat.

    Science.gov (United States)

    Houdeau, E; Boyer, P A; Rousseau, A; Rousseau, J P

    1997-05-01

    The present study investigates the distribution and coexpression of neuropeptide Y (NPY) and vasoactive intestinal peptide (VIP) in neurones of the accessory ganglion (AG), hypogastric plexus (HP) and paracervical ganglion (PCG), which compose the pelvic plexus in the female rat. Nerve cell bodies immunoreactive for NPY and VIP represent 84% and 46% of the neurone population in the PCG, respectively, while immunoreactivity for each peptide is observed in about 90% of the AG and HP neurones. Adjacent sections immunostained for NPY and VIP, as well as the use of immunocytochemistry combined with in situ hybridization show that 92% of the VIP-containing neurones in the pelvic plexus also contain NPY. In addition, a retrograde tracing study performed in combination with immunocytochemistry demonstrates that pelvic plexus neurones project preferentially to the lower part of the uterus and to the cervix, and that about 95% of these projecting neurones contain VIP. Taken together, our findings indicate that in the female rat, neurones of the pelvic plexus projecting to the lower genital tract mainly coexpress VIP and NPY, and supply nerve fibres to the vascular and nonvascular smooth muscle in the uterocervical region. Since NPY and VIP exert distinct effects according to the target tissue, our results suggest that neurones coexpressing these peptides play important roles in the local regulation of the vascular bed and motor activity of the lower genital tract.

  19. The transfection of BDNF to dopamine neurons potentiates the effect of dopamine D3 receptor agonist recovering the striatal innervation, dendritic spines and motor behavior in an aged rat model of Parkinson's disease.

    Directory of Open Access Journals (Sweden)

    Luis F Razgado-Hernandez

    Full Text Available The progressive degeneration of the dopamine neurons of the pars compacta of substantia nigra and the consequent loss of the dopamine innervation of the striatum leads to the impairment of motor behavior in Parkinson's disease. Accordingly, an efficient therapy of the disease should protect and regenerate the dopamine neurons of the substantia nigra and the dopamine innervation of the striatum. Nigral neurons express Brain Derived Neurotropic Factor (BDNF and dopamine D3 receptors, both of which protect the dopamine neurons. The chronic activation of dopamine D3 receptors by their agonists, in addition, restores, in part, the dopamine innervation of the striatum. Here we explored whether the over-expression of BDNF by dopamine neurons potentiates the effect of the activation of D3 receptors restoring nigrostriatal innervation. Twelve-month old Wistar rats were unilaterally injected with 6-hydroxydopamine into the striatum. Five months later, rats were treated with the D3 agonist 7-hydroxy-N,N-di-n-propy1-2-aminotetralin (7-OH-DPAT administered i.p. during 4½ months via osmotic pumps and the BDNF gene transfection into nigral cells using the neurotensin-polyplex nanovector (a non-viral transfection that selectively transfect the dopamine neurons via the high-affinity neurotensin receptor expressed by these neurons. Two months after the withdrawal of 7-OH-DPAT when rats were aged (24 months old, immunohistochemistry assays were made. The over-expression of BDNF in rats receiving the D3 agonist normalized gait and motor coordination; in addition, it eliminated the muscle rigidity produced by the loss of dopamine. The recovery of motor behavior was associated with the recovery of the nigral neurons, the dopamine innervation of the striatum and of the number of dendritic spines of the striatal neurons. Thus, the over-expression of BDNF in dopamine neurons associated with the chronic activation of the D3 receptors appears to be a promising strategy

  20. The Transfection of BDNF to Dopamine Neurons Potentiates the Effect of Dopamine D3 Receptor Agonist Recovering the Striatal Innervation, Dendritic Spines and Motor Behavior in an Aged Rat Model of Parkinson’s Disease

    Science.gov (United States)

    Razgado-Hernandez, Luis F.; Espadas-Alvarez, Armando J.; Reyna-Velazquez, Patricia; Sierra-Sanchez, Arturo; Anaya-Martinez, Veronica; Jimenez-Estrada, Ismael; Bannon, Michael J.; Martinez-Fong, Daniel; Aceves-Ruiz, Jorge

    2015-01-01

    The progressive degeneration of the dopamine neurons of the pars compacta of substantia nigra and the consequent loss of the dopamine innervation of the striatum leads to the impairment of motor behavior in Parkinson’s disease. Accordingly, an efficient therapy of the disease should protect and regenerate the dopamine neurons of the substantia nigra and the dopamine innervation of the striatum. Nigral neurons express Brain Derived Neurotropic Factor (BDNF) and dopamine D3 receptors, both of which protect the dopamine neurons. The chronic activation of dopamine D3 receptors by their agonists, in addition, restores, in part, the dopamine innervation of the striatum. Here we explored whether the over-expression of BDNF by dopamine neurons potentiates the effect of the activation of D3 receptors restoring nigrostriatal innervation. Twelve-month old Wistar rats were unilaterally injected with 6-hydroxydopamine into the striatum. Five months later, rats were treated with the D3 agonist 7-hydroxy-N,N-di-n-propy1-2-aminotetralin (7-OH-DPAT) administered i.p. during 4½ months via osmotic pumps and the BDNF gene transfection into nigral cells using the neurotensin-polyplex nanovector (a non-viral transfection) that selectively transfect the dopamine neurons via the high-affinity neurotensin receptor expressed by these neurons. Two months after the withdrawal of 7-OH-DPAT when rats were aged (24 months old), immunohistochemistry assays were made. The over-expression of BDNF in rats receiving the D3 agonist normalized gait and motor coordination; in addition, it eliminated the muscle rigidity produced by the loss of dopamine. The recovery of motor behavior was associated with the recovery of the nigral neurons, the dopamine innervation of the striatum and of the number of dendritic spines of the striatal neurons. Thus, the over-expression of BDNF in dopamine neurons associated with the chronic activation of the D3 receptors appears to be a promising strategy for restoring

  1. Localization of peripheral autonomic neurons innervating the boar urinary bladder trigone and neurochemical features of the sympathetic component

    Directory of Open Access Journals (Sweden)

    L. Ragionieri

    2013-05-01

    Full Text Available The urinary bladder trigone (UBT is a limited area through which the majority of vessels and nerve fibers penetrate into the urinary bladder and where nerve fibers and intramural neurons are more concentrated. We localized the extramural post-ganglionic autonomic neurons supplying the porcine UBT by means of retrograde tracing (Fast Blue, FB. Moreover, we investigated the phenotype of sympathetic trunk ganglion (STG and caudal mesenteric ganglion (CMG neurons positive to FB (FB+ by coupling retrograde tracing and double-labeling immunofluorescence methods. A mean number of 1845.1±259.3 FB+ neurons were localized bilaterally in the L1-S3 STG, which appeared as small pericarya (465.6±82.7 µm2 mainly localized along an edge of the ganglion. A large number (4287.5±1450.6 of small (476.1±103.9 µm2 FB+ neurons were localized mainly along a border of both CMG. The largest number (4793.3±1990.8 of FB+ neurons was observed in the pelvic plexus (PP, where labeled neurons were often clustered within different microganglia and had smaller soma cross-sectional area (374.9±85.4 µm2. STG and CMG FB+ neurons were immunoreactive (IR for tyrosine hydroxylase (TH (66±10.1% and 52.7±8.2%, respectively, dopamine beta-hydroxylase (DβH (62±6.2% and 52±6.2%, respectively, neuropeptide Y (NPY (59±8.2% and 65.8±7.3%, respectively, calcitonin-gene-related peptide (CGRP (24.1±3.3% and 22.1±3.3%, respectively, substance P (SP (21.6±2.4% and 37.7±7.5%, respectively, vasoactive intestinal polypeptide (VIP (18.9±2.3% and 35.4±4.4%, respectively, neuronal nitric oxide synthase (nNOS (15.3±2% and 32.9±7.7%, respectively, vesicular acetylcholine transporter (VAChT (15±2% and 34.7±4.5%, respectively, leu-enkephalin (LENK (14.3±7.1% and 25.9±8.9%, respectively, and somatostatin (SOM (12.4±3% and 31.8±7.3%, respectively. UBT-projecting neurons were also surrounded by VAChT-, CGRP-, LENK-, and nNOS-IR fibers. The possible role of these neurons and fibers

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

    Directory of Open Access Journals (Sweden)

    Chul-Kyu Park

    2015-01-01

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

  3. Nociceptive and Neuronal Evaluation of the Sciatic Nerve of Wistar Rats Subjected to Compression Injury and Treated with Resistive Exercise

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    Juliana Sobral Antunes

    2016-01-01

    Full Text Available Background. To investigate the climb stairs resistance exercise on nociception and axonal regeneration in the sciatic nerve of rats. Methods. 24 Wistar rats were divided: control group (CG—no injury, exercise group (EG—no injury with physical exercise, lesion group (LG—injury, but without exercise, and treated group (LEG—injury and physical exercise. LG and LEG were subjected to sciatic nerve compression with hemostat. From the 3rd day after injury began treatment with exercise, and after 22 days occurs the removal of a nerve fragment for morphological analysis. Results. Regarding allodynia, CG obtained values less than EG (p=0.012 and larger than LG and LEG (p<0.001. Histological results showed that CG and EG had normal appearance, as LG and LEG showed up with large amounts of inflammatory infiltration, degeneration and disruption of nerve fibers, and reduction of the myelin sheath; however LEG presented some regenerated fibers. From the morphometric data there were significant differences, for nerve fiber diameter, comparing CG with LG and LEG and comparing axon diameter and the thickness of the myelin of the CG to others. Conclusion. Climb stairs resistance exercise was not effective to speed up the regenerative process of axons.

  4. Estrogen receptor-alpha immunoreactivity in parasympathetic preganglionic neurons innervating the bladder in the adult ovariectomized cat

    NARCIS (Netherlands)

    VanderHorst, VGJM; Meijer, E; Holstege, G

    2001-01-01

    Estrogen affects autonomic functions such as micturition. The sacral cord is important in the control of micturition and contains numerous estrogen receptor-alpha immnoreactive (ER-alpha IR) neurons. Therefore, the present double labeling study examines whether sacral parasympathetic preganglionic

  5. In situ muscle power differs without varying in vitro mechanical properties in two insect leg muscles innervated by the same motor neuron.

    Science.gov (United States)

    Ahn, A N; Meijer, K; Full, R J

    2006-09-01

    The mechanical behavior of muscle during locomotion is often predicted by its anatomy, kinematics, activation pattern and contractile properties. The neuromuscular design of the cockroach leg provides a model system to examine these assumptions, because a single motor neuron innervates two extensor muscles operating at a single joint. Comparisons of the in situ measurements under in vivo running conditions of muscle 178 to a previously examined muscle (179) demonstrate that the same inputs (e.g. neural signal and kinematics) can result in different mechanical outputs. The same neural signal and kinematics, as determined during running, can result in different mechanical functions, even when the two anatomically similar muscles possess the same contraction kinetics, force-velocity properties and tetanic force-length properties. Although active shortening greatly depressed force under in vivo-like strain and stimulation conditions, force depression was similarly proportional to strain, similarly inversely proportional to stimulation level, and similarly independent of initial length and shortening velocity between the two muscles. Lastly, passive pre-stretch enhanced force similarly between the two muscles. The forces generated by the two muscles when stimulated with their in vivo pattern at lengths equal to or shorter than rest length differed, however. Overall, differences between the two muscles in their submaximal force-length relationships can account for up to 75% of the difference between the two muscles in peak force generated at short lengths observed during oscillatory contractions. Despite the fact that these muscles act at the same joint, are stimulated by the same motor neuron with an identical pattern, and possess many of the same in vitro mechanical properties, the mechanical outputs of two leg extensor muscles can be vastly different.

  6. Perineural capsaicin induces the uptake and transganglionic transport of choleratoxin B subunit by nociceptive C-fiber primary afferent neurons.

    Science.gov (United States)

    Oszlács, O; Jancsó, G; Kis, G; Dux, M; Sántha, P

    2015-12-17

    The distribution of spinal primary afferent terminals labeled transganglionically with the choleratoxin B subunit (CTB) or its conjugates changes profoundly after perineural treatment with capsaicin. Injection of CTB conjugated with horseradish peroxidase (HRP) into an intact nerve labels somatotopically related areas in the ipsilateral dorsal horn with the exceptions of the marginal zone and the substantia gelatinosa, whereas injection of this tracer into a capsaicin-pretreated nerve also results in massive labeling of these most superficial layers of the dorsal horn. The present study was initiated to clarify the role of C-fiber primary afferent neurons in this phenomenon. In L5 dorsal root ganglia, analysis of the size frequency distribution of neurons labeled after injection of CTB-HRP into the ipsilateral sciatic nerve treated previously with capsaicin or resiniferatoxin revealed a significant increase in the proportion of small neurons. In the spinal dorsal horn, capsaicin or resiniferatoxin pretreatment resulted in intense CTB-HRP labeling of the marginal zone and the substantia gelatinosa. Electron microscopic histochemistry disclosed a dramatic, ∼10-fold increase in the proportion of CTB-HRP-labeled unmyelinated dorsal root axons following perineural capsaicin or resiniferatoxin. The present results indicate that CTB-HRP labeling of C-fiber dorsal root ganglion neurons and their central terminals after perineural treatment with vanilloid compounds may be explained by their phenotypic switch rather than a sprouting response of thick myelinated spinal afferents which, in an intact nerve, can be labeled selectively with CTB-HRP. The findings also suggest a role for GM1 ganglioside in the modulation of nociceptor function and pain.

  7. Pain-related sensory innervation in monoiodoacetate-induced osteoarthritis in rat knees that gradually develops neuronal injury in addition to inflammatory pain

    Directory of Open Access Journals (Sweden)

    Toyone Tomoaki

    2011-06-01

    Full Text Available Abstract Background The exact mechanism of knee osteoarthritis (OA-associated pain is unclear, whereas mixed evidence of inflammatory pain and neuropathic pain has been noted. We aimed to investigate pain-related sensory innervation in a monoiodoacetate (MIA-induced model of OA. Methods Sixty of seventy female Sprague Dawley rats of six week-old underwent intra-articular MIA and fluorogold (FG retrograde neurotracer injection into their right (ipsilateral knee, while their left knees were treated with FG in saline as a control (contralateral knee. Other rats were treated with FG only bilaterally, and used as controls. Rats were evaluated for tactile allodynia using von Frey hairs. Proinflammatory mediators in the knee soft tissues, including tumor necrosis factor (TNF-α, interleukin (IL-6, and nerve growth factor (NGF, were quantified using ELISAs to evaluate inflammation in the knee after 1, 4, 7,14,21, and 28 days post injection:. Dorsal root ganglia (DRG were immunostained for three molecules after 7,14,21, and 28 days post injection: calcitonin gene-related peptide (CGRP, a marker of inflammatory pain; and activating transcription factor-3 (ATF3 and growth associated protein-43 (GAP43, as markers for nerve injury and regenerating axons. The distribution of microglia in the spinal cord were also evaluated, because they have been reported to increase in neuropathic pain states. These evaluations were performed up to 28 days postinjection. P Results Progressive tactile allodynia and elevated cytokine concentrations were observed in ipsilateral knees. CGRP-immunoreactive (-ir ipsilateral DRG neurons significantly increased, peaking at 14 days postinjection, while expression of FG-labeled ATF3-ir or ATF3-ir GAP43-ir DRG neurons significantly increased in a time-dependent manner. Significant proliferation of microglia were found with time in the ipsilateral dorsal horn. Conclusions Pain-related characteristics in a MIA-induced rat OA model can

  8. AB311. SPR-38 Clarification of the innervation of genitourinary structures: a neuronal tracing study in female mongrel hound dogs

    Science.gov (United States)

    Barbe, Mary F.; Gomez-Amaya, Sandra M.; Lamarre, Neil S.; Salvadeo, Danielle M.; Mazzei, Michael; Braverman, Alan S.; Ruggieri, Michael R.

    2016-01-01

    Objective Many studies focus on either afferent or efferent inputs (but not both), or on one structure of the genitourinary system. Only a few recent studies include information on inputs from sympathetic chain ganglia (SCG), and even fewer have examined the possibility of direct motor (autonomic or somatic) inputs from spinal cord ventral horns to genitourinary end organs. We sought to clarify origins of afferent and efferent information conveyed between the spinal cord, peripheral nervous system ganglia and genitourinary structures using retrograde and anterograde dye tracing methods. Methods Retrograde dyes were injected into the bladder wall, EUS and clitoris of 14 female mongrel dogs (fluorogold, true blue, or nuclear yellow). Dorsal root ganglia (DRG), SCG, caudal mesenteric ganglion (CMG), pelvic plexus ganglia and spinal cord ventral horns were collected and examined for dye-labeled neuronal cell bodies. Detrusor muscle intramural ganglia were examined by injecting an anterograde dye (DiI) into the pelvic nerve’s anterior vesicle branch. Results Retrograde labeled cells were observed in several DRG, representative of afferent input from the bladder, EUS and clitoris. Anterograde labeling revealed a number of intramural ganglia in the bladder wall after distal pelvic nerve labeling. Sympathetic efferents included: (I) labeled cells in the CMG primarily from the bladder, yet small numbers from the EUS and clitoris; (II) labeled cells in SCG primarily from the bladder (widespread) and more localized input from EUS and clitoris; and (III) labeled cells in the intermediolateral cell column of thoracolumbar cord segments directly to the bladder and clitoris, a locale typically considered as sympathetic. Parasympathetic efferents included: (I) labeled neurons in pelvic plexus ganglia in bladder mesenteries; and (II) cells in lamina VII of sacral cord segments directly to the bladder and clitoris, a locale typically considered as sympathetic. Lastly, somatic

  9. Innervation changes induced by inflammation of the rat thoracolumbar fascia.

    Science.gov (United States)

    Hoheisel, U; Rosner, J; Mense, S

    2015-08-06

    Recently, the fascia innervation has become an important issue, particularly the existence of nociceptive fibers. Fascia can be a source of pain in several disorders such as fasciitis and non-specific low back pain. However, nothing is known about possible changes of the fascia innervation under pathological circumstances. This question is important, because theoretically pain from the fascia cannot only be due to increased nociceptor discharges, but also to a denser innervation of the fascia by nociceptive endings. In this histological study, an inflammation was induced in the thoracolumbar fascia (TLF) of rats and the innervation by various fiber types compared between the inflamed and intact TLF. Although the TLF is generally considered to have proprioceptive functions, no corpuscular proprioceptors (Pacini and Ruffini corpuscles) were found. To obtain quantitative data, the length of fibers and free nerve endings were determined in the three layers of the rat TLF: inner layer (IL, adjacent to the multifidus muscle), middle layer (ML) and outer layer (OL). The main results were that the overall innervation density showed little change; however, there were significant changes in some of the layers. The innervation density was significantly decreased in the OL, but this change was partly compensated for by an increase in the IL. The density of substance P (SP)-positive - presumably nociceptive - fibers was significantly increased. In contrast, the postganglionic sympathetic fibers were significantly decreased. In conclusion, the inflamed TLF showed an increase of presumably nociceptive fibers, which may explain the pain from a pathologically altered fascia. The meaning of the decreased innervation by sympathetic fibers is obscure at present. The lack of proprioceptive corpuscular receptors within the TLF does not preclude its role as a proprioceptive structure, because some of the free nerve endings may function as proprioceptors. Copyright © 2015 IBRO. Published

  10. A machine learning methodology for the selection and classification of spontaneous spinal cord dorsum potentials allows disclosure of structured (non-random changes in neuronal connectivity induced by nociceptive stimulation

    Directory of Open Access Journals (Sweden)

    Mario eMartin

    2015-08-01

    Full Text Available Fractal analysis of spontaneous cord dorsum potentials (CDPs generated in the lumbosacral spinal segments has revealed that these potentials are generated by ongoing structured (non-random neuronal activity. Studies aimed to disclose the changes produced by nociceptive stimulation on the functional organization of the neuronal networks generating these potentials used predetermined templates to select specific classes of spontaneous CDPs. Since this procedure was time consuming and required continuous supervision, it was limited to the analysis of two types of CDPs (negative CDPs and negative positive CDPs, thus excluding potentials that may reflect activation of other neuronal networks of presumed functional relevance. We now present a novel procedure based in machine learning that allows the efficient and unbiased selection of a variety of spontaneous CDPs with different shapes and amplitudes. The reliability and performance of the method is evaluated by analyzing the effects on the probabilities of generation of different types of spontaneous CDPs induced by the intradermic injection of small amounts of capsaicin in the anesthetized cat.The results obtained with the selection method presently described allowed detection of spontaneous CDPs with specific shapes and amplitudes that are assumed to represent the activation of functionally coupled sets of dorsal horn neurones that acquire different, structured configurations in response to nociceptive stimuli.

  11. The Role of CGRPin Nociception?

    Directory of Open Access Journals (Sweden)

    R. G. Hill

    2001-01-01

    Full Text Available The failure of NK1 receptor antagonists to show analgesic activity in clinical trials in spite of abundant preclinical evidence for a role of this neuropeptide in nociception, makes it somewhat dangerous to speculate on the nociceptive role of other neuropeptides, especially with respect to therapeutic utility of receptor antagonists! However, CGRP is the primary afferent peptide with the strongest evidence of a role in pain perception. It is found in a greater proportion of sensory neurones than other peptides and is a constituent of A[delta ] as well as C-fibres. Inflammation of peripheral tissues upregulates production of CGRP in sensory ganglia, coincident with the development of hyperalgesia, and CGRP knockout mice have attenuated hyperalgesic responses. CGRP is released into the dorsal horn of the spinal cord (DHSC by noxious peripheral stimuli and excites nociceptive DHSC neurones on local application. The peptide antagonist CGRP8-37 blocks the response to exogenous CGRP and can reduce the response of DHSC neurones to noxious peripheral stimuli. CGRP8-37 has also been shown to have behavioural antinociceptive properties when given intrathecally. Conversely, injection of CGRP itself to the PAG or n. accumbens has been reported to have antinociceptive effects that are reversed by CGRP8-37. With the advent of potent non-peptide antagonists such as BIBN4096BS we should soon be able to determine whether systemic blockade of all CGRP receptors produces antinociception without limiting side effects.

  12. 大鼠脊髓背角神经元痛放电确定性行为的年龄相关变化%Age-related changes in deterministic behaviors of nociceptive firing of rat dorsal horn neurons

    Institute of Scientific and Technical Information of China (English)

    郑继宏; 冯威; 菅忠; 陈军

    2004-01-01

    为阐明脊髓背角神经元痛放电的年龄相关的动力学变化,本研究采用非线性预报方法,对两组不同年龄大鼠(成年青龄鼠3~4月龄,老年鼠>22月龄)组织损伤诱发的脊髓背角神经元痛放电峰峰间期序列进行了确定性行为的定量分析.结果显示,皮下注入蜜蜂毒,在两组大鼠均诱发脊髓背角广动力域神经元长时程放电,而老龄大鼠的痛放电峰峰间期序列表现出更高的可确定性.本研究表明,单个神经元的痛放电动力学在整个生命过程中并不是恒定不变的,伤害性神经元活动的年龄相关动力学变化可能是老年人群中多样化痛反应的内在机制之一.%To demonstrate the age-related changes in the dynamics of the nociceptive discharge of dorsal horn nociceptive neurons, the nonlinear prediction method was used to quantify the degree of deterministic behavior within the interspike interval series of tissue injuryinduced firing of spinal nociceptive neurons in anesthetized adult young (3~4 months) and aged (>22 months) rats. Subcutaneous bee venom injection induced long-term discharge of spinal wide dynamic range (WDR) neurons in both groups. However, the nociceptive discharge of single WDR neurons in the aged group showed higher determinism when compared with the adult young rats. This result suggests that the dynamics of single nocicepfive neurons may not remain constant throughout the life span, and this age-associated change may be an underlying mechanism for various pain manifestations in the elderly population.

  13. De novo expression of neurokinin-1 receptors by spinoparabrachial lamina I pyramidal neurons following a peripheral nerve lesion.

    Science.gov (United States)

    Saeed, Abeer W; Ribeiro-da-Silva, Alfredo

    2013-06-01

    Lamina I of the spinal dorsal horn is a major site of integration and transmission to higher centers of nociceptive information from the periphery. One important primary afferent population that transmits such information to the spinal cord expresses substance P (SP). These fibers terminate in contact with lamina I projection neurons that express the SP receptor, also known as the neurokinin-1 receptor (NK-1r). Three types of lamina I projection neurons have been described: multipolar, fusiform, and pyramidal. Most neurons of the first two types are thought to be nociceptive and express the NK-1r, whereas most pyramidal neurons are nonnociceptive and do not express the NK-1r. In this immunocytochemical and behavioral study, we induced a neuropathic pain-like condition in the rat by means of a polyethylene cuff placed around in the sciatic nerve. We document that this lesion led to a de novo expression of NK-1r on pyramidal neurons as well as a significant increase in SP-immunoreactive innervation onto these neurons. These phenotypic changes were evident at the time of onset of neuropathic pain-related behavior. Additionally, we show that, after a noxious stimulus (intradermal capsaicin injection), these NK-1r on pyramidal neurons were internalized, providing evidence that these neurons become responsive to peripheral noxious stimulation. We suggest that the changes following nerve lesion in the phenotype and innervation pattern of pyramidal neurons are of significance for neuropathic pain and/or limb temperature regulation.

  14. Fos, nociception and the dorsal horn.

    Science.gov (United States)

    Coggeshall, Richard E

    2005-12-01

    The protooncogene c-fos is rapidly activated after noxious stimuli to express the protein Fos in spinal dorsal horn neurons that are in the 'correct' locations for nociceptive information transfer. As such, therefore, mapping Fos expression in these neurons is at present the best global marker for efficiently locating populations of neurons in the awake animal that respond to nociceptive input. This allows, among other things, precise behavioral measurements to be correlated with Fos expression. Two arenas where mapping dorsal horn Fos expression has made a major impact are in the anatomy of nociceptive systems and as a useful assay for the analgesic properties of various therapeutic regimens. Also Fos expression is the only way to map populations of neurons that are responding to non-localized input such as withdrawal after addiction and vascular occlusion. Another insight is that it shows a clear activation of neurons in superficial 'pain-processing' laminae by innocuous stimuli after nerve lesions, a finding that presumably bears on the allodynia that often accompanies these lesions. It is to be understood, however, that the Fos localizations are not sufficient unto themselves, but the major function of these studies is to efficiently locate populations of cells in nociceptive pathways so that powerful anatomic and physiologic techniques can be brought to bear efficiently. Thus, the purpose of this review is to summarize the studies whose numbers are geometrically expanding that deal with Fos in the dorsal horn and the conclusions therefrom.

  15. Is it time for cardiac innervation imaging?

    Energy Technology Data Exchange (ETDEWEB)

    Knuuti, J. [Turku Univ., Turku (Finland) Turku PET Center; Sipola, P. [Kuopio Univ., Kuopio (Finland)

    2005-03-01

    The autonomic nervous system plays an important role in the regulation of cardiac function and the regional distribution of cardiac nerve terminals can be visualized using scintigraphic techniques. The most commonly used tracer is iodine-123-metaiodobenzylguanidine (MIBG) but C-11-hydroxyephedrine has also been used with PET. When imaging with MIBG, the ratio of heart-to-mediastinal counts is used as an index of tracer uptake, and regional distribution is also assessed from tomographic images. The rate of clearance of the tracer can also be measured and indicates the function of the adrenergic system. Innervation imaging has been applied in patients with susceptibility to arrythmias, coronary artery disease, hypertrophic and dilated cardiomyopathy and anthracycline induced cardiotoxicity. Abnormal adrenergic innervation or function appear to exist in many pathophysiological conditions indicating that sympathetic neurons are very susceptible to damage. Abnormal findings in innervation imaging also appear to have significant prognostic value especially in patients with cardiomyopathy. Recently, it has also been shown that innervation imaging can monitor drug-induced changes in cardiac adrenergic activity. Although innervation imaging holds great promise for clinical use, the method has not received wider clinical acceptance. Larger randomized studies are required to confirm the value of innervation imaging in various specific indications.

  16. Roles of phosphotase 2A in nociceptive signal processing

    Science.gov (United States)

    2013-01-01

    Multiple protein kinases affect the responses of dorsal horn neurons through phosphorylation of synaptic receptors and proteins involved in intracellular signal transduction pathways, and the consequences of this modulation may be spinal central sensitization. In contrast, the phosphatases catalyze an opposing reaction of de-phosphorylation, which may also modulate the functions of crucial proteins in signaling nociception. This is an important mechanism in the regulation of intracellular signal transduction pathways in nociceptive neurons. Accumulated evidence has shown that phosphatase 2A (PP2A), a serine/threonine specific phosphatase, is implicated in synaptic plasticity of the central nervous system and central sensitization of nociception. Therefore, targeting protein phosphotase 2A may provide an effective and novel strategy for the treatment of clinical pain. This review will characterize the structure and functional regulation of neuronal PP2A and bring together recent advances on the modulation of PP2A in targeted downstream substrates and relevant multiple nociceptive signaling molecules. PMID:24010880

  17. Activation of P2X7 receptors in glial satellite cells reduces pain through downregulation of P2X3 receptors in nociceptive neurons

    OpenAIRE

    Chen, Yong; Zhang, Xiaofei; Wang, Congying; Li, Guangwen; Gu, Yanping; Huang, Li-Yen Mae

    2008-01-01

    Purinergic ionotropic P2X7 receptors (P2X7Rs) are closely associated with excitotoxicity and nociception. Inhibition of P2X7R activation has been considered as a potentially useful strategy to improve recovery from spinal cord injury and reduce inflammatory damage to trauma. The physiological functions of P2X7Rs, however, are poorly understood, even though such information is essential for making the P2X7R an effective therapeutic target. We show here that P2X7Rs in satellite cells of dorsal ...

  18. [Physiology of nociception].

    Science.gov (United States)

    Guirimand, F; Le Bars, D

    1996-01-01

    Nociception is related to the mechanisms elicited by stimuli threatening the integrity of the organism. At the peripheral level, unmyelinated C fibres (C polymodal nociceptores) or fine myelinated A delta fibres are excited by noxious stimulation, directly or indirectly by inflammatory processes. Nociceptive afferent fibres terminate in the superficial laminae of the dorsal horn of the spinal cord where informations are integrated and controlled. These first synapses are modulated by excitatory amino acids (glutamate and aspartate) and many peptides (substance P, CGRP, CCK, endogenous opiods). The majority of ascending pathways involved in nociception are located in the ventrolateral controlateral quadrant of the cord (spinorelicular and spinothalamic tracts). Many supraspinal sites are activated following nociceptive stimuli, with relays in the reticular formation of the brain stem (including the subnucleus reticularis dorsalis), the ponto-mesencephalic regions (periaqueducal gray matter and parabrachial area) and thalamic sites. Amygdala and hypothamic targets could be involved in motivational reactions and neuroendocrine adaptations to a noxious event. The cingular, insular and somatosensory cortices also receive nociceptive informations. Nociceptive signals are modulated at all levels of their transmission; the more extensively studied controls are located at the spinal level. Segmental controls are inhibitory effects produced by non-noxious mechanical stimuli. Spinal signals can also be inhibited following activation of bulbopinal descending inhibitor pathways and release of serotonin, norepinephrine and, indirectly, endogenous opiods. Inhibitory controls triggered by noxious stimuli could facilitate the extraction of the nociceptive tone of informations having priority over other stimuli.

  19. Ligustrazine inhibits high voltage-gated Ca2+ and TTX-resistant Na+ channels of primary sensory neuron and thermal nociception in the rat:a study on peripheral mechanism

    Institute of Scientific and Technical Information of China (English)

    2006-01-01

    Objective Ligustrazine, also named as tetramethylpyrazine, is a compound purified from Ligusticum chuanxiong hort and has ever been testified to be a calcium antagonist. The present investigation was to determine the antinociceptive effect of ligustrazine and, if any, the peripheral ionic mechanism involved. Methods Paw withdrawal Latency(PWL) to noxious heating was measured in vivo and whole-cell patch recording was performed on small dorsal root ganglion (DRG) neurons. Results Intraplantar injection of ligustrazine (0.5 mg in 25 μl) significantly prolonged the withdrawal latency of ipsilateral hindpaw to noxious heating in the rat. Ligustrazine not only reversibly inhibited high-voltage gated calcium current of dorsal root ganglion (DRG) neuron in dose-dependent manner with IC50 of 1.89 mmol/L, but also decreased tetrodotoxin (TTX) -resistant sodium current in relatively selective and dose-dependent manner with IC50 of2.49 mmol/L. Conclusion The results suggested that ligustrazine could elevate the threshold of thermal nociception through inhibiting the high-voltage gated calcium current and TTX-resistant sodium current of DRG neuron .in the rat.

  20. A machine learning methodology for the selection and classification of spontaneous spinal cord dorsum potentials allows disclosure of structured (non-random) changes in neuronal connectivity induced by nociceptive stimulation.

    Science.gov (United States)

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

    2015-01-01

    Previous studies aimed to disclose the functional organization of the neuronal networks involved in the generation of the spontaneous cord dorsum potentials (CDPs) generated in the lumbosacral spinal segments used predetermined templates to select specific classes of spontaneous CDPs. Since this procedure was time consuming and required continuous supervision, it was limited to the analysis of two specific types of CDPs (negative CDPs and negative positive CDPs), thus excluding potentials that may reflect activation of other neuronal networks of presumed functional relevance. We now present a novel procedure based in machine learning that allows the efficient and unbiased selection of a variety of spontaneous CDPs with different shapes and amplitudes. The reliability and performance of the present method is evaluated by analyzing the effects on the probabilities of generation of different classes of spontaneous CDPs induced by the intradermic injection of small amounts of capsaicin in the anesthetized cat, a procedure known to induce a state of central sensitization leading to allodynia and hyperalgesia. The results obtained with the selection method presently described allowed detection of spontaneous CDPs with specific shapes and amplitudes that are assumed to represent the activation of functionally coupled sets of dorsal horn neurones that acquire different, structured configurations in response to nociceptive stimuli. These changes are considered as responses tending to adequate transmission of sensory information to specific functional requirements as part of homeostatic adjustments.

  1. A machine learning methodology for the selection and classification of spontaneous spinal cord dorsum potentials allows disclosure of structured (non-random) changes in neuronal connectivity induced by nociceptive stimulation

    Science.gov (United States)

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

    2015-01-01

    Previous studies aimed to disclose the functional organization of the neuronal networks involved in the generation of the spontaneous cord dorsum potentials (CDPs) generated in the lumbosacral spinal segments used predetermined templates to select specific classes of spontaneous CDPs. Since this procedure was time consuming and required continuous supervision, it was limited to the analysis of two specific types of CDPs (negative CDPs and negative positive CDPs), thus excluding potentials that may reflect activation of other neuronal networks of presumed functional relevance. We now present a novel procedure based in machine learning that allows the efficient and unbiased selection of a variety of spontaneous CDPs with different shapes and amplitudes. The reliability and performance of the present method is evaluated by analyzing the effects on the probabilities of generation of different classes of spontaneous CDPs induced by the intradermic injection of small amounts of capsaicin in the anesthetized cat, a procedure known to induce a state of central sensitization leading to allodynia and hyperalgesia. The results obtained with the selection method presently described allowed detection of spontaneous CDPs with specific shapes and amplitudes that are assumed to represent the activation of functionally coupled sets of dorsal horn neurones that acquire different, structured configurations in response to nociceptive stimuli. These changes are considered as responses tending to adequate transmission of sensory information to specific functional requirements as part of homeostatic adjustments. PMID:26379540

  2. Role of NHE1 in Nociception

    Directory of Open Access Journals (Sweden)

    Jorge Elías Torres-López

    2013-01-01

    Full Text Available Intracellular pH is a fundamental parameter to cell function that requires tight homeostasis. In the absence of any regulation, excessive acidification of the cytosol would have the tendency to produce cellular damage. Mammalian Na+/H+ exchangers (NHEs are electroneutral Na+-dependent proteins that exchange extracellular Na+ for intracellular H+. To date, there are 9 identified NHE isoforms where NHE1 is the most ubiquitous member, known as the housekeeping exchanger. NHE1 seems to have a protective role in the ischemia-reperfusion injury and other inflammatory diseases. In nociception, NHE1 is found in neurons along nociceptive pathways, and its pharmacological inhibition increases nociceptive behavior in acute pain models at peripheral and central levels. Electrophysiological studies also show that NHE modulates electrical activity of primary nociceptive terminals. However, its role in neuropathic pain still remains controversial. In humans, NHE1 may be responsible for inflammatory bowel diseases since its expression is reduced in Crohn’s disease and ulcerative colitis. The purpose of this work is to provide a review of the evidence about participation of NHE1 in the nociceptive processing.

  3. Sensory innervation of the thoracolumbar fascia in rats and humans.

    Science.gov (United States)

    Tesarz, J; Hoheisel, U; Wiedenhöfer, B; Mense, S

    2011-10-27

    The available data on the innervation of the thoracolumbar fascia (TLF) are inconsistent and partly contradictory. Therefore, the role of the fascia as a potential source of pain in the low back is difficult to assess. In the present study, a quantitative evaluation of calcitonin gene-related peptide (CGRP) and substance P (SP)-containing free nerve endings was performed in the rat TLF. A preliminary non-quantitative evaluation was also performed in specimens of the human TLF. The data show that the TLF is a densely innervated tissue with marked differences in the distribution of the nerve endings over the fascial layers. In the rat, we distinguished three layers: (1) Outer layer (transversely oriented collagen fibers adjacent to the subcutaneous tissue), (2) middle layer (massive collagen fiber bundles oriented obliquely to the animal's long axis), and (3) inner layer (loose connective tissue covering the paraspinal muscles). The subcutaneous tissue and the outer layer showed a particularly dense innervation with sensory fibers. SP-positive free nerve endings-which are assumed to be nociceptive-were exclusively found in these layers. Because of its dense sensory innervation, including presumably nociceptive fibers, the TLF may play an important role in low back pain.

  4. Comparison of trigeminal and spinal modulation of pain and nociception.

    Science.gov (United States)

    Rehberg, Benno; Baars, Jan H; Kotsch, Julia; Koppe, Peter; von Dincklage, Falk

    2012-06-01

    Modulation of pain and nociception by noxious counterstimulation, also called "diffuse noxious inhibitory controls" or DNIC-like effect, is often used in studies of pain disorders. It can be elicited in the trigeminal and spinal innervation areas, but no study has previously compared effects in both innervation areas. Therefore, we performed a study comparing DNIC-like effects on the nociceptive flexion reflex (NFR) and the nociceptive blink reflex as well as the respective pain sensations. In 50 healthy volunteers, the blink reflex elicited with a concentric electrode and the NFR were recorded before and after immersion of the contralateral hand in cold water. Responses were recorded as the subjective pain sensation and the reflex size. The cold water immersion of the contralateral hand elicited a reduction of both subjective pain sensation and reflex amplitude following the stimulation of both reflexes. However, there were no strong correlations between the individual reductions of both subjective pain sensation and reflex amplitude for both reflexes, and neither when results of the two reflexes were compared with each other. The dissociation between DNIC-like effects on pain and on nociception, which had been found previously already for the NFR, implies that both effects need to be studied separately.

  5. Locomotor-activated neurons of the cat. I. Serotonergic innervation and co-localization of 5-HT7, 5-HT2A, and 5-HT1A receptors in the thoraco-lumbar spinal cord.

    Science.gov (United States)

    Noga, Brian R; Johnson, Dawn M G; Riesgo, Mirta I; Pinzon, Alberto

    2009-09-01

    Monoamines are strong modulators and/or activators of spinal locomotor networks. Thus monoaminergic fibers likely contact neurons involved in generating locomotion. The aim of the present study was to investigate the serotonergic innervation of locomotor-activated neurons within the thoraco-lumbar spinal cord following induction of hindlimb locomotion. This was determined by immunohistochemical co-localization of serotonin (5-HT) fibers or 5-HT(7)/5-HT2A/5-HT1A receptors with cells expressing the activity-dependent marker c-fos. Experiments were performed on paralyzed, decerebrate cats in which locomotion was induced by electrical stimulation of the mesencephalic locomotor region. Abundant c-fos immunoreactive cells were observed in laminae VII and VIII throughout the thoraco-lumbar segments of locomotor animals. Control sections from the same segments showed significantly fewer labeled neurons, mostly within the dorsal horn. Multiple serotonergic boutons were found in close apposition to the majority (80-100%) of locomotor cells, which were most abundant in lumbar segments L3-7. 5-HT7 receptor immunoreactivity was observed on cells across the thoraco-lumbar segments (T7-L7), in a dorsoventral gradient. Most locomotor-activated cells co-localized with 5-HT7, 5-HT2A, and 5-HT1A receptors, with largest numbers in laminae VII and VIII. Co-localization of c-fos and 5-HT7 receptor was highest in the L5-L7 segments (>90%) and decreased rostrally (to approximately 50%) due to the absence of receptors on cells within the intermediolateral nucleus. In contrast, 60-80 and 35-80% of c-fos immunoreactive cells stained positive for 5-HT2A and 5-HT1A receptors, respectively, with no rostrocaudal gradient. These results indicate that serotonergic modulation of locomotion likely involves 5-HT(7)/5-HT2A/5-HT1A receptors located on the soma and proximal dendrites of serotonergic-innervated locomotor-activated neurons within laminae VII and VIII of thoraco-lumbar segments.

  6. Acupuncture inhibition on neuronal activity of spinal dorsal horn induced by noxious colorectal distention in rat

    Institute of Scientific and Technical Information of China (English)

    Pei-Jing Rong; Bing Zhu; Qi-Fu Huang; Xin-Yan Gao; Hui Ben; Yan-Hua Li

    2005-01-01

    AIM: To observe how acupuncture stimulation influences the visceral nociception in rat and to clarify the interactions between acupuncture or somatic input and visceral nociceptive inputs in the spinal dorsal horn. These will provide scientific base for illustrating the mechanism of acupuncture on visceral pain.METHODS: Experiments were performed on SpragueDawley rats and the visceral nociceptive stimulus was generated by colorectal distention (CRD). Unit discharges from individual single neuron were recorded extracellularly with glass-microelectrode in L1-3 spinal dorsal horn.Acupuncture stimulation was applied at contralateral heterotopic acupoint and ipsilateral homotopic acupoint,both of which were innervated by the same segments that innervate also the colorectal-gut.RESULTS: The visceral nociception could be inhibited at the spinal level by the heterotopic somatic mechanical stimulation and acupuncture. The maximal inhibition was induced by acupuncture or the somatic noxious stimulation at spinal dorsal horn level with inhibiting rate of 68.61%and 60.79%, respectively (P<0.01 and <0.001). In reversible spinalized rats (cervical-thoracic cold block)both spontaneous activity and responses to CRD increased significantly in 16/20 units examined, indicating the existence of tonic descending inhibition. The inhibition of acupuncture on the noxious CRD disappeared totally in the reversible spinalized rats (P<0.001).CONCLUSION: The inputs of noxious CRD and acupuncture may interact at the spinal level. The nociceptive visceral inputs could be inhibited by acupuncture applied to hetero-topic acupoint. The effect indicates that the spinal dorsal horn plays a significant role in mediating the inhibition of acupuncture and somatic stimulation on the neuronal response to the noxious visceral stimulation and the inhibition is modulated by upper cervical cord and/or supra-spinal center.

  7. Vagal innervation of the rat duodenum.

    Science.gov (United States)

    Zhang, X; Renehan, W E; Fogel, R

    2000-02-14

    Electrophysiologic and anterograde tract tracing studies have demonstrated that the vagus nerve innervates the duodenum. These studies, however, have provided little information regarding the finer anatomic topography within the vagal complex. In this study, the retrograde neuronal tracers WGA-HRP or DiI, applied to the duodenum, were used to characterize the vagal afferent and efferent innervation of this portion of the gastrointestinal tract. This approach labeled a substantial number of motor neurons in both the medial and lateral columns of the dorsal motor nucleus of the vagus (DMNV). Vagal motor neurons innervating the duodenum were seen across the medial-lateral extent of the DMNV and between 600 microm rostral to obex and 1600 microm caudal to obex. The three branches of the vagus nerve contained efferent fibers to the duodenum. The gastric branch of the vagus nerve was the pathway that connected the majority of DMNV neurons with the duodenum. These neurons were located in the medial and middle thirds of the DMNV. The celiac branch to the duodenum was composed of axons from the majority of lateral column neurons but also contained axons from neurons in the medial column. The hepatic branch of the vagus nerve contained only a small number of cell axons. Some neurons were located medially whereas others were in the lateral third of the duodenum. Although central terminations of vagal primary afferents from the duodenum were not found in previous tract tracing studies, we observed a large number of terminals in the subpostremal/commissural region of the nucleus of the solitary tract. Similar to the motor fibers, most afferent fibers from the duodenum were located in the gastric branch of the vagus nerve, although the hepatic and celiac branches also contained afferent neurons. These results demonstrate that the vagal innervation of the duodenum is unique, being an amalgam of what would be expected following labeling of more proximal and distal portions of the

  8. Subpopulations of neurokinin 1 receptor-expressing neurons in the rat lateral amygdala display a differential pattern of innervation from distinct glutamatergic afferents

    Science.gov (United States)

    Sreepathi, H.K.; Ferraguti, F.

    2012-01-01

    Substance P by acting on its preferred receptor neurokinin 1 (NK1) in the amygdala appears to be critically involved in the modulation of fear and anxiety. The present study was undertaken to identify neurochemically specific subpopulations of neuron expressing NK1 receptors in the lateral amygdaloid nucleus (LA), a key site for regulating these behaviors. We also analyzed the sources of glutamatergic inputs to these neurons. Immunofluorescence analysis of the co-expression of NK1 with calcium binding proteins in LA revealed that ∼35% of NK1-containing neurons co-expressed parvalbumin (PV), whereas no co-localization was detected in the basal amygdaloid nucleus. We also show that neurons expressing NK1 receptors in LA did not contain detectable levels of calcium/calmodulin kinase IIα, thus suggesting that NK1 receptors are expressed by interneurons. By using a dual immunoperoxidase/immunogold-silver procedure at the ultrastructural level, we found that in LA ∼75% of glutamatergic synapses onto NK1-expressing neurons were labeled for the vesicular glutamate transporter 1 indicating that they most likely are of cortical, hippocampal, or intrinsic origin. The remaining ∼25% were immunoreactive for the vesicular glutamate transporter 2 (VGluT2), and may then originate from subcortical areas. On the other hand, we could not detect VGluT2-containing inputs onto NK1/PV immunopositive neurons. Our data add to previous localization studies by describing an unexpected variation between LA and basal nucleus of the amygdala (BA) in the neurochemical phenotype of NK1-expressing neurons and reveal the relative source of glutamatergic inputs that may activate these neurons, which in turn regulate fear and anxiety responses. PMID:22210508

  9. Subpopulations of neurokinin 1 receptor-expressing neurons in the rat lateral amygdala display a differential pattern of innervation from distinct glutamatergic afferents

    OpenAIRE

    Sreepathi, H.K.; Ferraguti, F.

    2012-01-01

    Substance P by acting on its preferred receptor neurokinin 1 (NK1) in the amygdala appears to be critically involved in the modulation of fear and anxiety. The present study was undertaken to identify neurochemically specific subpopulations of neuron expressing NK1 receptors in the lateral amygdaloid nucleus (LA), a key site for regulating these behaviors. We also analyzed the sources of glutamatergic inputs to these neurons. Immunofluorescence analysis of the co-expression of NK1 with calciu...

  10. Sensory TRP channels: the key transducers of nociception and pain.

    Science.gov (United States)

    Mickle, Aaron D; Shepherd, Andrew J; Mohapatra, Durga P

    2015-01-01

    Peripheral detection of nociceptive and painful stimuli by sensory neurons involves a complex repertoire of molecular detectors and/or transducers on distinct subsets of nerve fibers. The majority of such molecular detectors/transducers belong to the transient receptor potential (TRP) family of cation channels, which comprise both specific receptors for distinct nociceptive stimuli, as well as for multiple stimuli. This chapter discusses the classification, distribution, and functional properties of individual TRP channel types that have been implicated in various nociceptive and/or painful conditions.

  11. Dual innervation of neonatal Merkel cells in mouse touch domes.

    Directory of Open Access Journals (Sweden)

    Jingwen Niu

    Full Text Available Merkel cell-neurite complexes are specialized mechanosensory end organs that mediate discriminative touch sensation. It is well established that type I slowly adapting (SAI mechanoreceptors, which express neural filament heavy chain (NFH, innervate Merkel cells. It was previously shown that neurotrophic factor NT3 and its receptor TrkC play crucial roles in controlling touch dome Merkel cell innervation of NFH+ fibers. In addition, nerve fibers expressing another neurotrophic tyrosine receptor kinase (NTRK, Ret, innervate touch dome Merkel cells as well. However, the relationship between afferents responsive to NT3/TrkC signaling and those expressing Ret is unclear. It is also controversial if these Ret+ fibers belong to the early or late Ret+ DRG neurons, which are defined based on the co-expression and developmental dependence of TrkA. To address these questions, we genetically traced Ret+ and TrkC+ fibers and analyzed their developmental dependence on TrkA. We found that Merkel cells in neonatal mouse touch domes receive innervation of two types of fibers: one group is Ret+, while the other subset expresses TrkC and NFH. In addition, Ret+ fibers depend on TrkA for their survival and normal innervation whereas NFH+ Merkel cell innervating fibers are almost unaltered in TrkA mutant mice, supporting that Ret+ and NFH+/TrkC+ afferents are two distinct groups. Ret signaling, on the other hand, plays a minor role for the innervation of neonatal touch domes. In contrast, Merkel cells in the glabrous skin are mainly contacted by NFH+/TrkC+ afferents. Taken together, our results suggest that neonatal Merkel cells around hair follicles receive dual innervation while Merkel cells in the glabrous skin are mainly innervated by only SAI mechanoreceptors. In addition, our results suggest that neonatal Ret+ Merkel cell innervating fibers most likely belong to the late but not early Ret+ DRG neurons.

  12. Effects of N- and L-type calcium channel antagonists on the responses of nociceptive spinal cord neurons to mechanical stimulation of the normal and the inflamed knee joint.

    Science.gov (United States)

    Neugebauer, V; Vanegas, H; Nebe, J; Rümenapp, P; Schaible, H G

    1996-12-01

    innocuous and noxious pressure applied to the noninflamed ankle joint. 3. The topical administration of nimodipine decreased the responses to innocuous and noxious pressure applied to the knee in a sample of 9 neurons with input from the normal joint and in a sample of 16 neurons with input from the inflamed knee joint (hyperexcitable neurons). Within administration times of 30 min, the responses were reduced to approximately 70% of the predrug values. In hyperexcitable neurons, the responses to innocuous and noxious pressure applied to the knee were also decreased during ionophoretic administration of nimodipine (6 neurons) and diltiazem (9 neurons). When the noninflamed ankle was stimulated, the responses to innocuous pressure were reduced neither in neurons with input from the normal knee nor in neurons with input from the inflamed knee, but the responses of hyperexcitable neurons to noxious pressure onto the ankle were reduced. The ionophoretic administration of the agonist at the L-type calcium channel, S(-)-Bay K 8644, enhanced the responses to mechanical stimulation of the knee joint in all 14 hyperexcitable neurons tested. The effect of S(-)-Bay K 8644 was counteracted by both diltiazem (in 6 of 6 neurons) and nimodipine (in 5 of 5 neurons). 4. These data show that antagonists at both the N- and the L-type voltage-dependent calcium channels influence the spinal processing of input from the knee joint. The data suggest, therefore, that voltage-dependent calcium calcium channels of both the N and the L type are important for the sensory functions of the spinal cord. They are involved in the spinal processing of nonnociceptive as well as nociceptive mechanosensory input from the joint, both under normal and inflammatory conditions. The present results show in particular that N- and L-type channels are likely to be involved in the generation of pain evoked by noxious mechanical stimulation in normal tissue as well as in the mechanical hyperalgesia that is usually pres

  13. The effect of the transplanted pineal gland on the sympathetic innervation of the rat sublingual gland.

    Science.gov (United States)

    Chanthaphavong, R S; Murphy, S M; Anderson, C R

    2004-08-01

    We investigated the effect of the pineal on sympathetic neurons that normally innervate the sublingual gland of the rat. When the pineal gland was transplanted into the sublingual gland, it remained as a distinct mass that was innervated by sympathetic axons. Injection of the retrograde tracer, Fast Blue, into the sublingual gland labelled sympathetic neurons in the ipsilateral superior cervical ganglion (SCG). Thirty per cent of all neurons labelled retrogradely by Fast Blue injection into transplanted pineal glands were immunoreactive for both neuropeptide Y (NPY) and calbindin. This combination is characteristic of sympathetic neurons innervating the pineal gland in its normal location, but not the sympathetic vasoconstrictor neurons normally innervating the sublingual gland. This, and our previous study in which the pineal gland was shown to similarly influence the phenotype of salivary secretomotor neurons, suggests that a range of different functional classes of sympathetic neuron are able to change their phenotype in response to signals released by the pineal gland.

  14. Capsaicin, Nociception and Pain.

    Science.gov (United States)

    Frias, Bárbara; Merighi, Adalberto

    2016-06-18

    Capsaicin, the pungent ingredient of the hot chili pepper, is known to act on the transient receptor potential cation channel vanilloid subfamily member 1 (TRPV1). TRPV1 is involved in somatic and visceral peripheral inflammation, in the modulation of nociceptive inputs to spinal cord and brain stem centers, as well as the integration of diverse painful stimuli. In this review, we first describe the chemical and pharmacological properties of capsaicin and its derivatives in relation to their analgesic properties. We then consider the biochemical and functional characteristics of TRPV1, focusing on its distribution and biological effects within the somatosensory and viscerosensory nociceptive systems. Finally, we discuss the use of capsaicin as an agonist of TRPV1 to model acute inflammation in slices and other ex vivo preparations.

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

    Science.gov (United States)

    Burrell, Brian D

    2017-04-01

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

  16. Conduction velocity is regulated by sodium channel inactivation in unmyelinated axons innervating the rat cranial meninges.

    Science.gov (United States)

    De Col, Roberto; Messlinger, Karl; Carr, Richard W

    2008-02-15

    Axonal conduction velocity varies according to the level of preceding impulse activity. In unmyelinated axons this typically results in a slowing of conduction velocity and a parallel increase in threshold. It is currently held that Na(+)-K(+)-ATPase-dependent axonal hyperpolarization is responsible for this slowing but this has long been equivocal. We therefore examined conduction velocity changes during repetitive activation of single unmyelinated axons innervating the rat cranial meninges. In direct contradiction to the currently accepted postulate, Na(+)-K(+)-ATPase blockade actually enhanced activity-induced conduction velocity slowing, while the degree of velocity slowing was curtailed in the presence of lidocaine (10-300 microm) and carbamazepine (30-500 microm) but not tetrodotoxin (TTX, 10-80 nm). This suggests that a change in the number of available sodium channels is the most prominent factor responsible for activity-induced changes in conduction velocity in unmyelinated axons. At moderate stimulus frequencies, axonal conduction velocity is determined by an interaction between residual sodium channel inactivation following each impulse and the retrieval of channels from inactivation by a concomitant Na(+)-K(+)-ATPase-mediated hyperpolarization. Since the process is primarily dependent upon sodium channel availability, tracking conduction velocity provides a means of accessing relative changes in the excitability of nociceptive neurons.

  17. TRPA1 is a component of the nociceptive response to CO2.

    Science.gov (United States)

    Wang, Yuanyuan Y; Chang, Rui B; Liman, Emily R

    2010-09-29

    In humans, high concentrations of CO(2), as found in carbonated beverages, evoke a mixture of sensations that include a stinging or pungent quality. The stinging sensation is thought to originate with the activation of nociceptors, which innervate the respiratory, nasal, and oral epithelia. The molecular basis for this sensation is unknown. Here we show that CO(2) specifically activates a subpopulation of trigeminal neurons that express TRPA1, a mustard oil- and cinnamaldehyde-sensitive channel, and that these responses are dependent on a functional TRPA1 gene. TRPA1 is sufficient to mediate responses to CO(2) as TRPA1 channels expressed in HEK-293 cells, but not TRPV1 channels, were activated by bath-applied CO(2). CO(2) can diffuse into cells and produce intracellular acidification, which could gate TRPA1 channels. Consistent with this mechanism, TRPA1 channels in excised patches were activated in a dose-dependent manner by intracellular protons. We conclude that TRPA1, by sensing intracellular acidification, constitutes an important component of the nociceptive response to CO(2).

  18. Altered nociception in mice with genetically induced hypoglutamatergic tone.

    Science.gov (United States)

    Kayser, V; Viguier, F; Melfort, M; Bourgoin, S; Hamon, M; Masson, J

    2015-05-07

    Extensive pharmacological evidence supports the idea that glutamate plays a key role in both acute and chronic pain. In the present study, we investigated the implication of the excitatory amino acid in physiological nociception by using mutant mice deficient in phosphate-activated glutaminase type 1 (GLS1), the enzyme that synthesizes glutamate in central glutamatergic neurons. Because homozygous GLS1-/- mutants die shortly after birth, assays for assessing mechanical, thermal and chemical (formalin) nociception were performed on heterozygous GLS1+/- mutants, which present a clear-cut decrease in glutamate synthesis in central neurons. As compared to paired wild-type mice, adult male GLS1+/- mutants showed decreased responsiveness to mechanical (von Frey filament and tail-pressure, but not tail-clip, tests) and thermal (Hargreaves' plantar, tail-immersion and hot-plate tests) nociceptive stimuli. Genotype-related differences were also found in the formalin test for which GLS1+/- mice exhibited marked decreases in the nociceptive responses (hindlimb lift, lick and flinch) during both phase 1 (0-5 min) and phase 2 (16-45 min) after formalin injection. On the other hand, acute treatment with memantine (1mg/kg i.p.), an uncompetitive antagonist at NMDA glutamate receptors, reduced nociception responses in wild-type but not GLS1+/- mice. Conversely, antinociceptive response to acute administration of a low dose (1mg/kg s.c.) of morphine was significantly larger in GLS1+/- mutants versus wild-type mice. Our findings indicate that genetically driven hypoactivity of central glutamatergic neurotransmission renders mice hyposensitive to nociceptive stimulations, and promotes morphine antinociception, further emphasizing the critical role of glutamate in physiological nociception and its opioid-mediated control.

  19. Synaptic Plasticity and Nociception

    Institute of Scientific and Technical Information of China (English)

    ChenJianguo

    2004-01-01

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

  20. The Role of PPK26 in Drosophila Larval Mechanical Nociception

    Directory of Open Access Journals (Sweden)

    Yanmeng Guo

    2014-11-01

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

  1. Oxidation-sensitive nociception involved in endometriosis-associated pain.

    Science.gov (United States)

    Ray, Kristeena; Fahrmann, Johannes; Mitchell, Brenda; Paul, Dennis; King, Holly; Crain, Courtney; Cook, Carla; Golovko, Mikhail; Brose, Stephen; Golovko, Svetlana; Santanam, Nalini

    2015-03-01

    Endometriosis is a disease characterized by the growth of endometrial tissue outside the uterus and is associated with chronic pelvic pain. Peritoneal fluid (PF) of women with endometriosis is a dynamic milieu and is rich in inflammatory markers, pain-inducing prostaglandins prostaglandin E2 and prostaglandin F2α, and lipid peroxides; and the endometriotic tissue is innervated with nociceptors. Our clinical study showed that the abundance of oxidatively modified lipoproteins in the PF of women with endometriosis and the ability of antioxidant supplementation to alleviate endometriosis-associated pain. We hypothesized that oxidatively modified lipoproteins present in the PF are the major source of nociceptive molecules that play a key role in endometriosis-associated pain. In this study, PF obtained from women with endometriosis or control women were used for (1) the detection of lipoprotein-derived oxidation-sensitive pain molecules, (2) the ability of such molecules to induce nociception, and (3) the ability of antioxidants to suppress this nociception. LC-MS/MS showed the generation of eicosanoids by oxidized-lipoproteins to be similar to that seen in the PF. Oxidatively modified lipoproteins induced hypothermia (intracerebroventricular) in CD-1 mice and nociception in the Hargreaves paw withdrawal latency assay in Sprague-Dawley rats. Antioxidants, vitamin E and N-acetylcysteine, and the nonsteroidal anti-inflammatory drug indomethacin suppressed the pain-inducing ability of oxidatively modified lipoproteins. Treatment of human endometrial cells with oxidatively modified lipoproteins or PF from women with endometriosis showed upregulation of similar genes belonging to opioid and inflammatory pathways. Our finding that oxidatively modified lipoproteins can induce nociception has a broader impact not only on the treatment of endometriosis-associated pain but also on other diseases associated with chronic pain.

  2. Roles of prefrontal cortex and paraventricular thalamus in affective and mechanical components of visceral nociception.

    Science.gov (United States)

    Jurik, Angela; Auffenberg, Eva; Klein, Sabine; Deussing, Jan M; Schmid, Roland M; Wotjak, Carsten T; Thoeringer, Christoph K

    2015-12-01

    Visceral pain represents a major clinical challenge in the management of many gastrointestinal disorders, eg, pancreatitis. However, cerebral neurobiological mechanisms underlying visceral nociception are poorly understood. As a representative model of visceral nociception, we applied cerulein hyperstimulation in C57BL6 mice to induce acute pancreatitis and performed a behavioral test battery and c-Fos staining of brains. We observed a specific pain phenotype and a significant increase in c-Fos immunoreactivity in the paraventricular nucleus of the thalamus (PVT), the periaqueductal gray, and the medial prefrontal cortex (mPFC). Using neuronal tracing, we observed projections of the PVT to cortical layers of the mPFC with contacts to inhibitory GABAergic neurons. These inhibitory neurons showed more activation after cerulein treatment suggesting thalamocortical "feedforward inhibition" in visceral nociception. The activity of neurons in pancreatitis-related pain centers was pharmacogenetically modulated by designer receptors exclusively activated by designer drugs, selectively and cell type specifically expressed in target neurons using adeno-associated virus-mediated gene transfer. Pharmacogenetic inhibition of PVT but not periaqueductal gray neurons attenuated visceral pain and induced an activation of the descending inhibitory pain pathway. Activation of glutamatergic principle neurons in the mPFC, but not inhibitory neurons, also reversed visceral nociception. These data reveal novel insights into central pain processing that underlies visceral nociception and may trigger the development of novel, potent centrally acting analgesic drugs.

  3. Nociceptive and Inflammatory Mediator Upregulation in a Mouse Model of Chronic Prostatitis

    Science.gov (United States)

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

    2015-01-01

    Chronic nonbacterial prostatitis, characterized by genitourinary pain in the pelvic region in the absence of an identifiable cause, is common in adult males. Surprisingly, the sensory innervation of the prostate and mediators that sensitize its innervation have received little attention. We thus characterized a mouse model of chronic prostatitis, focusing on the prostate innervation and how organ inflammation affects gene expression of putative nociceptive markers in prostate afferent somata in dorsal root ganglia (DRG) and mediators in the prostate. Retrograde tracing (fast blue, FB) from the prostate revealed that thoracolumbar (TL) and lumbosacral (LS) DRG are the principal sources of somata of prostate afferents. Nociceptive markers (e.g., TRP, TREK and P2X channels) were upregulated in FB-labeled TL and LS somata for up to four weeks after inflaming the prostate (intra-prostate injection of zymosan). Prostatic inflammation was evident histologically, by monocyte infiltration and a significant increase in mast cell tryptase activity 14, 21 and 28 days after zymosan injection. Interleukin-10 and NGF were also significantly upregulated in the prostate throughout the four weeks of inflammation. Open field pain-related behaviors (e.g., rearing) were unchanged in prostate-inflamed mice, suggesting the absence of ongoing nociception, but withdrawal thresholds to lower abdominal pressure were significantly reduced. The increases in IL-10, mast cell tryptase and NGF in the inflamed prostate were cotemporaneous with reduced thresholds to probing of the abdomen and upregulation of nociceptive markers in DRG somata innervating the prostate. The results provide insight and direction for study of mechanisms underlying pain in chronic prostatitis. PMID:25915147

  4. Branched oxytocinergic innervations from the paraventricular hypothalamic nuclei to superficial layers in the spinal cord.

    Science.gov (United States)

    Condés-Lara, Miguel; Martínez-Lorenzana, Guadalupe; Rojas-Piloni, Gerardo; Rodríguez-Jiménez, Javier

    2007-07-30

    The paraventricular nucleus (PVN) of the hypothalamus is an interesting structure with diverse functions due to its different neuronal populations, neurotransmitters, and projections to other central nervous system structures. The PVN is a primary source of oxytocin (OT) in the central nervous system. In fact, a direct PVN projection to the spinal cord has been demonstrated by retrograde and anterograde tracers, and more than the 50% of this projection is oxytocinergic. This OT descending projection is proposed to be an endogenous system that controls the nociceptive information arriving at the spinal cord. However, we have no information about the specific organization of the OT descending innervations to the different spinal cord segments. The aim of the present study was to determine whether the projecting PVN neurons arrive at cervical regions and then continue to lumbar regions. That is, we sought to establish if the OT projecting cells have a topic or a diffuse projection in order to obtain histological data to support the endogenous OT diffuse mechanism of analgesia described elsewhere. With this purpose in mind we combined the OT immunohistochemistry technique with retrograde neuronal tracers in the spinal cord. We applied Diamidino Yellow (DY) for the superficial dorsal horn cervical segments and True Blue (TB) for the lumbar segments. Data were collected from eight rats with well-placed injections. We only used the animals in which the tracer deposits were confined to superficial layers I and II of the dorsal horn. A mainly ipsilateral projection was observed, but stained neurons were also observed in the contralateral PVN. A large fraction of the stained PVN cells was doubled labeled but some were single labeled. Combining the retrograde tracer techniques and the OT detection procedure, we observed triple-labeled neurons. The present results demonstrate that PVN neurons send collaterals at least to the superficial cervical and lumbar segments of the

  5. THE ROLE OF RED NUCLEUS IN THE MODULATION OF SPINAL NOCICEPTIVE TRANSMISSION AND IN NOCICEPTION ELICITED BY MUSCLE SPINDLE AFFERENTS

    Institute of Scientific and Technical Information of China (English)

    唐斌; 樊小力; 吴苏娣

    2003-01-01

    Objective To analyse the antinociceptive effect of red nucleus (RN) and its role in the antinociceptive effect of muscle spindle afferents. Methods The single units of RN or wide dynamic range (WDR) neuron in the spinal cord dorsal horn were extracelluarly recorded. The effects of RN stimulation on nociceptive responses (C-fibers-evoked responses, C-responses) of WDR neurons were observed. The influence of muscle spindle afferents elicited by intravenous administration of succinylcholine (Sch) on the spontaneous discharge of RN neurons and on C-responses of WDR neurons were observed. The effect of muscle spindle afferents on C-responses of WDR neurons after unilateral lesions of RN was also observed. Results Electrical stimulation of the RN produced a significantly inhibitory effect on the nociceptive responses of WDR neurons. RN neurons were excited by muscle spindle afferents. Muscle spindle afferents significantly inhibited C-response of WDR neurons and this inhibitory effect was reduced by lesions of RN. Conclusion RN neurons have a significant antinociceptive effect and might be involved in the antinociceptive effects elicited by muscle spindle afferents.

  6. Innervation of ''painful'' lumbar discs

    NARCIS (Netherlands)

    Coppes, MH; Marani, E; Thomeer, RTWM; Groen, GJ

    1997-01-01

    Study Design. The authors investigated the innervation of discographically confirmed degenerated and ''painful'' human intervertebral discs. Objective. To determine the type and distribution patterns of nerve fibers present in degenerated human intervertebral discs. Summary of Background Data. The i

  7. Learned control over spinal nociception reduces supraspinal nociception as quantified by late somatosensory evoked potentials.

    Science.gov (United States)

    Ruscheweyh, Ruth; Bäumler, Maximilian; Feller, Moritz; Krafft, Stefanie; Sommer, Jens; Straube, Andreas

    2015-12-01

    We have recently shown that subjects can learn to use cognitive-emotional strategies to suppress their spinal nociceptive flexor reflex (RIII reflex) under visual RIII feedback and proposed that this reflects learned activation of descending pain inhibition. Here, we investigated whether learned RIII suppression also affects supraspinal nociception and whether previous relaxation training increases success. Subjects were trained over 3 sessions to reduce their RIII size by self-selected cognitive-emotional strategies. Two groups received true RIII feedback (with or without previous relaxation training) and a sham group received false feedback (15 subjects per group). RIII reflexes, late somatosensory evoked potentials (SEPs), and F-waves were recorded and pain intensity ratings collected. Both true feedback groups achieved significant (P Pain intensity was significantly reduced in all 3 groups and also correlated with RIII reduction (r = 0.44, P nociception as quantified by SEPs, although effects on pain ratings were less clear. Lower motor neuron excitability as quantified by F-waves was not affected. Previous relaxation training did not significantly improve RIII feedback training success.

  8. Specific activation of the paralemniscal pathway during nociception.

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    Frangeul, Laura; Porrero, Cesar; Garcia-Amado, Maria; Maimone, Benedetta; Maniglier, Madlyne; Clascá, Francisco; Jabaudon, Denis

    2014-05-01

    Two main neuronal pathways connect facial whiskers to the somatosensory cortex in rodents: (i) the lemniscal pathway, which originates in the brainstem principal trigeminal nucleus and is relayed in the ventroposterior thalamic nucleus and (ii) the paralemniscal pathway, originating in the spinal trigeminal nucleus and relayed in the posterior thalamic nucleus. While lemniscal neurons are readily activated by whisker contacts, the contribution of paralemniscal neurons to perception is less clear. Here, we functionally investigated these pathways by manipulating input from the whisker pad in freely moving mice. We report that while lemniscal neurons readily respond to neonatal infraorbital nerve sectioning or whisker contacts in vivo, paralemniscal neurons do not detectably respond to these environmental changes. However, the paralemniscal pathway is specifically activated upon noxious stimulation of the whisker pad. These findings reveal a nociceptive function for paralemniscal neurons in vivo that may critically inform context-specific behaviour during environmental exploration.

  9. Sensory innervation of rat contracture shoulder model.

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    Ochiai, Nobuyasu; Ohtori, Seiji; Kenmoku, Tomonori; Yamazaki, Hironori; Ochiai, Satoko; Saisu, Takashi; Matsuki, Keisuke; Takahashi, Kazuhisa

    2013-02-01

    To date, few studies have investigated the cause of pain experienced by patients with frozen shoulder. The purposes of this study were to establish a rat contracture model and clarify the innervation pattern of the glenohumeral (GH) joint and subacromial bursa (SAB) using immunohistochemistry in the dorsal root ganglion (DRG) neurons. The rat contracture models were made by tying the animal's humerus and scapula with No. 2-0 FiberWire (Arthrex, Naples, FL, USA). Contracture was confirmed on x-ray images taken 8 weeks after the operation. Subsequently, two kinds of neurotracers, Fluoro-Gold (FG) (Fluorochrome, Denver, CO, USA) and 1,1'-dioctadecyl-3,3,3',3'-tetramethyl-indocarbocyanine perchlorate (DiI) (Molecular Probes, Eugene, OR, USA), were used to detect the GH joints and SAB separately. FG tracers were injected into GH joints, and DiI tracers were injected into the SAB. At 7 days after injection, DRGs were harvested between C1 and T1. Immunohistochemistry by use of calcitonin gene-related peptide (CGRP) was performed. CGRP is thought to be one of the causes of pain sensation in joint disease. We evaluated the percentages of FG-labeled CGRP-immunoreactive (CGRP-ir) neurons in the total number of FG-labeled neurons and of DiI-labeled CGRP-ir neurons in the total number of DiI-labeled neurons. Abduction and total arc of the rotation were statistically significantly decreased in the contracture group. Furthermore, the percentage of CGRP-ir DRG neurons was significantly higher in the contracture group in both the GH joint and SAB. These results show that pain sensation in rat shoulder contracture may be induced by the up-regulation of CGRP expression in DRG neurons. Copyright © 2013 Journal of Shoulder and Elbow Surgery Board of Trustees. Published by Mosby, Inc. All rights reserved.

  10. Selective regulation of nerve growth factor expression in developing cutaneous tissue by early sensory innervation

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    Vizard Tom N

    2011-04-01

    Full Text Available Abstract Background In the developing vertebrate peripheral nervous system, the survival of sympathetic neurons and the majority of sensory neurons depends on a supply of nerve growth factor (NGF from tissues they innervate. Although neurotrophic theory presupposes, and the available evidence suggests, that the level of NGF expression is completely independent of innervation, the possibility that innervation may regulate the timing or level of NGF expression has not been rigorously investigated in a sufficiently well-characterized developing system. Results To address this important question, we studied the influence of innervation on the regulation of NGF mRNA expression in the embryonic mouse maxillary process in vitro and in vivo. The maxillary process receives its innervation from predominantly NGF-dependent sensory neurons of the trigeminal ganglion and is the most densely innervated cutaneous territory with the highest levels of NGF in the embryo. When early, uninnervated maxillary processes were cultured alone, the level of NGF mRNA rose more slowly than in maxillary processes cultured with attached trigeminal ganglia. In contrast to the positive influence of early innervation on NGF mRNA expression, the levels of brain-derived neurotrophic factor (BDNF mRNA and neurotrophin-3 (NT3 mRNA rose to the same extent in early maxillary processes grown with and without trigeminal ganglia. The level of NGF mRNA, but not BDNF mRNA or NT3 mRNA, was also significantly lower in the maxillary processes of erbB3-/- mice, which have substantially fewer trigeminal neurons than wild-type mice. Conclusions This selective effect of initial innervation on target field NGF mRNA expression provokes a re-evaluation of a key assertion of neurotrophic theory that the level of NGF expression is independent of innervation.

  11. Cell type-specific thalamic innervation in a column of rat vibrissal cortex.

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    Meyer, Hanno S; Wimmer, Verena C; Hemberger, Mike; Bruno, Randy M; de Kock, Christiaan P J; Frick, Andreas; Sakmann, Bert; Helmstaedter, Moritz

    2010-10-01

    This is the concluding article in a series of 3 studies that investigate the anatomical determinants of thalamocortical (TC) input to excitatory neurons in a cortical column of rat primary somatosensory cortex (S1). We used viral synaptophysin-enhanced green fluorescent protein expression in thalamic neurons and reconstructions of biocytin-labeled cortical neurons in TC slices to quantify the number and distribution of boutons from the ventral posterior medial (VPM) and posteromedial (POm) nuclei potentially innervating dendritic arbors of excitatory neurons located in layers (L)2-6 of a cortical column in rat somatosensory cortex. We found that 1) all types of excitatory neurons potentially receive substantial TC input (90-580 boutons per neuron); 2) pyramidal neurons in L3-L6 receive dual TC input from both VPM and POm that is potentially of equal magnitude for thick-tufted L5 pyramidal neurons (ca. 300 boutons each from VPM and POm); 3) L3, L4, and L5 pyramidal neurons have multiple (2-4) subcellular TC innervation domains that match the dendritic compartments of pyramidal cells; and 4) a subtype of thick-tufted L5 pyramidal neurons has an additional VPM innervation domain in L4. The multiple subcellular TC innervation domains of L5 pyramidal neurons may partly explain their specific action potential patterns observed in vivo. We conclude that the substantial potential TC innervation of all excitatory neuron types in a cortical column constitutes an anatomical basis for the initial near-simultaneous representation of a sensory stimulus in different neuron types.

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

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    Onozawa Kitaro

    2011-11-01

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

  13. Characterisation of the primary afferent spinal innervation of mouse uterus

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    Geraldine eHerweijer

    2014-07-01

    Full Text Available The primary afferent innervation of the uterus is incompletely understood. The aim of this study was to identify the location and characteristics of primary afferent neurons that innervate the uterine horn of mice and correlate the different morphological types of putative primary afferent nerve endings, immunoreactive to the sensory marker, calcitonin gene related peptide (CGRP. Using retrograde tracing, injection of 5-10µL of 1,1'-didodecyl-3,3,3,3'-tetramethylindocarbocyanine perchlorate (DiI into discrete single sites in each uterine horn revealed a biomodal distribution of sensory neurons in dorsal root ganglia (DRG with peak labelling occurring between T13-L3 and a second smaller peak between L6-S1. The mean cross sectional area of labelled cells was 463 µm2 +/- SEM. A significantly greater proportion of labelled neurons consisted of small cell bodies (<300 µm2 in the sacral spinal cord (S2 compared with peak labelling at the lumbar (L2 region. In both sections and whole mount preparations, immunohistochemical staining for CGRP revealed substantial innervation of the uterus by CGRP-positive nerve fibres located primarily at the border between the circular and longitudinal muscle layers (N=4. The nerve endings were classified into three distinct types: single, branching or complex, that often aligned preferentially in either the circular or longitudinal axis of the smooth muscles. Complex endings were often associated with mesenteric vessels. We have identified that the cell bodies of primary afferent neurons innervating the mouse uterus lie primarily in DRG at L2 and S1 spinal levels. Also, the greatest density of CGRP immunoreactivity lies within the myometrium, with at least three different morphological types of nerve endings identified. These findings will facilitate further investigations into the mechanisms underlying sensory transduction in mouse uterus.

  14. Remodelling sympathetic innervation in rat pancreatic islets ontogeny

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    Hiriart Marcia

    2009-06-01

    Full Text Available Abstract Background Pancreatic islets are not fully developed at birth and it is not clear how they are vascularised and innervated. Nerve Growth Factor (NGF is required to guide sympathetic neurons that innervate peripheral organs and also in cardiovascular system and ovary angiogenesis. Pancreatic beta cells of a transgenic mouse that over-expressed NGF in attracts sympathetic hyper-innervation towards them. Moreover, we have previously demonstrated that adult beta cells synthesize and secrete NGF; however, we do not know how is NGF secreted during development, nor if it might be trophic for sympathetic innervation and survival in the pancreas. We analyzed sympathetic innervation and vasculature development in rat pancreatic islets at different developmental stages; foetal (F19, early postnatal (P1, weaning period (P20 and adults. We temporarily correlated these events to NGF secretion by islet cells. Results Sympathetic fibres reached pancreatic islets in the early postnatal period, apparently following blood vessels. The maximal number of sympathetic fibres (TH immunopositive in the periphery of the islets was observed at P20, and then fibres entered the islets and reached the core where beta cells are mainly located. The number of fibres decreased from that stage to adulthood. At all stages studied, islet cells secreted NGF and also expressed the high affinity receptor TrkA. Foetal and neonatal isolated islet cells secreted more NGF than adults. TrkA receptors were expressed at all stages in pancreatic sympathetic fibres and blood vessels. These last structures were NGF–immunoreactive only at early stages (foetal and P0. Conclusion The results suggest that NGF signalling play an important role in the guidance of blood vessels and sympathetic fibres toward the islets during foetal and neonatal stages and could also preserve innervation at later stages of life.

  15. Descending control of nociception: Specificity, recruitment and plasticity.

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    Heinricher, M M; Tavares, I; Leith, J L; Lumb, B M

    2009-04-01

    The dorsal horn of the spinal cord is the location of the first synapse in pain pathways, and as such, offers a very powerful target for regulation of nociceptive transmission by both local segmental and supraspinal mechanisms. Descending control of spinal nociception originates from many brain regions and plays a critical role in determining the experience of both acute and chronic pain. The earlier concept of descending control as an "analgesia system" is now being replaced with a more nuanced model in which pain input is prioritized relative to other competing behavioral needs and homeostatic demands. Descending control arises from a number of supraspinal sites, including the midline periaqueductal gray-rostral ventromedial medulla (PAG-RVM) system, and the more lateral and caudal dorsal reticular nucleus (DRt) and ventrolateral medulla (VLM). Inhibitory control from the PAG-RVM system preferentially suppresses nociceptive inputs mediated by C-fibers, preserving sensory-discriminative information conveyed by more rapidly conducting A-fibers. Analysis of the circuitry within the RVM reveals that the neural basis for bidirectional control from the midline system is two populations of neurons, ON-cells and OFF-cells, that are differentially recruited by higher structures important in fear, illness and psychological stress to enhance or inhibit pain. Dynamic shifts in the balance between pain inhibiting and facilitating outflows from the brainstem play a role in setting the gain of nociceptive processing as dictated by behavioral priorities, but are also likely to contribute to pathological pain states.

  16. Anatomy, physiology and neurobiology of the nociception: a focus on low back pain (part A).

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    Mertens, P; Blond, S; David, R; Rigoard, P

    2015-03-01

    The treatment of Failed Back Surgery Syndrome (FBSS) remains a challenge for pain medicine due to the complexity in the interactions between [1] a residual mechanical pain after surgery and, [2] a progressive transition into chronic pain involving central nervous system plasticity and molecular reorganization. The aim of this paper is to provide a fundamental overview of the pain pathway supporting the nociceptive component of the back pain. Literature searches included an exhaustive review of 643 references and 74 book chapters updated by searching the major electronic databases from 1930 to August 2013. Pain input is gathered by the peripheral fibre from the innervated tissue's environment and relayed by two contiguous central axons to the brain, via the spinal cord. At this level, it is possible to characterize physical pain and emotional pain. These are supported by two different pathways, encoding two dimensions of pain perception: In Neo-spino-thalamic pathway, the wide dynamic range neuron system is able to provide the information needed for mapping the "sensory-discriminative" dimension of pain. The second projection system (Paleo-spino-thalamic pathway) also involves the ventromedial thalamus but projects to the amygdala, the insula and the anterior cingulate cortex. These areas are associated with emotionality and affect. The mechanical component of FBSS cannot be understood unless the functioning of the pain system is known. But ultimately, the highly variable nature of back pain expression among individuals would require a careful pathophysiological dissection of the potential generators of back pain to guide pain management strategies. Copyright © 2014 Elsevier Masson SAS. All rights reserved.

  17. [The adrenergic innervation of the normal rat uterus and during pregnancy].

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    Rakitskaia, V V; Chudinov, Iu V; Shaliapina, V G

    1990-09-01

    Histochemical analysis revealed that, normally, the main amount of adrenergic fibers in the rat uterus is connected with vascular innervation. The amount of neural elements projecting to the muscle cells in insignificant. In pregnancy, the amount of fibers with the specific fluorescence decreases and they completely disappear from the myometrium in parturient rats. Biochemical analysis corroborated the finding that the noradrenaline level is considerably decreased at the time in sympathetic neurons innervating the uterus thus leading to a physiological "desympathization" of the organ.

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

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    Aaron D. Mickle

    2016-11-01

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

  19. [The sources of the adrenergic innervation of the rat uterus].

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    Proĭmina, F I; Rakitskaia, V V

    1990-09-01

    Complete disappearance of adrenergic fibers in the rat uterus is only possible after complete removal of ovaries along with ovarian plexus, transection of the uterus-vaginal connexion and removal of a portion of sympathetic nervous trunk. "Long" adrenergic neurons situated in spinal sympathetic ganglia, seem not to be the only source of sympathetic innervation of the myometrium's vessels. A part of nervous fibers of vascular plexuses and all muscle nerves are represented by "short" neurons starting from the ganglionic structures of the uterus-vaginal connexion.

  20. Adaptive plasticity of vaginal innervation in term pregnant rats.

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    Liao, Zhaohui; Smith, Peter G

    2011-12-01

    Changes in reproductive status place varied functional demands on the vagina. These include receptivity to male intromission and sperm transport in estrus, barrier functions during early pregnancy, and providing a conduit for fetal passage at parturition. Peripheral innervation regulates vaginal function, which in turn may be influenced by circulating reproductive hormones. We assessed vaginal innervation in diestrus and estrus (before and after the estrous cycle surge in estrogen), and in the early (low estrogen) and late (high estrogen) stages in pregnancy. In vaginal sections from cycling rats, axons immunoreactive for the pan-neuronal marker protein gene product 9.5 (PGP 9.5) showed a small reduction at estrus relative to diestrus, but this difference did not persist after correcting for changes in target size. No changes were detected in axons immunoreactive for tyrosine hydroxylase (sympathetic), vesicular acetylcholine transporter (parasympathetic), or calcitonin gene-related peptide and transient receptor potential vanilloid type 1 (TRPV-1; sensory nociceptors). In rats at 10 days of pregnancy, innervation was similar to that observed in cycling rats. However, at 21 days of pregnancy, axons immunoreactive for PGP 9.5 and each of the subpopulation-selective markers were significantly reduced both when expressed as percentage of sectional area or after correcting for changes in target size. Because peripheral nerves regulate vaginal smooth muscle tone, blood flow, and pain sensitivity, reductions in innervation may represent important adaptive mechanisms facilitating parturition.

  1. Intraplantar injection of tetrahydrobiopterin induces nociception in mice.

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    Nasser, Arafat; Ali, Sawsan; Wilsbech, Signe; Bjerrum, Ole J; Møller, Lisbeth B

    2015-01-01

    Tetrahydrobiopterin (BH4) is implicated in the development and maintenance of chronic pain. After injury/inflammation, the biosynthesis of BH4 is markedly increased in sensory neurons, and the pharmacological and genetic inhibition of BH4 shows analgesic effects in pre-clinical animal pain models. Intrathecal injections of BH4 have been shown to induce and enhance pain-like behaviours in rats, suggesting that under chronic pain conditions BH4 may act by facilitating central sensitisation. So far it is unknown whether BH4 acts on peripheral sites of the somatosensory system or whether BH4 per se provokes nociceptive pain behaviours. The purpose of this study was therefore to investigate the acute nociceptive effects of intraplantar injection of BH4. BH4 was found to induce dose-dependent licking/biting of the paw lasting 5 min, which was not observed following an injection of biopterin (inactive BH4 metabolite). Paw swelling, measured as paw thickness and weight, was not observed after BH4 injection. To explore possible mechanisms of action of BH4, the effect of local pre-treatment with indomethacin, Nω-nitro-L-arginine methyl ester, Nω-nitro-L-arginine, capsazepine and ruthenium red was tested. Morphine served as a positive control. Intraplantar pre-injection of morphine dose-dependently inhibited BH4-induced nociception, while none of the other compounds showed any statistical significant antinociception. These results suggest that BH4 exhibits nociceptive properties at peripheral sites of the somatosensory system, proposing an as yet unexplored involvement of BH4 in peripheral nociceptive processes. However, this appears not to be mediated through nitric oxide and prostaglandin release or by activation of the transient receptor potential vanilloid 1.

  2. Microfluidics co-culture systems for studying tooth innervation

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    Pierfrancesco ePagella

    2014-08-01

    Full Text Available Innervation plays a key role in the development and homeostasis of organs and tissues of the orofacial complex. Among these structures, teeth are peculiar organs as they are not innervated until later stages of development. Furthermore, the implication of neurons in tooth initiation, morphogenesis and differentiation is still controversial. Co-cultures constitute a valuable method to investigate and manipulate the interactions of nerve fibres with their target organs in a controlled and isolated environment. Conventional co-cultures between neurons and their target tissues have already been performed, but these cultures do not offer optimal conditions that are closely mimicking the in vivo situation. Indeed, specific cell populations require different culture media in order to preserve their physiological properties. In this study we evaluate the usefulness of a microfluidics system for co-culturing mouse trigeminal ganglia and developing teeth. This device allows the application of specific media for the appropriate development of both neuronal and dental tissues. The results show that mouse trigeminal ganglia and teeth survive for long culture periods in this microfluidics system, and that teeth maintain the attractive or repulsive effect on trigeminal neurites that has been observed in vivo. Neurites are repealed when co-cultured with embryonic tooth germs, while postnatal teeth exert an attractive effect to trigeminal ganglia-derived neurons.In conclusion, microfluidics system devices provide a valuable tool for studying the behaviour of neurons during the development of orofacial tissues and organs, faithfully imitating the in vivo situation.

  3. Origin and chemical coding of primary afferent neurones supplying the prostate of the dog.

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    Arciszewski, M B; Zacharko, A

    2004-12-01

    Retrograde tracing technique combined with the double-fluorescent immunohistochemistry were used to investigate the distribution and chemical coding of primary afferent neurones supplying the canine prostate. After the injection of Fast Blue (FB) into the prostatic tissue retrogradely-labelled (FB(+)) primary afferent neurones were localized in bilateral L(1)-Ca(1) dorsal root ganglia (DRG). Statistical analysis using anova test showed that there are two major sources of afferent prostate innervation. The vast majority of prostate-supplying primary afferent neurones were located in bilateral L(2)-L(4) DRG (56.9 +/- 0.6%). The second source of the afferent innervation of canine prostate were bilateral S(1)-Ca(1) DRG (40.6 +/- 1.0%). No statistically significant differences were found between average number of FB(+) neurones localized in the left and right DRG (49.5 +/- 1.7 and 50.5 +/- 1.7%, respectively). Immunohistochemistry revealed that FB(+) primary afferent neurones contain several neuropeptides in various combinations. In the prostate-supplying neurones of lumbar and sacro-caudal DRG the immunoreactivity to substance P (SP) and calcitonin gene-related peptide (CGRP) was found most frequently (50 +/- 3.7 and 37.3 +/- 1.9%, respectively). Both in the lumbar and sacro-caudal DRG, considerable population of FB(+) neurones immunoreactive neither to SP nor CGRP were also found (23 +/- 2.6 and 32.8 +/- 2.3%, respectively). In the lumbar DRG 10.7 +/- 1.1% of SP-immunoreactive FB(+) neurones also contained galanin (GAL). In 9.2 +/- 2.2% of the prostate-supplying primary afferent neurones located in the sacro-caudal DRG the co-localization of SP and GAL was also reported. Results of the retrograde tracing experiment demonstrated for the first time sources of afferent innervation of the canine prostate. Double immunohistochemistry revealed that many of the prostate-supplying primary afferent neurones express some of sensory neuropeptides which presumably may be involved

  4. Voltage-Gated Calcium Channels in Nociception

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    Yasuda, Takahiro; Adams, David J.

    Voltage-gated calcium channels (VGCCs) are a large and functionally diverse group of membrane ion channels ubiquitously expressed throughout the central and peripheral nervous systems. VGCCs contribute to various physiological processes and transduce electrical activity into other cellular functions. This chapter provides an overview of biophysical properties of VGCCs, including regulation by auxiliary subunits, and their physiological role in neuronal functions. Subsequently, then we focus on N-type calcium (Cav2.2) channels, in particular their diversity and specific antagonists. We also discuss the role of N-type calcium channels in nociception and pain transmission through primary sensory dorsal root ganglion neurons (nociceptors). It has been shown that these channels are expressed predominantly in nerve terminals of the nociceptors and that they control neurotransmitter release. To date, important roles of N-type calcium channels in pain sensation have been elucidated genetically and pharmacologically, indicating that specific N-type calcium channel antagonists or modulators are particularly useful as therapeutic drugs targeting chronic and neuropathic pain.

  5. Responsiveness of electrical nociceptive detection thresholds to capsaicin (8 %)‑induced changes in nociceptive processing

    NARCIS (Netherlands)

    Doll, Robert J.; Amerongen, van Guido; Hay, Justin L.; Groeneveld, Geert J.; Veltink, Peter H.; Buitenweg, Jan R.

    2016-01-01

    Pain disorders can be initiated and maintained by malfunctioning of one or several mechanisms underlying the nociceptive function. Psychophysical procedures allow the estimation of nociceptive detection thresholds using intra-epidermal electrical stimuli. By varying the temporal properties of electr

  6. Chemosensory Information Processing between Keratinocytes and Trigeminal Neurons

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    Sondersorg, Anna Christina; Busse, Daniela; Kyereme, Jessica; Rothermel, Markus; Neufang, Gitta; Gisselmann, Günter; Hatt, Hanns; Conrad, Heike

    2014-01-01

    Trigeminal fibers terminate within the facial mucosa and skin and transmit tactile, proprioceptive, chemical, and nociceptive sensations. Trigeminal sensations can arise from the direct stimulation of intraepithelial free nerve endings or indirectly through information transmission from adjacent cells at the peripheral innervation area. For mechanical and thermal cues, communication processes between skin cells and somatosensory neurons have already been suggested. High concentrations of most odors typically provoke trigeminal sensations in vivo but surprisingly fail to activate trigeminal neuron monocultures. This fact favors the hypothesis that epithelial cells may participate in chemodetection and subsequently transmit signals to neighboring trigeminal fibers. Keratinocytes, the major cell type of the epidermis, express various receptors that enable reactions to multiple environmental stimuli. Here, using a co-culture approach, we show for the first time that exposure to the odorant chemicals induces a chemical communication between human HaCaT keratinocytes and mouse trigeminal neurons. Moreover, a supernatant analysis of stimulated keratinocytes and subsequent blocking experiments with pyrodoxalphosphate-6-azophenyl-2′,4′-disulfonate revealed that ATP serves as the mediating transmitter molecule released from skin cells after odor stimulation. We show that the ATP release resulting from Javanol® stimulation of keratinocytes was mediated by pannexins. Consequently, keratinocytes act as chemosensors linking the environment and the trigeminal system via ATP signaling. PMID:24790106

  7. ASIC3, an acid-sensing ion channel, is expressed in metaboreceptive sensory neurons

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    Fierro Leonardo

    2005-11-01

    Full Text Available Abstract Background ASIC3, the most sensitive of the acid-sensing ion channels, depolarizes certain rat sensory neurons when lactic acid appears in the extracellular medium. Two functions have been proposed for it: 1 ASIC3 might trigger ischemic pain in heart and muscle; 2 it might contribute to some forms of touch mechanosensation. Here, we used immunocytochemistry, retrograde labelling, and electrophysiology to ask whether the distribution of ASIC3 in rat sensory neurons is consistent with either of these hypotheses. Results Less than half (40% of dorsal root ganglion sensory neurons react with anti-ASIC3, and the population is heterogeneous. They vary widely in cell diameter and express different growth factor receptors: 68% express TrkA, the receptor for nerve growth factor, and 25% express TrkC, the NT3 growth factor receptor. Consistent with a role in muscle nociception, small ( Conclusion Our data indicates that: 1 ASIC3 is expressed in a restricted population of nociceptors and probably in some non-nociceptors; 2 co-expression of ASIC3 and CGRP, and the absence of P2X3, are distinguishing properties of a class of sensory neurons, some of which innervate blood vessels. We suggest that these latter afferents may be muscle metaboreceptors, neurons that sense the metabolic state of muscle and can trigger pain when there is insufficient oxygen.

  8. Auditory hair cell innervational patterns in lizards.

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    Miller, M R; Beck, J

    1988-05-22

    The pattern of afferent and efferent innervation of two to four unidirectional (UHC) and two to nine bidirectional (BHC) hair cells of five different types of lizard auditory papillae was determined by reconstruction of serial TEM sections. The species studies were Crotaphytus wislizeni (iguanid), Podarcis (Lacerta) sicula and P. muralis (lacertids), Ameiva ameiva (teiid), Coleonyx variegatus (gekkonid), and Mabuya multifasciata (scincid). The main object was to determine in which species and in which hair cell types the nerve fibers were innervating only one (exclusive innervation), or two or more hair cells (nonexclusive innervation); how many nerve fibers were supplying each hair cell; how many synapses were made by the innervating fibers; and the total number of synapses on each hair cell. In the species studies, efferent innervation was limited to the UHC, and except for the iguanid, C. wislizeni, it was nonexclusive, each fiber supplying two or more hair cells. Afferent innervation varied both with the species and the hair cell types. In Crotaphytus, both the UHC and the BHC were exclusively innervated. In Podarcis and Ameiva, the UHC were innervated exclusively by some fibers but nonexclusively by others (mixed pattern). In Coleonyx, the UHC were exclusively innervated but the BHC were nonexclusively innervated. In Mabuya, both the UHC and BHC were nonexclusively innervated. The number of afferent nerve fibers and the number of afferent synapses were always larger in the UHC than in the BHC. In Ameiva, Podarcis, and Mabuya, groups of bidirectionally oriented hair cells occur in regions of cytologically distinct UHC, and in Ameiva, unidirectionally oriented hair cells occur in cytologically distinct BHC regions.

  9. Neuropeptides amplify and focus the monoaminergic inhibition of nociception in Caenorhabditis elegans.

    Science.gov (United States)

    Hapiak, Vera; Summers, Philip; Ortega, Amanda; Law, Wen Jing; Stein, Andrew; Komuniecki, Richard

    2013-08-28

    Monoamines and neuropeptides interact to modulate most behaviors. To better understand these interactions, we have defined the roles of tyramine (TA), octopamine, and neuropeptides in the inhibition of aversive behavior in Caenorhabditis elegans. TA abolishes the serotonergic sensitization of aversive behavior mediated by the two nociceptive ASH sensory neurons and requires the expression of the adrenergic-like, Gαq-coupled, TA receptor TYRA-3 on inhibitory monoaminergic and peptidergic neurons. For example, TA inhibition requires Gαq and Gαs signaling in the peptidergic ASI sensory neurons, with an array of ASI neuropeptides activating neuropeptide receptors on additional neurons involved in locomotory decision-making. The ASI neuropeptides required for tyraminergic inhibition are distinct from those required for octopaminergic inhibition, suggesting that individual monoamines stimulate the release of different subsets of ASI neuropeptides. Together, these results demonstrate that a complex humoral mix of monoamines is focused by more local, synaptic, neuropeptide release to modulate nociception and highlight the similarities between the tyraminergic/octopaminergic inhibition of nociception in C. elegans and the noradrenergic inhibition of nociception in mammals that also involves inhibitory peptidergic signaling.

  10. Forebrain medial septum region facilitates nociception in a rat formalin model of inflammatory pain.

    Science.gov (United States)

    Lee, Andy Thiam-Huat; Ariffin, Mohammed Zacky; Zhou, Mingyi; Ye, Jenn Zhou; Moochhala, Shabbir M; Khanna, Sanjay

    2011-11-01

    The medial septum is anatomically and functionally linked to the hippocampus, a region implicated in nociception. However, the role of medial septum in nociception remains unclear. To investigate the role of the region in nociception in rats, muscimol, a GABA agonist, or zolpidem, a positive allosteric modulator of GABA(A) receptors, was microinjected into medial septum to attenuate the activity of neurons in the region. Electrophysiological studies in anesthetized rats indicated that muscimol evoked a stronger and longer-lasting suppression of medial septal-mediated activation of hippocampal theta field activity than zolpidem. Similarly, microinjection of muscimol (1 or 2 μg/0.5 μl) into the medial septum of awake rats suppressed both licking and flinching behaviors in the formalin test of inflammatory pain, whereas only the latter behavior was affected by zolpidem (8 or 12 μg/0.5 μl) administered into the medial septum. Interestingly, both drugs selectively attenuated nociceptive behaviors in the second phase of the formalin test that are partly driven by central plasticity. Indeed, muscimol reduced the second phase behaviors by 30% to 60%, which was comparable to the reduction seen with systemic administration of a moderate dose of the analgesic morphine. The reduction was accompanied by a decrease in formalin-induced expression of spinal c-Fos protein that serves as an index of spinal nociceptive processing. The drug effects on nociceptive behaviors were without overt sedation and were distinct from the effects observed after septal lateral microinjections. Taken together, these findings suggest that the activation of medial septum is pro-nociceptive and facilitates aspects of central neural processing underlying nociception.

  11. Operant nociception in nonhuman primates.

    Science.gov (United States)

    Kangas, Brian D; Bergman, Jack

    2014-09-01

    The effective management of pain is a longstanding public health concern. Morphine-like opioids have long been front-line analgesics, but produce undesirable side effects that can limit their application. Slow progress in the introduction of novel improved medications for pain management over the last 5 decades has prompted a call for innovative translational research, including new preclinical assays. Most current in vivo procedures (eg, tail flick, hot plate, warm water tail withdrawal) assay the effects of nociceptive stimuli on simple spinal reflexes or unconditioned behavioral reactions. However, clinical treatment goals may include the restoration of previous behavioral activities, which can be limited by medication-related side effects that are not measured in such procedures. The present studies describe an apparatus and procedure to study the disruptive effects of nociceptive stimuli on voluntary behavior in nonhuman primates, and the ability of drugs to restore such behavior through their analgesic actions. Squirrel monkeys were trained to pull a cylindrical thermode for access to a highly palatable food. Next, sessions were conducted in which the temperature of the thermode was increased stepwise until responding stopped, permitting the determination of stable nociceptive thresholds. Tests revealed that several opioid analgesics, but not d-amphetamine or Δ(9)-THC, produced dose-related increases in threshold that were antagonist sensitive and efficacy dependent, consistent with their effects using traditional measures of antinociception. Unlike traditional reflex-based measures, however, the results also permitted the concurrent evaluation of response disruption, providing an index with which to characterize the behavioral selectivity of antinociceptive drugs.

  12. Intraplantar injection of tetrahydrobiopterin induces nociception in mice

    DEFF Research Database (Denmark)

    Nasser, Arafat; Ali, Sawsan; Wilsbech, Signe

    2015-01-01

    Tetrahydrobiopterin (BH4) is implicated in the development and maintenance of chronic pain. After injury/inflammation, the biosynthesis of BH4 is markedly increased in sensory neurons, and the pharmacological and genetic inhibition of BH4 shows analgesic effects in pre-clinical animal pain models...... sites of the somatosensory system, proposing an as yet unexplored involvement of BH4 in peripheral nociceptive processes. However, this appears not to be mediated through nitric oxide and prostaglandin release or by activation of the transient receptor potential vanilloid 1....

  13. Acute estrogen surge enhances inflammatory nociception without altering spinal Fos expression.

    Science.gov (United States)

    Ralya, Andrew; McCarson, Kenneth E

    2014-07-11

    Chronic pain is a major neurological disorder that can manifest differently between genders or sexes. The complex actions of sex hormones may underlie these differences; previous studies have suggested that elevated estrogen levels can enhance pain perception. The purpose of this study was to investigate the hypothesis that acute, activational effects of estradiol (E2) increase persistent inflammatory nociception, and anatomically where this modulation occurs. Spinal expression of Fos is widely used as a marker of nociceptive activation. This study used formalin-evoked nociception in ovariectomized (OVX) adult female rats and measured late-phase hindlimb flinching and Fos expression in the spinal cord, and their modification by acute estrogen supplementation similar to a proestrus surge. Six days after ovariectomy, female rats were injected subcutaneously (s.c.) with 10μg/kg E2 or vehicle. Twenty-four hours later, 50μL of 1.25% or 100μL of 5% formalin was injected into the right hindpaw; hindlimb flinches were counted, and spinal cords removed 2h after formalin injection. The numbers of Fos-expressing neurons in sections of the lumbar spinal cord were analyzed using immunohistochemistry. Formalin-induced inflammation produced a dose-dependent increase in late-phase hindlimb flinching, and E2 pretreatment increased flinching following 5%, but not 1.25% formalin injection. Despite the modification of behavior by E2, the number of spinal Fos-positive neurons was not altered by E2 pretreatment. These findings demonstrate that an acute proestrus-like surge in serum estrogen can produce a stimulus-intensity-dependent increase in inflammation-evoked nociceptive behavior. However, the lack of effect on spinal Fos expression suggests that this enhancement of nociceptive signaling by estrogen is independent of changes in peripheral activation of, expression of the immediate early gene Fos by, or signal throughput of spinal nociceptive neurons.

  14. Characterization of the autonomic innervation of mammary gland in lactating rats studied by retrograde transynaptic virus labeling and immunohistochemistry.

    Science.gov (United States)

    Köves, Katalin; Györgyi, Z; Szabó, F K; Boldogkői, Zs

    2012-06-01

    The aim of experiments was to characterize the neurons of the autonomic chain that innervates the nipple and the mammary gland of lactating rats using retrograde transynaptic virus labeling and neurotransmitter and neuropeptide immunohistochemistry. Two days after injection of green fluorescence protein labeled virus in two nipples and underlying mammary glands, labeling was observed in the ipsilateral paravertebral sympathetic trunk and the lateral horn. Three days after inoculation the labeling appeared in the brain stem and the hypothalamic paraventricular nucleus. Above the spinal cord the labeling was bilateral. A subpopulation of virus labeled cells in the paraventricular nuclei synthesized oxytocin. Labeled neurons in the lateral horn showed cholinergic immunoreactivity. These cholinergic neurons innervated the paravertebral ganglia where the virus labeled neurons were partially noradrenergic. The noradrenergic fibers in the mammary gland innervate the smooth muscle wall of vessels, but not the mammary gland in rats. The neurons in the lateral horn receive afferents from the brain stem, and paraventricular nucleus and these afferents are noradrenergic and oxytocinergic. New findings in our work: Some oxytocinergic fibers may descend to the neurons of the lateral horn which innervate noradrenergic neurons in the paravertebral sympathetic trunk, and in turn these noradrenergic neurons reach the vessels of the mammary gland.

  15. Corneal Sulfated Glycosaminoglycans and Their Effects on Trigeminal Nerve Growth Cone Behavior In Vitro: Roles for ECM in Cornea Innervation

    OpenAIRE

    Schwend, Tyler; Deaton, Ryan J.; Zhang, Yuntao; Caterson, Bruce; Conrad, Gary W.

    2012-01-01

    In this investigation, we describe differential spatiotemporal expression patterns of glycosaminoglycans KS, DS, and CSA/C during developmental stages of cornea innervation. We show that purified GAGs have divergent effects on trigeminal neuron behavior using in vitro neuronal explant cultures.

  16. Fos induction in lamina I projection neurons in response to noxious thermal stimuli.

    Science.gov (United States)

    Todd, A J; Spike, R C; Young, S; Puskár, Z

    2005-01-01

    Lamina I of the spinal cord contains many projection neurons: the majority of these are activated by noxious stimulation, although some respond to other stimuli, such as innocuous cooling. In the rat, approximately 80% of lamina I projection neurons express the neurokinin 1 (NK1) receptor, on which substance P acts. Lamina I neurons can be classified into three main morphological classes: pyramidal, fusiform and multipolar cells. It has been reported that in the cat, pyramidal cells respond to innocuous cooling, and whilst both fusiform and multipolar cells are activated by noxious mechanical and heat stimuli, only cells in the latter group respond to noxious cold [Nat Neurosci 1 (1998) 218]. However, we have previously shown that NK1 receptor-immunoreactive projection neurons belonging to each morphological class are equally likely to up-regulate the transcription factor Fos after noxious chemical stimulation, and that the density of innervation by substance P-containing (nociceptive) afferents is similar for cells of each type [J Neurosci 22 (2002) 4103]. This suggests that the morphological-physiological correlation that has been reported in the cat may not apply in the rat. We have tested this further by examining Fos expression in lamina I spinoparabrachial neurons in the rat after application of noxious heat or noxious cold stimuli under general anesthesia. Following noxious heat, 57-69% of NK1 receptor-immunoreactive spinoparabrachial neurons expressed Fos, and the proportion did not differ significantly between morphological groups. However, after noxious cold stimulation Fos was present in 63% of multipolar neurons, but only 19-26% of fusiform or pyramidal cells. These results suggest that although most NK1 receptor-expressing spinoparabrachial neurons are activated by noxious stimuli, responsiveness to noxious cold is significantly more common in those of the multipolar type. There therefore appears to be a correlation between morphology and function for

  17. Inhibitory Interneurons That Express GFP in the PrP-GFP Mouse Spinal Cord Are Morphologically Heterogeneous, Innervated by Several Classes of Primary Afferent and Include Lamina I Projection Neurons among Their Postsynaptic Targets.

    Science.gov (United States)

    Ganley, Robert P; Iwagaki, Noboru; del Rio, Patricia; Baseer, Najma; Dickie, Allen C; Boyle, Kieran A; Polgár, Erika; Watanabe, Masahiko; Abraira, Victoria E; Zimmerman, Amanda; Riddell, John S; Todd, Andrew J

    2015-05-13

    The superficial dorsal horn of the spinal cord contains numerous inhibitory interneurons, which regulate the transmission of information perceived as touch, pain, or itch. Despite the importance of these cells, our understanding of their roles in the neuronal circuitry is limited by the difficulty in identifying functional populations. One group that has been identified and characterized consists of cells in the mouse that express green fluorescent protein (GFP) under control of the prion protein (PrP) promoter. Previous reports suggested that PrP-GFP cells belonged to a single morphological class (central cells), received inputs exclusively from unmyelinated primary afferents, and had axons that remained in lamina II. However, we recently reported that the PrP-GFP cells expressed neuronal nitric oxide synthase (nNOS) and/or galanin, and it has been shown that nNOS-expressing cells are more diverse in their morphology and synaptic connections. We therefore used a combined electrophysiological, pharmacological, and anatomical approach to reexamine the PrP-GFP cells. We provide evidence that they are morphologically diverse (corresponding to "unclassified" cells) and receive synaptic input from a variety of primary afferents, with convergence onto individual cells. We also show that their axons project into adjacent laminae and that they target putative projection neurons in lamina I. This indicates that the neuronal circuitry involving PrP-GFP cells is more complex than previously recognized, and suggests that they are likely to have several distinct roles in regulating the flow of somatosensory information through the dorsal horn.

  18. 猫扣带回前部内脏与躯体伤害感受神经元膜电学特性的对比研究%A Comparative Study of Membrane Electrical Properties of Visceral and Somatic Nociceptive Neurons of Anterior Cingulate Gyrus in Cats

    Institute of Scientific and Technical Information of China (English)

    吴敏范; 张勇; 杨宇; 姚阳; 马积昊; 商丽宏

    2015-01-01

    Objective To perform a comparative study on membrane electrical properties of visceral and somatic nociceptive neurons of anterior cin⁃gulate gyrus(ACG)in cats,so as to provide the experimental basis for elucidating the mechanism of differences in perceptual qualities between vis⁃ceral pain and somatic pain from the membrane electrical aspects. Methods A total of 77 adult cats,female or male,weighting 2.0 to 3.5 kg were selected for the study. According to the properties of the greater splanchnic nerve(GSN)or saphenous nerve(SN)evoked responses of neurons in ACG and effect of morphine on the evoked responses,visceral nociceptive neurons(VNNs)having the long latency(≥50 ms)GSN evoked re⁃sponses or somatic nociceptive neurons(SNNs)having the long latency(≥50 ms)SN evoked responses were detected. With a glass microelectrode in vivo,a series of polarizing current of different intensity from-5 nA to+5 nA with a 50 ms duration were injected to these neurons in ACG,and the membrane electrical responses of these neurons were recorded. Finally,the membrane electrical parameters of these neurons were calculated. Re⁃sults Totally 254 VNNs and 172 SNNs were recorded in ACG. GSN evoked response threshold of VNNs were higher than SN evoked response threshold of SNNs. Compared with SNNs,the membrane resistance,the membrane capacity and the time constant of VNNs were larger. Conclusion Our data proved that there are some differences in the membrane electrical properties between VNNs and SNNs in ACG,which might be the mem⁃brane electrical basis for differences in perceptual qualities between visceral pain and somatic pain.%目的:对比研究猫扣带回前部内脏伤害感受神经元与躯体伤害感受神经元膜电学特性,从膜电学方面为阐明内脏痛与躯体痛具有不同感受特性的机制提供实验依据。方法选择成龄猫77只,体质量2.0~3.5 kg,雄雌不限。根据在体微电极记录的扣带回前部神经元对电刺激

  19. Epibranchial placode-derived neurons produce BDNF required for early sensory neuron development.

    Science.gov (United States)

    Harlow, Danielle E; Yang, Hui; Williams, Trevor; Barlow, Linda A

    2011-02-01

    In mice, BDNF provided by the developing taste epithelium is required for gustatory neuron survival following target innervation. However, we find that expression of BDNF, as detected by BDNF-driven β-galactosidase, begins in the cranial ganglia before its expression in the central (hindbrain) or peripheral (taste papillae) targets of these sensory neurons, and before gustatory ganglion cells innervate either target. To test early BDNF function, we examined the ganglia of bdnf null mice before target innervation, and found that while initial neuron survival is unaltered, early neuron development is disrupted. In addition, fate mapping analysis in mice demonstrates that murine cranial ganglia arise from two embryonic populations, i.e., epibranchial placodes and neural crest, as has been described for these ganglia in non-mammalian vertebrates. Only placodal neurons produce BDNF, however, which indicates that prior to innervation, early ganglionic BDNF produced by placode-derived cells promotes gustatory neuron development.

  20. Lateral inhibition during nociceptive processing

    DEFF Research Database (Denmark)

    Quevedo, Alexandre S.; Mørch, Carsten Dahl; Andersen, Ole Kæseler

    2017-01-01

    of skin. Thus, the stimulation of the skin region between the endpoints of the lines appears to produce inhibition. These findings indicate that lateral inhibition limits spatial summation of pain and is an intrinsic component of nociceptive information processing. Disruption of such lateral inhibition......Spatial summation of pain is the increase of perceived intensity that occurs as the stimulated area increases. Spatial summation of pain is sub-additive in that increasing the stimulus area produces a disproportionately small increase in the perceived intensity of pain. A possible explanation...... for sub-additive summation may be that convergent excitatory information is modulated by lateral inhibition. To test the hypothesis that lateral inhibition may limit spatial summation of pain, we delivered different patterns of noxious thermal stimuli to the abdomens of 15 subjects using a computer...

  1. Mechanisms involved in the nociception triggered by the venom of the armed spider Phoneutria nigriventer.

    Directory of Open Access Journals (Sweden)

    Camila Gewehr

    Full Text Available BACKGROUND: The frequency of accidental spider bites in Brazil is growing, and poisoning due to bites from the spider genus Phoneutria nigriventer is the second most frequent source of such accidents. Intense local pain is the major symptom reported after bites of P. nigriventer, although the mechanisms involved are still poorly understood. Therefore, the aim of this study was to identify the mechanisms involved in nociception triggered by the venom of Phoneutria nigriventer (PNV. METHODOLOGY/PRINCIPAL FINDINGS: Twenty microliters of PNV or PBS was injected into the mouse paw (intraplantar, i.pl.. The time spent licking the injected paw was considered indicative of the level of nociception. I.pl. injection of PNV produced spontaneous nociception, which was reduced by arachnid antivenin (ArAv, local anaesthetics, opioids, acetaminophen and dipyrone, but not indomethacin. Boiling or dialysing the venom reduced the nociception induced by the venom. PNV-induced nociception is not dependent on glutamate or histamine receptors or on mast cell degranulation, but it is mediated by the stimulation of sensory fibres that contain serotonin 4 (5-HT4 and vanilloid receptors (TRPV1. We detected a kallikrein-like kinin-generating enzyme activity in tissue treated with PNV, which also contributes to nociception. Inhibition of enzymatic activity or administration of a receptor antagonist for kinin B2 was able to inhibit the nociception induced by PNV. PNV nociception was also reduced by the blockade of tetrodotoxin-sensitive Na(+ channels, acid-sensitive ion channels (ASIC and TRPV1 receptors. CONCLUSION/SIGNIFICANCE: Results suggest that both low- and high-molecular-weight toxins of PNV produce spontaneous nociception through direct or indirect action of kinin B2, TRPV1, 5-HT4 or ASIC receptors and voltage-dependent sodium channels present in sensory neurons but not in mast cells. Understanding the mechanisms involved in nociception caused by PNV are of

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

    DEFF Research Database (Denmark)

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

    2012-01-01

    in spinal nociceptive processing. Intrathecal challenging of mice with the GPER agonist G-1 results in pain-related behaviors. GPER antagonism with G15 reduces the G-1-induced response. Electrophysiological recordings from superficial dorsal horn neurons indicate neuronal membrane depolarization with G-1......Human and animal studies suggest that estrogens are involved in the processing of nociceptive sensory information and analgesic responses in the central nervous system. Rapid pronociceptive estrogenic effects have been reported, some of which likely involve G protein-coupled estrogen receptor (GPER......) activation. Membrane depolarization and increases in cytosolic calcium and reactive oxygen species (ROS) levels are markers of neuronal activation, underlying pain sensitization in the spinal cord. Using behavioral, electrophysiological, and fluorescent imaging studies, we evaluated GPER involvement...

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

    Science.gov (United States)

    Dimov, Luiz Fabio; Franciosi, Adriano Cardozo; Campos, Ana Carolina Pinheiro; Brunoni, André Russowsky

    2016-01-01

    Transcranial direct current stimulation (tDCS) is an emerging, noninvasive technique of neurostimulation for treating pain. However, the mechanisms and pathways involved in its analgesic effects are poorly understood. Therefore, we investigated the effects of direct current stimulation (DCS) on thermal and mechanical nociceptive thresholds and on the activation of the midbrain periaqueductal gray (PAG) and the dorsal horn of the spinal cord (DHSC) in rats; these central nervous system areas are associated with pain processing. Male Wistar rats underwent cathodal DCS of the motor cortex and, while still under stimulation, were evaluated using tail-flick and paw pressure nociceptive tests. Sham stimulation and naive rats were used as controls. We used a randomized design; the assays were not blinded to the experimenter. Immunoreactivity of the early growth response gene 1 (Egr-1), which is a marker of neuronal activation, was evaluated in the PAG and DHSC, and enkephalin immunoreactivity was evaluated in the DHSC. DCS did not change the thermal nociceptive threshold; however, it increased the mechanical nociceptive threshold of both hind paws compared with that of controls, characterizing a topographical effect. DCS decreased the Egr-1 labeling in the PAG and DHSC as well as the immunoreactivity of spinal enkephalin. Altogether, the data suggest that DCS disinhibits the midbrain descending analgesic pathway, consequently inhibiting spinal nociceptive neurons and causing an increase in the nociceptive threshold. This study reinforces the idea that the motor cortex participates in the neurocircuitry that is involved in analgesia and further clarifies the mechanisms of action of tDCS in pain treatment. PMID:27071073

  4. Anticipation of pain enhances the nociceptive transmission and functional connectivity within pain network in rats

    Directory of Open Access Journals (Sweden)

    Baccalá Luiz A

    2008-08-01

    Full Text Available Abstract Background Expectation is a very potent pain modulator in both humans and animals. There is evidence that pain transmission neurons are modulated by expectation preceding painful stimuli. Nonetheless, few studies have examined the influence of pain expectation on the pain-related neuronal activity and the functional connectivity within the central nociceptive network. Results This study used a tone-laser conditioning paradigm to establish the pain expectation in rats, and simultaneously recorded the anterior cingulate cortex (ACC, the medial dorsal thalamus (MD, and the primary somatosensory cortex (SI to investigate the effect of pain expectation on laser-induced neuronal responses. Cross-correlation and partial directed coherence analysis were used to determine the functional interactions within and between the recorded areas during nociceptive transmission. The results showed that under anticipation condition, the neuronal activity to the auditory cue was significantly increased in the ACC area, whereas those to actual noxious stimuli were enhanced in all the recorded areas. Furthermore, neuronal correlations within and between these areas were significantly increased under conditions of expectation compared to those under non-expectation conditions, indicating an enhanced synchronization of neural activity within the pain network. In addition, information flow from the medial (ACC and MD to the lateral (SI cortex pain pathway increased, suggesting that the emotion-related neural circuits may modulate the neuronal activity in the somatosensory pathway during nociceptive transmission. Conclusion These results demonstrate that the nociceptive processing in both medial and lateral pain systems is modulated by the expectation of pain.

  5. Connectivity of Pacemaker Neurons in the Neonatal Rat Superficial Dorsal Horn

    Science.gov (United States)

    Ford, Neil C.; Arbabi, Shahriar; Baccei, Mark L.

    2014-01-01

    Pacemaker neurons with an intrinsic ability to generate rhythmic burst-firing have been characterized in lamina I of the neonatal spinal cord, where they are innervated by high-threshold sensory afferents. However, little is known about the output of these pacemakers, as the neuronal populations which are targeted by pacemaker axons have yet to be identified. The present study combines patch clamp recordings in the intact neonatal rat spinal cord with tract-tracing to demonstrate that lamina I pacemaker neurons contact multiple spinal motor pathways during early life. Retrograde labeling of premotor interneurons with the trans-synaptic virus PRV-152 revealed the presence of burst-firing in PRV-infected lamina I neurons, thereby confirming that pacemakers are synaptically coupled to motor networks in the spinal ventral horn. Notably, two classes of pacemakers could be distinguished in lamina I based on cell size and the pattern of their axonal projections. While small pacemaker neurons possessed ramified axons which contacted ipsilateral motor circuits, large pacemaker neurons had unbranched axons which crossed the midline and ascended rostrally in the contralateral white matter. Recordings from identified spino-parabrachial and spino-PAG neurons indicated the presence of pacemaker activity within neonatal lamina I projection neurons. Overall, these results show that lamina I pacemakers are positioned to regulate both the level of activity in developing motor circuits as well as the ascending flow of nociceptive information to the brain, thus highlighting a potential role for pacemaker activity in the maturation of pain and sensorimotor networks in the CNS. PMID:25380417

  6. The role of Drosophila Piezo in mechanical nociception.

    Science.gov (United States)

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

    2012-02-19

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

  7. Endocannabinoid-dependent long-term depression in a nociceptive synapse requires coordinated presynaptic and postsynaptic transcription and translation.

    Science.gov (United States)

    Yuan, Sharleen; Burrell, Brian D

    2013-03-06

    Endocannabinoids (eCBs) play an important role in long-term regulation of synaptic signaling in both vertebrates and invertebrates. In this study, the role of transcription- and translation-dependent processes in presynaptic versus postsynaptic neurons was examined during eCB-mediated synaptic plasticity in the CNS of the leech. Low-frequency stimulation (LFS) of non-nociceptive afferents elicits eCB-dependent long-term depression (eCB-LTD) heterosynaptically in nociceptive synapses that lasts at least 2 h. Bath application of emetine, a protein synthesis inhibitor, blocked eCB-LTD after afferent LFS or exogenous eCB application, indicating that this depression was translation dependent. Bath application of actinomycin D, an irreversible RNA synthesis inhibitor, or 5,6-dichlorobenzimidazole 1-β-d-ribofurandoside (DRB), a reversible RNA synthesis inhibitor, also prevented eCB-LTD. Selective injection of DRB or emetine into the presynaptic or postsynaptic neuron before LFS indicated that eCB-LTD required transcription and translation in the postsynaptic neuron but only translation in the presynaptic cell. Depression observed immediately after LFS was also blocked when these transcription- and translation-dependent processes were inhibited. It is proposed that induction of eCB-LTD in this nociceptive synapse requires the coordination of presynaptic protein synthesis and postsynaptic mRNA and protein synthesis. These findings provide significant insights into both eCB-based synaptic plasticity and understanding how activity in non-nociceptive afferents modulates nociceptive pathways.

  8. Regression of polyneural innervation in the human psoas muscle

    NARCIS (Netherlands)

    Gramsbergen, A; IjkemaPaassen, J; Nikkels, PGJ; HaddersAlgra, M

    1997-01-01

    During the early stages of mammalian ontogeny muscle fibres are innervated by more than one axon. This polyneural innervation is replaced by mononeural innervation in the course of development. The regression of polyneural innervation in the psoas muscle in the human is the topic of the present stud

  9. Endocannabinoids in the brainstem modulate dural trigeminovascular nociceptive traffic via CB1 and "triptan" receptors: implications in migraine.

    Science.gov (United States)

    Akerman, Simon; Holland, Philip R; Lasalandra, Michele P; Goadsby, Peter J

    2013-09-11

    Activation and sensitization of trigeminovascular nociceptive pathways is believed to contribute to the neural substrate of the severe and throbbing nature of pain in migraine. Endocannabinoids, as well as being physiologically analgesic, are known to inhibit dural trigeminovascular nociceptive responses. They are also involved in the descending modulation of cutaneous-evoked C-fiber spinal nociceptive responses from the brainstem. The purpose of this study was to determine whether endocannabinoids are involved in the descending modulation of dural and/or cutaneous facial trigeminovascular nociceptive responses, from the brainstem ventrolateral periaqueductal gray (vlPAG). CB1 receptor activation in the vlPAG attenuated dural-evoked Aδ-fiber neurons (maximally by 19%) and basal spontaneous activity (maximally by 33%) in the rat trigeminocervical complex, but there was no effect on cutaneous facial receptive field responses. This inhibitory vlPAG-mediated modulation was inhibited by specific CB1 receptor antagonism, given via the vlPAG, and with a 5-HT1B/1D receptor antagonist, given either locally in the vlPAG or systemically. These findings demonstrate for the first time that brainstem endocannabinoids provide descending modulation of both basal trigeminovascular neuronal tone and Aδ-fiber dural-nociceptive responses, which differs from the way the brainstem modulates spinal nociceptive transmission. Furthermore, our data demonstrate a novel interaction between serotonergic and endocannabinoid systems in the processing of somatosensory nociceptive information, suggesting that some of the therapeutic action of triptans may be via endocannabinoid containing neurons in the vlPAG.

  10. Effects of the re-innervation of organotypic skin explants on the epidermis.

    Science.gov (United States)

    Lebonvallet, Nicolas; Boulais, Nicholas; Le Gall, Christelle; Pereira, Ulysse; Gauché, Dominique; Gobin, Eric; Pers, Jacques-Olivier; Jeanmaire, Christine; Danoux, Louis; Pauly, Gilles; Misery, Laurent

    2012-02-01

    The nervous system takes part in skin homeostasis and interacts with skin cells. In in vitro organotypic skin models, these interactions are lost owing to the absence of nerve endings. We have developed an in vitro organotypic skin model based on a re-innervated human skin explant using primary sensory neurons from the dorsal root ganglia of rats. After 10 days of co-culture between skin explant and neurons, a dense network of nerve fibres was observed. The epidermis and dermis presented nerve fibres associated with cellular body from sensory neurons introduced in the co-culture. Epidermal thickness, cell density and quality of re-innervated skin explant were all higher when skin explants were re-innervated by sensory neurons at 10 days of culture. Proliferation of epidermal cell was not modified, but the apoptosis was significantly diminished. Hence, this innovative model of co-cultured skin explants and neurons allows better epidermal integrity and could be useful for studies concerning interactions between the skin and its peripheral nervous system.

  11. Characterization of sensory neuron subpopulations selectively expressing green fluorescent protein in phosphodiesterase 1C BAC transgenic mice

    Directory of Open Access Journals (Sweden)

    Anderson Rebecca L

    2006-05-01

    Full Text Available Abstract Background The complex neuronal circuitry of the dorsal horn of the spinal cord is as yet poorly understood. However, defining the circuits underlying the transmission of information from primary afferents to higher levels is critical to our understanding of sensory processing. In this study, we have examined phosphodiesterase 1C (Pde1c BAC transgenic mice in which a green fluorescent protein (GFP reporter gene reflects Pde1c expression in sensory neuron subpopulations in the dorsal root ganglia and spinal cord. Results Using double labeling immunofluorescence, we demonstrate GFP expression in specific subpopulations of primary sensory neurons and a distinct neuronal expression pattern within the spinal cord dorsal horn. In the dorsal root ganglia, their distribution is restricted to those subpopulations of primary sensory neurons that give rise to unmyelinated C fibers (neurofilament 200 negative. A small proportion of both non-peptidergic (IB4-binding and peptidergic (CGRP immunoreactive subclasses expressed GFP. However, GFP expression was more common in the non-peptidergic than the peptidergic subclass. GFP was also expressed in a subpopulation of the primary sensory neurons immunoreactive for the vanilloid receptor TRPV1 and the ATP-gated ion channel P2X3. In the spinal cord dorsal horn, GFP positive neurons were largely restricted to lamina I and to a lesser extent lamina II, but surprisingly did not coexpress markers for key neuronal populations present in the superficial dorsal horn. Conclusion The expression of GFP in subclasses of nociceptors and also in dorsal horn regions densely innervated by nociceptors suggests that Pde1c marks a unique subpopulation of nociceptive sensory neurons.

  12. Lateral inhibition during nociceptive processing.

    Science.gov (United States)

    Quevedo, Alexandre S; Mørch, Carsten Dahl; Andersen, Ole K; Coghill, Robert C

    2017-06-01

    Spatial summation of pain (SSP) is the increase of perceived intensity that occurs as the stimulated area increases. Spatial summation of pain is subadditive in that increasing the stimulus area produces a disproportionately small increase in the perceived intensity of pain. A possible explanation for subadditive summation may be that convergent excitatory information is modulated by lateral inhibition. To test the hypothesis that lateral inhibition may limit SSP, we delivered different patterns of noxious thermal stimuli to the abdomens of 15 subjects using a computer-controlled CO2 laser. Lines (5 mm wide) of variable lengths (4, 8 cm) were compared with 2-point stimuli delivered at the same position/separation as the length of lines. When compared with one-point control stimuli, 2-point stimulus patterns produced statistically significant SSP, while no such summation was detected during line stimulus patterns. Direct comparison of pain intensity evoked by 2-point pattern stimuli with line pattern stimuli revealed that 2-point patterns were perceived as significantly more painful, despite the fact that the 2-point pattern stimulated far smaller areas of skin. Thus, the stimulation of the skin region between the endpoints of the lines appears to produce inhibition. These findings indicate that lateral inhibition limits SSP and is an intrinsic component of nociceptive information processing. Disruption of such lateral inhibition may contribute substantially to the radiation of some types of chronic pain.

  13. Succinate dehydrogenase activity and soma size of motoneurons innervating different portions of the rat tibialis anterior

    Science.gov (United States)

    Ishihara, A.; Roy, R. R.; Edgerton, V. R.

    1995-01-01

    The spatial distribution, soma size and oxidative enzyme activity of gamma and alpha motoneurons innervating muscle fibres in the deep (away from the surface of the muscle) and superficial (close to the surface of the muscle) portions of the tibialis anterior in normal rats were determined. The deep portion had a higher percentage of high oxidative fibres than the superficial portion of the muscle. Motoneurons were labelled by retrograde neuronal transport of fluorescent tracers: Fast Blue and Nuclear Yellow were injected into the deep portion and Nuclear Yellow into the superficial portion of the muscle. Therefore, motoneurons innervating the deep portion were identified by both a blue fluorescent cytoplasm and a golden-yellow fluorescent nucleus, while motoneurons innervating the superficial portion were identified by only a golden-yellow fluorescent nucleus. After staining for succinate dehydrogenase activity on the same section used for the identification of the motoneurons, soma size and succinate dehydrogenase activity of the motoneurons were measured. The gamma and alpha motoneurons innervating both the deep and superficial portions were located primarily at L4 and were intermingled within the same region of the dorsolateral portion of the ventral horn in the spinal cord. Mean soma size was similar for either gamma or alpha motoneurons in the two portions of the muscle. The alpha motoneurons innervating the superficial portion had a lower mean succinate dehydrogenase activity than those innervating the deep portion of the muscle. An inverse relationship between soma size and succinate dehydrogenase activity of alpha, but not gamma, motoneurons innervating both the deep and superficial portions was observed. Based on three-dimensional reconstructions within the spinal cord, there were no apparent differences in the spatial distribution of the motoneurons, either gamma or alpha, associated with the deep and superficial compartments of the muscle. The data

  14. Localization of Biogenic Amines in the Foregut of Aplysia californica: Catecholaminergic and Serotonergic Innervation

    Science.gov (United States)

    Martínez-Rubio, Clarissa; Serrano, Geidy E.; Miller, Mark W.

    2009-01-01

    This study examined the catecholaminergic and serotonergic innervation of the foregut of Aplysia californica, a model system in which the control of feeding behaviors can be investigated at the cellular level. Similar numbers (15-25) of serotonin-like-immunoreactive (5HTli) and tyrosine hydroxylase-like-immunoreactive (THli) fibers were present in each (bilateral) esophageal nerve (En), the major source of pregastric neural innervation in this system. The majority of En 5HTli and THli fibers originated from the anterior branch (En2), which innervates the pharynx and the anterior esophagus. Fewer fibers were present in the posterior branch (En1), which innervates the majority of the esophagus and the crop. Backfills of the two En branches toward the central nervous system (CNS) labeled a single, centrifugally projecting serotonergic fiber, originating from the metacerebral cell (MCC). The MCC fiber projected only to En2. No central THli neurons were found to project to the En. Surveys of the pharynx and esophagus revealed major differences between their patterns of catecholaminergic (CA) and serotonergic innervation. Whereas THli fibers and cell bodies were distributed throughout the foregut, 5HTli fibers were present in restricted plexi, and no 5HTli somata were detected. Double-labeling experiments in the periphery revealed THli neurons projecting toward the buccal ganglion via En2. Other afferents received dense perisomatic serotonergic innervation. Finally, qualitative and quantitative differences were observed between the buccal motor programs (BMPs) produced by stimulation of the two En branches. These observations increase our understanding of aminergic contributions to the pregastric regulation of Aplysia feeding behaviors. PMID:19330814

  15. A critical period for experience-dependent remodeling of adult-born neuron connectivity.

    Science.gov (United States)

    Bergami, Matteo; Masserdotti, Giacomo; Temprana, Silvio G; Motori, Elisa; Eriksson, Therese M; Göbel, Jana; Yang, Sung Min; Conzelmann, Karl-Klaus; Schinder, Alejandro F; Götz, Magdalena; Berninger, Benedikt

    2015-02-18

    Neurogenesis in the dentate gyrus (DG) of the adult hippocampus is a process regulated by experience. To understand whether experience also modifies the connectivity of new neurons, we systematically investigated changes in their innervation following environmental enrichment (EE). We found that EE exposure between 2-6 weeks following neuron birth, rather than merely increasing the number of new neurons, profoundly affected their pattern of monosynaptic inputs. Both local innervation by interneurons and to even greater degree long-distance innervation by cortical neurons were markedly enhanced. Furthermore, following EE, new neurons received inputs from CA3 and CA1 inhibitory neurons that were rarely observed under control conditions. While EE-induced changes in inhibitory innervation were largely transient, cortical innervation remained increased after returning animals to control conditions. Our findings demonstrate an unprecedented experience-dependent reorganization of connections impinging onto adult-born neurons, which is likely to have important impact on their contribution to hippocampal information processing.

  16. Annexin A2 regulates TRPA1-dependent nociception.

    Science.gov (United States)

    Avenali, Luca; Narayanan, Pratibha; Rouwette, Tom; Cervellini, Ilaria; Sereda, Michael; Gomez-Varela, David; Schmidt, Manuela

    2014-10-29

    The transient receptor potential A1 (TRPA1) channel is essential for vertebrate pain. Even though TRPA1 activation by ligands has been studied extensively, the molecular machinery regulating TRPA1 is only poorly understood. Using an unbiased proteomics-based approach we uncovered the physical association of Annexin A2 (AnxA2) with native TRPA1 in mouse sensory neurons. AnxA2 is enriched in a subpopulation of sensory neurons and coexpressed with TRPA1. Furthermore, we observe an increase of TRPA1 membrane levels in cultured sensory neurons from AnxA2-deficient mice. This is reflected by our calcium imaging experiments revealing higher responsiveness upon TRPA1 activation in AnxA2-deficient neurons. In vivo these findings are associated with enhanced nocifensive behaviors specifically in TRPA1-dependent paradigms of acute and inflammatory pain, while heat and mechanical sensitivity as well as TRPV1-mediated pain are preserved in AnxA2-deficient mice. Our results support a model whereby AnxA2 limits the availability of TRPA1 channels to regulate nociceptive signaling in vertebrates.

  17. The sympathetic postganglionic and sensory innervation of oviducal magnum in hen: a choleratoxin subunit B-conjugated horseradish peroxidase study

    Science.gov (United States)

    Liu, Jinxiong; Wang, Wenjie; Feng, Yamei; Li, Meiying; Bao, Huijun; Chen, Qiusheng

    2007-01-01

    The anatomy of the extrinsic innervation of the avian magnum has not been accurately demonstrated previously. In the present study, choleratoxin subunit B-conjugated horseradish peroxidase (CB-HRP) was used as a retrograde tracer to determine the sympathetic postganglionic and sensory innervation of the magnum of hens. With regard to the sympathetic postganglionic innervation, following CB-HRP injections under the serosa of the magnum, CB-HRP-positive neurons were found bilaterally in the C12–LS13 ganglia of the sympathetic chain, splanchnic ganglia and adrenal ganglia. The number of labelled neurons in the left ganglia of the sympathetic chain and splanchnic ganglia was approximately 2.1 times that in the right ganglia. This suggests that the unilateral magnum is bilaterally innervated with sympathetic postganglionic nerves, the left nerves being predominant. With regard to the sensory innervation, following tracer injections, CB-HRP-positive neurons were found bilaterally in the spinal ganglia C13–LS12, jugular ganglia and nodose ganglia. The number of positive cells in the left ganglia was about 2.2 times that in the right ganglia. In the spinal ganglia, 85.6% of the labelled neurons were in the T5–LS2 and LS8–LS11 ganglia. These results suggest that the sensory nerve fibres of the magnum reach the central nervous system principally via two groups of spinal ganglia and vagus nerves, and that the innervation is bilateral although the left-hand route predominates. Moreover, 45.7% of all the CB-HRP-labelled neurons were found in the rectal region of the intestinal nerve of Remak (INR), which suggests that the INR plays a very important role in the functional regulation of the magnum. PMID:17328711

  18. Trigemino-hypoglossal somatic reflex in the pharmacological studies of nociception in orofacial area.

    Science.gov (United States)

    Zubrzycki, Marek; Janecka, Anna; Zubrzycka, Maria

    2015-01-01

    Disorders involving the orofacial area represent a major medical and social problem. They are a consequence of central nociceptive processes associated with stimulation of the trigeminal nerve nucleus. A rat model of trigeminal pain, utilizing tongue jerks evoked by electrical tooth pulp stimulation during perfusion of the cerebral ventricles with various neuropeptide solutions, can be used in the pharmacological studies of nociception in orofacial area. The investigated neuropeptides diffuse through the cerebroventricular lining producing an analgesic effect either directly, through the trigemino-hypoglossal reflex arc neurons or indirectly through the periaqueductal central gray, raphe nuclei or locus coeruleus neurons. The aim of this review is to present the effect of pharmacological activity of various neuropeptides affecting the transmission of the sensory information from the orofacial area on the example of trigemino-hypoglossal reflex in rats.

  19. The role of Sema3–Npn-1 signaling during diaphragm innervation and muscle development

    Science.gov (United States)

    Huettl, Rosa-Eva; Hanuschick, Philipp; Amend, Anna-Lena; Alberton, Paolo; Aszodi, Attila; Huber, Andrea B.

    2016-01-01

    ABSTRACT Correct innervation of the main respiratory muscle in mammals, namely the thoracic diaphragm, is a crucial pre-requisite for the functionality of this muscle and the viability of the entire organism. Systemic impairment of Sema3A–Npn-1 (Npn-1 is also known as NRP1) signaling causes excessive branching of phrenic nerves in the diaphragm and into the central tendon region, where the majority of misguided axons innervate ectopic musculature. To elucidate whether these ectopic muscles are a result of misguidance of myoblast precursors due to the loss of Sema3A–Npn-1 signaling, we conditionally ablated Npn-1 in somatic motor neurons, which led to a similar phenotype of phrenic nerve defasciculation and, intriguingly, also formation of innervated ectopic muscles. We therefore hypothesize that ectopic myocyte fusion is caused by additional factors released by misprojecting growth cones. Slit2 and its Robo receptors are expressed by phrenic motor axons and migrating myoblasts, respectively, during innervation of the diaphragm. In vitro analyses revealed a chemoattractant effect of Slit2 on primary diaphragm myoblasts. Thus, we postulate that factors released by motor neuron growth cones have an influence on the migration properties of myoblasts during establishment of the diaphragm. PMID:27466379

  20. Nociception, Pain, Negative Moods, and Behavior Selection.

    Science.gov (United States)

    Baliki, Marwan N; Apkarian, A Vania

    2015-08-05

    Recent neuroimaging studies suggest that the brain adapts with pain, as well as imparts risk for developing chronic pain. Within this context, we revisit the concepts for nociception, acute and chronic pain, and negative moods relative to behavior selection. We redefine nociception as the mechanism protecting the organism from injury, while acute pain as failure of avoidant behavior, and a mesolimbic threshold process that gates the transformation of nociceptive activity to conscious pain. Adaptations in this threshold process are envisioned to be critical for development of chronic pain. We deconstruct chronic pain into four distinct phases, each with specific mechanisms, and outline current state of knowledge regarding these mechanisms: the limbic brain imparting risk, and the mesolimbic learning processes reorganizing the neocortex into a chronic pain state. Moreover, pain and negative moods are envisioned as a continuum of aversive behavioral learning, which enhance survival by protecting against threats.

  1. Sensory and sympathetic innervation of cervical facet joint in rats

    Institute of Scientific and Technical Information of China (English)

    ZHOU Hai-yu; CHEN An-min; GUO Feng-jing; LIAO Guang-jun; XIAO Wei-dong

    2006-01-01

    Objective: To explore the patterns of innervation of cervical facet joints and determine the pathways from facet joints to dorsal root ganglions (DRGs) in order to clarify the causes of diffuse neck pain, headache, and shoulder pain.Methods: Forty-two male Sprague-Dawley rats,weighing 250-300 g, were randomly divided into three groups: Group A ( n = 18), Group B ( n = 18), and Group C (n = 6 ). Under anesthesia with intraperitoneal pentobarbital sodium (45 mg/kg body weight), a midline dorsal longitudinal incision was made over the cervical spine to expose the left cervical facet joint capsule of all the rats under a microscope. The rats in Group A underwent sympathectomy, but the rats in Group B and Group C did not undergo sympathectomy. Then 0.6 μl 5 % bisbenzimide (Bb) were injected into the C1-2, C3-4 and C5-6 facet joints of 6 rats respectively in Group A and Group B. The holes were immediately sealed with mineral wax to prevent leakage of Bb and the fascia and skin were closed. But in Group C, 0.9% normal saline was injected into the corresponding joint capsules. Then under deep reanesthesia with intraperitoneal pentobarbital sodium (45 mg/kg body weight), C1-C8 left DRGs in all rats and the sympathetic ganglions in Group B were obtained and the number of the labeled neurons was determined.Results: Neurons labeled with Bb were present in C1-C8 DRGs in both Group A and Group B, and sympathetic ganglions in Group B. In the C1-2 and C3-4 subgroups,labeled neurons were present from C1 to C8 DRGs, while in C5-6 subgroups they were from C, to C8. The number of Bb ( + ) neurons after sympathectomy was not significantly different in the injected level from that without sympathectomy. But in the other levels, the number of Bb ( + ) neurons after sympathectomy was significantly less than that without sympathectomy.Conclusions: The innervation of the cervical facet joints is derived from both sensory and sympathetic nervous system, and DRGs are associated with

  2. Endometriosis-induced vaginal hyperalgesia in the rat: role of the ectopic growths and their innervation.

    Science.gov (United States)

    McAllister, Stacy L; McGinty, Kristina A; Resuehr, David; Berkley, Karen J

    2009-12-15

    Endometriosis is a painful disorder defined by extrauteral endometrial growths whose contribution to pain symptoms is poorly understood. Endometriosis is created in rats by autotransplanting on abdominal arteries pieces of either uterus (ENDO), which form cysts, or fat (shamENDO), which do not form cysts. ENDO, but not shamENDO induces vaginal hyperalgesia. We tested the hypothesis that the cysts are necessary to maintain vaginal hyperalgesia by assessing the effect of surgically removing them. Complete-cyst-removal eliminated ENDO-induced vaginal hyperalgesia up to 4 months post-operatively. Sham-cyst-removal in ENDO rats, in which cysts were not removed, or partial cyst-removal increased the ENDO-induced hyperalgesia. The decreases and increases both took 3-6 weeks to develop. Changes in ENDO-induced hyperalgesia did not occur in a control group of ENDO rats who had no surgery after ENDO. In a double-surgery control group, neither shamENDO surgery nor a subsequent sham surgery that mimicked "removal" of non-existent cysts influenced vaginal nociception. In a no-surgery control group, vaginal nociception remained stable for >6 months. The increases in ENDO-induced hyperalgesia produced by the sham-cyst-removal surgery were smaller in proestrus than in other estrous stages. During the other stages (but not during proestrus), sympathetic innervation of the cysts increased. These results suggest that maintenance of ENDO-induced vaginal hyperalgesia requires continued presence of at least some ectopic endometrial tissue, and that surgical treatment that fails to remove ectopic endometrial tissue can exacerbate the hyperalgesia, possibly due in part to an increase in the cysts' sympathetic innervation.

  3. Peptidergic innervation of human esophageal and cardiac carcinoma

    Institute of Scientific and Technical Information of China (English)

    Shuang-Hong Lü; Yan Zhou; Hai-Ping Que; Shao-Jun Liu

    2003-01-01

    AIM: To investigate the distribution of neuropeptideimmunoreactive nerve fibers in esophageal and cardiac carcinoma as well as their relationship with tumor cells so as to explore if there is nerve innervation in esophageal and cardiac carcinoma.METHODS: Esophageal and cardiac carcinoma specimens were collected from surgical operation. One part of them were fixed immediately with 4 % paraformaldehyde and then cut with a cryostat into 40-pm-thick sections to perform immunohistochemical analysis. Antibodies of ten kinds of neuropeptide including calcitonin gene-related peptide (CGRP), galanin (GAL), substance P (SP), etc. were used for immunostaining of nerve fibers. The other part of the tumor specimens were cut into little blocks (1 mm3) and cocultured with chick embryo dorsal root ganglia (DRG) to investigate if the tumor blocks could induce the neurons of DRG to extend processes, so as to probe into the possiblereasons for the nerve fibers growing into tumors. RESULTS: Substantial amounts of neuropeptide including GAL-, NPY-, SP-immunoreactive nerve bundles and scattered nerve fibers were distributed in esophageal and cardiac carcinomas. The scattered nerve fibers waved their way among tumor cells and contacted with tumor cells closely. Some of them even encircled tumor cells. There were many varicosities aligned on the nerve fibers like beads. They were also closely related to tumor cells. In the co-culture group, about 63 %and 67 % of DRG co-cultured with esophageal and cardiac tumor blocks respectively extended enormous processes,especially on the side adjacent to the tumor, whereas in the control group (without tumor blocks), no processes grew out.CONCLUSION: Esophageal and cardiac carcinomas may be innervated by peptidergic nerve fibers, and they can induce neurons of DRG to extend processes in vitro.

  4. TRPC1 contributes to light-touch sensation and mechanical responses in low-threshold cutaneous sensory neurons.

    Science.gov (United States)

    Garrison, Sheldon R; Dietrich, Alexander; Stucky, Cheryl L

    2012-02-01

    The cellular proteins that underlie mechanosensation remain largely enigmatic in mammalian systems. Mechanically sensitive ion channels are thought to distinguish pressure, stretch, and other types of tactile signals in skin. Transient receptor potential canonical 1 (TRPC1) is a candidate mechanically sensitive channel that is expressed in primary afferent sensory neurons. However, its role in the mechanical sensitivity of these neurons is unclear. Here, we investigated TRPC1-dependent responses to both innocuous and noxious mechanical force. Mechanically evoked action potentials in cutaneous myelinated A-fiber and unmyelinated C-fiber neurons were quantified using the ex vivo skin-nerve preparation to record from the saphenous nerve, which terminates in the dorsal hairy skin of the hindpaw. Our data reveal that in TRPC1-deficient mice, mechanically evoked action potentials were decreased by nearly 50% in slowly adapting Aβ-fibers, which largely innervate Merkel cells, and in rapidly adapting Aδ-Down-hair afferent fibers compared with wild-type controls. In contrast, differences were not found in slowly adapting Aδ-mechanoreceptors or unmyelinated C-fibers, which primarily respond to nociceptive stimuli. These results suggest that TRPC1 may be important in the detection of innocuous mechanical force. We concurrently investigated the role of TRPC1 in behavioral responses to mechanical force to the plantar hindpaw skin. For innocuous stimuli, we developed a novel light stroke assay using a "puffed out" cotton swab. Additionally, we used repeated light, presumably innocuous punctate stimuli with a low threshold von Frey filament (0.68 mN). In agreement with our electrophysiological data in light-touch afferents, TRPC1-deficient mice exhibited nearly a 50% decrease in behavioral responses to both the light-stroke and light punctate mechanical assays when compared with wild-type controls. In contrast, TRPC1-deficient mice exhibited normal paw withdrawal response to

  5. Non-peptidergic primary afferents are presynaptic to neurokinin-1 receptor immunoreactive lamina I projection neurons in rat spinal cord

    Directory of Open Access Journals (Sweden)

    Saeed Abeer W

    2012-09-01

    Full Text Available Abstract Background Pain-related (nociceptive information is carried from the periphery to the dorsal horn of the spinal cord mostly by two populations of small diameter primary afferents, the peptidergic and the non-peptidergic. The peptidergic population expresses neuropeptides, such as substance P and calcitonin gene-related peptide, while the non-peptidergic fibers are devoid of neuropeptides, express the purinergic receptor P2X3, and bind the isolectin B4 (IB4. Although it has been known for some time that in rat the peptidergic afferents terminate mostly in lamina I and outer lamina II and non-peptidergic afferents in inner lamina II, the extent of the termination of the latter population in lamina I was never investigated as it was considered as very minor. Because our preliminary evidence suggested otherwise, we decided to re-examine the termination of non-peptidergic afferents in lamina I, in particular with regards to their innervation of projection neurons expressing substance P receptors (NK-1r. We used retrograde labeling of neurons from the parabrachial nucleus combined with lectin IB4 binding and immunocytochemistry. Samples were examined by confocal and electron microscopy. Results By confocal microscopy, we studied the termination of non-peptidergic afferents in lamina I using IB4 binding and P2X3 immunoreactivity as markers, in relation to CGRP immunoreactivy, a marker of peptidergic afferents. The number of IB4 or P2X3-labeled fibers in lamina I was higher than previously thought, although they were less abundant than CGRP-labeled afferents. There were very few fibers double-labeled for CGRP and either P2X3 or IB4. We found a considerable number of IB4-positive fiber varicosities in close apposition to NK-1r-positive lamina I projection neurons, which were distinct from peptidergic varicosities. Furthermore, we confirmed at the ultrastructural level that there were bona fide synapses between P2X3-immunoreactive non

  6. The degree of acute descending control of spinal nociception in an area of primary hyperalgesia is dependent on the peripheral domain of afferent input.

    Science.gov (United States)

    Drake, Robert A R; Hulse, Richard P; Lumb, Bridget M; Donaldson, Lucy F

    2014-08-15

    Descending controls of spinal nociceptive processing play a critical role in the development of inflammatory hyperalgesia. Acute peripheral nociceptor sensitization drives spinal sensitization and activates spino-supraspinal-spinal loops leading to descending inhibitory and facilitatory controls of spinal neuronal activity that further modify the extent and degree of the pain state. The afferent inputs from hairy and glabrous skin are distinct with respect to both the profile of primary afferent classes and the degree of their peripheral sensitization. It is not known whether these differences in afferent input differentially engage descending control systems to different extents or in different ways. Injection of complete Freund's adjuvant resulted in inflammation and swelling of hairy hind foot skin in rats, a transient thermal hyperalgesia lasting hyperalgesia (≥7 days). Much longer lasting thermal hyperalgesia was apparent in glabrous skin (1 h to >72 h). In hairy skin, transient hyperalgesia was associated with sensitization of withdrawal reflexes to thermal activation of either A- or C-nociceptors. The transience of the hyperalgesia was attributable to a rapidly engaged descending inhibitory noradrenergic mechanism, which affected withdrawal responses to both A- and C-nociceptor activation and this could be reversed by intrathecal administration of yohimbine (α-2-adrenoceptor antagonist). In glabrous skin, yohimbine had no effect on an equivalent thermal inflammatory hyperalgesia. We conclude that acute inflammation and peripheral nociceptor sensitization in hind foot hairy skin, but not glabrous skin, rapidly activates a descending inhibitory noradrenergic system. This may result from differences in the engagement of descending control systems following sensitization of different primary afferent classes that innervate glabrous and hairy skin.

  7. Mild Hyperbaric Oxygen Improves Decreased Oxidative Capacity of Spinal Motoneurons Innervating the Soleus Muscle of Rats with Type 2 Diabetes.

    Science.gov (United States)

    Takemura, Ai; Ishihara, Akihiko

    2016-09-01

    Rats with type 2 diabetes exhibit decreased oxidative capacity, such as reduced oxidative enzyme activity, low-intensity staining for oxidative enzymes in fibers, and no high-oxidative type IIA fibers, in the skeletal muscle, especially in the soleus muscle. In contrast, there are no data available concerning the oxidative capacity of spinal motoneurons innervating skeletal muscle of rats with type 2 diabetes. This study examined the oxidative capacity of motoneurons innervating the soleus muscle of non-obese rats with type 2 diabetes. In addition, this study examined the effects of mild hyperbaric oxygen at 1.25 atmospheres absolute with 36 % oxygen for 10 weeks on the oxidative capacity of motoneurons innervating the soleus muscle because mild hyperbaric oxygen improves the decreased oxidative capacity of the soleus muscle in non-obese rats with type 2 diabetes. Spinal motoneurons innervating the soleus muscle were identified using nuclear yellow, a retrograde fluorescent neuronal tracer. Thereafter, the cell body sizes and succinate dehydrogenase activity of identified motoneurons were analyzed. Decreased succinate dehydrogenase activity of small-sized alpha motoneurons innervating the soleus muscle was observed in rats with type 2 diabetes. The decreased succinate dehydrogenase activity of these motoneurons was improved by mild hyperbaric oxygen. Therefore, we concluded that rats with type 2 diabetes have decreased oxidative capacity in motoneurons innervating the soleus muscle and this decreased oxidative capacity is improved by mild hyperbaric oxygen.

  8. Preganglionic innervation of the pancreas islet cells in the rat

    NARCIS (Netherlands)

    LUITEN, PGM; TERHORST, GJ; KOOPMANS, SJ; RIETBERG, M; STEFFENS, AB

    1984-01-01

    The position and number of preganglionic somata innervating the insulin-secreting β-cells of the endocrine pancreas were investigated in Wistar rats. This question was approached by comparing the innervation of the pancreas of normal rats with the innervation of the pancreas in alloxan-induced diabe

  9. Potent analgesic effects of anticonvulsants on peripheral thermal nociception in rats

    Science.gov (United States)

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

    2003-01-01

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

  10. Excitatory orexinergic innervation of rat nucleus incertus--Implications for ascending arousal, motivation and feeding control.

    Science.gov (United States)

    Blasiak, Anna; Siwiec, Marcin; Grabowiecka, Agnieszka; Blasiak, Tomasz; Czerw, Anna; Blasiak, Ewa; Kania, Alan; Rajfur, Zenon; Lewandowski, Marian H; Gundlach, Andrew L

    2015-12-01

    Orexin/hypocretin peptides play a central role in the integrated control of feeding/reward and behavioural activation, principally via interactions with other neural systems. A brainstem area involved in behavioural activation is the nucleus incertus (NI), located in the posterior ventromedial central grey. Several studies have implicated NI in control of arousal/stress and reward/feeding responses. Orexin receptor mRNA expression identifies NI as a putative target of orexin modulation. Therefore, in this study we performed neural tract-tracing and immunofluorescence staining to characterise the orexinergic innervation of NI. Our results indicate a convergent innervation of the NI area by different orexin neuron populations, with an abundance of orexin-A-containing axons making putative synaptic contacts with relaxin-3-positive NI neurons. The influence of orexin-A on NI neuron activity was investigated using patch-clamp recordings. Orexin-A depolarised the majority (64%) of recorded neurons and this effect was maintained in the presence of tetrodotoxin and glutamate and GABA receptor antagonists, indicating a likely postsynaptic action. Voltage-clamp experiments revealed that in 'type I' NI neurons comprising relaxin-3-positive cells, orexin-A acted via L-type calcium channels, whereas in 'type II' relaxin-3-negative neurons, activation of a sodium/calcium exchanger was involved. A majority of the orexin-A sensitive neurons tested for the presence of orexin receptor mRNA, were OX2 mRNA-positive. Immunohistochemical staining for putative orexin receptors on NI neurons, confirmed stronger expression of OX2 than OX1 receptors. Our data demonstrate a strong influence of orexin-A on NI neurons, consistent with an important role for this hypothalamic/tegmental circuit in the regulation of arousal/vigilance and motivated behaviours.

  11. Neuropeptidergic Signaling and Active Feeding State Inhibit Nociception in Caenorhabditis elegans

    Science.gov (United States)

    Ezcurra, Marina; Walker, Denise S.; Beets, Isabel; Swoboda, Peter

    2016-01-01

    Food availability and nutritional status are important cues affecting behavioral states. Here we report that, in Caenorhabditis elegans, a cascade of dopamine and neuropeptide signaling acts to inhibit nociception in food-poor environments. In the absence of food, animals show decreased sensitivity and increased adaptation to soluble repellents sensed by the polymodal ASH nociceptors. The effects of food on adaptation are affected by dopamine and neuropeptide signaling; dopamine acts via the DOP-1 receptor to decrease adaptation on food, whereas the neuropeptide receptors NPR-1 and NPR-2 act to increase adaptation off food. NPR-1 and NPR-2 function cell autonomously in the ASH neurons to increase adaptation off food, whereas the DOP-1 receptor controls neuropeptide release from interneurons that modulate ASH activity indirectly. These results indicate that feeding state modulates nociception through the interaction of monoamine and neuropeptide signaling pathways. PMID:26985027

  12. Experimental evidence for alleviating nociceptive hypersensitivity by single application of capsaicin.

    Science.gov (United States)

    Ma, Xiao-Li; Zhang, Fang-Xiong; Dong, Fei; Bao, Lan; Zhang, Xu

    2015-04-22

    The single application of high-concentration of capsaicin has been used as an analgesic therapy of persistent pain. However, its effectiveness and underlying mechanisms remain to be further evaluated with experimental approaches. The present study provided evidence showing that the single application of capsaicin dose-dependently alleviated nociceptive hypersensitivity, and reduced the action potential firing in small-diameter neurons of the dorsal root ganglia (DRG) in rats and mice. Pre-treatment with capsaicin reduced formalin-induced acute nocifensive behavior after a brief hyperalgesia in rats and mice. The inhibitory effects of capsaicin were calcium-dependent, and mediated by the capsaicin receptor (transient receptor potential vanilloid type-1). We further found that capsaicin exerted inhibitory effects on the persistent nociceptive hypersensitivity induced by peripheral inflammation and nerve injury. Thus, these results support the long-lasting and inhibitory effects of topical capsaicin on persistent pain, and the clinic use of capsaicin as a pain therapy.

  13. Lacosamide: A novel antiepileptic and anti-nociceptive drug on the block

    Directory of Open Access Journals (Sweden)

    Sukhminder Jit Singh Bajwa

    2014-01-01

    Full Text Available With an increasing demand for newer anti-epileptic agents having a better pharmacological profile, many newer agents are being investigated. Lacosamide is a newer functional amino acid being developed as an adjunctive therapy for resistant partial-onset seizures owing to its activity of enhancing the slow inactivation of voltage-gated sodium channels thereby reducing pathologic hyperactivity in neurons. It has also being investigated for its role as anti-nociceptive in variety of pain scenarios specifically in diabetic neuropathic pain. It is well-absorbed orally, metabolized in liver and excreted by the kidneys. It has a favorable pharmacologic profile in having minimal drug interactions. The adverse effects include mild dizziness, behavioral changes and dose dependent prolongation of PR interval. This review is directed toward the development of lacosamide and its potential usefulness as an anti-epileptic and an anti-nociceptive drug.

  14. Neuropeptidergic Signaling and Active Feeding State Inhibit Nociception in Caenorhabditis elegans.

    Science.gov (United States)

    Ezcurra, Marina; Walker, Denise S; Beets, Isabel; Swoboda, Peter; Schafer, William R

    2016-03-16

    Food availability and nutritional status are important cues affecting behavioral states. Here we report that, in Caenorhabditis elegans, a cascade of dopamine and neuropeptide signaling acts to inhibit nociception in food-poor environments. In the absence of food, animals show decreased sensitivity and increased adaptation to soluble repellents sensed by the polymodal ASH nociceptors. The effects of food on adaptation are affected by dopamine and neuropeptide signaling; dopamine acts via the DOP-1 receptor to decrease adaptation on food, whereas the neuropeptide receptors NPR-1 and NPR-2 act to increase adaptation off food. NPR-1 and NPR-2 function cell autonomously in the ASH neurons to increase adaptation off food, whereas the DOP-1 receptor controls neuropeptide release from interneurons that modulate ASH activity indirectly. These results indicate that feeding state modulates nociception through the interaction of monoamine and neuropeptide signaling pathways.

  15. Light and electron microscopic analysis of the somata and parent axons innervating the rat upper molar and lower incisor pulp.

    Science.gov (United States)

    Paik, S K; Park, K P; Lee, S K; Ma, S K; Cho, Y S; Kim, Y K; Rhyu, I J; Ahn, D K; Yoshida, A; Bae, Y C

    2009-09-15

    The morphology of intradental nerve fibers of permanent teeth and of continuously growing rodent incisors has been studied in detail but little information is available on the parent axons that give rise to these fibers. Here we examined the axons and somata of trigeminal neurons that innervate the rat upper molar and lower incisor pulp using tracing with horseradish peroxidase and light and electron microscopic analysis. The majority (approximately 80%) of the parent axons in the proximal root of the trigeminal ganglion that innervated either molar or incisor pulp were small myelinated fibers (fibers were almost exclusively large myelinated for the molar pulp and unmyelinated for the incisor pulp. The majority of neuronal somata in the trigeminal ganglion that innervated either molar (48%) or incisor pulp (62%) were medium in size (300-600 microm(2) cross-sectional area). Large somata (>600 microm(2)) constituted 34% and 20% of the trigeminal neurons innervating molar and incisor pulp, respectively, while small somata (fiber function may be carried out differently in the molar and incisor pulp in the rat.

  16. Glial activation in the collagenase model of nociception associated with osteoarthritis

    Science.gov (United States)

    Almeida, Lígia; Potes, Catarina S; Ferreira, Ana Rita; Castro-Lopes, José M; Ferreira-Gomes, Joana; Neto, Fani L

    2017-01-01

    Background Experimental osteoarthritis entails neuropathic-like changes in dorsal root ganglia (DRG) neurons. Since glial activation has emerged as a key player in nociception, being reported in numerous models of neuropathic pain, we aimed at evaluating if glial cell activation may also occur in the DRG and spinal cord of rats with osteoarthritis induced by intra-articular injection of collagenase. Methods Osteoarthritis was induced by two injections, separated by three days, of 500 U of type II collagenase into the knee joint of rats. Movement-induced nociception was evaluated by the Knee-Bend and CatWalk tests during the following six weeks. Glial fibrillary acidic protein (GFAP) expression in satellite glial cells of the DRG was assessed by immunofluorescence and Western Blot analysis; the pattern of GFAP and activating transcription factor-3 (ATF-3) expression was also compared through double immunofluorescence analysis. GFAP expression in astrocytes and IBA-1 expression in microglia of the L3–L5 spinal cord segments was assessed by immunohistochemistry and Western Blot analysis. The effect of the intrathecal administration of fluorocitrate, an inhibitor of glial activation, on movement-induced nociception was evaluated six weeks after the first collagenase injection. Results GFAP expression in satellite glial cells of collagenase-injected animals was significantly increased six weeks after osteoarthritis induction. Double immunofluorescence showed GFAP upregulation in satellite glial cells surrounding ATF-3-positive neurons. In the spinal cord of collagenase-injected animals, an ipsilateral upregulation of GFAP and IBA-1 was also observed. The inhibition of glial activation with fluorocitrate decreased movement- and loading-induced nociception. Conclusion Collagenase-induced knee osteoarthritis leads to the development of nociception associated with movement of the affected joint and to the activation of glial cells in both the DRG and the spinal cord

  17. Glial activation in the collagenase model of nociception associated with osteoarthritis.

    Science.gov (United States)

    Adães, Sara; Almeida, Lígia; Potes, Catarina S; Ferreira, Ana Rita; Castro-Lopes, José M; Ferreira-Gomes, Joana; Neto, Fani L

    2017-01-01

    Background Experimental osteoarthritis entails neuropathic-like changes in dorsal root ganglia (DRG) neurons. Since glial activation has emerged as a key player in nociception, being reported in numerous models of neuropathic pain, we aimed at evaluating if glial cell activation may also occur in the DRG and spinal cord of rats with osteoarthritis induced by intra-articular injection of collagenase. Methods Osteoarthritis was induced by two injections, separated by three days, of 500 U of type II collagenase into the knee joint of rats. Movement-induced nociception was evaluated by the Knee-Bend and CatWalk tests during the following six weeks. Glial fibrillary acidic protein (GFAP) expression in satellite glial cells of the DRG was assessed by immunofluorescence and Western Blot analysis; the pattern of GFAP and activating transcription factor-3 (ATF-3) expression was also compared through double immunofluorescence analysis. GFAP expression in astrocytes and IBA-1 expression in microglia of the L3-L5 spinal cord segments was assessed by immunohistochemistry and Western Blot analysis. The effect of the intrathecal administration of fluorocitrate, an inhibitor of glial activation, on movement-induced nociception was evaluated six weeks after the first collagenase injection. Results GFAP expression in satellite glial cells of collagenase-injected animals was significantly increased six weeks after osteoarthritis induction. Double immunofluorescence showed GFAP upregulation in satellite glial cells surrounding ATF-3-positive neurons. In the spinal cord of collagenase-injected animals, an ipsilateral upregulation of GFAP and IBA-1 was also observed. The inhibition of glial activation with fluorocitrate decreased movement- and loading-induced nociception. Conclusion Collagenase-induced knee osteoarthritis leads to the development of nociception associated with movement of the affected joint and to the activation of glial cells in both the DRG and the spinal cord

  18. Hippocampal CA3 pyramidal cells selectively innervate aspiny interneurons.

    Science.gov (United States)

    Wittner, Lucia; Henze, Darrell A; Záborszky, László; Buzsáki, György

    2006-09-01

    The specific connectivity among principal cells and interneurons determines the flow of activity in neuronal networks. To elucidate the connections between hippocampal principal cells and various classes of interneurons, CA3 pyramidal cells were intracellularly labelled with biocytin in anaesthetized rats and the three-dimensional distribution of their axon collaterals was reconstructed. The sections were double-stained for substance P receptor (SPR)- or metabotropic glutamate receptor 1alpha (mGluR-1alpha)-immunoreactivity to investigate interneuron targets of the CA3 pyramidal cells. SPR-containing interneurons represent a large portion of the GABAergic population, including spiny and aspiny classes. Axon terminals of CA3 pyramidal cells contacted SPR-positive interneuron dendrites in the hilus and in all hippocampal strata in both CA3 and CA1 regions (7.16% of all boutons). The majority of axons formed single contacts (87.5%), but multiple contacts (up to six) on single target neurons were also found. CA3 pyramidal cell axon collaterals innervated several types of morphologically different aspiny SPR-positive interneurons. In contrast, spiny SPR-interneurons or mGluR-1alpha-positive interneurons in the hilus, CA3 and CA1 regions were rarely contacted by the filled pyramidal cells. These findings indicate a strong target selection of CA3 pyramidal cells favouring the activation of aspiny classes of interneurons.

  19. Medulla Oblongata Mechanism of Inhibitory Effect of Thermal Stimulation to Nociceptive Colorectal Distention in Rats

    Institute of Scientific and Technical Information of China (English)

    Liang Li; Pei-Jing Rong; Xin-Yan Gao; Hui Ben; Hong Cai; Bing Zhu

    2016-01-01

    Objective: To discuss mechanism of moxibustion (thermal stimulation) effect and best moxibustion stimulus parameter. Methods: Experiments were performed on 48 male Sprague-Dawley rats. Unit discharges from individual single neuron were recorded extracellularly with glass-microelectrode in Subnucleus Reticularis Dorsalis (SRD). Visceral-intrusive stimulation is done by colorectal distension. Thermal stimulation with different temperature (40°C, 42°C, 44°C, 46°C, 48°C, 50°C, 52°C) and different stimulus area (diameter of circle:1.0 cm, 1.5 cm, 2.0 cm, 2.5 cm, 3.0 cm, 3.5 cm, 4.0cm) was applied around RN12 during nociceptive colorectal distension. Results: SRD neurons could be activated by visceral stimulation within noxious range. Under low temperature of stimulus, especially under 45°C of pain threshold to ordinary people, visceral nociceptive afferent facilitated thermal stimulus from the body surface. While after thermal stimulation reached a harmful degree, the thermal stimulus will inhibit visceral nociceptive afferent. Moreover, statistics show that the higher the temperature is, the smaller the size of stimulation area is needed, and they correlate with each other negatively. Conclusion: Visceral nociception could be inhibited by somatic thermal stimulation with specific parameter at medulla level. According to our finding, best thermal stimulation temperature is around 48°C and the best size of stimulation area is around 3.14-7.07cm2 (with 2.0-3.0cm diameter).

  20. Origins of serotonin innervation of forebrain structures

    Science.gov (United States)

    Kellar, K. J.; Brown, P. A.; Madrid, J.; Bernstein, M.; Vernikos-Danellis, J.; Mehler, W. R.

    1977-01-01

    The tryptophan hydroxylase activity and high-affinity uptake of (3H) serotonin ((3H)5-HT) were measured in five discrete brain regions of rats following lesions of the dorsal or median raphe nuclei. Dorsal raphe lesions reduced enzyme and uptake activity in the striatum only. Median raphe lesions reduced activities in the hippocampus, septal area, frontal cortex, and, to a lesser extent, in the hypothalamus. These data are consistent with the suggestion that the dorsal and median raphe nuclei are the origins of two separate ascending serotonergic systems - one innervating striatal structures and the other mesolimbic structures, predominantly. In addition, the data suggest that measurements of high-affinity uptake of (3H)5-HT may be a more reliable index of innervation than either 5-HT content or tryptophan hydroxylase activity.

  1. Development of Postural Muscles and Their Innervation

    Directory of Open Access Journals (Sweden)

    J. IJkema-Paassen

    2005-01-01

    Full Text Available Control of posture is a prerequisite for efficient motor performance. Posture depends on muscles capable of enduring contractions, whereas movements often require quick, forceful muscle actions. To serve these different goals, muscles contain fibers that meet these different tasks. Muscles with strong postural functions mainly consist of slow muscle fibers with a great resistance against fatigue. Flexor muscles in the leg and arm muscles are mainly composed of fast muscle fibers producing relatively large forces that are rapidly fatigable. Development of the neuromuscular system continues after birth. We discuss in the human baby and in animal experiments changes in muscle fiber properties, regression from polyneural into mononeural innervation, and developmental changes in the motoneurons of postural muscles during that period. The regression of poly-neural innervation in postural muscles and the development of dendrite bundles of their motoneurons seem to be linked to the transition from the immature into the adult-like patterns of moving and postural control.

  2. Nociceptive Effects of Locally Treated Metoprolol

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    Nursima Cukadar

    2015-06-01

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

  3. TRPV1 and TRPA1 mediate peripheral nitric oxide-induced nociception in mice.

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    Takashi Miyamoto

    Full Text Available Nitric oxide (NO can induce acute pain in humans and plays an important role in pain sensitization caused by inflammation and injury in animal models. There is evidence that NO acts both in the central nervous system via a cyclic GMP pathway and in the periphery on sensory neurons through unknown mechanisms. It has recently been suggested that TRPV1 and TRPA1, two polymodal ion channels that sense noxious stimuli impinging on peripheral nociceptors, are activated by NO in heterologous systems. Here, we investigate the relevance of this activation. We demonstrate that NO donors directly activate TRPV1 and TRPA1 in isolated inside-out patch recordings. Cultured primary sensory neurons display both TRPV1- and TRPA1-dependent responses to NO donors. BH4, an essential co-factor for NO production, causes activation of a subset of DRG neurons as assayed by calcium imaging, and this activation is at least partly dependent on nitric oxide synthase activity. We show that BH4-induced calcium influx is ablated in DRG neurons from TRPA1/TRPV1 double knockout mice, suggesting that production of endogenous levels of NO can activate these ion channels. In behavioral assays, peripheral NO-induced nociception is compromised when TRPV1 and TRPA1 are both ablated. These results provide genetic evidence that the peripheral nociceptive action of NO is mediated by both TRPV1 and TRPA1.

  4. Organization of the motoneurons innervating the pelvic muscles of the male rat

    DEFF Research Database (Denmark)

    Schrøder, H D

    1980-01-01

    The cytoarchitecture of the motoneuron pool of the male rat was studied at the lumbo-sacral transition area, particularly in L6. In the latter segment a dorso-medial (DM), ventral (V), dorso-lateral (DL), and retrodorso-lateral group (RDL) could be defined. The DL group was associated with a prom......The cytoarchitecture of the motoneuron pool of the male rat was studied at the lumbo-sacral transition area, particularly in L6. In the latter segment a dorso-medial (DM), ventral (V), dorso-lateral (DL), and retrodorso-lateral group (RDL) could be defined. The DL group was associated......, and sphincter ani were each innervated by two populations of neurons that were situated in separate areas which had different histochemical properties, and which thus probably have different compositions of their afferent inputs. The duality in the motoneuron pool that innervates the pelvic mucscle might...

  5. [Efferent innervation of pulmonary blood vessels and bronchi in rat (an immunohistochemical study)].

    Science.gov (United States)

    Chumasov, E I; Voronchikhin, P A; Korzhevskiĭ, D É

    2012-01-01

    In this investigation the peculiarities of innervation of bronchi and blood vessels of the lung were studied in 20 rats using immunohistochemical demonstration of synaptophysin and alpha-actin. The results obtained have showen that the densest innervation is typical for bronchial walls, particularly, for the muscular lamina. Synaptophysin-immunoreactive terminals (SFIT) were detected in the bronchi in close association with both circular bundles of smooth muscle cells and microganglia. Dense network of SFIT was found in the pulmonary vein--in its middle tunic formed by cardiomyocytes. In contrast to the bronchi and pulmonary vein, large branches of the pulmonary artery contained no SFIT. We briefly discuss the problem of the origin of the nerve fibers described and their functions and suggest that SFIT are formed by efferent fibers (axons) of neurons arising from either the intrapulmonary parasympathetic ganglia.

  6. Macrophages associated with the intrinsic and extrinsic autonomic innervation of the rat gastrointestinal tract.

    Science.gov (United States)

    Phillips, Robert J; Powley, Terry L

    2012-07-02

    Interactions between macrophages and the autonomic innervation of gastrointestinal (GI) tract smooth muscle have received little experimental attention. To better understand this relationship, immunohistochemistry was performed on GI whole mounts from rats at three ages. The phenotypes, morphologies, and distributions of gut macrophages are consistent with the cells performing extensive housekeeping functions in the smooth muscle layers. Specifically, a dense population of macrophages was located throughout the muscle wall where they were distributed among the muscle fibers and along the vasculature. Macrophages were also associated with ganglia and connectives of the myenteric plexus and with the sympathetic innervation. Additionally, these cells were in tight registration with the dendrites and axons of the myenteric neurons as well as the varicosities along the length of the sympathetic axons, suggestive of a contribution by the macrophages to the homeostasis of both synapses and contacts between the various elements of the enteric circuitry. Similarly, macrophages were involved in the presumed elimination of neuropathies as indicated by their association with dystrophic neurons and neurites which are located throughout the myenteric plexus and smooth muscle wall of aged rats. Importantly, the patterns of macrophage-neuron interactions in the gut paralleled the much more extensively characterized interactions of macrophages (i.e., microglia) and neurons in the CNS. The present observations in the PNS as well as extrapolations from homologous microglia in the CNS suggest that GI macrophages play significant roles in maintaining the nervous system of the gut in the face of wear and tear, disease, and aging.

  7. Spatiotemporal dynamics of re-innervation and hyperinnervation patterns by uninjured CGRP fibers in the rat foot sole epidermis after nerve injury.

    Science.gov (United States)

    Duraku, Liron S; Hossaini, Mehdi; Hoendervangers, Sieske; Falke, Lukas L; Kambiz, Shoista; Mudera, Vivek C; Holstege, Joan C; Walbeehm, Erik T; Ruigrok, Tom J H

    2012-08-30

    The epidermis is innervated by fine nerve endings that are important in mediating nociceptive stimuli. However, their precise role in neuropathic pain is still controversial. Here, we have studied the role of epidermal peptidergic nociceptive fibers that are located adjacent to injured fibers in a rat model of neuropathic pain. Using the Spared Nerve Injury (SNI) model, which involves complete transections of the tibial and common peroneal nerve while sparing the sural and saphenous branches, mechanical hypersensitivity was induced of the uninjured lateral (sural) and medial (saphenous) area of the foot sole. At different time points, a complete foot sole biopsy was taken from the injured paw and processed for Calcitonin Gene-Related Peptide (CGRP) immunohistochemistry. Subsequently, a novel 2D-reconstruction model depicting the density of CGRP fibers was made to evaluate the course of denervation and re-innervation by uninjured CGRP fibers. The results show an increased density of uninjured CGRP-IR epidermal fibers on the lateral and medial side after a SNI procedure at 5 and 10 weeks. Furthermore, although in control animals the density of epidermal CGRP-IR fibers in the footpads was lower compared to the surrounding skin of the foot, 10 weeks after the SNI procedure, the initially denervated footpads displayed a hyper-innervation. These data support the idea that uninjured fibers may play a considerable role in development and maintenance of neuropathic pain and that it is important to take larger biopsies to test the relationship between innervation of injured and uninjured nerve areas.

  8. Spatiotemporal dynamics of re-innervation and hyperinnervation patterns by uninjured CGRP fibers in the rat foot sole epidermis after nerve injury

    Directory of Open Access Journals (Sweden)

    Duraku Liron S

    2012-08-01

    Full Text Available Abstract The epidermis is innervated by fine nerve endings that are important in mediating nociceptive stimuli. However, their precise role in neuropathic pain is still controversial. Here, we have studied the role of epidermal peptidergic nociceptive fibers that are located adjacent to injured fibers in a rat model of neuropathic pain. Using the Spared Nerve Injury (SNI model, which involves complete transections of the tibial and common peroneal nerve while sparing the sural and saphenous branches, mechanical hypersensitivity was induced of the uninjured lateral (sural and medial (saphenous area of the foot sole. At different time points, a complete foot sole biopsy was taken from the injured paw and processed for Calcitonin Gene-Related Peptide (CGRP immunohistochemistry. Subsequently, a novel 2D-reconstruction model depicting the density of CGRP fibers was made to evaluate the course of denervation and re-innervation by uninjured CGRP fibers. The results show an increased density of uninjured CGRP-IR epidermal fibers on the lateral and medial side after a SNI procedure at 5 and 10 weeks. Furthermore, although in control animals the density of epidermal CGRP-IR fibers in the footpads was lower compared to the surrounding skin of the foot, 10 weeks after the SNI procedure, the initially denervated footpads displayed a hyper-innervation. These data support the idea that uninjured fibers may play a considerable role in development and maintenance of neuropathic pain and that it is important to take larger biopsies to test the relationship between innervation of injured and uninjured nerve areas.

  9. Sensory innervation of the dorsal longitudinal ligament and the meninges in the lumbar spine of the dog.

    Science.gov (United States)

    Waber-Wenger, Barbara; Forterre, Franck; Kuehni-Boghenbor, Kathrin; Danuser, Renzo; Stein, Jens Volker; Stoffel, Michael Hubert

    2014-10-01

    Although intervertebral disc herniation is a well-known disease in dogs, pain management for this condition has remained a challenge. The goal of the present study is to address the lack of information regarding the innervation of anatomical structures within the canine vertebral canal. Immunolabeling was performed with antibodies against protein gene product 9.5, Tuj-1 (neuron-specific class III β-tubulin), calcitonin gene-related peptide, and neuropeptide Y in combination with the lectin from Lycopersicon esculentum as a marker for blood vessels. Staining was indicative of both sensory and sympathetic fibers. Innervation density was the highest in lateral areas, intermediate in dorsal areas, and the lowest in ventral areas. In the dorsal longitudinal ligament (DLL), the highest innervation density was observed in the lateral regions. Innervation was lower at mid-vertebral levels than at intervertebral levels. The presence of sensory and sympathetic fibers in the canine dura and DLL suggests that pain may originate from both these structures. Due to these regional differences in sensory innervation patterns, trauma to intervertebral DLL and lateral dura is expected to be particularly painful. The results ought to provide a better basis for the assessment of medicinal and surgical procedures.

  10. Disruption of persistent nociceptive behavior in rats with learning impairment.

    Directory of Open Access Journals (Sweden)

    Yuxin Ma

    Full Text Available Despite the subjective nature of pain experience with cognitive and affective dimensions, preclinical pain research has largely focused on its sensory dimension. Here, we examined the relationship between learning/memory and nociceptive behavior in rats with combined learning impairment and persistent nociception. Learning impairment was induced by bilateral hippocampal injection of a mixed Aβ solution, whereas persistent nociception produced in these rats by complete Freund's adjuvant-induced ankle inflammation. Those rats with learning impairment showed a diminished development of thermal hyperalgesia and mechanical allodynia and a shorter time course of nociceptive behavior without alteration of their baseline nociceptive threshold. In rats with pre-established hyperalgesia and allodynia due to ankle inflammation, bilateral intra-hippocampal injection of cycloheximide (a protein synthesis inhibitor promoted the earlier recovery of nociceptive behavior. Moreover, expression of Aβ, NR1 subunit of the N-methyl-D-aspartate receptor, and protein kinase Cγ was upregulated, whereas the choline acetyl transferase expression was downregulated, in the hippocampus, thalamus, amygdala, and/or spinal cord of rats with combined learning impairment and persistent nociception. The data indicate that learning impairment could disrupt the response to a state of persistent nociception, suggesting an important role for cognitive maladaptation in the mechanisms of chronic pain. These results also suggest that a preclinical model of combined learning impairment and persistent nociception may be useful to explore the brain mechanisms underlying the transition from acute to chronic pain.

  11. The Role of Neuromediators and Innervation in Cutaneous Wound Healing.

    Science.gov (United States)

    Ashrafi, Mohammed; Baguneid, Mohamed; Bayat, Ardeshir

    2016-06-15

    The skin is densely innervated with an intricate network of cutaneous nerves, neuromediators and specific receptors which influence a variety of physiological and disease processes. There is emerging evidence that cutaneous innervation may play an important role in mediating wound healing. This review aims to comprehensively examine the evidence that signifies the role of innervation during the overlapping stages of cutaneous wound healing. Numerous neuropeptides that are secreted by the sensory and autonomic nerve fibres play an essential part during the distinct phases of wound healing. Delayed wound healing in diabetes and fetal cutaneous regeneration following wounding further highlights the pivotal role skin innervation and its associated neuromediators play in wound healing. Understanding the mechanisms via which cutaneous innervation modulates wound healing in both the adult and fetus will provide opportunities to develop therapeutic devices which could manipulate skin innervation to aid wound healing.

  12. Differential molecular profiles of astrocytes in degeneration and re-innervation after sensory deafferentation of the adult rat cochlear nucleus.

    Science.gov (United States)

    Fredrich, Michaela; Zeber, Anne C; Hildebrandt, Heika; Illing, Robert-Benjamin

    2013-07-01

    Ablating the cochlea causes total sensory deafferentation of the cochlear nucleus. Over the first postoperative week, degeneration of the auditory nerve and its synaptic terminals in the cochlear nucleus temporally overlaps with its re-innervation by axon collaterals of medial olivocochlear neurons. At the same time, astrocytes increase in size and density. We investigated the time courses of the expression of ezrin, polysialic acid, matrix metalloprotease-9 and matrix metalloprotease-2 within these astrocytes during the first week following cochlear ablation. All four proteins are known to participate in degeneration, regeneration, or both, following injury of the central nervous system. In a next step, stereotaxic injections of kainic acid were made into the ventral nucleus of the trapezoid body prior to cochlear ablation to destroy the neurons that re-innervate the deafferented cochlear nucleus by axon collaterals developing growth-associated protein 43 immunoreactivity. This experimental design allowed us to distinguish between molecular processes associated with degeneration and those associated with re-innervation. Under these conditions, astrocytic growth and proliferation showed an unchanged deafferentation-induced pattern. Similarly, the distribution and amount of ezrin and matrix metalloprotease-9 in astrocytes after cochlear ablation developed in the same way as under cochlear ablation alone. In sharp contrast, the astrocytic expression of polysialic acid and matrix metalloprotease-2 normally invoked by cochlear ablation collapsed when re-innervation of the cochlear nucleus was inhibited by lesioning medial olivocochlear neurons with kainic acid. In conclusion, re-innervation, including axonal growth and synaptogenesis, seems to prompt astrocytes to recompose their molecular profile, paving the way for tissue reorganisation after nerve degeneration and loss of synaptic contacts.

  13. Dose-dependent expression of neuronal injury markers during experimental osteoarthritis induced by monoiodoacetate in the rat

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    Ferreira-Gomes Joana

    2012-07-01

    Full Text Available Abstract Background It was recently reported that the mono-iodoacetate (MIA experimental model of osteoarthritis (OA courses with changes of neurons innervating the affected joints that are commonly interpreted as a neuronal response to axonal injury. To better characterize these changes, we evaluated the expression of two markers of neuronal damage, ATF-3 and NPY, and the growth associated protein GAP-43, in primary afferent neurons of OA animals injected with three different doses of MIA (0.3, 1 or 2 mg. Measurements were performed at days 3, 7, 14, 21 and 31 post-MIA injection. Results OA animals showed the characteristic histopathological changes of the joints and the accompanying nociceptive behaviour, evaluated by the Knee-Bed and CatWalk tests. An increase of ATF-3 expression was detected in the DRG of OA animals as early as 3 days after the injection of 1 or 2 mg of MIA and 7 days after the injection of 0.3 mg. NPY expression was increased in animals injected with 1 or 2 mg of MIA, at day 3 or in all time-points, respectively. From day 7 onwards there was a massive increase of GAP-43 expression in ATF-3 cells. Conclusions The expression of the neuronal injury markers ATF-3 and NPY as well as an up-regulation of GAP-43 expression, indicative of peripheral fibre regeneration, suggests that axonal injury and a regeneration response may be happening in this model of OA. This opens new perspectives in the unravelling of the physiopathology of the human disease.

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

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    Mark S. Cooper

    2011-01-01

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

  15. Involvement of group III metabotropic glutamate receptors in the modulation of spinal nociceptive signals

    Institute of Scientific and Technical Information of China (English)

    Xiaorong Yang; Yu Zhang; Xin Zhao; Naihong Liu; Jiantian Qiao; Ce Zhang

    2009-01-01

    BACKGROUND:Previous morphological studies have demonstrated that group III metabotropic glutamate receptors (mGluRs) are commonly found in nociceptive pathways,particularly in the terminals of primary afferent fibers in the spinal dorsal horn.OBJECTIVE:To investigate the role of group III mGluRs in a rat model of spinal nociception by intrathecal administration of a selective agonist,L-Serine-O-phosphate (L-SOP).DESIGN,TIME AND SETTING:A randomized,controlled,animal experiment.The study was performed at the Department of Physiology and Neurobiology,Shanxi Medical University,between March 2007 and May 2008.MATERIALS:L-SOP of group III mGluRs (Tocris Cookson Ltd,UK),formalin (Sigma,USA),rabbit anti-c-Fos polyclonal antibody and biotin-labeled goat anti-rabbit IgG (Cell Signaling Technology,USA) were used in this study.METHODS:A total of 26 healthy Wistar rats,aged 1 month and weighing 100-120 g,were subjected to intrathecal catheter implantation.After 5-8 days,10 rats were selected according to experimental requirements.L-SOP 250 nmol in 10 μL,or the equivalent volume of normal saline,was administered by intrathecal injection into the L3-5 region of the spinal cord in the experimental and control groups,respectively.After 15 minutes,formalin (5%,50 μL) was subcutaneously injected into the plantar of the left hindpaw of each rat to establish formalin-induced pain models.MAIN OUTCOME MEASURES:Nociceptive behavioral responses and immunohistochemical examination of Fos expression.RESULTS:Intrathecal injection of L-SOP significantly attenuated the second phase nociceptive response compared with the control group (P<0.05),and Fos expression in the spinal dorsal horn was significantly decreased along with the number of Fos-like immunoreactive neurons (P<0.05).CONCLUSION:Group III mGluRs are involved in the modulation of nociceptive signals,and their activation suppresses the transmission of nociceptive signals.

  16. 大鼠口面部躯体和上消化道内脏伤害性传入汇聚于三叉神经脊束间质核含CB神经元%Somatic and visceral nociceptive inputs from the orofacial area and the upper alimentary tract converge onto CB-containing neurons in interstitial nucleus of the spinal trigeminal tract in rats

    Institute of Scientific and Technical Information of China (English)

    马文领; 张文斌; 郭峰

    2004-01-01

    The interstitial nucleus of the spinal trigeminal tract (INV) contains many calbindin-D28k-containing neurons (CB-neurons) receiving convergence information from the somatic and visceral structures. The purpose of the present study was to confirm whether the primary afferent terminals from the inferior alveolar nerve (IAN) make close contact and synaptic connections with the same CB-neurons receiving visceral nociceptive signals in INV. Biotinylated dextran amine (BDA) and horseradish peroxidase (H) tracing combined with CB and Fos proteins immunohistochimistry were used. After injections of BDA and formalin into unilateral IAN and upper alimentary tract,respectively, the transganglionic labeled afferent fibers and terminals from IAN were observed in the ipsilateral INV, especially in its enlarged part. A large number of CB- and Fos-like immunoreactive (LI) neurons were found in bilateral INV. These CB- and Fos-LI neurons mostly overlapped with BDA-labeled terminals in the enlarged part of INV. About one half of the CB-LI neurons were double labeled with Fos-LI nuclei (74/153). The terminals from IAN were to made close contacts with many CB/Fos-double labeled or CB-single labeled neurons. After injection of HRP into IAN, HRP-labeled fibers and terminals in INV were similar to that labeled with BDA. Under the electron microscope,a large number of CB-LI dendrites and a few soma in the enlarged part of INV were found to form asymmetrical axo-dendritic and axo-somal synapses with the HRP-labeled axon terminals. These results indicate that the orofacial somatic inputs from IAN and the visceral nociceptive inputs from the upper alimentary tract converge onto the same CB-containing neurons in INV. These CB-containing neurons in INV probably play an important role in information integration as well as visceral and cardiovascular activity.%三叉神经脊束间质核(interstitial nucleus ofthe spinaltrigeminal tract,INV)为位于三叉神经脊束内的一些灰质团块,

  17. Optogenetic activation of serotonergic terminals facilitates GABAergic inhibitory input to orexin/hypocretin neurons

    OpenAIRE

    Srikanta Chowdhury; Akihiro Yamanaka

    2016-01-01

    Orexin/hypocretin neurons play a crucial role in the regulation of sleep/wakefulness, primarily in the maintenance of wakefulness. These neurons innervate wide areas of the brain and receive diverse synaptic inputs including those from serotonergic (5-HT) neurons in the raphe nucleus. Previously we showed that pharmacological application of 5-HT directly inhibited orexin neurons via 5-HT1A receptors. However, it was still unclear how 5-HT neurons regulated orexin neurons since 5-HT neurons co...

  18. Roles of the periaqueductal gray in descending facilitatory and inhibitory controls of intramuscular hypertonic saline induced muscle nociception.

    Science.gov (United States)

    Lei, Jing; Sun, Tao; Lumb, Bridget M; You, Hao-Jun

    2014-07-01

    Despite the importance of the periaqueductal gray (PAG) in the modulation of nociception and pain, many aspects of the roles of the different columns of the PAG in descending controls: facilitation and inhibition, are not understood. Employing a tonic muscle pain model established by i.m. injection of 5.8% saline into the gastrocnemius muscle, we now report the results of investigations designed to explore any differences in Fos expression in the different functional columns of the PAG in male Sprague-Dawley rats. In a second series of experiments, effects of the PAG on descending control of spinally-organized nociception were assessed by measuring hind paw withdrawal reflexes to noxious mechanical and heat stimulation before and after electrolytic lesion of specific columns of the PAG. Our results show that Fos expression within different columns of the PAG increases significantly and differentially following i.m. injection of 5.8% saline. The mean number of Fos positive neurons in the dorsolateral (dl), lateral (l), dorsomedial (dm) PAG elicited by i.m. injection of 5.8% saline reached a peak at 4h with a gradual decrease over time, whereas the maximum number of Fos-positive neurons in the ventrolateral (vl) PAG was observed 8h after i.m. injection. Contralateral lesion of the dl PAG significantly depressed ipsilateral secondary mechanical hyperalgesia in intramuscularly induced (5.8% saline) nociception (P0.05). By contrast, contralateral lesion of the vl PAG completely blocked the occurrence of ipsilateral heat hypoalgesia (P0.05). In conclusion, functions of specific columns of the PAG in the control of spinal nociceptive activities are not homogeneous. It is suggested that, in this muscle pain model, the dl PAG and vl PAG participate in descending facilitation and inhibition of nociception, respectively.

  19. Pain-related mediators underlie incision-induced mechanical nociception in the dorsal root ganglia

    Institute of Scientific and Technical Information of China (English)

    Xiuhong Yuan; Xiangyan Liu; Qiuping Tang; Yunlong Deng

    2013-01-01

    Approximately 50-70% of patients experience incision-induced mechanical nociception after sur-gery. However, the mechanism underlying incision-induced mechanical nociception is stil unclear. Interleukin-10 and brain-derived neurotrophic factor are important pain mediators, but whether in-terleukin-10 and brain-derived neurotrophic factor are involved in incision-induced mechanical no-ciception remains uncertain. In this study, forty rats were divided randomly into the incision surgery (n=32) and sham surgery (n=8) groups. Plantar incision on the central part of left hind paw was performed under anesthesia in rats from the surgery group. Rats in the sham surgery group re-ceived anesthesia, but not an incision. Von Frey test results showed that, compared with the sham surgery group, incision surgery decreased the withdrawal threshold of rats at 0.5, 3, 6 and 24 hours after incision. Immunofluorescence staining in the dorsal root ganglia of the spinal cord (L 3-5 ) showed that interleukin-10 and brain-derived neurotrophic factor were expressed mainly on smal-and medium-sized neurons (diameter40μm) at 6 and 24 hours after incision surgery, which corresponded to the decreased mechanical withdrawal threshold of rats in the surgery group. These experimental findings suggest that expression pattern shift of interleukin-10 and brain-derived neurotrophic factor induced by inci-sion surgery in dorsal root ganglia of rats was closely involved in lowering the threshold to me-chanical stimulus in the hind paw fol owing incision surgery. Pain-related mediators induced by in-cision surgery in dorsal root ganglia of rats possibly underlie mechanical nociception in ipsilateral hind paws.

  20. Nucleotide homeostasis and purinergic nociceptive signaling in rat meninges in migraine-like conditions.

    Science.gov (United States)

    Yegutkin, Gennady G; Guerrero-Toro, Cindy; Kilinc, Erkan; Koroleva, Kseniya; Ishchenko, Yevheniia; Abushik, Polina; Giniatullina, Raisa; Fayuk, Dmitriy; Giniatullin, Rashid

    2016-09-01

    Extracellular ATP is suspected to contribute to migraine pain but regulatory mechanisms controlling pro-nociceptive purinergic mechanisms in the meninges remain unknown. We studied the peculiarities of metabolic and signaling pathways of ATP and its downstream metabolites in rat meninges and in cultured trigeminal cells exposed to the migraine mediator calcitonin gene-related peptide (CGRP). Under resting conditions, meningeal ATP and ADP remained at low nanomolar levels, whereas extracellular AMP and adenosine concentrations were one-two orders higher. CGRP increased ATP and ADP levels in meninges and trigeminal cultures and reduced adenosine concentration in trigeminal cells. Degradation rates for exogenous nucleotides remained similar in control and CGRP-treated meninges, indicating that CGRP triggers nucleotide release without affecting nucleotide-inactivating pathways. Lead nitrate-based enzyme histochemistry of whole mount meninges revealed the presence of high ATPase, ADPase, and AMPase activities, primarily localized in the medial meningeal artery. ATP and ADP induced large intracellular Ca(2+) transients both in neurons and in glial cells whereas AMP and adenosine were ineffective. In trigeminal glia, ATP partially operated via P2X7 receptors. ATP, but not other nucleotides, activated nociceptive spikes in meningeal trigeminal nerve fibers providing a rationale for high degradation rate of pro-nociceptive ATP. Pro-nociceptive effect of ATP in meningeal nerves was reproduced by α,β-meATP operating via P2X3 receptors. Collectively, extracellular ATP, which level is controlled by CGRP, can persistently activate trigeminal nerves in meninges which considered as the origin site of migraine headache. These data are consistent with the purinergic hypothesis of migraine pain and suggest new targets against trigeminal pain.

  1. Collateral projections of neurons in laminae I, III, and IV of rat spinal cord to thalamus, periaqueductal gray matter, and lateral parabrachial area.

    Science.gov (United States)

    Al-Khater, Khulood M; Todd, Andrew J

    2009-08-20

    Projection neurons in lamina I, together with those in laminae III-IV that express the neurokinin 1 receptor (NK1r), form a major route through which nociceptive information reaches the brain. Axons of these cells innervate various targets, including thalamus, periaqueductal gray matter (PAG), and lateral parabrachial area (LPb), and many cells project to more than one target. The aims of this study were to quantify projections from cervical enlargement to PAG and LPb, to determine the proportion of spinothalamic neurons at lumbar and cervical levels that were labelled from PAG and LPb, and to investigate morphological differences between projection populations. The C7 segment contained fewer lamina I spinoparabrachial cells than L4, but a similar number of spino-PAG cells. Virtually all spinothalamic lamina I neurons at both levels were labelled from LPb and between one-third and one-half from PAG. This suggests that significant numbers project to all three targets. Spinothalamic lamina I neurons differed from those labelled only from LPb in that they were generally larger, were more often multipolar, and (in cervical enlargement) had stronger NK1r immunoreactivity. Most lamina III/IV NK1r cells at both levels projected to LPb, but few were labelled from PAG. The great majority of these cells in C7 and over one-fourth of those in L4 were spinothalamic, and at each level some projected to both thalamus and LPb. These results confirm that neurons in these laminae have extensive collateral projections and suggest that different neuronal subpopulations in lamina I have characteristic patterns of supraspinal projection.

  2. Cartography of human diaphragmatic innervation: preliminary data.

    Science.gov (United States)

    Verin, Eric; Marie, Jean-Paul; Similowski, Thomas

    2011-04-30

    In humans, anatomy indicates that the phrenic nerve mainly arises from the C4 cervical root, with variable C3 and C5 contributions. How this translates into functional innervation is unknown. The diaphragm response to electrical stimulation of C3, C4 and C5 was described in three patients undergoing surgical laryngeal reinnervation with an upper phrenic root (surface chest electrodes at anterior, lateral and posterior sites; oesophageal and gastric pressures (Pes and Pga) to derive transdiaphragmatic pressure (Pdi)). Anatomically, the phrenic nerve predominantly originated from C4. Phrenic stimulation elicited motor responses at the three sites in the three patients, as did C4 stimulation. It produced Pdi values of 9, 11, and 14cmH(2)O in the three patients, respectively, vs. 9, 9, and 7cmH(2)O for C4. C3 stimulation produced modest Pdi responses, whereas C5 stimulation could produce Pdi responses close to those observed with C4 stimulation. These singular observations confirm the dominance of C4 in diaphragm innervation but suggest than C5 can be of importance. Copyright © 2010 Elsevier B.V. All rights reserved.

  3. Social feeding in Caenorhabditis elegans is induced by neurons that detect aversive stimuli

    Science.gov (United States)

    de Bono, Mario; Tobin, David M.; Davis, M. Wayne; Avery, Leon; Bargmann, Cornelia I.

    2014-01-01

    Natural Caenorhabditis elegans isolates exhibit either social or solitary feeding on bacteria. We show here that social feeding is induced by nociceptive neurons that detect adverse or stressful conditions. Ablation of the nociceptive neurons ASH and ADL transforms social animals into solitary feeders. Social feeding is probably due to the sensation of noxious chemicals by ASH and ADL neurons; it requires the genes ocr-2 and osm-9, which encode TRP-related transduction channels, and odr-4 and odr-8, which are required to localize sensory chemoreceptors to cilia. Other sensory neurons may suppress social feeding, as social feeding in ocr-2 and odr-4 mutants is restored by mutations in osm-3, a gene required for the development of 26 ciliated sensory neurons. Our data suggest a model for regulation of social feeding by opposing sensory inputs: aversive inputs to nociceptive neurons promote social feeding, whereas antagonistic inputs from neurons that express osm-3 inhibit aggregation. PMID:12410303

  4. Effect of postnatal lead exposure on the development of sympathetic innervation of the heart. [Rats

    Energy Technology Data Exchange (ETDEWEB)

    Abreu, M.E.

    1983-01-01

    To determine possible mechanisms for this Pb-induced cardiotoxicity, several neutrochemical parameters indicative of cardiac sympathetic innervation were measured in developing rats. Presynaptic indices of nerve terminal development which were studied included steady-state levels of norepinephrine, neuronal uptake and vesicular storage of /sup 3/H-norepinephrine. Analysis of postsynaptic development was accomplished by quantitating the density of ..beta..-adrenergic receptors and by measuring the activity of adenylate cyclase. Rat pups were exposed to Pb from birth to weaning (21 days) via the milk of dams whose drinking water contained 0.2% Pb acetate. This method and level of Pb treatment had no effect on body or heart weight development, however, it did result in a seven-fold increase in the blood Pb content (70-75 ..mu..g/dl) of the treated pups during the period of exposure. Pb exposure accelerated the development of sympathetic innervation of the heart as detected by significant increases in the vesicular uptake of /sup 3/H-norepinephrine and the steady-state concentration of norepinephrine measured at postnatal day 4. On the other hand, ontogeny of the neutronal uptake of /sup 3/H-norepinephrine in the heart and in the forebrain was not affected by Pb treatment. The apparent premature development of sympathetic innervation induced by Pb treatment was not reflected in significant alterations in either the density or the affinity of ..beta..-adrenergic receptor sites determined by the binding kinetics of /sup 3/H-dihydroalprenolol.

  5. Ontogeny of neuro-insular complexes and islets innervation in the human pancreas.

    Directory of Open Access Journals (Sweden)

    Alexandra E. Proshchina

    2014-04-01

    Full Text Available The ontogeny of the neuro-insular complexes (NIC and the islets innervation in human pancreas has not been studied in detail. Our aim was to describe the developmental dynamics and distribution of the nervous system structures in the endocrine part of human pancreas. We used doublestaining with antibodies specific to pan-neural markers (neuron-specific enolase (NSE and S100 protein and to hormones of pancreatic endocrine cells. NSE and S100-positive nerves and ganglia were identified in the human fetal pancreas from gestation week (gw 10 onwards. Later the density of S100 and NSE-positive fibers increased. In adults this network was sparse. The islets innervation started to form from gw 14. NSE-containing endocrine cells were identified from gw 12 onwards. Additionally, S100-positive cells were detected both in the periphery and within some of the islets starting at gw 14. The analysis of islets innervation has shown that the fetal pancreas contained neuro-insular complexes and the number of these complexes was reduced in adults. The highest density of neuro-insular complexes is detected during middle and late fetal periods, when the mosaic islets, typical for adults, form. The close integration between the developing pancreatic islets and the nervous system structures may play an important role not only in the hormone secretion, but also in the islets morphogenesis.

  6. Prostaglandin metabolite induces inhibition of TRPA1 and channel-dependent nociception

    Directory of Open Access Journals (Sweden)

    Weng Yingqi

    2012-09-01

    Full Text Available Abstract Background The Transient Receptor Potential (TRP ion channel TRPA1 is a key player in pain pathways. Irritant chemicals activate ion channel TRPA1 via covalent modification of N-terminal cysteines. We and others have shown that 15-Deoxy-Δ12, 14-prostaglandin J2 (15d-PGJ2 similarly activates TRPA1 and causes channel-dependent nociception. Paradoxically, 15d-PGJ2 can also be anti-nociceptive in several pain models. Here we hypothesized that activation and subsequent desensitization of TRPA1 in dorsal root ganglion (DRG neurons underlies the anti-nociceptive property of 15d-PGJ2. To investigate this, we utilized a battery of behavioral assays and intracellular Ca2+ imaging in DRG neurons to test if pre-treatment with 15d-PGJ2 inhibited TRPA1 to subsequent stimulation. Results Intraplantar pre-injection of 15d-PGJ2, in contrast to mustard oil (AITC, attenuated acute nocifensive responses to subsequent injections of 15d-PGJ2 and AITC, but not capsaicin (CAP. Intraplantar 15d-PGJ2—administered after the induction of inflammation—reduced mechanical hypersensitivity in the Complete Freund’s Adjuvant (CFA model for up to 2 h post-injection. The 15d-PGJ2-mediated reduction in mechanical hypersensitivity is dependent on TRPA1, as this effect was absent in TRPA1 knockout mice. Ca2+ imaging studies of DRG neurons demonstrated that 15d-PGJ2 pre-exposure reduced the magnitude and number of neuronal responses to AITC, but not CAP. AITC responses were not reduced when neurons were pre-exposed to 15d-PGJ2 combined with HC-030031 (TRPA1 antagonist, demonstrating that inhibitory effects of 15d-PGJ2 depend on TRPA1 activation. Single daily doses of 15d-PGJ2, administered during the course of 4 days in the CFA model, effectively reversed mechanical hypersensitivity without apparent tolerance or toxicity. Conclusions Taken together, our data support the hypothesis that 15d-PGJ2 induces activation followed by persistent inhibition of TRPA1 channels

  7. Controlling attention to nociceptive stimuli with working memory.

    Directory of Open Access Journals (Sweden)

    Valéry Legrain

    Full Text Available BACKGROUND: Because pain often signals the occurrence of potential tissue damage, a nociceptive stimulus has the capacity to involuntarily capture attention and take priority over other sensory inputs. Whether distraction by nociception actually occurs may depend upon the cognitive characteristics of the ongoing activities. The present study tested the role of working memory in controlling the attentional capture by nociception. METHODOLOGY AND PRINCIPAL FINDINGS: Participants performed visual discrimination and matching tasks in which visual targets were shortly preceded by a tactile distracter. The two tasks were chosen because of the different effects the involvement of working memory produces on performance, in order to dissociate the specific role of working memory in the control of attention from the effect of general resource demands. Occasionally (i.e. 17% of the trials, tactile distracters were replaced by a novel nociceptive stimulus in order to distract participants from the visual tasks. Indeed, in the control conditions (no working memory, reaction times to visual targets were increased when the target was preceded by a novel nociceptive distracter as compared to the target preceded by a frequent tactile distracter, suggesting attentional capture by the novel nociceptive stimulus. However, when the task required an active rehearsal of the visual target in working memory, the novel nociceptive stimulus no longer induced a lengthening of reaction times to visual targets, indicating a reduction of the distraction produced by the novel nociceptive stimulus. This effect was independent of the overall task demands. CONCLUSION AND SIGNIFICANCE: Loading working memory with pain-unrelated information may reduce the ability of nociceptive input to involuntarily capture attention, and shields cognitive processing from nociceptive distraction. An efficient control of attention over pain is best guaranteed by the ability to maintain active goal

  8. Presynaptic modulation of spinal nociceptive transmission by glial cell line-derived neurotrophic factor (GDNF).

    Science.gov (United States)

    Salio, Chiara; Ferrini, Francesco; Muthuraju, Sangu; Merighi, Adalberto

    2014-10-01

    The role of glial cell line-derived neurotrophic factor (GDNF) in nociceptive pathways is still controversial, as both pronociceptive and antinociceptive actions have been reported. To elucidate this role in the mouse, we performed combined structural and functional studies in vivo and in acute spinal cord slices where C-fiber activation was mimicked by capsaicin challenge. Nociceptors and their terminals in superficial dorsal horn (SDH; laminae I-II) constitute two separate subpopulations: the peptidergic CGRP/somatostatin+ cells expressing GDNF and the nonpeptidergic IB4+ neurons expressing the GFRα1-RET GDNF receptor complex. Ultrastructurally the dorsal part of inner lamina II (LIIid) harbors a mix of glomeruli that either display GDNF/somatostatin (GIb)-IR or GFRα1/IB4 labeling (GIa). LIIid thus represents the preferential site for ligand-receptor interactions. Functionally, endogenous GDNF released from peptidergic CGRP/somatostatin+ nociceptors upon capsaicin stimulation exert a tonic inhibitory control on the glutamate excitatory drive of SDH neurons as measured after ERK1/2 phosphorylation assay. Real-time Ca(2+) imaging and patch-clamp experiments with bath-applied GDNF (100 nM) confirm the presynaptic inhibition of SDH neurons after stimulation of capsaicin-sensitive, nociceptive primary afferent fibers. Accordingly, the reduction of the capsaicin-evoked [Ca(2+)]i rise and of the frequency of mEPSCs in SDH neurons is specifically abolished after enzymatic ablation of GFRα1. Therefore, GDNF released from peptidergic CGRP/somatostatin+ nociceptors acutely depresses neuronal transmission in SDH signaling to nonpeptidergic IB4+ nociceptors at glomeruli in LIIid. These observations are of potential pharmacological interest as they highlight a novel modality of cross talk between nociceptors that may be relevant for discrimination of pain modalities.

  9. The subgenual organ complex in the cave cricket Troglophilus neglectus (Orthoptera: Rhaphidophoridae): comparative innervation and sensory evolution

    OpenAIRE

    Strauß, Johannes; Stritih, Nataša; Lakes-Harlan, Reinhard

    2014-01-01

    Comparative studies of the organization of nervous systems and sensory organs can reveal their evolution and specific adaptations. In the forelegs of some Ensifera (including crickets and tettigoniids), tympanal hearing organs are located in close proximity to the mechanosensitive subgenual organ (SGO). In the present study, the SGO complex in the non-hearing cave cricket Troglophilus neglectus (Rhaphidophoridae) is investigated for the neuronal innervation pattern and for organs homologous t...

  10. INNERVATED RECTUS-ABDOMINIS MYOFASCIAL FLAP FOR DYNAMIC CARDIOMYOPLASTY

    NARCIS (Netherlands)

    WIJNBERG, DS; EBELS, T; ROBINSON, PH

    1994-01-01

    This study examined the rectus abdominis myofascial flap as an innervated nap for dynamic cardiomyoplastic purposes. It is common to use the latissimus dorsi to wrap or patch around or in the heart, but there is a need for more innervated skeletal muscle for a variety of reasons. The rectus abdomini

  11. Innervation of the renal proximal convoluted tubule of the rat

    Energy Technology Data Exchange (ETDEWEB)

    Barajas, L.; Powers, K. (Harbor-UCLA Medical Center, Torrance (USA))

    1989-12-01

    Experimental data suggest the proximal tubule as a major site of neurogenic influence on tubular function. The functional and anatomical axial heterogeneity of the proximal tubule prompted this study of the distribution of innervation sites along the early, mid, and late proximal convoluted tubule (PCT) of the rat. Serial section autoradiograms, with tritiated norepinephrine serving as a marker for monoaminergic nerves, were used in this study. Freehand clay models and graphic reconstructions of proximal tubules permitted a rough estimation of the location of the innervation sites along the PCT. In the subcapsular nephrons, the early PCT (first third) was devoid of innervation sites with most of the innervation occurring in the mid (middle third) and in the late (last third) PCT. Innervation sites were found in the early PCT in nephrons located deeper in the cortex. In juxtamedullary nephrons, innervation sites could be observed on the PCT as it left the glomerulus. This gradient of PCT innervation can be explained by the different tubulovascular relationships of nephrons at different levels of the cortex. The absence of innervation sites in the early PCT of subcapsular nephrons suggests that any influence of the renal nerves on the early PCT might be due to an effect of neurotransmitter released from renal nerves reaching the early PCT via the interstitium and/or capillaries.

  12. THE NEURONAL DISTRIBUTION OF CANNABINOID RECEPTOR TYPE 1 IN THE TRIGEMINAL GANGLION OF THE RAT

    OpenAIRE

    2003-01-01

    Cannabinoid compounds have been shown to produce antinociception and antihyperalgesia by acting upon cannabinoid receptors located in both the CNS and the periphery. A potential mechanism by which cannabinoids could inhibit nociception in the periphery is the activation of cannabinoid receptors located on one or more classes of primary nociceptive neurons. To address this hypothesis, we evaluated the neuronal distribution of cannabinoid receptor type 1 (CB1) in the trigeminal ganglion (TG) of...

  13. Vagal cardiac efferent innervation in F344 rats: Effects of chronic intermittent hypoxia.

    Science.gov (United States)

    Cheng, Zixi Jack

    2017-03-01

    Chronic intermittent hypoxia (CIH), which is a physiological consequence of obstructive sleep apnea, reduces baroreflex control of heart rate (HR). Previously, we showed that the heart rate (HR) response to electrical stimulation of the vagal efferent nerve was significantly increased following CIH in F344 rats. Since vagal cardiac efferent from the nucleus ambiguus (NA) project to cardiac ganglia and regulate HR, we hypothesized that vagal cardiac efferent innervation of cardiac ganglia is reorganized. Young adult F344 rats were exposed either to room air (RA) or to intermittent hypoxia for 35-50days. Fluorescent tracer DiI was injected into the NA to label vagal efferent innervation of cardiac ganglia which had been counterstained by Fluoro-Gold (FG) injections (i.p). Confocal microscopy was used to examine vagal cardiac efferent axons and terminals in cardiac ganglia. NA axons entered cardiac ganglia and innervated principal neurons (PNs) with robust basket endings in both RA control and CIH animals. In addition, the percentage of PNs which were innervated by DiI-labeled fibers in ganglia was similar. In CIH rats, abnormally large swollen cardiac axon segments and disorganized terminals as well as leaky endings were observed. In general, vagal efferent terminal varicosities around PNs appeared larger and the number of varicosities was significantly increased. Interestingly, some cardiac axons had sprouting-like terminal structures in the cardiac ganglia as well as in cardiac muscle, which had not been found in RA control. Finally, CIH increased the size of PNs and reduced the ratio of nucleus to PN somata. Thus, CIH significantly remodeled the structure of vagal cardiac axons and terminals in cardiac ganglia as well as cardiac PNs.

  14. Catecholaminergic innervation of central and peripheral auditory circuitry varies with reproductive state in female midshipman fish, Porichthys notatus.

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    Paul M Forlano

    Full Text Available In seasonal breeding vertebrates, hormone regulation of catecholamines, which include dopamine and noradrenaline, may function, in part, to modulate behavioral responses to conspecific vocalizations. However, natural seasonal changes in catecholamine innervation of auditory nuclei is largely unexplored, especially in the peripheral auditory system, where encoding of social acoustic stimuli is initiated. The plainfin midshipman fish, Porichthys notatus, has proven to be an excellent model to explore mechanisms underlying seasonal peripheral auditory plasticity related to reproductive social behavior. Recently, we demonstrated robust catecholaminergic (CA innervation throughout the auditory system in midshipman. Most notably, dopaminergic neurons in the diencephalon have widespread projections to auditory circuitry including direct innervation of the saccule, the main endorgan of hearing, and the cholinergic octavolateralis efferent nucleus (OE which also projects to the inner ear. Here, we tested the hypothesis that gravid, reproductive summer females show differential CA innervation of the auditory system compared to non-reproductive winter females. We utilized quantitative immunofluorescence to measure tyrosine hydroxylase immunoreactive (TH-ir fiber density throughout central auditory nuclei and the sensory epithelium of the saccule. Reproductive females exhibited greater density of TH-ir innervation in two forebrain areas including the auditory thalamus and greater density of TH-ir on somata and dendrites of the OE. In contrast, non-reproductive females had greater numbers of TH-ir terminals in the saccule and greater TH-ir fiber density in a region of the auditory hindbrain as well as greater numbers of TH-ir neurons in the preoptic area. These data provide evidence that catecholamines may function, in part, to seasonally modulate the sensitivity of the inner ear and, in turn, the appropriate behavioral response to reproductive acoustic

  15. The neuronal distribution of cannabinoid receptor type 1 in the trigeminal ganglion of the rat.

    Science.gov (United States)

    Price, T J; Helesic, G; Parghi, D; Hargreaves, K M; Flores, C M

    2003-01-01

    Cannabinoid compounds have been shown to produce antinociception and antihyperalgesia by acting upon cannabinoid receptors located in both the CNS and the periphery. A potential mechanism by which cannabinoids could inhibit nociception in the periphery is the activation of cannabinoid receptors located on one or more classes of primary nociceptive neurons. To address this hypothesis, we evaluated the neuronal distribution of cannabinoid receptor type 1 (CB1) in the trigeminal ganglion (TG) of the adult rat through combined in situ hybridization (ISH) and immunohistochemistry (IHC). CB1 receptor mRNA was localized mainly to medium and large diameter neurons of the maxillary and mandibular branches of the TG. Consistent with this distribution, in a de facto nociceptive sensory neuron population that exhibited vanilloid receptor type 1 immunoreactivity, colocalization with CB1 mRNA was also sparse (CB1 mRNA. In contrast, and consistent with the neuron-size distribution for CB1, nearly 75% of CB1-positive neurons exhibited N52-immunoreactivity, a marker of myelinated axons. These results indicate that in the rat TG, CB1 receptors are expressed predominantly in neurons that are not thought to subserve nociceptive neurotransmission in the noninjured animal. Taken together with the absence of an above background in situ signal for CB2 mRNA in TG neurons, these findings suggest that the peripherally mediated antinociceptive effects of cannabinoids may involve either as yet unidentified receptors or interaction with afferent neuron populations that normally subserve non-nociceptive functions.

  16. TRPA1 is a Component of the Nociceptive Response to CO2 (CO2 Sensing by TRPA1)

    OpenAIRE

    Wang, Yuanyuan Y.; Chang, Rui B.; Liman, Emily R.

    2010-01-01

    In humans, high concentrations of CO2, as found in carbonated beverages, evoke a mixture of sensations that include a stinging or pungent quality. The stinging sensation is thought to originate with the activation of nociceptors which innervate the respiratory, nasal and oral epithelia. The molecular basis for this sensation is unknown. Here we show that CO2 specifically activates a subpopulation of trigeminal neurons that express TRPA1, a mustard oil and cinnamaldehyde-sensitive channel, and...

  17. Inflammation-induced changes in BKCa currents in cutaneous dorsal root ganglion neurons from the adult rat

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    Zhang Xiu-Lin

    2012-07-01

    Full Text Available Abstract Background Inflammation-induced sensitization of primary afferents is associated with a decrease in K+ current. However, the type of K+ current and basis for the decrease varies as a function of target of innervation. Because glabrous skin of the rat hindpaw is used often to assess changes in nociception in models of persistent pain, the purpose of the present study was to determine the type and extent to which K+ currents contribute to the inflammation-induced sensitization of cutaneous afferents. Acutely dissociated retrogradely labeled cutaneous dorsal root ganglion neurons from naïve and inflamed (3 days post complete Freund’s adjuvant injection rats were studied with whole cell and perforated patch techniques. Results Inflammation-induced sensitization of small diameter cutaneous neurons was associated with an increase in action potential duration and rate of decay of the afterhyperpolarization. However, no changes in voltage-gated K+ currents were detected. In contrast, Ca2+ modulated iberiotoxin sensitive and paxilline sensitive K+ (BKCa currents were significantly smaller in small diameter IB4+ neurons. This decrease in current was not associated with a detectable change in total protein levels of the BKCa channel α or β subunits. Single cell PCR analysis revealed a significant change in the pattern of expression of α subunit splice variants and β subunits that were consistent, at least in part, with inflammation-induced changes in the biophysical properties of BKCa currents in cutaneous neurons. Conclusions Results of this study provide additional support for the conclusion that it may be possible, if not necessary to selectively treat pain arising from specific body regions. Because a decrease in BKCa current appears to contribute to the inflammation-induced sensitization of cutaneous afferents, BKCa channel openers may be effective for the treatment of inflammatory pain.

  18. Glucocorticoid receptor gene inactivation in dopamine-innervated areas selectively decreases behavioral responses to amphetamine

    Directory of Open Access Journals (Sweden)

    Sebastien eParnaudeau

    2014-02-01

    Full Text Available The meso-cortico-limbic system, via dopamine release, encodes the rewarding and reinforcing properties of natural rewards. It is also activated in response to abused substances and is believed to support drug-related behaviors. Dysfunctions of this system lead to several psychiatric conditions including feeding disorders and drug addiction. These disorders are also largely influenced by environmental factors and in particular stress exposure. Stressors activate the corticotrope axis ultimately leading to glucocorticoid hormone (GCs release. GCs bind the glucocorticoid receptor (GR a transcription factor ubiquitously expressed including within the meso-cortico-limbic tract. While the GR within dopamine-innervated areas drives cocaine’s behavioral responses, its implication in responses to other psychostimulants such as amphetamine has never been clearly established. Moreover, while extensive work has been made to uncover the role of this receptor in addicted behaviors, its contribution to the rewarding and reinforcing properties of food has yet to be investigated. Using mouse models carrying GR gene inactivation in either dopamine neurons or in dopamine-innervated areas, we found that GR in dopamine responsive neurones is essential to properly build amphetamine-induced conditioned place preference and locomotor sensitization. c-Fos quantification in the nucleus accumbens further confirmed defective neuronal activation following amphetamine injection. These diminished neuronal and behavioral responses to amphetamine may involve alterations in glutamate transmission as suggested by the decreased MK801-elicited hyperlocomotion and by the hyporeactivity to glutamate of a subpopulation of medium spiny neurons. In contrast, GR inactivation did not affect rewarding and reinforcing properties of food suggesting that responding for natural reward under basal conditions is preserved in these mice.

  19. Fine structure of the pinealopetal innervation of the mammalian pineal gland

    DEFF Research Database (Denmark)

    Møller, M.

    1992-01-01

    Anatomi, ultrastructure, neuropeptides, central innervation, mammals, sympathitic, heman fetus, parasymathetic......Anatomi, ultrastructure, neuropeptides, central innervation, mammals, sympathitic, heman fetus, parasymathetic...

  20. Innervation of the sheep pineal gland by nonsympathetic nerve fibers containing NADPH-diaphorase activity

    DEFF Research Database (Denmark)

    López-Figueroa, Manuel O.; Ravault, Jean-Paul; Cozzi, Bruno;

    1997-01-01

    Neuroanatomy, NADPH-diaphorase, nitric oxide, innervation, superior cervical ganglionectomy, neuropeptide Y.......Neuroanatomy, NADPH-diaphorase, nitric oxide, innervation, superior cervical ganglionectomy, neuropeptide Y....

  1. Mast Cell-Mediated Mechanisms of Nociception.

    Science.gov (United States)

    Aich, Anupam; Afrin, Lawrence B; Gupta, Kalpna

    2015-12-04

    Mast cells are tissue-resident immune cells that release immuno-modulators, chemo-attractants, vasoactive compounds, neuropeptides and growth factors in response to allergens and pathogens constituting a first line of host defense. The neuroimmune interface of immune cells modulating synaptic responses has been of increasing interest, and mast cells have been proposed as key players in orchestrating inflammation-associated pain pathobiology due to their proximity to both vasculature and nerve fibers. Molecular underpinnings of mast cell-mediated pain can be disease-specific. Understanding such mechanisms is critical for developing disease-specific targeted therapeutics to improve analgesic outcomes. We review molecular mechanisms that may contribute to nociception in a disease-specific manner.

  2. Spinal modulation of nociception by music.

    Science.gov (United States)

    Roy, M; Lebuis, A; Hugueville, L; Peretz, I; Rainville, P

    2012-07-01

    Numerous studies have demonstrated the capacity of music to modulate pain. However, the neurophysiological mechanisms responsible for this phenomenon remain unknown. In order to assess the involvement of descending modulatory mechanisms in the modulation of pain by music, we evaluated the effects of musical excerpts conveying different emotions (pleasant-stimulating, pleasant-relaxing, unpleasant-stimulating) on the spinally mediated nociceptive flexion reflex (or RIII), as well as on pain ratings and skin conductance responses. The RIII reflex and pain ratings were increased during the listening of unpleasant music compared with pleasant music, suggesting the involvement of descending pain-modulatory mechanisms in the effects of musical emotions on pain. There were no significant differences between the pleasant-stimulating and pleasant-relaxing musical condition, indicating that the arousal of music had little influence on pain processing. © 2012 European Federation of International Association for the Study of Pain Chapters.

  3. Afferent innervation of the utricular macula in pigeons

    Science.gov (United States)

    Si, Xiaohong; Zakir, Mridha Md; Dickman, J. David

    2003-01-01

    Biotinylated dextran amine (BDA) was used to retrogradely label afferents innervating the utricular macula in adult pigeons. The pigeon utriclar macula consists of a large rectangular-shaped neuroepithelium with a dorsally curved anterior edge and an extended medioposterior tail. The macula could be demarcated into several regions based on cytoarchitectural differences. The striola occupied 30% of the macula and contained a large density of type I hair cells with fewer type II hair cells. Medial and lateral extrastriola zones were located outside the striola and contained only type II hair cells. A six- to eight-cell-wide band of type II hair cells existed near the center of the striola. The reversal line marked by the morphological polarization of hair cells coursed throughout the epithelium, near the peripheral margin, and through the center of the type II band. Calyx afferents innervated type I hair cells with calyceal terminals that contained between 2 and 15 receptor cells. Calyx afferents were located only in the striola region, exclusive of the type II band, had small total fiber innervation areas and low innervation densities. Dimorph afferents innervated both type I and type II hair cells with calyceal and bouton terminals and were primarily located in the striola region. Dimorph afferents had smaller calyceal terminals with few type I hair cells, extended fiber branches with bouton terminals and larger innervation areas. Bouton afferents innervated only type II hair cells in the extrastriola and type II band regions. Bouton afferents innervating the type II band had smaller terminal fields with fewer bouton terminals and smaller innervation areas than fibers located in the extrastriolar zones. Bouton afferents had the most bouton terminals on the longest fibers, the largest innervation areas with the highest innervation densities of all afferents. Among all afferents, smaller terminal innervation fields were observed in the striola and large fields were

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

    Science.gov (United States)

    Colon, E; Legrain, V; Mouraux, A

    2012-10-01

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

  5. The subgenual organ complex in the cave cricket Troglophilus neglectus (Orthoptera: Rhaphidophoridae): comparative innervation and sensory evolution

    Science.gov (United States)

    Strauß, Johannes; Stritih, Nataša; Lakes-Harlan, Reinhard

    2014-01-01

    Comparative studies of the organization of nervous systems and sensory organs can reveal their evolution and specific adaptations. In the forelegs of some Ensifera (including crickets and tettigoniids), tympanal hearing organs are located in close proximity to the mechanosensitive subgenual organ (SGO). In the present study, the SGO complex in the non-hearing cave cricket Troglophilus neglectus (Rhaphidophoridae) is investigated for the neuronal innervation pattern and for organs homologous to the hearing organs in related taxa. We analyse the innervation pattern of the sensory organs (SGO and intermediate organ (IO)) and its variability between individuals. In T. neglectus, the IO consists of two major groups of closely associated sensilla with different positions. While the distal-most sensilla superficially resemble tettigoniid auditory sensilla in location and orientation, the sensory innervation does not show these two groups to be distinct organs. Though variability in the number of sensory nerve branches occurs, usually either organ is supplied by a single nerve branch. Hence, no sensory elements clearly homologous to the auditory organ are evident. In contrast to other non-hearing Ensifera, the cave cricket sensory structures are relatively simple, consistent with a plesiomorphic organization resembling sensory innervation in grasshoppers and stick insects. PMID:26064547

  6. The utility of the Golgi-Cox method in the morphological characterization of the autonomic innervation in the rat heart.

    Science.gov (United States)

    Gómez-Villalobos, M J; Gordillo, Aurora Calvo; López, José Rubicel Hernández; Flores, Gonzalo

    2009-04-30

    The autonomic innervation in the heart is predominantly by postganglionic, parasympathetic, and sympathetic neurons, which are organized in a plexus of ganglions into the heart. The knowledge of the density, distribution, location, morphology, and intrinsic connection of this system that constitute the heart autonomic innervation is limited and controversial. Methods that provide clear information in this field are desirable. A widely used method to study the morphology of the nerve cells in the central nervous system (CNS) is used in this study to characterize the autonomic innervation in rat hearts. The method consisted of impregnation of the fresh whole heart of 12 adult male Wistar rats with the Golgi-Cox stain for 30 days, after which they were incubated in 30% sucrose solution for 2-3 days and then were sectioned (200 microm) with a vibratome. The tissues were mounted on gelatin-covered slides and analyzed by using the Sholl method under light microscopy adapted to a camera lucida. The results clearly show a distribution of the ganglion plexuses in the epicardium, myocardium, and endocardium, joined by an extensive network of nerve fibers in the four cardiac chambers. We also identified and characterized the morphology of an isolated cardiac nerve cell. As results similar to that in the CNS, the Golgi-Cox method is a simple, efficient, and an accessible tool to study the autonomic innervation in the rat heart and provides a good resolution of the morphology of the plexuses of the ganglions and nerve fibers.

  7. Sympathetic re-innervation after heart transplantation: dual-isotope neurotransmitter scintigraphy, norepinephrine content and historical examination

    Energy Technology Data Exchange (ETDEWEB)

    Guertner, C. [Univ. Hospital Frankfurt am Main (Germany). Dept. of Nuclear Medicine; Krause, B.J. [Univ. Hospital Frankfurt am Main (Germany). Dept. of Nuclear Medicine; Klepzig, H. Jr. [Univ. Hospital Frankfurt am Main (Germany). Dept. of Cardiology; Herrmann, G. [Univ. Hospital Frankfurt am Main (Germany). Dept. of Pathology; Lelbach, S. [Univ. Hospital Frankfurt am Main (Germany). Dept. of Nuclear Medicine; Vockert, E.K. [Biocenter Niederursel, Frankfurt am Main (Germany). Dept. of Pharmacology; Hartmann, A. [Univ. Hospital Frankfurt am Main (Germany). Dept. of Cardiology; Maul, F.D. [Univ. Hospital Frankfurt am Main (Germany). Dept. of Nuclear Medicine; Kranert, T.W. [Univ. Hospital Frankfurt am Main (Germany). Dept. of Nuclear Medicine; Mutschler, E. [Biocenter Niederursel, Frankfurt am Main (Germany). Dept. of Pharmacology; Huebner, K. [Univ. Hospital Frankfurt am Main (Germany). Dept. of Pathology; Hoer, G. [Univ. Hospital Frankfurt am Main (Germany). Dept. of Nuclear Medicine

    1995-05-01

    Cardiac transplantation entails surgical disruption of the sympathetic nerve fibres from their somata, resulting in sympathetic denervation. In order to investigate the occurrence of sympathetic re-innervation, neurotransmitter scintigraphy using the norepinephrine analogue iodine-123 metaiodobenzylguanidine (MIBG) was performed in 15 patients 2-69 months after transplantation. In addition, norepinephrine content and immunohistochemical reactions of antibodies to Schwann cell-associated S100 protein, to neuron-specific enolase (NSE) and to norepinephrine were examined in 34 endomyocardial biopsies of 29 patients 1-88 months after transplantation. Anterobasal {sup 123}I-MIBG uptake indicating partial sympathetic re-innervation could be shown in 40% of the scintigraphically investigated patients 37-69 months after transplantation. In immunohistochemical studies 83% of the patients investigated 1-72 Months after transplantation showed nerve fibres in their biopsies but not positive reaction to norepinephrine. Significant norepinephrine content indicating re-innervation could not be detected in any biopsy. It was concluded that in spite of the lack of norepinephrine content there seemed to be immunohistological and scintigraphic evidence of sympathetic re-innervation. An explanation for this contradictory finding may be the reduced or missing norepinephrine storage ability compared to the restored uptake ability of regenerated sympathetic nerve fibres. (orig.)

  8. The subgenual organ complex in the cave cricket Troglophilus neglectus (Orthoptera: Rhaphidophoridae): comparative innervation and sensory evolution.

    Science.gov (United States)

    Strauß, Johannes; Stritih, Nataša; Lakes-Harlan, Reinhard

    2014-10-01

    Comparative studies of the organization of nervous systems and sensory organs can reveal their evolution and specific adaptations. In the forelegs of some Ensifera (including crickets and tettigoniids), tympanal hearing organs are located in close proximity to the mechanosensitive subgenual organ (SGO). In the present study, the SGO complex in the non-hearing cave cricket Troglophilus neglectus (Rhaphidophoridae) is investigated for the neuronal innervation pattern and for organs homologous to the hearing organs in related taxa. We analyse the innervation pattern of the sensory organs (SGO and intermediate organ (IO)) and its variability between individuals. In T. neglectus, the IO consists of two major groups of closely associated sensilla with different positions. While the distal-most sensilla superficially resemble tettigoniid auditory sensilla in location and orientation, the sensory innervation does not show these two groups to be distinct organs. Though variability in the number of sensory nerve branches occurs, usually either organ is supplied by a single nerve branch. Hence, no sensory elements clearly homologous to the auditory organ are evident. In contrast to other non-hearing Ensifera, the cave cricket sensory structures are relatively simple, consistent with a plesiomorphic organization resembling sensory innervation in grasshoppers and stick insects.

  9. Transplantation of Xenopus laevis tissues to determine the ability of motor neurons to acquire a novel target.

    Directory of Open Access Journals (Sweden)

    Karen L Elliott

    Full Text Available The evolutionary origin of novelties is a central problem in biology. At a cellular level this requires, for example, molecularly resolving how brainstem motor neurons change their innervation target from muscle fibers (branchial motor neurons to neural crest-derived ganglia (visceral motor neurons or ear-derived hair cells (inner ear and lateral line efferent neurons. Transplantation of various tissues into the path of motor neuron axons could determine the ability of any motor neuron to innervate a novel target. Several tissues that receive direct, indirect, or no motor innervation were transplanted into the path of different motor neuron populations in Xenopus laevis embryos. Ears, somites, hearts, and lungs were transplanted to the orbit, replacing the eye. Jaw and eye muscle were transplanted to the trunk, replacing a somite. Applications of lipophilic dyes and immunohistochemistry to reveal motor neuron axon terminals were used. The ear, but not somite-derived muscle, heart, or liver, received motor neuron axons via the oculomotor or trochlear nerves. Somite-derived muscle tissue was innervated, likely by the hypoglossal nerve, when replacing the ear. In contrast to our previous report on ear innervation by spinal motor neurons, none of the tissues (eye or jaw muscle was innervated when transplanted to the trunk. Taken together, these results suggest that there is some plasticity inherent to motor innervation, but not every motor neuron can become an efferent to any target that normally receives motor input. The only tissue among our samples that can be innervated by all motor neurons tested is the ear. We suggest some possible, testable molecular suggestions for this apparent uniqueness.

  10. Nerve growth factor facilitates perivascular innervation in neovasculatures of mice

    Directory of Open Access Journals (Sweden)

    Mitsuhiro Goda

    2016-08-01

    Full Text Available It is well known that blood vessels including arterioles have a perivascular innervation. It is also widely accepted that perivascular nerves maintain vascular tone and regulate blood flow. Although there are currently prevailing opinions, unified views on the innervation of microcirculation in any organs have not been established. The present study was designed to investigate whether there are perivascular nerves innervated in microvessels and neovessels. Furthermore, we examined whether nerve growth factor (NGF can exert a promotional effect on perivascular nerve innervation in neovessels of Matrigel plugs. A Matrigel was subcutaneously implanted in mouse. The presence of perivascular nerves in Matrigel on Day 7–21 after the implantation was immunohistochemically studied. NGF or saline was subcutaneously administered by an osmotic mini-pump for a period of 3–14 days. The immunostaining of neovasculatures in Matrigel showed the presence of perivascular nerves on Day 21 after Matrigel injection. Perivascular nerve innervation of neovessels within Matrigel implanted in NGF-treated mice was observed in Day 17 after Matrigel implantation. However, NGF treatment did not increase numbers of neovessels in Matrigel. These results suggest that perivascular nerves innervate neovessels as neovasculatures mature and that NGF accelerates the innervation of perivascular nerves in neovessels.

  11. 大鼠延髓背角内5-羟色胺、脑啡肽、γ-氨基丁酸、甘氨酸或P-物质能终末与钙结合蛋白阳性神经元间的联系%CONNECTIONS BETWEEN SEROTONERGIC, ENKEPHALINERGIC,GABAERGIC, GLYCINERGIC, SUBSTANCE P-ERGIC TERMINALS AND CALCIUM BINDING PROTEINS-CONTAINING NOCICEPTIVE NEURONS IN RAT MEDULLARY DORSAL HORN

    Institute of Scientific and Technical Information of China (English)

    李辉; 吴乐; 李云庆

    2006-01-01

    (5-HT) or substance P (SP). Under the light microscope,we observed that: (1) neuronal cell bodies exhibiting FOS-immunoreactivity were present throughout all laminae of the MOH, with the highest concentration in lamina Ⅱ; (2) most CB-, CR- and PV-immunoreactive (IR) neurons were located in lamina Ⅱ , but some were also encountered in laminae Ⅰ and Ⅲ; (3) 5-HT-, GABA-, GlyT2-, ENK- and SP-IR fibers and terminals were also chiefly located in laminae Ⅰ and Ⅱ of the MDH; (4) some FOS-IR neurons showed CB-, CR-, or PV-immunoreactivity; (5) 5-HT-, GABA-, GlyT2- and ENK-IR terminals made close contacts with FOS/CB, FOS/CR or FOS/PV double-labeled neurons; (6) SP-IR terminals, as well as 5-HT-, GABA-, GlyT2- or ENK-IR terminals, closely contacted CB-, CR- or PV-containing neurons. Under the electron microscope, 5-HT-, GABA-, GlyT2- and ENK-IR terminals principally made symmetric (inhibitory) synaptic connections with CB-, CR- and PV-containing neurons were observed. These results suggest that 5-HT, GABA, glycine (Gly) and ENK may modulate transmission of orofacial noxious information by inhibiting nociceptive neurons that contain CaBPs in the rat MDH.

  12. Motor innervation of respiratory muscles and an opercular display muscle in Siamese fighting fish Betta splendens.

    Science.gov (United States)

    Gorlick, D L

    1989-12-15

    Horseradish peroxidase was used to identify motor neurons projecting to the adductor mandibulae, levator hyomandibulae, levator operculi, adductor operculi, and dilator operculi muscles in Siamese fighting fish, Betta splendens. These muscles participate in the production of respiratory and feeding movements in teleost fishes. The dilator operculi is also the effector muscle for gill-cover erection behavior that is part of Betta's aggressive display. The motor innervation of these muscles in Betta was compared to that previously described for carp. Motor neurons of the adductor mandibulae, levator hyomandibulae, and dilator operculi are located in the trigeminal motor nucleus, and motor neurons of the adductor operculi and levator operculi are located in the facial motor nucleus in Betta and in carp. The trigeminal motor nucleus in both species is divided into rostral and caudal subnuclei. However, there are substantial differences in the organization of the subnuclei, and in the distribution of motor neurons within them. In Betta, the rostral trigeminal subnucleus consists of a single part but the caudal subnucleus is divided into two parts. Motor neurons for the dilator operculi and levator hyomandibulae muscles are located in the lateral part of the caudal subnucleus; the medial part of the caudal subnucleus contains only dilator operculi motor neurons. The single caudal subnucleus in carp is located laterally, and contains motor neurons of both the dilator operculi and levator hyomandibulae muscles. Differences in the organization of the trigeminal motor nucleus may relate to the use of the dilator operculi muscle for aggressive display behavior by perciform fishes such as Betta but not by cypriniform fishes such as carp. Five species of perciform fishes that perform gill-cover erection behavior had a Betta-like pattern of organization of the caudal trigeminal nucleus and a similar distribution of dilator operculi motor neurons. Goldfish, which like carp are

  13. Synaptic innervation to rat hippocampus by vasopressin-immuno-positive fibres from the hypothalamic supraoptic and paraventricular nuclei.

    Science.gov (United States)

    Zhang, L; Hernández, V S

    2013-01-03

    The neuropeptide arginine vasopressin (AVP) exerts a modulatory role on hippocampal excitability through vasopressin V(1A) and V(1B) receptors. However, the origin and mode of termination of the AVP innervation of the hippocampus remain unknown. We have used light and electron microscopy to trace the origin, distribution and synaptic relationships of AVP-immuno-positive fibres and nerve terminals in the rat hippocampus. Immuno-positive fibres were present in all areas (CA1-3, dentate gyrus) of the whole septo-temporal extent of the hippocampus; they had the highest density in the CA2 region, strongly increasing in density towards the ventral hippocampus. Two types of fibres were identified, both establishing synaptic junctions. Type A had large varicosities packed with immuno-positive large-granulated peptidergic vesicles and few small clear vesicles forming type I synaptic junctions with pyramidal neuron dendrites, dendritic spines and with axonal spines. Type B had smaller varicosities containing mostly small clear vesicles and only a few large-granulated vesicles and established type II synaptic junctions mainly with interneuron dendrites. The AVP-positive axons in stratum oriens appeared to follow and contact metabotropic glutamate receptor 1α (mGluR1α)-immuno-positive interneuron dendrites. Fluoro-Gold injection into the hippocampus revealed retrogradely labelled AVP-positive somata in hypothalamic supraoptic and paraventricular nuclei. Hypothalamo-hippocampal AVP-positive axons entered the hippocampus mostly through a ventral route, also innervating the amygdala and to a lesser extent through the dorsal fimbria fornix, in continuation of the septal AVP innervation. Thus, it appears the AVP-containing neurons of the magnocellular hypothalamic nuclei serve as important sources for hippocampal AVP innervation, although the AVP-expressing neurons located in amygdala and bed nucleus of the stria terminalis reported previously may also contribute.

  14. Innervation of the thick ascending limb of Henle

    Energy Technology Data Exchange (ETDEWEB)

    Barajas, L.; Powers, K.V.

    1988-08-01

    The overlap of accumulations of autoradiographic grains (AAGs) on profiles of the thick ascending limb of Henle (TALH) was measured in autoradiograms of sections from rat kidneys with monoaminergic nerves labeled by means of tritiated norepinephrine. The amount of AAG overlap was used as an indirect means of quantifying innervation along the TALHs of superficial, mid-cortical, and juxtamedullary nephrons. The density of innervation along the TALH showed nephron heterogeneity; the juxtamedullary nephrons with a high pre- and postjuxtaglomerular apparatus (JGA) TALH density of innervation and the upper and midcortical nephrons with high TALH innervation densities at the level of the JGA. The pre-JGA TALH of the juxtamedullary nephrons had a significantly higher (P less than 0.001) density of innervation than the midcortical or superficial nephrons. The TALHs of juxtamedullary nephrons were found to have substantially more innervation than the TALHs of the other nephrons. For all three populations of nephrons, the pre-JGA TALH had the greatest amount of innervation. Neural regulation of TALH function would occur mainly along the pre-JGA and level of the JGA TALH. This regulation would increase TALH NaCl reabsorption (decrease luminal NaCl concentration) and therefore influence 1) the urinary concentrating mechanism, and 2) renin secretion via the macula densa mechanism. The innervation of the TALH was predominantly associated with the vasculature of the TALH's own nephron. However, innervation associated with medullary ray capillary beds from deeper nephrons was observed on pre-JGA TALHs from superficial and midcortical nephrons.

  15. The rise and fall of mesodiencephalic dopaminergic neurons : Molecular programming by transcription factors Engrailed 1, Pitx3, and Nkx2.9 during the development of mesodiencephalic neurons

    NARCIS (Netherlands)

    Kouwenhoven, W.M.

    2016-01-01

    The mid- and hindbrain harbor two essential monoaminergic neuronal populations: the mesodiencephalic dopaminergic (mdDA) neurons in the midbrain and the serotonergic (5HT) neurons in the hindbrain. Both systems innervate multiple regions in the forebrain and are involved in the guidance of our mood,

  16. The rise and fall of mesodiencephalic dopaminergic neurons : Molecular programming by transcription factors Engrailed 1, Pitx3, and Nkx2.9 during the development of mesodiencephalic neurons

    NARCIS (Netherlands)

    Kouwenhoven, W.M.

    2016-01-01

    The mid- and hindbrain harbor two essential monoaminergic neuronal populations: the mesodiencephalic dopaminergic (mdDA) neurons in the midbrain and the serotonergic (5HT) neurons in the hindbrain. Both systems innervate multiple regions in the forebrain and are involved in the guidance of our mood,

  17. Intrinsic innervation of the uterus in guinea pig and rat.

    Science.gov (United States)

    Mustafa, F; Fatani, J A; el-Eishi, H; el-Badawi, M G

    1987-01-01

    The pattern of distribution of cholinergic and adrenergic nerves in the uterus of albino rats and guinea pigs was examined histochemically. In the albino rat, the uterus was found well-innervated by both adrenergic and cholinergic nerves with a clear regional variation. Dense innervation was demonstrated at the tubal and cervical ends of the uterus and in the cervix. Cholinergic nerves supplying the glands were more numerous than the adrenergic nerves which were relatively few. In the guinea-pigs, the uterus was richly innervated by adrenergic nerves with a clear regional variation. No cholinesterase-positive nerves or nerve cells were demonstrated.

  18. Parthenolide inhibits nociception and neurogenic vasodilatation in the trigeminovascular system by targeting the TRPA1 channel.

    Science.gov (United States)

    Materazzi, Serena; Benemei, Silvia; Fusi, Camilla; Gualdani, Roberta; De Siena, Gaetano; Vastani, Nisha; Andersson, David A; Trevisan, Gabriela; Moncelli, Maria Rosa; Wei, Xiaomei; Dussor, Gregory; Pollastro, Federica; Patacchini, Riccardo; Appendino, Giovanni; Geppetti, Pierangelo; Nassini, Romina

    2013-12-01

    Although feverfew has been used for centuries to treat pain and headaches and is recommended for migraine treatment, the mechanism for its protective action remains unknown. Migraine is triggered by calcitonin gene-related peptide (CGRP) release from trigeminal neurons. Peptidergic sensory neurons express a series of transient receptor potential (TRP) channels, including the ankyrin 1 (TRPA1) channel. Recent findings have identified agents either inhaled from the environment or produced endogenously that are known to trigger migraine or cluster headache attacks, such as TRPA1 simulants. A major constituent of feverfew, parthenolide, may interact with TRPA1 nucleophilic sites, suggesting that feverfew's antimigraine effect derives from its ability to target TRPA1. We found that parthenolide stimulates recombinant (transfected cells) or natively expressed (rat/mouse trigeminal neurons) TRPA1, where it, however, behaves as a partial agonist. Furthermore, in rodents, after initial stimulation, parthenolide desensitizes the TRPA1 channel and renders peptidergic TRPA1-expressing nerve terminals unresponsive to any stimulus. This effect of parthenolide abrogates nociceptive responses evoked by stimulation of peripheral trigeminal endings. TRPA1 targeting and neuronal desensitization by parthenolide inhibits CGRP release from trigeminal neurons and CGRP-mediated meningeal vasodilatation, evoked by either TRPA1 agonists or other unspecific stimuli. TRPA1 partial agonism, together with desensitization and nociceptor defunctionalization, ultimately resulting in inhibition of CGRP release within the trigeminovascular system, may contribute to the antimigraine effect of parthenolide.

  19. Parthenolide inhibits nociception and neurogenic vasodilatation in the trigeminovascular system by targeting TRPA1 channel

    Science.gov (United States)

    Materazzi, Serena; Benemei, Silvia; Fusi, Camilla; Gualdani, Roberta; De Siena, Gaetano; Vastani, Nisha; Andersson, David A.; Trevisan, Gabriela; Moncelli, Maria Rosa; Wei, Xiaomei; Dussor, Gregory; Pollastro, Federica; Patacchini, Riccardo; Appendino, Giovanni; Geppetti, Pierangelo; Nassini, Romina

    2013-01-01

    While feverfew has been used for centuries to treat pain and headaches and is recommended for migraine treatment, the mechanism for its protective action remains unknown. Migraine is triggered by calcitonin gene-related peptide (CGRP) release from trigeminal neurons. Peptidergic sensory neurons, express a series of transient receptor potential (TRP) channels, including the ankyrin 1 (TRPA1) channel. Recent findings have identified agents either inhaled from the environment or produced endogenously, which are known to trigger migraine or cluster headache attacks, as TRPA1 simulants. A major constituent of feverfew, parthenolide, may interact with TRPA1 nucleophilic sites, suggesting that feverfew antimigraine effect derives from its ability to target TRPA1. We found that parthenolide stimulates recombinant (transfected cells) or natively expressed (rat/mouse trigeminal neurons) TRPA1, where it, however, behaves as a partial agonist. Furthermore, in rodents, after initial stimulation, parthenolide desensitizes the TRPA1 channel, and renders peptidergic, TRPA1-expressing nerve terminals unresponsive to any stimulus. This effect of parthenolide abrogates nociceptive responses evoked by stimulation of peripheral trigeminal endings. TRPA1 targeting and neuronal desensitization by parthenolide inhibits CGRP release from trigeminal neurons and CGRP-mediated meningeal vasodilatation, evoked by either TRPA1 agonists or other unspecific stimuli. TRPA1 partial agonism, together with desensitization and nociceptor defunctionalization, ultimately resulting in inhibition of CGRP release within the trigeminovascular system, may contribute to the antimigraine effect of parthenolide. PMID:23933184

  20. Investigation of the anti-inflammatory and anti- nociceptive activities ...

    African Journals Online (AJOL)

    PRECIOUS

    2009-06-15

    Jun 15, 2009 ... out these side effects are therefore being researched as alternatives to .... accompanied by stretching of hind limbs in response to pain. Anti- nociceptive .... writhing, which is the visceral pain model, the processor releases ...

  1. Central nervous system mast cells in peripheral inflammatory nociception

    Directory of Open Access Journals (Sweden)

    Ellmeier Wilfried

    2011-06-01

    Full Text Available Abstract Background Functional aspects of mast cell-neuronal interactions remain poorly understood. Mast cell activation and degranulation can result in the release of powerful pro-inflammatory mediators such as histamine and cytokines. Cerebral dural mast cells have been proposed to modulate meningeal nociceptor activity and be involved in migraine pathophysiology. Little is known about the functional role of spinal cord dural mast cells. In this study, we examine their potential involvement in nociception and synaptic plasticity in superficial spinal dorsal horn. Changes of lower spinal cord dura mast cells and their contribution to hyperalgesia are examined in animal models of peripheral neurogenic and non-neurogenic inflammation. Results Spinal application of supernatant from activated cultured mast cells induces significant mechanical hyperalgesia and long-term potentiation (LTP at spinal synapses of C-fibers. Lumbar, thoracic and thalamic preparations are then examined for mast cell number and degranulation status after intraplantar capsaicin and carrageenan. Intradermal capsaicin induces a significant percent increase of lumbar dural mast cells at 3 hours post-administration. Peripheral carrageenan in female rats significantly increases mast cell density in the lumbar dura, but not in thoracic dura or thalamus. Intrathecal administration of the mast cell stabilizer sodium cromoglycate or the spleen tyrosine kinase (Syk inhibitor BAY-613606 reduce the increased percent degranulation and degranulated cell density of lumbar dural mast cells after capsaicin and carrageenan respectively, without affecting hyperalgesia. Conclusion The results suggest that lumbar dural mast cells may be sufficient but are not necessary for capsaicin or carrageenan-induced hyperalgesia.

  2. Development of neuropeptide Y-mediated heart innervation in rats.

    Science.gov (United States)

    Masliukov, Petr M; Moiseev, Konstantin; Emanuilov, Andrey I; Anikina, Tatyana A; Zverev, Alexey A; Nozdrachev, Alexandr D

    2016-02-01

    Neuropeptide Y (NPY) plays a trophic role in the nervous and vascular systems and in cardiac hypertrophy. However, there is no report concerning the expression of NPY and its receptors in the heart during postnatal development. In the current study, immunohistochemistry and Western blot analysis was used to label NPY, and Y1R, Y2R, and Y5R receptors in the heart tissue and intramural cardiac ganglia from rats of different ages (newborn, 10 days old, 20 days old, 30 days old, 60 days old, 1 year old, and 2 years old).The obtained data suggest age-dependent changes of NPY-mediated heart innervation. The density of NPY-immunoreactive (IR) fibers was the least in newborn animals and increased in the first 20 days of life. In the atria of newborn and 10-day-old rats, NPY-IR fibers were more abundant compared with the ventricles. The vast majority of NPY-IR fibers also contained tyrosine hydroxylase, a key enzyme in catecholamine synthesis.The expression of Y1R increased between 10 and 20 days of life. Faint Y2R immunoreactivity was observed in the atria and ventricles of 20-day-old and older rats. In contrast, the highest level of the expression of Y5R was found in newborn pups comparing with more adult rats. All intramural ganglionic neurons were also Y1R-IR and Y5R-IR and Y2R-negative in all studied animals.Thus, the increasing of density of NPY-containing nerve fibers accompanies changes in relation of different subtypes of NPY receptors in the heart during development.

  3. Regulation of Irregular Neuronal Firing by Autaptic Transmission

    Science.gov (United States)

    Guo, Daqing; Wu, Shengdun; Chen, Mingming; Perc, Matjaž; Zhang, Yangsong; Ma, Jingling; Cui, Yan; Xu, Peng; Xia, Yang; Yao, Dezhong

    2016-05-01

    The importance of self-feedback autaptic transmission in modulating spike-time irregularity is still poorly understood. By using a biophysical model that incorporates autaptic coupling, we here show that self-innervation of neurons participates in the modulation of irregular neuronal firing, primarily by regulating the occurrence frequency of burst firing. In particular, we find that both excitatory and electrical autapses increase the occurrence of burst firing, thus reducing neuronal firing regularity. In contrast, inhibitory autapses suppress burst firing and therefore tend to improve the regularity of neuronal firing. Importantly, we show that these findings are independent of the firing properties of individual neurons, and as such can be observed for neurons operating in different modes. Our results provide an insightful mechanistic understanding of how different types of autapses shape irregular firing at the single-neuron level, and they highlight the functional importance of autaptic self-innervation in taming and modulating neurodynamics.

  4. Choline acetyltransferase-containing neurons in the human parietal neocortex

    Directory of Open Access Journals (Sweden)

    V Benagiano

    2009-06-01

    Full Text Available A number of immunocytochemical studies have indicated the presence of cholinergic neurons in the cerebral cortex of various species of mammals. Whether such cholinergic neurons in the human cerebral cortex are exclusively of subcortical origin is still debated. In this immunocytochemical study, the existence of cortical cholinergic neurons was investigated on surgical samples of human parietal association neocortex using a highly specific monoclonal antibody against choline acetyltransferase (ChAT, the acetylcholine biosynthesising enzyme. ChAT immunoreactivity was detected in a subpopulation of neurons located in layers II and III. These were small or medium-sized pyramidal neurons which showed cytoplasmic immunoreactivity in the perikarya and processes, often in close association to blood microvessels. This study, providing demonstration of ChAT neurons in the human parietal neocortex, strongly supports the existence of intrinsic cholinergic innervation of the human neocortex. It is likely that these neurons contribute to the cholinergic innervation of the intracortical microvessels.

  5. Galanin-Expressing GABA Neurons in the Lateral Hypothalamus Modulate Food Reward and Noncompulsive Locomotion.

    Science.gov (United States)

    Qualls-Creekmore, Emily; Yu, Sangho; Francois, Marie; Hoang, John; Huesing, Clara; Bruce-Keller, Annadora; Burk, David; Berthoud, Hans-Rudolf; Morrison, Christopher D; Münzberg, Heike

    2017-06-21

    The lateral hypothalamus (LHA) integrates reward and appetitive behavior and is composed of many overlapping neuronal populations. Recent studies associated LHA GABAergic neurons (LHA (GABA) ), which densely innervate the ventral tegmental area (VTA), with modulation of food reward and consumption; yet, LHA (GABA) projections to the VTA exclusively modulated food consumption, not reward. We identified a subpopulation of LHA (GABA) neurons that coexpress the neuropeptide galanin (LHA (Gal) ). These LHA (Gal) neurons also modulate food reward, but lack direct VTA innervation. We hypothesized that LHA (Gal) neurons may represent a subpopulation of LHA (GABA) neurons that mediates food reward independent of direct VTA innervation. We used chemogenetic activation of LHA (Gal) or LHA (GABA) neurons in mice to compare their role in feeding behavior. We further analyzed locomotor behavior to understand how differential VTA connectivity and transmitter release in these LHA neurons influences this behavior. LHA (Gal) or LHA (GABA) neuronal activation both increased operant food-seeking behavior, but only activation of LHA (GABA) neurons increased overall chow consumption. Additionally, LHA (Gal) or LHA (GABA) neuronal activation similarly induced locomotor activity, but with striking differences in modality. Activation of LHA (GABA) neurons induced compulsive-like locomotor behavior; while LHA (Gal) neurons induced locomotor activity without compulsivity. Thus, LHA (Gal) neurons define a subpopulation of LHA (GABA) neurons without direct VTA innervation that mediate noncompulsive food-seeking behavior. We speculate that the striking difference in compulsive-like locomotor behavior is also based on differential VTA innervation. The downstream neural network responsible for this behavior and a potential role for galanin as neuromodulator remains to be identified.SIGNIFICANCE STATEMENT The lateral hypothalamus (LHA) regulates motivated feeding behavior via GABAergic LHA neurons

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

    Directory of Open Access Journals (Sweden)

    MARINA eDE TOMMASO

    2015-01-01

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

  7. Increased response of muscle sensory neurons to decreases in pH after muscle inflammation

    OpenAIRE

    Gautam, M; Benson, C J; Sluka, K.A.

    2010-01-01

    Acid sensing ion channels (ASIC) are found in sensory neurons, including those that innervate muscle tissue. After peripheral inflammation there is an increase in proton concentration in the inflamed tissue, which likely activates ASICs. Previous studies from our laboratory in an animal model of muscle inflammation show that hyperalgesia does not occur in ASIC3 and ASIC1 knockout mice. Therefore, in the present study we investigated if pH activated currents in sensory neurons innervating musc...

  8. Innervation of ectopic endometrium in a rat model of endometriosis

    OpenAIRE

    Berkley, Karen J; Dmitrieva, Natalia; Curtis, Kathleen S.; Papka, Raymond E

    2004-01-01

    Endometriosis (ENDO) is a disorder in which vascularized growths of endometrial tissue occur outside the uterus. Its symptoms include reduced fertility and severe pelvic pain. Mechanisms that maintain the ectopic growths and evoke symptoms are poorly understood. One factor not yet considered is that the ectopic growths develop their own innervation. Here, we tested the hypothesis that the growths develop both an autonomic and a sensory innervation. We used a rat model of surgically induced EN...

  9. DNA Methylation Modulates Nociceptive Sensitization after Incision.

    Directory of Open Access Journals (Sweden)

    Yuan Sun

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

  10. Calpain inhibitor, MDL 28170 confer electrophysiological, nociceptive and biochemical improvement in diabetic neuropathy.

    Science.gov (United States)

    Kharatmal, Shivsharan B; Singh, Jitendra N; Sharma, Shyam S

    2015-10-01

    Calpain plays an important role in the pathophysiology of neurological and cardiovascular complications, but its functional association in diabetic neuropathy is not yet elucidated. Therefore, we investigated the role of calpain in modulation of tetrodotoxin-resistant sodium channels (TTX-R Na(+) channels) in dorsal root ganglion (DRG) neurons using a pharmacological approach. The effects of a calpain inhibitor, MDL 28170 (3 and 10 mg/kg, i.p.) on TTX-R Na(+) channels in DRG neurons of streptozotocin-induced diabetic rats were assessed by using whole-cell patch-clamp technique. In addition to this biochemical, functional and behavioral deficits were also measured. Diabetic rats demonstrated the mechanical allodynia and thermal hyperalgesia with reduced nerve perfusion and conduction velocity as compared to control. MDL 28170 treatments significantly recovered these functional and nociceptive deficits. Moreover, diabetic rats exhibited increased calpain activation, lipid peroxidation and proinflammatory cytokines as compared to control. Drug treatment significantly improved these biochemical deficits. Additionally, DRG neurons from diabetic rats illustrated a significant increase in TTX-R sodium current (INa) density as compared to control. MDL 28170 treatments in diabetic rats significantly blocked the altered channel kinetics with hyperpolarizing shift in voltage-dependence of steady-state activation and inactivation curves. All together, our study provides evidence that calpain activation is directly associated with alterations in TTX-R Na(+) channels and triggers functional, nociceptive and biochemical deficits in experimental diabetic neuropathy. The calpain inhibitor, MDL 28710 have shown beneficial effects in alleviating diabetic neuropathy via modulation of TTX-R Na(+) channel kinetics and reduction of oxidative stress and neuro-inflammation.

  11. Elucidating the Neuronal Architecture of Olfactory Glomeruli in the Drosophila Antennal Lobe

    Directory of Open Access Journals (Sweden)

    Veit Grabe

    2016-09-01

    Full Text Available Olfactory glomeruli are morphologically conserved spherical compartments of the olfactory system, distinguishable solely by their chemosensory repertoire, anatomical position, and volume. Little is known, however, about their numerical neuronal composition. We therefore characterized their neuronal architecture and correlated these anatomical features with their functional properties in Drosophila melanogaster. We quantitatively mapped all olfactory sensory neurons (OSNs innervating each glomerulus, including sexually dimorphic distributions. Our data reveal the impact of OSN number on glomerular dimensions and demonstrate yet unknown sex-specific differences in several glomeruli. Moreover, we quantified uniglomerular projection neurons for each glomerulus, which unraveled a glomerulus-specific numerical innervation. Correlation between morphological features and functional specificity showed that glomeruli innervated by narrowly tuned OSNs seem to possess a larger number of projection neurons and are involved in less lateral processing than glomeruli targeted by broadly tuned OSNs. Our study demonstrates that the neuronal architecture of each glomerulus encoding crucial odors is unique.

  12. Expression and localization of pChAT as a novel method to study cholinergic innervation of rat adrenal gland.

    Science.gov (United States)

    Elnasharty, Mohamed A; Sayed-Ahmed, Ahmed

    2014-10-01

    Cholinergic innervation of the rat adrenal gland has been analyzed previously using cholinergic markers including acetylcholinesterase (AChE), choline acetyltransferase (ChAT) and vesicular acetylcholine transporter (VAChT). In the present study, we demonstrate putative cholinergic neurons in the rat adrenal gland using an antibody to pChAT, which is the product of a splice variant of ChAT mRNA that is preferentially localized in peripheral cholinergic nerves. Most of the ganglionic neurons as well as small single sporadic neurons in the adrenal gland were stained intensely for pChAT. The density of pChAT-immunoreactive (IR) fibers was distinct in the adrenal cortex and medulla. AChE-, cChAT- and VAChT-immunoreactivities were also observed in some cells and fibers of the adrenal medulla, while the cortex had few positive nerve fibers. These results indicate that ganglionic neurons of the adrenal medulla and nerve fibers heterogeneously express cholinergic markers, especially pChAT. Furthermore, the innervation of the adrenal gland, cortex and medulla, by some cholinergic fibers provides additional morphological evidence for a significant role of cholinergic mechanisms in adrenal gland functions.

  13. Efferent innervation of turtle semicircular canal cristae: comparisons with bird and mouse.

    Science.gov (United States)

    Jordan, Paivi M; Fettis, Margaret; Holt, Joseph C

    2015-06-01

    In the vestibular periphery of nearly every vertebrate, cholinergic vestibular efferent neurons give rise to numerous presynaptic varicosities that target hair cells and afferent processes in the sensory neuroepithelium. Although pharmacological studies have described the postsynaptic actions of vestibular efferent stimulation in several species, characterization of efferent innervation patterns and the relative distribution of efferent varicosities among hair cells and afferents are also integral to understanding how efferent synapses operate. Vestibular efferent markers, however, have not been well characterized in the turtle, one of the animal models used by our laboratory. Here we sought to identify reliable efferent neuronal markers in the vestibular periphery of turtle, to use these markers to understand how efferent synapses are organized, and to compare efferent neuronal labeling patterns in turtle with two other amniotes using some of the same markers. Efferent fibers and varicosities were visualized in the semicircular canal of red-eared turtles (Trachemys scripta elegans), zebra finches (Taeniopygia guttata), and mice (Mus musculus) utilizing fluorescent immunohistochemistry with antibodies against choline acetyltransferase (ChAT). Vestibular hair cells and afferents were counterstained using antibodies to myosin VIIa and calretinin. In all species, ChAT labeled a population of small diameter fibers giving rise to numerous spherical varicosities abutting type II hair cells and afferent processes. That these ChAT-positive varicosities represent presynaptic release sites were demonstrated by colabeling with antibodies against the synaptic vesicle proteins synapsin I, SV2, or syntaxin and the neuropeptide calcitonin gene-related peptide. Comparisons of efferent innervation patterns among the three species are discussed. © 2015 Wiley Periodicals, Inc.

  14. Distribution and ultrastructural features of the serotonin innervation in rat and squirrel monkey subthalamic nucleus.

    Science.gov (United States)

    Parent, Martin; Wallman, Marie-Josée; Descarries, Laurent

    2010-04-01

    The main purpose of this light and electron microscopic immunocytochemical study was to characterize and compare the serotonin (5-HT) innervation of the subthalamic nucleus (STN) in rats and squirrel monkeys (Saimiri sciureus) following labeling with an antibody against the 5-HT transporter (SERT). Unbiased counts of SERT+ axon varicosities revealed an average density of 5-HT innervation higher in monkeys (1.52 x 10(6) varicosities/mm3) than rats (1.17 x 10(6)), particularly in the anterior half of the nucleus (1.70 x 10(6)). As measured by electron microscopy, SERT+ axon varicosity profiles in the STN of both species were smaller than unlabeled profiles. The number of SERT+ profiles displaying a synaptic junction indicated that, in both rat and monkey STN, approximately half of 5-HT axon varicosities were asynaptic. In monkeys, all synaptic junctions made by SERT+ varicosities were asymmetrical, as opposed to only 77% in rats. Despite the higher density of 5-HT innervation in the anterior half of monkey STN, the ultrastructural features of its SERT+ varicosities, including synaptic incidence, did not significantly differ from those in its posterior half. These findings suggest that, throughout the rat and monkey STN, 5-HT afferents may exert their influence via both synaptic delivery and diffusion of 5-HT, and that an ambient level of 5-HT maintained in STN by these two modes of transmission might also modulate neuronal activity and influence motor behavior. A better understanding of the factors governing the complex interplay between these signaling processes would greatly improve our knowledge of the physiopathology of the STN.

  15. Removal of half the sympathetic innervation does not reduce vasoconstrictor responses in rat tail artery.

    Science.gov (United States)

    Tripovic, Diana; McLachlan, Elspeth M; Brock, James A

    2013-06-01

    Following reinnervation of denervated rat tail arteries, nerve-evoked contractions are at least as large as those evoked in normally innervated arteries despite a much lower nerve terminal density. Here nerve-evoked contractions have been investigated after transection of half the sympathetic innervation of normal tail arteries. After 1 week, the noradrenergic plexus 50-70 mm along the tail was about half as dense as control. Excitatory junction potentials recorded in smooth muscle cells of arterial segments isolated in vitro were half their normal amplitude. Surprisingly, nerve-evoked contractions of isometrically mounted segments were not reduced in amplitude, as was also the case after only 3 days. After 1 week, enhancement of nerve-evoked contractions by blocking either neuronal re-uptake of noradrenaline with desmethylimipramine or prejunctional α2-adrenoceptors with idazoxan was similar to control, suggesting that these mechanisms are matched to the number of innervating axons. The relative contribution of postjunctional α2-adrenoceptors to contractions evoked by long trains of stimuli was enhanced but that of α1-adrenoceptors was unchanged. Transiently, sensitivity to the α1-adrenoceptor agonist phenylephrine was slightly increased. After 7 weeks, amplitudes of nerve-evoked contractions remained similar to control, and sensitivity to phenylephrine had recovered but that to the α2-adrenoceptor agonist clonidine was slightly raised. The normal amplitude of nerve-evoked contractions after partial denervation is only partly explained by the greater contribution of α2-adrenoceptors. While the post-receptor mechanisms activated by nerve-released transmitter may be modified to amplify the contractions after partial denervation, our findings suggest that these mechanisms are normally saturated, at least in this artery.

  16. Immunomodulation stimulates the innervation of engineered tooth organ.

    Directory of Open Access Journals (Sweden)

    Tunay Kökten

    Full Text Available The sensory innervation of the dental mesenchyme is essential for tooth function and protection. Sensory innervation of the dental pulp is mediated by axons originating from the trigeminal ganglia and is strictly regulated in time. Teeth can develop from cultured re-associations between dissociated dental epithelial and mesenchymal cells from Embryonic Day 14 mouse molars, after implantation under the skin of adult ICR mice. In these conditions however, the innervation of the dental mesenchyme did not occur spontaneously. In order to go further with this question, complementary experimental approaches were designed. Cultured cell re-associations were implanted together with trigeminal ganglia for one or two weeks. Although axonal growth was regularly observed extending from the trigeminal ganglia to all around the forming teeth, the presence of axons in the dental mesenchyme was detected in less than 2.5% of samples after two weeks, demonstrating a specific impairment of their entering the dental mesenchyme. In clinical context, immunosuppressive therapy using cyclosporin A was found to accelerate the innervation of transplanted tissues. Indeed, when cultured cell re-associations and trigeminal ganglia were co-implanted in cyclosporin A-treated ICR mice, nerve fibers were detected in the dental pulp, even reaching odontoblasts after one week. However, cyclosporin A shows multiple effects, including direct ones on nerve growth. To test whether there may be a direct functional relationship between immunomodulation and innervation, cell re-associations and trigeminal ganglia were co-implanted in immunocompromised Nude mice. In these conditions as well, the innervation of the dental mesenchyme was observed already after one week of implantation, but axons reached the odontoblast layer after two weeks only. This study demonstrated that immunodepression per se does stimulate the innervation of the dental mesenchyme.

  17. Intrathecal rimantadine induces motor, proprioceptive, and nociceptive blockades in rats.

    Science.gov (United States)

    Tzeng, Jann-Inn; Wang, Jieh-Neng; Wang, Jhi-Joung; Chen, Yu-Wen; Hung, Ching-Hsia

    2016-04-01

    The purpose of the experiment was to evaluate the local anesthetic effect of rimantadine in spinal anesthesia. Rimantadine in a dose-dependent fashion was constructed after intrathecally injecting the rats with four different doses. The potency and duration of rimantadine were compared with that of the local anesthetic lidocaine at producing spinal motor, nociceptive, and proprioceptive blockades. We demonstrated that intrathecal rimantadine dose-dependently produced spinal motor, nociceptive, and proprioceptive blockades. On the 50% effective dose (ED50) basis, the ranks of potencies at inducing spinal motor, nociceptive, and proprioceptive blockades was lidocaine>rimantadine (P<0.01). Rimantadine exhibited more nociceptive block (ED50) than motor block (P<0.05). At equi-anesthetic doses (ED25, ED50, and ED75), the spinal block duration produced by rimantadine was longer than that produced by lidocaine (P<0.01). Furthermore, rimantadine (26.52μmol/kg) prolonged the nociceptive nerve block more than the motor block (P<0.001). Our preclinical data showed that rimantadine, with a more sensory-selective action over motor block, was less potent than lidocaine. Rimantadine produced longer duration in spinal anesthesia when compared with lidocaine.

  18. Ionotropic glutamate receptor expression in preganglionic neurons of the rat inferior salivatory nucleus.

    Science.gov (United States)

    Kim, M; Chiego, D J; Bradley, R M

    2008-02-29

    Glutamate receptor (GluR) subunit composition of inferior salivatory nucleus (ISN) neurons was studied by immunohistochemical staining of retrogradely labeled neurons. Preganglionic ISN neurons innervating the von Ebner or parotid salivary glands were labeled by application of a fluorescent tracer to the lingual-tonsilar branch of the glossopharyngeal nerve or the otic ganglion respectively. We used polyclonal antibodies to glutamate receptor subunits NR1, NR2A, NR2B, (NMDA receptor subunits) GluR1, GluR2, GluR3, GluR4 (AMPA receptor subunits), and GluR5-7, KA2 (kainate receptor subunits) to determine their expression in ISN neurons. The distribution of the NMDA, AMPA and kainate receptor subunits in retrogradely labeled ISN neurons innervating the von Ebner and parotid glands was qualitatively similar. The percentage of retrogradley labeled ISN neurons innervating the parotid gland expressing the GluR subunits was always greater than those innervating the von Ebner gland. For both von Ebner and parotid ISN neurons, NR2A subunit staining had the highest expression and the lowest expression of GluR subunit staining was NR2B for von Ebner ISN neurons and GluR1 for parotid ISN neurons. The percentage of NR2B and GluR4 expressing ISN neurons was significantly different between the two glands. The percentage of ISN neurons that expressed GluR receptor subunits ranged widely indicating that the distribution of GluR subunit expression differs amongst the ISN neurons. While ISN preganglionic neurons express all the GluR subunits, differences in the percentage of ISN neurons expression between neurons innervating the von Ebner and parotid glands may relate to the different functional roles of these glands.

  19. Centrifugal innervation of the mammalian olfactory bulb.

    Science.gov (United States)

    Matsutani, Shinji; Yamamoto, Noboru

    2008-12-01

    Although it has been known for decades that the mammalian olfactory bulb receives a substantial number of centrifugal inputs from other regions of the brain, relatively few data have been available on the function of the centrifugal olfactory system. Knowing the role of the centrifugal projection and how it works is of critical importance to fully understanding olfaction. The centrifugal fibers can be classified into two groups, a group that release neuromodulators, such as noradrenaline, serotonin, or acetylcholine, and a group originating in the olfactory cortex. Accumulating evidence suggests that centrifugal neuromodulatory inputs are associated with acquisition of odor memory. Because the distribution of the terminals on these fibers is diffuse and widespread, the neuromodulatory inputs must affect diverse subsets of bulbar neurons at the same time. In contrast, knowledge of the role of centrifugal fibers from the olfactory cortical areas is limited. Judging from recent morphological evidence, these fibers may modify the activity of neurons located in sparse and discrete loci in the olfactory bulb. Given the modular organization of the olfactory bulb, centrifugal fibers from the olfactory cortex may help coordinate the activities of restricted subsets of neurons belonging to distinct functional modules in an odor-specific manner. Because the olfactory cortex receives inputs from limbic and neocortical areas in addition to inputs from the bulb, the centrifugal inputs from the cortex can modulate odor processing in the bulb in response to non-olfactory as well as olfactory cues.

  20. Identification of motor neurons and a mechanosensitive sensory neuron in the defecation circuitry of Drosophila larvae.

    Science.gov (United States)

    Zhang, Wei; Yan, Zhiqiang; Li, Bingxue; Jan, Lily Yeh; Jan, Yuh Nung

    2014-10-30

    Defecation allows the body to eliminate waste, an essential step in food processing for animal survival. In contrast to the extensive studies of feeding, its obligate counterpart, defecation, has received much less attention until recently. In this study, we report our characterizations of the defecation behavior of Drosophila larvae and its neural basis. Drosophila larvae display defecation cycles of stereotypic frequency, involving sequential contraction of hindgut and anal sphincter. The defecation behavior requires two groups of motor neurons that innervate hindgut and anal sphincter, respectively, and can excite gut muscles directly. These two groups of motor neurons fire sequentially with the same periodicity as the defecation behavior, as revealed by in vivo Ca(2+) imaging. Moreover, we identified a single mechanosensitive sensory neuron that innervates the anal slit and senses the opening of the intestine terminus. This anus sensory neuron relies on the TRP channel NOMPC but not on INACTIVE, NANCHUNG, or PIEZO for mechanotransduction.

  1. Abnormal innervation patterns in the anorectum of ETU-induced fetal rats with anorectal malformations.

    Science.gov (United States)

    Wang, Weilin; Jia, Huimin; Zhang, Hailan; Chen, Qingjiang; Zhang, Tao; Bai, Yuzuo; Yuan, Zhengwei

    2011-05-16

    To investigate whether anorectal malformations (ARMs) were associated with a global neuromuscular maldevelopment of the lower gastrointestinal (GI) tract and anorectum, the distribution of neuronal markers protein gene product (PGP9.5), nitric oxide synthases (NOs), neuromuscular junction markers (synaptophysin, SYP), interstitial cells of Cajal (ICC) marker (c-kit) within the terminal rectum were analyzed by immunohistochemistry and Western blot in rat embryos with ethylenethiourea (ETU) induced ARMs. From Gestational day16 (Gd16) to Gd21, neural crest-derived cells (NCC) migrated from the proximal gut into the terminal colon, colonising it along its entire length, gradually proliferated and differentiated to innervate the distal gut. From Gd19 to Gd21, significant gross-morphological differences of the anorectum of normal (n=90) and ARMs (n=90) embryos were found. Different myenteric plexus (MPs) development of the anorectum suggested that ARMs were associated with a global abnormal innervation patterns in the anorectum in gestational course and might have some postoperative effect.

  2. Structure, innervation and response properties of integumentary sensory organs in crocodilians.

    Science.gov (United States)

    Leitch, Duncan B; Catania, Kenneth C

    2012-12-01

    Integumentary sensory organs (ISOs) are densely distributed on the jaws of crocodilians and on body scales of members of the families Crocodilidae and Gavialidae. We examined the distribution, anatomy, innervation and response properties of ISOs on the face and body of crocodilians and documented related behaviors for an alligatorid (Alligator mississippiensis) and a crocodylid (Crocodylus niloticus). Each of the ISOs (roughly 4000 in A. mississippiensis and 9000 in C. niloticus) was innervated by networks of afferents supplying multiple different mechanoreceptors. Electrophysiological recordings from the trigeminal ganglion and peripheral nerves were made to isolate single-unit receptive fields and to test possible osmoreceptive and electroreceptive functions. Multiple small (100 mm(2)) and higher thresholds (13.725 mN). Rapidly adapting, slowly adapting type I and slowly adapting type II responses were identified based on neuronal responses. Several rapidly adapting units responded maximally to vibrations at 20-35 Hz, consistent with reports of the ISOs' role in detecting prey-generated water surface ripples. Despite crocodilians' armored bodies, the ISOs imparted a mechanical sensitivity exceeding that of primate fingertips. We conclude that crocodilian ISOs have diverse functions, including detection of water movements, indicating when to bite based on direct contact of pursued prey, and fine tactile discrimination of items held in the jaws.

  3. Does the histaminergic system play a role in spinal nociception?

    Science.gov (United States)

    Harasawa, K

    2000-07-01

    The author studied whether the histaminergic system is involved in spinal nociception or not. A nociception-related, slow ventral root potential of rats, which is an integrated output of motoneurons, was recorded as an index of the intensity of nociception when an electric stimulation was applied to the dorsal root. Histamine dissolved in an artificial cerebrospinal fluid caused small reduction in the potential; however, mepyramine (10 nM to 10 microM, as an H1 receptor antagonist), ranitidine (1 nM to 1 microM, as an H2 receptor antagonist), R(-)-alpha-methylhistamine (2 pM to 200 nM, as an H3 receptor agonist), and thioperamide (1 nM to 10 microM, as an H3 receptor antagonist) dose-dependently reduced the potential down to around a half of each control level. These results indicate that the histaminergic system may affect the spinal withdrawal reflex.

  4. Effect of temporal stimulus properties on the nociceptive detection probability using intra‑epidermal electrical stimulation

    NARCIS (Netherlands)

    Doll, Robert J.; Maten, Annefloor C.A.; Spaan, Sjoerd P.G.; Veltink, Peter H.; Buitenweg, Jan R.

    2016-01-01

    Chronic pain disorders can be initiated and maintained by malfunctioning of one or several mechanisms underlying the nociceptive function. Although several quantitative sensory testing methods exist to characterize the nociceptive function, it remains difficult to distinguish the contributions of in

  5. The origin of sensory innervation of the peritoneum in the rat.

    Science.gov (United States)

    Tanaka, Koichi; Matsugami, Toshiko; Chiba, Tanemichi

    2002-07-01

    The distribution of sensory neurons innervating the peritoneum was studied using axonal transport of fluoro-gold. The tracer was injected into parietal peritoneum, diaphragm, mesentery, mesocolon, visceral peritoneum covering the stomach, small intestine, colon, liver, spleen, kidney, urinary bladder or uterus. After ten days of survival bilateral dorsal root ganglia from C2 to S6, and the nodose ganglia were dissected. The cryostat sections of these ganglia were mounted on glass slides and observed with a fluorescence microscope. In cases where the tracer was placed on the peritoneum covering the abdominal wall, labeled neurons were observed only in the ipsilateral dorsal root ganglia. A small number of neurons in nodose and cervical dorsal root ganglia of both sides were labeled after placing the tracer on the central part of the diaphragm. When fluoro-gold was applied to the peripheral part of the diaphragm, nodose ganglion was negative, and dorsal root ganglia from T6 to T12 were positive. Many neurons in the nodose ganglia in addition to somata in the dorsal root ganglia from T4 to T13 were labeled when the tracer was placed on the peritoneum lining the stomach, small intestine or caecum. After applying the tracer onto the colon, labeled neurons were observed in the dorsal root ganglia from T13 to L2 and L5 to S1. Ganglion cells in the nodose and dorsal root ganglia from T5 to T13 were positive when fluoro-gold was placed on the mesentery. No labeled neurons were observed in any ganglia when the tracer was applied to the peritoneum covering the spleen, kidney, uterus, urinary bladder and liver. These results suggest that most of the parietal peritoneum receives sensory nerves from dorsal root ganglia and the visceral peritoneum from both spinal nerves and the vagus nerve.

  6. Delayed focal involvement of upper motor neurons in the Madras pattern of motor neuron disease.

    Science.gov (United States)

    Massa, R; Scalise, A; Iani, C; Palmieri, M G; Bernardi, G

    1998-12-01

    We report the case of a young man from the south of India, initially presenting the typical signs of benign monomelic amyotrophy (BMA) in the left upper limb. After several years, the involvement of other limbs and the appearance of bulbar signs suggested the possible diagnosis of the Madras pattern of motor neuron disease (MMND). Serial motor evoked potential (MEP) recordings allowed detection of the onset of a focal involvement of upper motor neurons (UMN) controlling innervation in the originally amyotrophic limb. Therefore, serial MEP recordings can be useful for the early detection of sub-clinical UMN damage in motor neuron disease presenting with pure lower motor neuron (LMN) signs.

  7. Identification of CNS neural circuitry involved in the innervation of C7 spinal nerve: a viral transsynaptic tracing study

    Directory of Open Access Journals (Sweden)

    WEI Hai-feng

    2012-02-01

    Full Text Available 【Abstract】 Objective: Contralateral C7 spinal nerve transfer is a useful operation for the treatment of brachial plexus root avulsion. The recovery of the independent function at the ipsilateral side, however, depends on neural circuitry reorganization in the central nervous system (CNS. This study tried to locate the CNS neuronal elements involved in the innervation of C7 spinal nerve. Method: Pseudorabies virus (PRV, TK/gG-, 2 祃, which expressed green fluorescent protein (GFP, was injected into the left C7 spinal nerve in 20 adult Sprague Dawley rats. After rats survived for 6 h, 12 h, 24 h and 36 h, the C1-C7 segments of the spinal cord and brain were processed using a polyclonal immunohistochemical antibody against PRV. Results: PRV-labeled neurons were found mainly in gray matter of the C1-C7 segments of the spinal cord and at the following structures of the brain: lateral vestibular nucleus, lateral paragigantocellular nucleus, A5 cells, red nucleus, primary and secondary motor cortexes, primary and secondary somatosensory cortexes. Although located bilaterally, the PRV-labeled neurons existed predominantly in the ipsilateral side of the spinal cord and the contralateral side of the brain at 6-12 h after injection (p.i.. The number of PRV-labeled neurons in the CNS was increasing with rat抯 survival time and the distribution of these neurons turned bilateral with no obvious dominance to either side at 24 h and 36 h (p.i.. Conclusion: By use of transsynaptic tracing technique with PRV, the anatomically connected set of neurons, which modulates the activity of C7 spinal nerve, is located successfully in the CNS. Key words: Brachial plexus; Innervation; Spinal nerves; Central nervous system

  8. Identification of neurons that express ghrelin receptors in autonomic pathways originating from the spinal cord.

    Science.gov (United States)

    Furness, John B; Cho, Hyun-Jung; Hunne, Billie; Hirayama, Haruko; Callaghan, Brid P; Lomax, Alan E; Brock, James A

    2012-06-01

    Functional studies have shown that subsets of autonomic preganglionic neurons respond to ghrelin and ghrelin mimetics and in situ hybridisation has revealed receptor gene expression in the cell bodies of some preganglionic neurons. Our present goal has been to determine which preganglionic neurons express ghrelin receptors by using mice expressing enhanced green fluorescent protein (EGFP) under the control of the promoter for the ghrelin receptor (also called growth hormone secretagogue receptor). The retrograde tracer Fast Blue was injected into target organs of reporter mice under anaesthesia to identify specific functional subsets of postganglionic sympathetic neurons. Cryo-sections were immunohistochemically stained by using anti-EGFP and antibodies to neuronal markers. EGFP was detected in nerve terminal varicosities in all sympathetic chain, prevertebral and pelvic ganglia and in the adrenal medulla. Non-varicose fibres associated with the ganglia were also immunoreactive. No postganglionic cell bodies contained EGFP. In sympathetic chain ganglia, most neurons were surrounded by EGFP-positive terminals. In the stellate ganglion, neurons with choline acetyltransferase immunoreactivity, some being sudomotor neurons, lacked surrounding ghrelin-receptor-expressing terminals, although these terminals were found around other neurons. In the superior cervical ganglion, the ghrelin receptor terminals innervated subgroups of neurons including neuropeptide Y (NPY)-immunoreactive neurons that projected to the anterior chamber of the eye. However, large NPY-negative neurons projecting to the acini of the submaxillary gland were not innervated by EGFP-positive varicosities. In the celiaco-superior mesenteric ganglion, almost all neurons were surrounded by positive terminals but the VIP-immunoreactive terminals of intestinofugal neurons were EGFP-negative. The pelvic ganglia contained groups of neurons without ghrelin receptor terminal innervation and other groups with

  9. Function and innervation of the involuntary m. retroauricularis.

    Science.gov (United States)

    Heuser, M

    1976-10-01

    Beside the automatic, obligatory and tonic coinnervation of the involuntary m. retroauricularis in conjugate lateral gaze (oculoauricular phenomenon, nystagmus) several other physiological ways of accidental coinnervation are described. In talking, chewing, swallowing and during involuntary inspiration irregular bursts of innervation may be registered. In sleep regular rhythmic inspiratory innervation is demonstrated as well as myoclonic jerks. With reservation, an allusion is made to rem-sleep. In "nervous subjects" irregular involuntary innervation of the m. retroauricularis might serve as a measurement instrument for the involuntary somatomotor nervous system, i.e. the degree of neurotic tensity. An early myasthenic reaction is gained from the M. retroauricularis in patients with ocular forms of the disease. A common motor nucleus of abducens and facial nerve is discussed. Complementary studies are announced on the various forms of facial paralysis, strabismus and nystagmus. A further diagnostic use is presumed.

  10. The Lesser Palatine Nerve Innervates the Levator Veli Palatini Muscle

    Science.gov (United States)

    Matsuura, Yoshitaka; Kawai, Katsuya; Yamada, Shigehito; Suzuki, Shigehiko

    2016-01-01

    Summary: When the lesser palatine nerve (LPN) is supposed to be a branch of the trigeminal nerve and innervate sensation of the soft palate, whether the LPN contains motor fibers is unclear. In this study, we monitored the electromyogram of the levator veli palatini (LVP) muscle on stimulating the LPN during palatoplasty in 3 patients. The electromyogram of the muscles showed the myogenic potential induced by electrostimulation of the LPN. Taken together with the finding from our previous anatomical study that the motor fibers come from the facial nerve, this result supports the double innervation theory of the LVP, which posits that both the pharyngeal plexus and the facial nerve innervate it. Identifying and preserving the LPN during palatoplasty might improve postoperative speech results. PMID:27757354

  11. Pox neuro control of cell lineages that give rise to larval poly-innervated external sensory organs in Drosophila.

    Science.gov (United States)

    Jiang, Yanrui; Boll, Werner; Noll, Markus

    2015-01-15

    The Pox neuro (Poxn) gene of Drosophila plays a crucial role in the development of poly-innervated external sensory (p-es) organs. However, how Poxn exerts this role has remained elusive. In this study, we have analyzed the cell lineages of all larval p-es organs, namely of the kölbchen, papilla 6, and hair 3. Surprisingly, these lineages are distinct from any previously reported cell lineages of sensory organs. Unlike the well-established lineage of mono-innervated external sensory (m-es) organs and a previously proposed model of the p-es lineage, we demonstrate that all wild-type p-es lineages exhibit the following features: the secondary precursor, pIIa, gives rise to all three support cells-socket, shaft, and sheath, whereas the other secondary precursor, pIIb, is neuronal and gives rise to all neurons. We further show that in one of the p-es lineages, that of papilla 6, one cell undergoes apoptosis. By contrast in Poxn null mutants, all p-es lineages have a reduced number of cells and their pattern of cell divisions is changed to that of an m-es organ, with the exception of a lineage in a minority of mutant kölbchen that retains a second bipolar neuron. Indeed, the role of Poxn in p-es lineages is consistent with the specification of the developmental potential of secondary precursors and the regulation of cell division but not apoptosis.

  12. CROSSING ANASTOMOSIS OF NERVE BUNDLES NEAR INNERVATED ORGANS TO TREAT IRREPARABLE NERVE INJURIES

    Institute of Scientific and Technical Information of China (English)

    2006-01-01

    Objective To study the therapeutical effects of crossing anastomosis of nerve on the peripheral and central nerve injuries.Methods Twelve kinds of central and peripheral nerve disorders and their complications were treated with 11 kinds of crossing anastomosis of nerve bundles near the innervated organs. After nerve injury and repair, somatosensory evoked potentials (SEPs) and horseradish peroxidase (HRP) retrograde tracing studies were used to investigate the rabbit's nerve function and morphology.Results The ulcers of all patients healed. Sensation, voluntary movement, and joint function recovered. Four weeks after the anastomosis of distal stump of radialis superficialis nerve and median nerve, pain sensation regained and SEPs appeared. HRP retrograde tracing studies demonstrated sensory nerve ending of medial nerve formed new connection with the body of neuron.Conclusion Crossing anastomosis of nerve is an effective method to treat peripheral and central nerve injuries.

  13. Noradrenergic mechanism involved in the nociceptive modulation of hippocampal CA3 region of normal rats.

    Science.gov (United States)

    Jin, Hua; Teng, Yueqiu; Zhang, Xuexin; Yang, Chunxiao; Xu, Manying; Yang, Lizhuang

    2014-06-27

    Norepinephrine (NE) is an important neurotransmitter in the brain, and regulates antinociception. However, the mechanism of action of NE on pain-related neurons in the hippocampal CA3 region is not clear. This study examines the effects of NE, phentolamine on the electrical activities of pain-excited neurons (PENs) and pain-inhibited neurons (PINs) in the hippocampal CA3 region of rats. Trains of electric impulses applied to the right sciatic nerve were used as noxious stimulation. The electrical activities of PENs or PINs in the hippocampal CA3 region were recorded by using a glass microelectrode. Our results revealed that, in the hippocampal CA3 region, the intra-CA3 region microinjection of NE decreased the pain-evoked discharged frequency and prolonged the discharged latency of PEN, and increased the pain-evoked discharged frequency and shortened discharged inhibitory duration (ID) of PIN, exhibiting the specific analgesic effect of NE. While intra-CA3 region microinjection of phentolamine produced the opposite response. It implies that phentolamine can block the effect of endogenous NE to cause the enhanced response of PEN and PIN to noxious stimulation. On the basis of above findings we can deduce that NE, phentolamine and alpha-adrenoceptor are involved in the modulation of nociceptive information transmission in the hippocampal CA3 region.

  14. Less than 15% of the spinothalamic fibers originate from neurons in lamina I in cat

    NARCIS (Netherlands)

    Klop, EM; Mouton, LJ; Holstege, G

    2004-01-01

    Lamina I neurons sending their axons into the spinothalamic tract are thought to play a crucial role in nociception, but many spinothalamic fibers do not originate from lamina I neurons. In cat, no consensus exists about what percentage of the spinothatamic tract cells are located in lamina I. After

  15. Bergmann glia and the recognition molecule CHL1 organize GABAergic axons and direct innervation of Purkinje cell dendrites.

    Directory of Open Access Journals (Sweden)

    Fabrice Ango

    2008-04-01

    Full Text Available The geometric and subcellular organization of axon arbors distributes and regulates electrical signaling in neurons and networks, but the underlying mechanisms have remained elusive. In rodent cerebellar cortex, stellate interneurons elaborate characteristic axon arbors that selectively innervate Purkinje cell dendrites and likely regulate dendritic integration. We used GFP BAC transgenic reporter mice to examine the cellular processes and molecular mechanisms underlying the development of stellate cell axons and their innervation pattern. We show that stellate axons are organized and guided towards Purkinje cell dendrites by an intermediate scaffold of Bergmann glial (BG fibers. The L1 family immunoglobulin protein Close Homologue of L1 (CHL1 is localized to apical BG fibers and stellate cells during the development of stellate axon arbors. In the absence of CHL1, stellate axons deviate from BG fibers and show aberrant branching and orientation. Furthermore, synapse formation between aberrant stellate axons and Purkinje dendrites is reduced and cannot be maintained, leading to progressive atrophy of axon terminals. These results establish BG fibers as a guiding scaffold and CHL1 a molecular signal in the organization of stellate axon arbors and in directing their dendritic innervation.

  16. Myocardial sympathetic innervation, function, and oxidative metabolism in non-infarcted myocardium in patients with prior myocardial infarction.

    Science.gov (United States)

    Aoki, Hirofumi; Matsunari, Ichiro; Nomura, Yusuke; Fujita, Wataru; Komatsu, Ryoko; Miyazaki, Yoshiharu; Nekolla, Stephan G; Kajinami, Kouji

    2013-07-01

    The purpose of this study was to investigate the relationship between sympathetic innervation, contractile function, and the oxidative metabolism of the non-infarcted myocardium in patients with prior myocardial infarction. In 19 patients (14 men, 5 women, 65 ± 9 years) after prior myocardial infarction, sympathetic innervation was assessed by (11)C-hydroxyephedrine (HED) positron emission tomography (PET). Oxidative metabolism was quantified using (11)C-acetate PET. Left ventricular systolic function was measured by echocardiography with speckle tracking technique. The (11)C-HED retention was positively correlated with left ventricular ejection fraction (LVEF) (r = 0.566, P infarcted myocardium (r = -0.561, P infarcted myocardium. When the patients were divided into two groups based on the median value of left ventricular end-systolic volume index (LVESVI) (41 mL), there were no significant differences in age, sex, and rate pressure product between the groups. However, the large LVESVI group (>41 mL) was associated with reduced (11)C-HED retention and peak longitudinal strain in systole, whereas Kmono was similar between the groups. This study indicates that remodeled LV after myocardial infarction is associated with impaired sympathetic innervation and function even in the non-infarcted myocardial tissue. Furthermore, oxidative metabolism in the non-infarcted myocardium seems to be operated by normal regulatory mechanisms rather than pre-synaptic sympathetic neuronal function.

  17. Optical imaging of nociception in primary somatosensory cortex of non-human primates

    Institute of Scientific and Technical Information of China (English)

    Li-Min CHEN; Robert M. Friedman; Anna W. Roe

    2008-01-01

    While the activation of primary somatosensory (SI) cortex during pain perception is consistently reported in functional imaging studies on normal subjects and chronic pain patients, the specific roles of SI, particularly the subregions within SI, in the processing of sensory aspects of pain are still largely unknown. Using optical imaging of intrinsic signal (OIS) and single unit electrophysiology, we studied cortical activation patterns within SI cortex (among Brodmann areas 3a, 3b and 1) and signal amplitude changes to various intensities of non-nociceptive, thermal nociceptive and mechanical nociceptive stimulation of individual distal finerpads in anesthetized squirrel monkeys. We have demonstrated that areas 3a and 1 are preferentially involved in the processing of nociceptive information while areas 3b and 1 are preferentially activated in the processing of non-nociceptive (touch) information. Nociceptive activations of individual fingerpad were organized topographically suggesting that nociceptive topographic map exits in areas 3a and 1. Signal amplitude was enhanced to increasing intensity of mechanical nociceptive stimuli in areas 3a, 3b and 1. Within area 1, nociceptive response co-localizes with the non-nociceptive response. Therefore, we hypothesize that nocicepitve information is area-specifically represented within SI cortex, in which nociceptive inputs are preferentially represented in areas 3a and 1 while non-nociceptive inputs are preferentially represented in areas 3b and 1.

  18. Localization of cholecystokininlike immunoreactivity in the rat spinal cord, with particular reference to the autonomic innervation of the pelvic organs

    DEFF Research Database (Denmark)

    Schrøder, H D

    1983-01-01

    . It thus appears that the unique lumbosacral cholecystokinin is related to nuclei influencing pelvic structures, pointing to a special need for regulation of the organs involved in evacuation and sexual functions. Moreover, it is demonstrated that the caudal part of the spinal sympathetic system differs...... tracing and immunocytochemistry revealed that the two cholecystokinin terminal fields characteristic for L1-L2 and that surrounding the intermediolateral nucleus in L6-S1 were situated corresponding to preganglionic neurons innervating pelvic organs through the hypogastric nerve or the pelvic nerves...

  19. [Application of the immunohistochemical detection of PGP 9.5 protein for the study of rat and human heart innervation].

    Science.gov (United States)

    Korzhevskiy, D E; Sukhorukova, Ye G; Petrova, Ye S; Tzukanova, A F; Chumasov, Ye I

    2013-01-01

    In this paper we describe the modern immunohistochemical method detecting the neuronal marker PGP 9.5. The application of this method for the study of the innervation of rat and human heart, the detailed examination of the topography of the cardiac nervous apparatus, as well as their changes in pathological states, is demonstrated. Structural organization and the nature of the terminal branches of nerve apparatus suggest that they have afferent function. Protocol of the reaction demonstrating PGP 9.5 on paraffin sections is presented.

  20. Differences in host serotonin innervation of intrastriatal grafts are not determined by a glial scar or chondroitin sulfate proteoglycans.

    Science.gov (United States)

    Petit, Audrey; Quenneville, Nancy; Vallée, Annie; Pierret, Philippe; Doucet, Guy

    2002-09-01

    Serotoninergic (5-HT) neurons of adult recipients provide a much denser innervation of striatal than ventral mesencephalic grafts implanted into the neostriatum of the rat. Moreover, grafts from both brain regions are more innervated by host 5-HT axons after implantation in neonatal than adult hosts. To test the hypothesis that differences in glial scarring or expression of the growth inhibitory molecules, chondroitin sulfate proteoglycans (CSPG), be responsible for these differences in 5-HT innervation of neural grafts, we examined the 5-HT innervation, the astroglial reaction and the expression of CSPG in ventral mesencephalic grafts implanted into newborn (1-5 days old), juvenile (15 days old), or adult rats and in striatal grafts implanted in adult rats, using immunohistochemistry against 5-HT, glial fibrillary acidic protein (GFAP) and CSPG. Immunostaining for GFAP showed a stronger initial gliosis (1-10 days after grafting) in neonatal than adult recipients of mesencephalic grafts, but this gliosis subsided gradually at later time points. Nevertheless, a glial scar formed at the graft-host interface in both neonatal and adult recipients, 5-10 days after transplantation, although it decreased over a longer time course--up to 60 days--in adults. Immunostained astrocytes appeared first in the host brain tissue around the graft and then immunoreactive processes and perikarya gradually invaded the graft. Immunoreactivity for CSPG was similar in neonatal and adult hosts: it was strongly expressed inside the graft early after transplantation, and almost completely down-regulated at 60 days. The reaction of adult hosts to striatal and mesencephalic grafts was similar, although GFAP was more heterogeneously distributed and CSPG immunoreactivity remained in patches inside striatal grafts, even after 60 days. The 5-HT innervation of mesencephalic grafts was much denser after implantation in newborns than in adults. It was also stronger in striatal than in mesencephalic

  1. Migration pathways of sacral neural crest during development of lower urogenital tract innervation.

    Science.gov (United States)

    Wiese, Carrie B; Deal, Karen K; Ireland, Sara J; Cantrell, V Ashley; Southard-Smith, E Michelle

    2017-09-01

    The migration and fate of cranial and vagal neural crest-derived progenitor cells (NCPCs) have been extensively studied; however, much less is known about sacral NCPCs particularly in regard to their distribution in the urogenital system. To construct a spatiotemporal map of NCPC migration pathways into the developing lower urinary tract, we utilized the Sox10-H2BVenus transgene to visualize NCPCs expressing Sox10. Our aim was to define the relationship of Sox10-expressing NCPCs relative to bladder innervation, smooth muscle differentiation, and vascularization through fetal development into adulthood. Sacral NCPC migration is a highly regimented, specifically timed process, with several potential regulatory mileposts. Neuronal differentiation occurs concomitantly with sacral NCPC migration, and neuronal cell bodies are present even before the pelvic ganglia coalesce. Sacral NCPCs reside within the pelvic ganglia anlagen through 13.5 days post coitum (dpc), after which they begin streaming into the bladder body in progressive waves. Smooth muscle differentiation and vascularization of the bladder initiate prior to innervation and appear to be independent processes. In adult bladder, the majority of Sox10+ cells express the glial marker S100β, consistent with Sox10 being a glial marker in other tissues. However, rare Sox10+ NCPCs are seen in close proximity to blood vessels and not all are S100β+, suggesting either glial heterogeneity or a potential nonglial role for Sox10+ cells along vasculature. Taken together, the developmental atlas of Sox10+ NCPC migration and distribution profile of these cells in adult bladder provided here will serve as a roadmap for future investigation in mouse models of lower urinary tract dysfunction. Copyright © 2017 Elsevier Inc. All rights reserved.

  2. Changes in cardiac innervation during maturation in long-term diabetes.

    Science.gov (United States)

    Bakovic, Marija; Juric Paic, Marina; Zdrilic, Elena; Vukojevic, Katarina; Ferhatovic, Lejla; Marin, Ana; Filipovic, Natalija; Grkovic, Ivica; Puljak, Livia

    2013-12-01

    Diabetic autonomic neuropathy being a common complication of diabetes mellitus (DM) is related to an increased risk of cardiovascular mortality. However, mechanisms underlying changes of innervation density in affected hearts remain insufficiently understood. Hence, the aim of this study was to describe quantitative changes of intra-myocardial nerve terminals in hearts of diabetic rats of various ages. Male Sprague-Dawley rats were injected with 55mg/kg streptozotocin (STZ) (DM group) or with citrate buffer (control). After 2weeks, 2months, 6months and 12months, sections of their hearts were analyzed in five areas-left ventricle, interventricular septum, right ventricle, anterior and posterior wall. Nerve fibers were visualized immunohistochemically, using antibody against a general neuronal marker, protein gene product 9.5 (PGP 9.5). Significant increase in total nerve fibers from all heart areas was observed 2weeks and 2months after diabetes induction, followed by a decrease at 6months and again increase at 12months was observed in both control and diabetic rats. Significant difference between control and diabetic rats was visible after 2weeks and 2months, with diabetic rats exhibiting significantly more nerve fibers. There were no consistent differences in quantity of nerve fibers in different areas of the heart within a particular age-related group of animals. In conclusion, cardiac innervation undergoes dynamic changes both in control and in diabetic rats, with a time-dependent significant increase in neuronal fiber density in diabetic animals. This novel information may contribute to our understanding of pathophysiological changes associated with diabetic cardiac neuropathy.

  3. Clitoral sexual arousal: an immunocytochemical and innervation study of the clitoris.

    Science.gov (United States)

    Martin-Alguacil, Nieves; Pfaff, Donald W; Shelley, Deborah N; Schober, Justine M

    2008-06-01

    To further define neural pathways and mechanisms responsible for the arousing properties of the epithelium of the clitoris as well as related neural pathways associated with sexual arousal in a murine model. Adult female C57B1/6 mice were used for gross dissection, facilitated by resin injection of the vascular system, and silver staining, and immunostaining for S-100 and neuronal nitric oxide synthase (nNOS). We also comprehensively reviewed relevant published clinical and histological material from both human and non-human vertebrate studies. The distal innervation consists of three nerve bundles: one related to the perineal region, one through the corpus cavernosum, and the third between the dorsal part of the clitoris and the urethra. Communicating nerve fibres were identified between the perineal, the corpus cavernous nerve (CN) and the dorsal nerve of the clitoris. Immunostaining for nNOS showed that the CN sends nNOS-positive fibres to join the dorsal nerve of the clitoris. In the same distal area of the clitoris, the connecting branches between the perineal nerve and the dorsal nerve of the clitoris are also nNOS positive. A rich network of nerve bundles and terminal branches were identified and associated with nNOS immunostaining in the cavernosal tissue of the body of clitoris. NO control of vasodilatation and neuronal signalling between the CN and the dorsal nerve of the clitoris could contribute to the engorgement and subsidence of clitoral tissue. This supports the initiation of sexual arousal by tactile stimuli. The distribution pattern of the general and peptidergic innervation in the murine clitoris is similar to that of the penis.

  4. Morphology, innervation, and peripheral sensory cells of the siphon of aplysia californica.

    Science.gov (United States)

    Carrigan, Ian D; Croll, Roger P; Wyeth, Russell C

    2015-11-01

    The siphon of Aplysia californica has several functions, including involvement in respiration, excretion, and defensive inking. It also provides sensory input for defensive withdrawals that have been studied extensively to examine mechanisms that underlie learning. To better understand the neuronal bases of these functions, we used immunohistochemistry to catalogue peripheral cell types and innervation of the siphon in stage 12 juveniles (chosen to allow observation of tissues in whole-mounts). We found that the siphon nerve splits into three major branches, leading ultimately to a two-part FMRFamide-immunoreactive plexus and an apparently separate tyrosine hydroxylase-immunoreactive plexus. Putative sensory neurons included four distinct types of tubulin-immunoreactive bipolar cells (one likely also tyrosine hydroxylase immunoreactive) that bore ciliated dendrites penetrating the epithelium. A fifth bipolar neuron type (tubulin- and FMRFamide-immunoreactive) occurred deeper in the tissue, associated with part of the FMRFamide-immunoreactive plexus. Our observations emphasize the structural complexity of the peripheral nervous system of the siphon, and the importance of direct tests of the various components to better understand the functioning of the entire organ, including its role in defensive withdrawal responses.

  5. Diacetyl increases sensory innervation and substance P production in rat trachea.

    Science.gov (United States)

    Goravanahally, Madhusudan P; Hubbs, Ann F; Fedan, Jeffery S; Kashon, Michael L; Battelli, Lori A; Mercer, Robert R; Goldsmith, W Travis; Jackson, Mark C; Cumpston, Amy; Frazer, David G; Dey, Richard D

    2014-01-01

    Inhalation of diacetyl, a butter flavoring, causes airway responses potentially mediated by sensory nerves. This study examines diacetyl-induced changes in sensory nerves of tracheal epithelium. Rats (n = 6/group) inhaled 0-, 25-, 249-, or 346-ppm diacetyl for 6 hr. Tracheas and vagal ganglia were removed 1-day postexposure and labeled for substance P (SP) or protein gene product 9.5 (PGP9.5). Vagal ganglia neurons projecting to airway epithelium were identified by axonal transport of fluorescent microspheres intratracheally instilled 14 days before diacetyl inhalation. End points were SP and PGP9.5 nerve fiber density (NFD) in tracheal epithelium and SP-positive neurons projecting to the trachea. PGP9.5-immunoreactive NFD decreased in foci with denuded epithelium, suggesting loss of airway sensory innervation. However, in the intact epithelium adjacent to denuded foci, SP-immunoreactive NFD increased from 0.01 ± 0.002 in controls to 0.05 ± 0.01 after exposure to 346-ppm diacetyl. In vagal ganglia, SP-positive airway neurons increased from 3.3 ± 3.0% in controls to 25.5 ± 6.6% after inhaling 346-ppm diacetyl. Thus, diacetyl inhalation increases SP levels in sensory nerves of airway epithelium. Because SP release in airways promotes inflammation and activation of sensory nerves mediates reflexes, neural changes may contribute to flavorings-related lung disease pathogenesis.

  6. Role of capsaicin-sensitive C-fiber afferents in neuropathic pain-induced synaptic potentiation in the nociceptive amygdala

    Directory of Open Access Journals (Sweden)

    Nakao Ayano

    2012-07-01

    Full Text Available Abstract Background Neurons in the capsular part of the central nucleus of the amygdala (CeC, a region also called "nociceptive amygdala," receive nociceptive information from the dorsal horn via afferent pathways relayed from the lateral parabrachial nucleus (LPB. As the central amygdala is known to be involved in the acquisition and expression of emotion, this pathway is thought to play central roles in the generation of affective responses to nociceptive inputs. Excitatory synaptic transmission between afferents arising from the LPB and these CeC neurons is potentiated in arthritic, visceral, neuropathic, inflammatory and muscle pain models. In neuropathic pain models following spinal nerve ligation (SNL, in which we previously showed a robust LPB-CeC potentiation, the principal behavioral symptom is tactile allodynia triggered by non-C-fiber low-threshold mechanoreceptor afferents. Conversely, recent anatomical studies have revealed that most of the spinal neurons projecting to the LPB receive C-fiber afferent inputs. Here, we examined the hypothesis that these C-fiber-mediated inputs are necessary for the full establishment of robust synaptic potentiation of LPB-CeC transmission in the rats with neuropathic pain. Results Postnatal capsaicin treatment, which has been shown to denervate the C-fibers expressing transient receptor potential vanilloid type-1 (TRPV1 channels, completely abolished eye-wiping responses to capsaicin eye instillation in rats, but this treatment did not affect mechanical allodynia in the nerve-ligated animals. However, the postnatal capsaicin treatment prevented LPB-CeC synaptic potentiation after SNL, unlike in the vehicle-treated rats, primarily due to the decreased incidence of potentiated transmission by elimination of TRPV1-expressing C-fiber afferents. Conclusions C-fiber-mediated afferents in the nerve-ligated animals may be a required facilitator of the establishment of nerve injury-evoked synaptic

  7. The Interface of Mechanics and Nociception in Joint Pathophysiology: Insights From the Facet and Temporomandibular Joints.

    Science.gov (United States)

    Sperry, Megan M; Ita, Meagan E; Kartha, Sonia; Zhang, Sijia; Yu, Ya-Hsin; Winkelstein, Beth

    2017-02-01

    Chronic joint pain is a widespread problem that frequently occurs with aging and trauma. Pain occurs most often in synovial joints, the body's load bearing joints. The mechanical and molecular mechanisms contributing to synovial joint pain are reviewed using two examples, the cervical spinal facet joints and the temporomandibular joint (TMJ). Although much work has focused on the macroscale mechanics of joints in health and disease, the combined influence of tissue mechanics, molecular processes, and nociception in joint pain has only recently become a focus. Trauma and repeated loading can induce structural and biochemical changes in joints, altering their microenvironment and modifying the biomechanics of their constitutive tissues, which themselves are innervated. Peripheral pain sensors can become activated in response to changes in the joint microenvironment and relay pain signals to the spinal cord and brain where pain is processed and perceived. In some cases, pain circuitry is permanently changed, which may be a potential mechanism for sustained joint pain. However, it is most likely that alterations in both the joint microenvironment and the central nervous system (CNS) contribute to chronic pain. As such, the challenge of treating joint pain and degeneration is temporally and spatially complicated. This review summarizes anatomy, physiology, and pathophysiology of these joints and the sensory pain relays. Pain pathways are postulated to be sensitized by many factors, including degeneration and biochemical priming, with effects on thresholds for mechanical injury and/or dysfunction. Initiators of joint pain are discussed in the context of clinical challenges including the diagnosis and treatment of pain.

  8. Extrinsic and local glutamatergic inputs of the rat hippocampal CA1 area differentially innervate pyramidal cells and interneurons.

    Science.gov (United States)

    Takács, Virág T; Klausberger, Thomas; Somogyi, Peter; Freund, Tamás F; Gulyás, Attila I

    2012-06-01

    The two main glutamatergic pathways to the CA1 area, the Schaffer collateral/commissural input and the entorhinal fibers, as well as the local axons of CA1 pyramidal cells innervate both pyramidal cells and interneurons. To determine whether these inputs differ in their weights of activating GABAergic circuits, we have studied the relative proportion of pyramidal cells and interneurons among their postsynaptic targets in serial electron microscopic sections. Local axons of CA1 pyramidal cells, intracellularly labeled in vitro or in vivo, innervated a relatively high proportion of interneuronal postsynaptic targets (65.9 and 53.8%, in vitro and in vivo, respectively) in stratum (str.) oriens and alveus. In contrast, axons of in vitro labeled CA3 pyramidal cells in str. oriens and str. radiatum of the CA1 area made synaptic junctions predominantly with pyramidal cell spines (92.9%). The postsynaptic targets of anterogradely labeled medial entorhinal cortical boutons in CA1 str. lacunosum-moleculare were primarily pyramidal neuron dendritic spines and shafts (90.8%). The alvear group of the entorhinal afferents, traversing str. oriens, str. pyramidale, and str. radiatum showed a higher preference for innervating GABAergic cells (21.3%), particularly in str. oriens/alveus. These data demonstrate that different glutamatergic pathways innervate CA1 GABAergic cells to different extents. The results suggest that the numerically smaller CA1 local axonal inputs together with the alvear part of the entorhinal input preferentially act on GABAergic interneurons in contrast to the CA3, or the entorhinal input in str. lacunosum-moleculare. The results highlight differences in the postsynaptic target selection of the feed-forward versus recurrent glutamatergic inputs to the CA1 and CA3 areas.

  9. Intracisternal octreotide does not ameliorate orthodromic trigeminovascular nociception

    NARCIS (Netherlands)

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

    2000-01-01

    Octreotide is a long-acting somatostatin analogue that has been effectively used to treat migraine. Octreotide poorly penetrates the blood-brain barrier, but has potential central target sites in the trigeminal nucleus caudalis, which is the primary central relay station for trigeminal nociceptive i

  10. Tests and models of nociception and pain in rodents.

    Science.gov (United States)

    Barrot, M

    2012-06-01

    Nociception and pain is a large field of both neuroscience and medical research. Over time, various tests and models were developed in rodents to provide tools for fundamental and translational research on the topic. Tests using thermal, mechanical, and chemical stimuli, measures of hyperalgesia and allodynia, models of inflammatory or neuropathic pain, constitute a toolbox available to researchers. These tests and models allowed rapid progress on the anatomo-molecular basis of physiological and pathological pain, even though they have yet to translate into new analgesic drugs. More recently, a growing effort has been put forth trying to assess pain in rats or mice, rather than nociceptive reflexes, or at studying complex states affected by chronic pain. This aids to further improve the translational value of preclinical research in a field with balanced research efforts between fundamental research, preclinical work, and human studies. This review describes classical tests and models of nociception and pain in rodents. It also presents some recent and ongoing developments in nociceptive tests, recent trends for pain evaluation, and raises the question of the appropriateness between tests, models, and procedures.

  11. Citral reduces nociceptive and inflammatory response in rodents

    Directory of Open Access Journals (Sweden)

    Lucindo J. Quintans-Júnior

    2011-06-01

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

  12. Nociception at the diabetic foot, an uncharted territory.

    Science.gov (United States)

    Chantelau, Ernst A

    2015-04-15

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

  13. Nociception and Conditioned Fear in Rats: Strains Matter

    NARCIS (Netherlands)

    Schaap, M.W.H.; van Oostrom, H.; Doornenbal, A.; van 't Klooster, J.; Baars, A.M.; Arndt, S.S.; Hellebrekers, L.J.

    2013-01-01

    When using rats in pain research, strain-related differences in outcomes of tests for pain and nociception are acknowledged. However, very little is known about the specific characteristics of these strain differences. In this study four phylogenetically distant inbred rat strains, i.e. Wistar Kyoto

  14. Nociception and escape behavior in planarians

    Science.gov (United States)

    Schoetz Collins, Eva-Maria

    2015-03-01

    Planarians are famous and widely studied for their regenerative capabilities. When a moving planarian is cut through the middle, the resulting head and tail pieces instantaneously retract and exhibit a characteristic escape response that differs from normal locomotion. In asexual animals, a similar reaction is observed when the planarian undergoes fission, suggesting that reproduction through self-tearing is a rather traumatic event for the animal. Using a multiscale approach, we unravel the dynamics, mechanics, and functional aspects of the planarian escape response. This musculature-driven gait was found to be a dominating response that supersedes the urge to feed or reproduce and quantitatively differs from other modes of planarian locomotion (gliding, peristalsis). We show that this escape gait constitutes the animal's pain response mediated by TRP like receptors and the neurotransmitter histamine, and that it can be induced through adverse thermal, mechanical, electrical or chemical stimuli. Ultimately, we will examine the neuronal subpopulations involved in mediating escape reflexes in planarians and how they are functionally restored during regeneration, thereby gaining mechanistic insight into the neuronal circuits required for specific behaviors. Supported by BWF CASI and Sloan Foundation.

  15. Sympathetic innervation of the upper and lower regions of the uterus and cervix in the rat have different origins and routes.

    Science.gov (United States)

    Houdeau, E; Rousseau, A; Meusnier, C; Prud'Homme, M J; Rousseau, J P

    1998-09-28

    The origins and routes of the postganglionic sympathetic nerve supply to the upper and lower uterus and to the cervix were investigated in the rat by using denervation procedures combined with immunohistochemistry and retrograde tracing. The sympathetic nerve fibers of the upper part of the uterus arise from the ovarian plexus nerve. They mainly originate (90%) from neurons of the suprarenal ganglia (SRG) and of the T10 to L3 ganglia of the paravertebral sympathetic chain. Fluoro-Gold injections into different regions of the upper uterus showed that the SRG neurons mainly provide innervation to the tubal extremity (52%) rather than to the uterine portion below this area (26%). Very few neurons of the celiac ganglion or the aorticorenal ganglia participated in this innervation. Most of the sympathetic innervation of the lower uterus and the cervix (90%) originates from neurons of the paravertebral ganglia T13 to S2, principally at the L2-L4 levels. By using immunocytochemistry, we show that very few tyrosine hydroxylase-positive neurons of the pelvic plexus project to these areas, where they represent only 3% of the sympathetic nerve supply. Again, very few neurons of the inferior mesenteric ganglion (IMG) supply the lower uterus and the cervix. The comparison between retrograde tracing experiments in intact animals and after the removal of the IMG shows that very few sympathetic postganglionic axons from the paravertebral chain pass through the IMG to reach the lower uterus and the cervix. In contrast, these axons mainly project to splanchnic nerves bypassing the IMG to connect with the hypogastric nerves. In addition, some axons supplying the lower uterus follow the superior vesical arteries and then reach the organ. Taken together, these results show that the upper region of the uterus receives a sympathetic innervation that is different in origin and route from that of the lower uterus and the cervix. Such a marked region-specific innervation suggests that nerve

  16. Polyneural innervation in the psoas muscle of the developing rat

    NARCIS (Netherlands)

    Ijkema-Paassen, J; Gramsbergen, A

    1998-01-01

    Polyneural innervation was studied in the psoas muscle in developing rats from P4 till P25 and at adult age, with the combined silver-acetylcholinesterase technique. Nerve endings were counted, and endplates were measured. These data were compared with such data in the human. The end of polyneural i

  17. Autonomic innervation of the heart. Role of molecular imaging

    Energy Technology Data Exchange (ETDEWEB)

    Slart, Riemer H.J.A; Elsinga, Philip H. [Univ. Medical Center Groningen (Netherlands). Nuclear Medicine and Molecular Imaging; Tio, Rene A. [Univ. Medical Center Groningen (Netherlands). Thorax Center Cardiology; Schwaiger, Markus (ed.) [Technische Univ. Muenchen Klinikum Rechts der Isar (Germany). Nuklearmedizinische Klinik

    2015-03-01

    Reviews in detail the value of SPECT-CT and PET-CT in the imaging of cardiac innervation. Details the role of imaging in a range of conditions and diseases. Includes important background on pathophysiology, tracers, radiopharmaceutical production, and kinetic modeling software. This book explains in detail the potential value of the hybrid modalities, SPECT-CT and PET-CT, in the imaging of cardiac innervation in a wide range of conditions and diseases, including ischemic heart disease, diabetes mellitus, heart failure, amyloidosis, heart transplantation, and ventricular arrhythmias. Imaging of the brain-heart axis in neurodegenerative disease and stress and of cardiotoxicity is also discussed. The roles of the various available tracers are fully considered, and individual chapters address radiopharmaceutical development under GMP, imaging physics, and kinetic modeling software. Highly relevant background information is included on the autonomic nervous system of the heart and its pathophysiology, and in addition future perspectives are discussed. Awareness of the importance of autonomic innervation of the heart for the optimal management of cardiac patients is growing, and there is an evident need for objective measurement techniques or imaging modalities. In this context, Autonomic Innervation of the Heart will be of wide interest to clinicians, researchers, and industry.

  18. Functional Reconstruction of Sarcoma Defects Utilising Innervated Free Flaps

    Directory of Open Access Journals (Sweden)

    Damien Grinsell

    2012-01-01

    Full Text Available Soft-tissue reconstruction following preoperative radiotherapy and wide resection of soft tissue sarcoma remains a challenge. Pedicled and free tissue transfers are an essential part of limb sparing surgery. We report 22 cases of sarcoma treated with radiotherapy and wide excision followed by one-stage innervated free or pedicled musculocutaneous flap transfers. The resection involved the upper limb in 3 cases, the lower limb in 17, and the abdominal wall in 2. The flaps used for the reconstruction were mainly latissimus dorsi and gracilis. The range of motion was restored fully in 14 patients. The muscle strength of the compartment reconstructed was of grades 4 and 5 in all patients except one. The overall function was excellent in all the cases with functional scores of 71.2% in the upper limb and 84% in the lower limb. The only 2 major complications were flap necrosis, both revised with another flap, one of which was innervated with restoration of function. Innervated flaps are valuable alternatives for reconstruction after sarcoma resection in the extremity and in the abdominal wall. The excellent functional results are encouraging, and we believe that innervated muscle reconstruction should be encouraged in the treatment of sarcoma after radiotherapy and wide resection.

  19. Innervation of the hard palate of the rat

    NARCIS (Netherlands)

    Liem, Swie Bing

    1989-01-01

    This study is undertaken to gain more insight into the pattern of innervation of the hard palate of the rat and into the morphology of the sensory structures found there. Since the main research project of the Department of Neurobiology and Oral Physiology is dedicated to the formulation of a model

  20. p-Cymene reduces orofacial nociceptive response in mice

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    Michele F. Santana

    2011-12-01

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

  1. Emotional modulation of pain and spinal nociception in fibromyalgia.

    Science.gov (United States)

    Rhudy, Jamie L; DelVentura, Jennifer L; Terry, Ellen L; Bartley, Emily J; Olech, Ewa; Palit, Shreela; Kerr, Kara L

    2013-07-01

    Fibromyalgia (FM) is characterized by widespread pain, as well as affective disturbance (eg, depression). Given that emotional processes are known to modulate pain, a disruption of emotion and emotional modulation of pain and nociception may contribute to FM. The present study used a well-validated affective picture-viewing paradigm to study emotional processing and emotional modulation of pain and spinal nociception. Participants were 18 individuals with FM, 18 individuals with rheumatoid arthritis (RA), and 19 healthy pain-free controls (HC). Mutilation, neutral, and erotic pictures were presented in 4 blocks; 2 blocks assessed only physiological-emotional reactions (ie, pleasure/arousal ratings, corrugator electromyography, startle modulation, skin conductance) in the absence of pain, and 2 blocks assessed emotional reactivity and emotional modulation of pain and the nociceptive flexion reflex (NFR, a physiological measure of spinal nociception) evoked by suprathreshold electric stimulations over the sural nerve. In general, mutilation pictures elicited displeasure, corrugator activity, subjective arousal, and sympathetic activation, whereas erotic pictures elicited pleasure, subjective arousal, and sympathetic activation. However, FM was associated with deficits in appetitive activation (eg, reduced pleasure/arousal to erotica). Moreover, emotional modulation of pain was observed in HC and RA, but not FM, even though all 3 groups evidenced modulation of NFR. Additionally, NFR thresholds were not lower in the FM group, indicating a lack of spinal sensitization. Together, these results suggest that FM is associated with a disruption of supraspinal processes associated with positive affect and emotional modulation of pain, but not brain-to-spinal cord circuitry that modulates spinal nociceptive processes.

  2. Impact of behavioral control on the processing of nociceptive stimulation

    Directory of Open Access Journals (Sweden)

    James W Grau

    2012-08-01

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

  3. Nociception originating from the crural fascia in rats.

    Science.gov (United States)

    Taguchi, Toru; Yasui, Masaya; Kubo, Asako; Abe, Masahiro; Kiyama, Hiroshi; Yamanaka, Akihiro; Mizumura, Kazue

    2013-07-01

    Little is documented in the literature as to the function of muscle fascia in nociception and pain. The aim of this study was to examine the distribution of presumptive nociceptive nerve fibers, to characterize fascial thin-fiber sensory receptors, and to examine the spinal projection of nociceptive input from the rat crural fascia (CF). Nerve fibers labeled with specific antibodies to calcitonin gene-related peptide (CGRP) and peripherin were found to be densely distributed in the distal third of the CF. Thin-fiber receptors (Aδ- and C-fibers) responding to pinching stimuli to the CF with sharpened watchmaker's forceps, identified in vivo with the teased fiber technique from the common peroneal nerve, exist in the CF. Forty-three percent of the mechano-responsive fascial C-fibers were polymodal receptors (nociceptors) responding to mechanical, chemical (bradykinin), and heat stimuli, whereas almost all Aδ-fibers were responsive only to mechanical stimuli. Repetitive pinching stimulus to the CF induced c-Fos protein expression in the middle to medial part of superficial layers ie, laminae I-II of the spinal dorsal horn at segments L2 to L4, peaking at L3. These results clearly demonstrate the following: 1) peptidergic and non-peptidergic axons of unmyelinated C-fibers with nerve terminals are distributed in the CF; 2) peripheral afferents responding to noxious stimuli exist in the fascia, and 3) nociceptive information from the CF is mainly processed in the spinal dorsal horn at the segments L2 to L4. These results together indicate that the "muscle fascia," a tissue often overlooked in pain research, can be an important source of nociception under normal conditions. Copyright © 2013 International Association for the Study of Pain. Published by Elsevier B.V. All rights reserved.

  4. [The epiglottis, a glosso-laryngeal structure: an anatomic study of its innervation].

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    Touré, G; Vacher, C

    2005-09-01

    The epiglottis is known as a laryngeal structure. The authors studied the innervation of epiglottis using the Sihler method on six human epiglottises. Innervation of the epiglottis depended on the rami from the vagus, glossopharyngeal and hypoglossal nerves. By its innervation, epiglottis seems to be a glosso-laryngeal structure, as is confirmed by embryology, histology and clinical applications.

  5. Variations of lumbrical muscle innervation patterns in the hand, focusing on the dual innervation of the third lumbrical muscle.

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    Hur, Mi-Sun

    2017-02-01

    This study was conducted to clarify the innervation patterns of the lumbrical muscles by identifying the origin of the nerve fascicles innervating these muscles. The lumbricals in the hand were investigated in 50 specimens of embalmed Korean adult cadavers. Dual innervation of the third lumbrical was most frequently observed in 64.0%. The third lumbrical was innervated by a branch arising from the median nerve (MN) distal to site at which the superficial branch of the ulnar nerve (sUN) joins the MN in 34%. When separating and tracing the nerve fascicles from the MN distal to the communicating branch from the sUN to MN, the fascicles contained parts of the MN and sUN in 18% and part of the MN in 16%. These results will be helpful for accurate diagnoses, surgical procedures, and electrophysiological examinations in lesions of the MN and ulnar nerve in the hand. Muscle Nerve, 2016 Muscle Nerve 55: 160-165, 2017. © 2016 Wiley Periodicals, Inc.

  6. In vivo patch-clamp analysis of response properties of rat primary somatosensory cortical neurons responding to noxious stimulation of the facial skin

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    Nasu Masanori

    2010-05-01

    Full Text Available Abstract Background Although it has been widely accepted that the primary somatosensory (SI cortex plays an important role in pain perception, it still remains unclear how the nociceptive mechanisms of synaptic transmission occur at the single neuron level. The aim of the present study was to examine whether noxious stimulation applied to the orofacial area evokes the synaptic response of SI neurons in urethane-anesthetized rats using an in vivo patch-clamp technique. Results In vivo whole-cell current-clamp recordings were performed in rat SI neurons (layers III-IV. Twenty-seven out of 63 neurons were identified in the mechanical receptive field of the orofacial area (36 neurons showed no receptive field and they were classified as non-nociceptive (low-threshold mechanoreceptive; 6/27, 22% and nociceptive neurons. Nociceptive neurons were further divided into wide-dynamic range neurons (3/27, 11% and nociceptive-specific neurons (18/27, 67%. In the majority of these neurons, a proportion of the excitatory postsynaptic potentials (EPSPs reached the threshold, and then generated random discharges of action potentials. Noxious mechanical stimuli applied to the receptive field elicited a discharge of action potentials on the barrage of EPSPs. In the case of noxious chemical stimulation applied as mustard oil to the orofacial area, the membrane potential shifted depolarization and the rate of spontaneous discharges gradually increased as did the noxious pinch-evoked discharge rates, which were usually associated with potentiated EPSP amplitudes. Conclusions The present study provides evidence that SI neurons in deep layers III-V respond to the temporal summation of EPSPs due to noxious mechanical and chemical stimulation applied to the orofacial area and that these neurons may contribute to the processing of nociceptive information, including hyperalgesia.

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

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    Marchand Fabien

    2011-11-01

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

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

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    Ohtani, Norimasa; Masaki, Eiji

    2016-01-01

    Background Approximately half of all patients who undergo surgery develop postoperative pain, the mechanisms of which are not well understood by anesthesiologists. D2-like receptors in the descending dopaminergic pathway play an important role in regulation of pain transmission in the spinal cord. Impairment of inhibitory neurons in the spinal cord is suggested as part of the mechanism for neuropathic pain, which is one component of postoperative pain. The purpose of this study was to investigate whether impairment of D2-like receptors in the descending dopaminergic pathway in the spinal cord is involved in the decreased postoperative nociceptive threshold in rats. Methods Male Sprague-Dawley rats (250–300 g) were anesthetized with sevoflurane and an intrathecal (IT) catheter was implanted. Six days later, a plantar incision was made. On the following day, saline, a D2-like receptor agonist (quinpirole), or a D2-like receptor antagonist (sulpiride) was administered intrathecally. Thermal and mechanical nociceptive responses were assessed by exposure to infrared radiant heat and the von Frey filament test before and after plantar incision. Results Plantar incision decreased both thermal latency and the mechanical nociceptive threshold. IT administration of quinpirole inhibited the nociceptive responses induced by plantar incision, but sulpiride had no effect. Conclusion A D2-like receptor agonist had antinociceptive effects on the hypersensitivity response triggered by a surgical incision, but a D2-like receptor antagonist had no effect on this response. These results suggest that impairment and/or modification of D2-like receptors in the descending dopaminergic pathway in the spinal cord is not involved in the postoperative decrease in nociceptive threshold. PMID:27799818

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

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    Ohtani N

    2016-10-01

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

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

    Science.gov (United States)

    Ohtani, Norimasa; Masaki, Eiji

    2016-01-01

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

  11. Neurosensory Differentiation and Innervation Patterning in the Human Fetal Vestibular End Organs between the Gestational Weeks 8–12

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    Johnson Chacko, Lejo; Pechriggl, Elisabeth J.; Fritsch, Helga; Rask-Andersen, Helge; Blumer, Michael J. F.; Schrott-Fischer, Anneliese; Glueckert, Rudolf

    2016-01-01

    Balance orientation depends on the precise operation of the vestibular end organs and the vestibular ganglion neurons. Previous research on the assemblage of the neuronal network in the developing fetal vestibular organ has been limited to data from animal models. Insights into the molecular expression profiles and signaling moieties involved in embryological development of the human fetal inner ear have been limited. We present an investigation of the cells of the vestibular end organs with specific focus on the hair cell differentiation and innervation pattern using an uninterrupted series of unique specimens from gestational weeks 8–12. Nerve fibers positive for peripherin innervate the entire fetal crista and utricle. While in rodents only the peripheral regions of the cristae and the extra-striolar region of the statolithic organs are stained. At week 9, transcription factors PAX2 and PAX8 were observed in the hair cells whereas PAX6 was observed for the first time among the supporting cells of the cristae and the satellite glial cells of the vestibular ganglia. Glutamine synthetase, a regulator of the neurotransmitter glutamate, is strongly expressed among satellite glia cells, transitional zones of the utricle and supporting cells in the sensory epithelium. At gestational week 11, electron microscopic examination reveals bouton contacts at hair cells and first signs of the formation of a protocalyx at type I hair cells. Our study provides first-hand insight into the fetal development of the vestibular end organs as well as their pattern of innervation by means of immunohistochemical and EM techniques, with the aim of contributing toward our understanding of balance development. PMID:27895556

  12. Neurosensory Differentiation and Innervation Patterning in the Human Fetal Vestibular End Organs between the Gestational Weeks 8-12.

    Science.gov (United States)

    Johnson Chacko, Lejo; Pechriggl, Elisabeth J; Fritsch, Helga; Rask-Andersen, Helge; Blumer, Michael J F; Schrott-Fischer, Anneliese; Glueckert, Rudolf

    2016-01-01

    Balance orientation depends on the precise operation of the vestibular end organs and the vestibular ganglion neurons. Previous research on the assemblage of the neuronal network in the developing fetal vestibular organ has been limited to data from animal models. Insights into the molecular expression profiles and signaling moieties involved in embryological development of the human fetal inner ear have been limited. We present an investigation of the cells of the vestibular end organs with specific focus on the hair cell differentiation and innervation pattern using an uninterrupted series of unique specimens from gestational weeks 8-12. Nerve fibers positive for peripherin innervate the entire fetal crista and utricle. While in rodents only the peripheral regions of the cristae and the extra-striolar region of the statolithic organs are stained. At week 9, transcription factors PAX2 and PAX8 were observed in the hair cells whereas PAX6 was observed for the first time among the supporting cells of the cristae and the satellite glial cells of the vestibular ganglia. Glutamine synthetase, a regulator of the neurotransmitter glutamate, is strongly expressed among satellite glia cells, transitional zones of the utricle and supporting cells in the sensory epithelium. At gestational week 11, electron microscopic examination reveals bouton contacts at hair cells and first signs of the formation of a protocalyx at type I hair cells. Our study provides first-hand insight into the fetal development of the vestibular end organs as well as their pattern of innervation by means of immunohistochemical and EM techniques, with the aim of contributing toward our understanding of balance development.

  13. NEUROSENSORY DIFFERENTIATION AND INNERVATION PATTERNING IN THE HUMAN FOETAL VESTIBULAR END ORGANS BETWEEN THE GESTATIONAL WEEKS 8 TO 12

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    Lejo Johnson Chacko

    2016-11-01

    Full Text Available Balance orientation depends on the precise operation of the vestibular end organs and the vestibular ganglion neurons. Previous research on the assemblage of the neuronal network in the developing foetal vestibular organ has been limited to data from animal models. Insights into the molecular expression profiles and signalling moieties involved in embryological development of the human foetal inner ear have been limited. We present an investigation of the cells of the vestibular end organs with specific focus on the hair cell differentiation and innervation pattern using an uninterrupted series of unique specimens from gestational weeks 8 to 12.Nerve fibres positive for peripherin innervate the entire foetal crista and utricle. While in rodents only the peripheral regions of the cristae and the extra-striolar region of the statolithic organs are stained. At week nine, transcription factors PAX2 and PAX8 were observed in the hair cells whereas PAX6 was observed for the first time among the supporting cells of the cristae and the satellite glial cells of the vestibular ganglia. Glutamine synthetase, a regulator of the neurotransmitter glutamate, is strongly expressed among satellite glia cells, transitional zones of the utricle and supporting cells in the sensory epithelium. At gestational week 11, electron microscopic examination reveals bouton contacts at hair cells and first signs of the formation of a protocalyx at type I hair cells.Our study provides first-hand insight into the foetal development of the vestibular end organs as well as their pattern of innervation by means of immunohistochemical and EM techniques, with the aim of contributing towards our understanding of balance development.

  14. Innervation of the rabbit cardiac ventricles.

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    Pauziene, Neringa; Alaburda, Paulius; Rysevaite-Kyguoliene, Kristina; Pauza, Audrys G; Inokaitis, Hermanas; Masaityte, Aiste; Rudokaite, Gabriele; Saburkina, Inga; Plisiene, Jurgita; Pauza, Dainius H

    2016-01-01

    The rabbit is widely used in experimental cardiac physiology, but the neuroanatomy of the rabbit heart remains insufficiently examined. This study aimed to ascertain the architecture of the intrinsic nerve plexus in the walls and septum of rabbit cardiac ventricles. In 51 rabbit hearts, a combined approach involving: (i) histochemical acetylcholinesterase staining of intrinsic neural structures in total cardiac ventricles; (ii) immunofluorescent labelling of intrinsic nerves, nerve fibres (NFs) and neuronal somata (NS); and (iii) transmission electron microscopy of intrinsic ventricular nerves and NFs was used. Mediastinal nerves access the ventral and lateral surfaces of both ventricles at a restricted site between the root of the ascending aorta and the pulmonary trunk. The dorsal surface of both ventricles is supplied by several epicardial nerves extending from the left dorsal ganglionated nerve subplexus on the dorsal left atrium. Ventral accessing nerves are thicker and more numerous than dorsal nerves. Intrinsic ventricular NS are rare on the conus arteriosus and the root of the pulmonary trunk. The number of ventricular NS ranged from 11 to 220 per heart. Four chemical phenotypes of NS within ventricular ganglia were identified, i.e. ganglionic cells positive for choline acetyltransferase (ChAT), neuronal nitric oxide synthase (nNOS), and biphenotypic, i.e. positive for both ChAT/nNOS and for ChAT/tyrosine hydroxylase. Clusters of small intensely fluorescent cells are distributed within or close to ganglia on the root of the pulmonary trunk, but not on the conus arteriosus. The largest and most numerous intrinsic nerves proceed within the epicardium. Scarce nerves were found near myocardial blood vessels, but the myocardium contained only a scarce meshwork of NFs. In the endocardium, large numbers of thin nerves and NFs proceed along the bundle of His and both its branches up to the apex of the ventricles. The endocardial meshwork of fine NFs was

  15. Involvement of the pelvic plexus and the suprarenal ganglia in the neuropeptide Y (NPY) innervation of the cervix and the uterus of the rat.

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    Serghini, R; Prud'homme, M J; Vaudry, H; Rousseau, J P

    1997-12-03

    The involvement of the pelvic plexus and suprarenal ganglia in the neuropeptide Y (NPY) innervation of the genital tract was studied in the female rat by means of denervation experiments and retrograde tracing studies. Removal of the paracervical ganglia caused a significant decrease of the NPY-immunoreactive nerve density and NPY concentration in the lower part of the genital tract: cervix, uterine body and lower part of the uterine horn. The decrease in NPY concentration in these three regions was more pronounced after lesion of the pelvic plexus. Lesion of the ovarian nerve plexus caused a depletion in the NPY-immunoreactive nerve fibres and a decrease in NPY concentration in the upper part of the uterine horn. Pelvic nerve section, inferior mesenteric ganglia excision and superior ovarian nerve section had no effect on the NPY innervation in the genital tract. Injection of fluorogold into the cervix and lower part of the uterus combined with immunohistochemistry revealed that 87.5% of labelled neurons in the pelvic plexus were NPY-immunoreactive. Following injection of fluorogold into the upper part of the uterus, 92% of labelled neurons in the suprarenal ganglia were NPY-immunoreactive. Treatment with 6-hydroxydopamine revealed that the NPY-immunoreactive nerve fibres were non-noradrenergic in the cervix, but were noradrenergic in the upper part of the uterus. In the uterine body and lower part of the uterine horn, both noradrenergic and non-noradrenergic NPY-immunoreactive nerve fibres were observed. These data demonstrate the major contribution of pelvic plexus neurons in the non-noradrenergic NPY innervation of the lower part of the genital tract, and the involvement of the suprarenal ganglia in the noradrenergic NPY innervation of the upper part of the uterus via the ovarian nerve plexus.

  16. Different requirements for GFRα2-signaling in three populations of cutaneous sensory neurons.

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    Jussi Kupari

    Full Text Available Many primary sensory neurons in mouse dorsal root ganglia (DRG express one or several GFRα's, the ligand-binding receptors of the GDNF family, and their common signaling receptor Ret. GFRα2, the principal receptor for neurturin, is expressed in most of the small nonpeptidergic DRG neurons, but also in some large DRG neurons that start to express Ret earlier. Previously, GFRα2 has been shown to be crucial for the soma size of small nonpeptidergic nociceptors and for their target innervation of glabrous epidermis. However, little is known about this receptor in other Ret-expressing DRG neuron populations. Here we have investigated two populations of Ret-positive low-threshold mechanoreceptors that innervate different types of hair follicles on mouse back skin: the small C-LTMRs and the large Aβ-LTMRs. Using GFRα2-KO mice and immunohistochemistry we found that, similar to the nonpeptidergic nociceptors, GFRα2 controls the cell size but not the survival of both C-LTMRs and Aβ-LTMRs. In contrast to the nonpeptidergic neurons, GFRα2 is not required for the target innervation of C-LTMRs and Aβ-LTMRs in the back skin. These results suggest that different factors drive target innervation in these three populations of neurons. In addition, the observation that the large Ret-positive DRG neurons lack GFRα2 immunoreactivity in mature animals suggests that these neurons switch their GFRα signaling pathways during postnatal development.

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

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    Sonja M Mueller-Tribbensee

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

  18. Effects of acid on vagal nociceptive afferent subtypes in guinea pig esophagus.

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    Yu, Xiaoyun; Hu, Youtian; Yu, Shaoyong

    2014-08-15

    Acid reflux-induced heartburn and noncardiac chest pain are processed peripherally by sensory nerve endings in the wall of the esophagus, but the underlying mechanism is still unclear. This study aims to determine the effects of acid on esophageal vagal nociceptive afferent subtypes. Extracellular single-unit recordings were performed in guinea pig vagal nodose or jugular C fiber neurons by using ex vivo esophageal-vagal preparations with intact nerve endings in the esophagus. We recorded action potentials (AP) of esophageal nodose or jugular C fibers evoked by acid perfusion and compared esophageal distension-evoked AP before and after acid perfusion. Acid perfusion for 30 min (pH range 7.4 to 5.8) did not evoke AP in nodose C fibers but significantly decreased their responses to esophageal distension, which could be recovered after washing out acid for 90 min. In jugular C fibers, acid perfusion not only evoked AP but also inhibited their responses to esophageal distension, which were not recovered after washing out acid for 120 min. Lower concentration of capsaicin perfusion mimicked acid-induced effects in nodose and jugular C fibers. Pretreatment with TRPV1 antagonist AMG9810, but not acid-sensing ion channel (ASIC) inhibitor amiloride, significantly inhibited acid-induced effects in nodose and jugular C fiber. These results demonstrate that esophageal vagal nociceptive afferent nerve subtypes display distinctive responses to acid. Acid activates jugular, but not nodose, C fibers and inhibits both of their responses to esophageal distension. These effects are mediated mainly through TRPV1. This inhibitory effect is a novel finding and may contribute to esophageal sensory/motor dysfunction in acid reflux diseases.

  19. Entanglement between thermoregulation and nociception in the rat: the case of morphine.

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    El Bitar, Nabil; Pollin, Bernard; Karroum, Elias; Pincedé, Ivanne; Le Bars, Daniel

    2016-12-01

    In thermoneutral conditions, rats display cyclic variations of the vasomotion of the tail and paws, the most widely used target organs in current acute or chronic animal models of pain. Systemic morphine elicits their vasoconstriction followed by hyperthermia in a naloxone-reversible and dose-dependent fashion. The dose-response curves were steep with ED50 in the 0.5-1 mg/kg range. Given the pivotal functional role of the rostral ventromedial medulla (RVM) in nociception and the rostral medullary raphe (rMR) in thermoregulation, two largely overlapping brain regions, the RVM/rMR was blocked by muscimol: it suppressed the effects of morphine. "On-" and "off-" neurons recorded in the RVM/rMR are activated and inhibited by thermal nociceptive stimuli, respectively. They are also implicated in regulating the cyclic variations of the vasomotion of the tail and paws seen in thermoneutral conditions. Morphine elicited abrupt inhibition and activation of the firing of on- and off-cells recorded in the RVM/rMR. By using a model that takes into account the power of the radiant heat source, initial skin temperature, core body temperature, and peripheral nerve conduction distance, one can argue that the morphine-induced increase of reaction time is mainly related to the morphine-induced vasoconstriction. This statement was confirmed by analyzing in psychophysical terms the tail-flick response to random variations of noxious radiant heat. Although the increase of a reaction time to radiant heat is generally interpreted in terms of analgesia, the present data question the validity of using such an approach to build a pain index. Copyright © 2016 the American Physiological Society.

  20. microRNAs in nociceptive circuits as predictors of future clinical applications

    Science.gov (United States)

    Kress, Michaela; Hüttenhofer, Alexander; Landry, Marc; Kuner, Rohini; Favereaux, Alexandre; Greenberg, David; Bednarik, Josef; Heppenstall, Paul; Kronenberg, Florian; Malcangio, Marzia; Rittner, Heike; üçeyler, Nurcan; Trajanoski, Zlatko; Mouritzen, Peter; Birklein, Frank; Sommer, Claudia; Soreq, Hermona

    2013-01-01

    Neuro-immune alterations in the peripheral and central nervous system play a role in the pathophysiology of chronic pain, and non-coding RNAs – and microRNAs (miRNAs) in particular – regulate both immune and neuronal processes. Specifically, miRNAs control macromolecular complexes in neurons, glia and immune cells and regulate signals used for neuro-immune communication in the pain pathway. Therefore, miRNAs may be hypothesized as critically important master switches modulating chronic pain. In particular, understanding the concerted function of miRNA in the regulation of nociception and endogenous analgesia and defining the importance of miRNAs in the circuitries and cognitive, emotional and behavioral components involved in pain is expected to shed new light on the enigmatic pathophysiology of neuropathic pain, migraine and complex regional pain syndrome. Specific miRNAs may evolve as new druggable molecular targets for pain prevention and relief. Furthermore, predisposing miRNA expression patterns and inter-individual variations and polymorphisms in miRNAs and/or their binding sites may serve as biomarkers for pain and help to predict individual risks for certain types of pain and responsiveness to analgesic drugs. miRNA-based diagnostics are expected to develop into hands-on tools that allow better patient stratification, improved mechanism-based treatment, and targeted prevention strategies for high risk individuals. PMID:24151455

  1. microRNAs in nociceptive circuits as predictors of future clinical applications

    Directory of Open Access Journals (Sweden)

    Michaela eKress

    2013-10-01

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

  2. Co-localization of Gamma-Aminobutyric Acid and Glutamate in Neurons of the Spider Central Nervous System.

    Science.gov (United States)

    Fabian-Fine, Ruth; Meisner, Shannon; Torkkeli, Päivi H; Meinertzhagen, Ian A

    2015-12-01

    Spider sensory neurons with cell bodies close to various sensory organs are innervated by putative efferent axons from the central nervous system (CNS). Light and electronmicroscopic imaging of immunolabeled neurons has demonstrated that neurotransmitters present at peripheral synapses include γ-aminobutyric acid (GABA), glutamate and octopamine. Moreover, electrophysiological studies show that these neurotransmitters modulate the sensitivity of peripheral sensory neurons. Here, we undertook immunocytochemical investigations to characterize GABA and glutamate-immunoreactive neurons in three-dimensional reconstructions of the spider CNS. We document that both neurotransmitters are abundant in morphologically distinct neurons throughout the CNS. Labeling for the vesicular transporters, VGAT for GABA and VGLUT for glutamate, showed corresponding patterns, supporting the specificity of antibody binding. Whereas some neurons displayed strong immunolabeling, others were only weakly labeled. Double labeling showed that a subpopulation of weakly labeled neurons present in all ganglia expresses both GABA and glutamate. Double labeled, strongly and weakly labeled GABA and glutamate immunoreactive axons were also observed in the periphery along muscle fibers and peripheral sensory neurons. Electron microscopic investigations showed presynaptic profiles of various diameters with mixed vesicle populations innervating muscle tissue as well as sensory neurons. Our findings provide evidence that: (1) sensory neurons and muscle fibers are innervated by morphologically distinct, centrally located GABA- and glutamate immunoreactive neurons; (2) a subpopulation of these neurons may co-release both neurotransmitters; and (3) sensory neurons and muscles are innervated by all of these neurochemically and morphologically distinct types of neurons. The biochemical diversity of presynaptic innervation may contribute to how spiders filter natural stimuli and coordinate appropriate response

  3. Brn3c null mutant mice show long-term, incomplete retention of some afferent inner ear innervation

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    Pirvola Ulla

    2003-01-01

    Full Text Available Abstract Background Ears of Brn3c null mutants develop immature hair cells, identifiable only by certain molecular markers, and undergo apoptosis in neonates. This partial development of hair cells could lead to enough neurotrophin expression to sustain sensory neurons through embryonic development. We have therefore investigated in these mutants the patterns of innervation and of expression of known neurotrophins. Results At birth there is a limited expression of BDNF and NT-3 in the mutant sensory epithelia and DiI tracing shows no specific reduction of afferents or efferents that resembles neurotrophin null mutations. At postnatal day 7/8 (P7/8, innervation is severely reduced both qualitatively and quantitatively. 1% of myosin VIIa-positive immature hair cells are present in the mutant cochlea, concentrated in the base. Around 20% of immature hair cells exist in the mutant vestibular sensory epithelia. Despite more severe loss of hair cells (1% compared to 20%, the cochlea retains many more sensory neurons (46% compared to 15% than vestibular epithelia. Even 6 months old mutant mice have some fibers to all vestibular sensory epithelia and many more to the cochlear apex which lacks MyoVIIa positive hair cells. Topologically organized central cochlea projections exist at least until P8, suggesting that functional hair cells are not required to establish such projections. Conclusion The limited expression of neurotrophins in the cochlea of Brn3c null mice suffices to support many sensory neurons, particularly in the cochlea, until birth. The molecular nature of the long term survival of apical spiral neurons remains unclear.

  4. Looking at the hand modulates the brain responses to nociceptive and non-nociceptive somatosensory stimuli but does not necessarily modulate their perception.

    Science.gov (United States)

    Torta, Diana M; Legrain, Valéry; Mouraux, André

    2015-08-01

    Previous studies have suggested that looking at the hand can reduce the perception of pain and the magnitude of the ERPs elicited by nociceptive stimuli delivered onto the hand. In contrast, other studies have suggested that looking at the hand can increase tactile sensory discrimination performance, and enhance the magnitude of the ERPs elicited by tactile stimulation. These opposite effects could be related to differences in the crossmodal effects between vision, nociception, and touch. However, these differences could also be related to the use of different experimental designs. Importantly, most studies on the effects of vision on pain have relied on a mirror to create the illusion that the reflected hand is a direct view of the stimulated hand. Here, we compared the effects of direct versus mirror vision of the hand versus an object on the perception and ERPs elicited by non-nociceptive and nociceptive stimuli. We did not observe any significant effect of vision on the perceived intensity. However, vision of the hand did reduce the magnitude of the nociceptive N240 wave, and enhanced the magnitude of the non-nociceptive P200. Our results confirm that vision of the body differentially affects nociceptive and non-nociceptive processing, but question the robustness of visual analgesia.

  5. Physiological Signal Processing for Individualized Anti-nociception Management During General Anesthesia: a Review.

    Science.gov (United States)

    De Jonckheere, J; Bonhomme, V; Jeanne, M; Boselli, E; Gruenewald, M; Logier, R; Richebé, P

    2015-08-13

    The aim of this paper is to review existing technologies for the nociception / anti-nociception balance evaluation during surgery under general anesthesia. General anesthesia combines the use of analgesic, hypnotic and muscle-relaxant drugs in order to obtain a correct level of patient non-responsiveness during surgery. During the last decade, great efforts have been deployed in order to find adequate ways to measure how anesthetic drugs affect a patient's response to surgical nociception. Nowadays, though some monitoring devices allow obtaining information about hypnosis and muscle relaxation, no gold standard exists for the nociception / anti-nociception balance evaluation. Articles from the PubMed literature search engine were reviewed. As this paper focused on surgery under general anesthesia, articles about nociception monitoring on conscious patients, in post-anesthesia care unit or in intensive care unit were not considered. In this article, we present a review of existing technologies for the nociception / anti-nociception balance evaluation, which is based in all cases on the analysis of the autonomous nervous system activity. Presented systems, based on sensors and physiological signals processing algorithms, allow studying the patients' reaction regarding anesthesia and surgery. Some technological solutions for nociception / antinociception balance monitoring were described. Though presented devices could constitute efficient solutions for individualized anti-nociception management during general anesthesia, this review of current literature emphasizes the fact that the choice to use one or the other mainly relies on the clinical context and the general purpose of the monitoring.

  6. Age-related synaptic loss of the medial olivocochlear efferent innervation

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    Schrader Angela

    2010-11-01

    Full Text Available Abstract Age-related functional decline of the nervous system is consistently observed, though cellular and molecular events responsible for this decline remain largely unknown. One of the most prevalent age-related functional declines is age-related hearing loss (presbycusis, a major cause of which is the loss of outer hair cells (OHCs and spiral ganglion neurons. Previous studies have also identified an age-related functional decline in the medial olivocochlear (MOC efferent system prior to age-related loss of OHCs. The present study evaluated the hypothesis that this functional decline of the MOC efferent system is due to age-related synaptic loss of the efferent innervation of the OHCs. To this end, we used a recently-identified transgenic mouse line in which the expression of yellow fluorescent protein (YFP, under the control of neuron-specific elements from the thy1 gene, permits the visualization of the synaptic connections between MOC efferent fibers and OHCs. In this model, there was a dramatic synaptic loss between the MOC efferent fibers and the OHCs in older mice. However, age-related loss of efferent synapses was independent of OHC status. These data demonstrate for the first time that age-related loss of efferent synapses may contribute to the functional decline of the MOC efferent system and that this synaptic loss is not necessary for age-related loss of OHCs.

  7. Attention effects on vicarious modulation of nociception and pain.

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    Khatibi, Ali; Vachon-Presseau, Etienne; Schrooten, Martien; Vlaeyen, Johan; Rainville, Pierre

    2014-10-01

    The observation of others' facial expressions of pain has been shown to facilitate the observer's nociceptive responses and to increase pain perception. We investigated how this vicarious facilitation effect is modulated by directing the observer's attention toward the meaning of pain expression or the facial movements. In separate trials, participants were instructed to assess the "intensity of the pain expression"(meaning) or to "discriminate the facial movements" in the upper vs lower part of the face shown in 1-second dynamic clips displaying mild, moderate, or strong pain expressions or a neutral control. In 50% of the trials, participants received a painful electrical stimulation to the sural nerve immediately after the presentation of the expression. Low-level nociceptive reactivity was measured with the RIII-response, and pain perception was assessed using pain ratings. Pain induced by the electrical stimulation increased after viewing stronger pain expressions in both tasks, but the RIII-response showed this vicarious facilitation effect only in the movement discrimination task at the strongest expression intensity. These findings are consistent with the notion that vicarious processes facilitate self-pain and may prime automatic nociceptive responses. However, this priming effect is influenced by top-down attentional processes. These results provide another case of dissociation between reflexive and perceptual processes, consistent with the involvement of partly separate brain networks in the regulation of cortical and lower-level nociceptive responses. Combined with previous results, these findings suggest that vicarious pain facilitation is an automatic process that may be diminished by top-down attentional processes directed at the meaning of the expression.

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

    Science.gov (United States)

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

    2017-02-01

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

  9. Sacral neuromodulation of nociceptive bladder overactivity in cats.

    Science.gov (United States)

    Zhang, Zhaocun; Bandari, Jathin; Bansal, Utsav; Shen, Bing; Wang, Jicheng; Lamm, Vladimir; Roppolo, James R; de Groat, William C; Tai, Changfeng

    2017-06-01

    To investigate the effects of electrical stimulation of sacral dorsal/ventral roots on irritation-induced bladder overactivity, reveal possible different mechanisms under nociceptive bladder conditions, and establish a large animal model of sacral neuromodulation. Intravesical infusion of 0.5% acetic acid (AA) was used to irritate the bladder and induce bladder overactivity in cats under α-chloralose anesthesia. Electrical stimulation (5, 15, or 30 Hz) was applied to individual S1-S3 dorsal or ventral roots at or below motor threshold intensity. Repeated cystometrograms (CMGs) were performed with/without the stimulation to determine the inhibition of bladder overactivity. AA irritation induced bladder overactivity and significantly (P < 0.05) reduced the bladder capacity to 62.6 ± 11.7% of control capacity measured during saline CMGs. At threshold intensity for inducing reflex twitching of the anal sphincter or toe, S1/S2 dorsal root stimulation at 5 Hz but not at 15 or 30 Hz inhibited bladder overactivity and significantly (P < 0.05) increased bladder capacity to 187.3 ± 41.6% and 155.5 ± 9.7% respectively, of AA control capacity. Stimulation of S3 dorsal root or S1-S3 ventral roots was not effective. Repeated stimulation of S1-S3 dorsal root did not induced a post-stimulation inhibition. This study established a cat model of sacral neuromodualation of nociceptive bladder overactivity. The results revealed that the mechanisms underlying sacral neuromodulation are different for nociceptive and non-nociceptive bladder activity. © 2016 Wiley Periodicals, Inc.

  10. In vivo imaging of C. elegans ASH neurons: cellular response and adaptation to chemical repellents

    OpenAIRE

    Hilliard, Massimo A.; Apicella, Alfonso J.; Kerr, Rex; Suzuki, Hiroshi; Bazzicalupo, Paolo; Schafer, William R

    2004-01-01

    ASH sensory neurons are required in Caenorhabditis elegans for a wide range of avoidance behaviors in response to chemical repellents, high osmotic solutions and nose touch. The ASH neurons are therefore hypothesized to be polymodal nociceptive neurons. To understand the nature of polymodal sensory response and adaptation at the cellular level, we expressed the calcium indicator protein cameleon in ASH and analyzed intracellular Ca2+ responses following stimulation with chemical repellents, o...

  11. Measurement of functional cholinergic innervation in rat heart with a novel vesamicol receptor ligand

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    Coffeen, Paul R.; Efange, S.M.N.; Haidet, George C.; McKnite, Scott; Langason, Rosemary B.; Khare, A.B.; Pennington, Jennifer; Lurie, Keith G

    1996-10-01

    Regional differences in cholinergic activity in the cardiac conduction system have been difficult to study. We tested the utility of (+)-m-[{sup 125}I]iodobenzyl)trozamicol(+)-[{sup 125}I]MIBT), a novel radioligand that binds to the vesamicol receptor located on the synaptic vesicle in presynaptic cholinergic neurons, as a functional marker of cholinergic activity in the conduction system. The (+)-[{sup 125}I]MIBT was injected intravenously into four rats. Three hours later, the rats were killed and their hearts were frozen. Quantitative autoradiography was performed on 20-micron-thick sections that were subsequently stained for acetylcholinesterase to identify specific conduction-system elements. Marked similarities existed between (+)-[{sup 125}I]MIBT uptake and acetylcholinesterase-positive regions. Optical densitometric analysis of regional (+)-[{sup 125}I]MIBT uptake revealed significantly greater (+)-[{sup 125}I]MIBT binding (nCi/mg) in the atrioventricular node (AVN) and His bundle regions compared with other conduction and contractile elements (AVN: 3.43 {+-} 0.37; His bundle: 2.16 {+-} 0.30; right bundle branch: 0.95 {+-} 0.13; right atrium: 0.68 {+-} 0.05; right ventricle: 0.57 {+-} 0.03; and left ventricle: 0.57 {+-} 0.03; p < 0.05 comparing conduction elements with ventricular muscle). This study demonstrates that (+)-[{sup 125}I]MIBT binds avidly to cholinergic nerve tissue innervating specific conduction-system elements. Thus, (+)-[{sup 125}I]MIBT may be a useful functional marker in studies on cholinergic innervation in the cardiac conduction system.

  12. Medial septal and median raphe innervation of vasoactive intestinal polypeptide-containing interneurons in the hippocampus.

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    Papp, E C; Hajos, N; Acsády, L; Freund, T F

    1999-05-01

    Vasoactive intestinal polypeptide-immunoreactive interneurons are known to form three anatomically and neurochemically well-characterized neuron populations in the hippocampus. Two of these establish synaptic contacts selectively with other GABAergic cells (interneuron-selective cells), whereas the third type innervates pyramidal cell bodies and proximal dendrites like a conventional basket cell. Our aim was to examine which of the vasoactive intestinal polypeptide-containing interneuron populations are among the targets of GABAergic septohippocampal and serotonergic raphe-hippocampal pathways. Anterograde tracing with Phaseolus vulgaris leucoagglutinin combined with double immunocytochemistry for vasoactive intestinal polypeptide was used at the light and electron microscopic levels. Our results show that both interneuron-selective cells and vasoactive intestinal polypeptide-containing basket cells receive synaptic input from the medial septum and median raphe nucleus. The GABAergic component of the septohippocampal pathway establishes multiple contacts on both cell types. In the case of the raphe-hippocampal projection, single or double contacts were more frequent on vasoactive intestinal polypeptide-positive interneuron selective cells (76%), whereas multiple contacts predominated on basket cells (83%). The extrinsic GABAergic innervation of interneuron-selective cells in the hippocampus indicates a complex interaction among GABAergic systems, which might ensure the timing and rhythmic synchronization of inhibitory processes in the hippocampus. On the other hand, our results suggest that the serotonergic effect on perisomatic inhibition is exerted via vasoactive intestinal polypeptide-containing basket cells that are functionally distinct from their parvalbumin-positive relatives, which appear to escape control of serotonergic as well as local interneuron-selective cells.

  13. Alterations in perivascular sympathetic and nitrergic innervation function induced by late pregnancy in rat mesenteric arteries.

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    Esther Sastre

    Full Text Available We investigated whether pregnancy was associated with changed function in components of perivascular mesenteric innervation and the mechanism/s involved.We used superior mesenteric arteries from female Sprague-Dawley rats divided into two groups: control rats (in oestrous phase and pregnant rats (20 days of pregnancy. Modifications in the vasoconstrictor response to electrical field stimulation (EFS were analysed in the presence/absence of phentolamine (alpha-adrenoceptor antagonist or L-NAME (nitric oxide synthase-NOS- non-specific inhibitor. Vasomotor responses to noradrenaline (NA, and to NO donor DEA-NO were studied, NA and NO release measured and neuronal NOS (nNOS expression/activation analysed.EFS induced a lower frequency-dependent contraction in pregnant than in control rats. Phentolamine decreased EFS-induced vasoconstriction in segments from both experimental groups, but to a greater extent in control rats. EFS-induced vasoconstriction was increased by L-NAME in arteries from both experimental groups. This increase was greater in segments from pregnant rats. Pregnancy decreased NA release while increasing NO release. nNOS expression was not modified but nNOS activation was increased by pregnancy. Pregnancy decreased NA-induced vasoconstriction response and did not modify DEA-NO-induced vasodilation response.Neural control of mesenteric vasomotor tone was altered by pregnancy. Diminished sympathetic and enhanced nitrergic components both contributed to the decreased vasoconstriction response to EFS during pregnancy. All these changes indicate the selective participation of sympathetic and nitrergic innervations in vascular adaptations produced during pregnancy.

  14. [Adrenergic innervation and norepinephrine content in postnatal rat uterus].

    Science.gov (United States)

    Itoh, M

    1983-03-01

    Using fluorescent histochemical method and high performance liquid chromatography with electrochemical detector, we investigated adrenergic innervation and norepinephrine content in the rat uterus in the process of the growth. The adrenergic nerve terminals in the rat uterus developed with age and reached to adult level at 7 weeks of age after birth, although the short adrenergic ganglionic cells and small intense fluorescent cells were present even at birth. Norepinephrine content per organ also increased with age and reached to adult level at 10 weeks of age after birth, while NE content per gram wet tissue weight had a peak in 3-day-old rat uterus. These morphological and biochemical data revealed that the sympathetic nervous system in rat uterus matures in 7 to 10 weeks after birth, while the short adrenergic nervous system is accomplished in earlier stage. The maturation of adrenergic innervation in the uterus was considerably later than in the other organs of rat and developed with the sexual maturation.

  15. Negative cerebral blood volume fMRI response coupled with Ca²⁺-dependent brain activity in a dopaminergic road map of nociception.

    Science.gov (United States)

    Hsu, Yi-Hua; Chang, Chen; Chen, Chiao-Chi V

    2014-04-15

    Decreased cerebral blood volume/flow (CBV/CBF) contributes to negative blood-oxygen-level-dependent (BOLD) functional MRI (fMRI) signals. But it is still strongly debated whether these negative BOLD or CBV/CBF signals are indicative of decreased or increased neuronal activity. The fidelity of Ca(2+) signals in reflecting neuronal excitation is well documented. However, the roles of Ca(2+) signals and Ca(2+)-dependent activity in negative fMRI signals have never been explored; an understanding of this is essential to unraveling the underlying mechanisms and correctly interpreting the hemodynamic response of interest. The present study utilized a nociception-induced negative CBV fMRI response as a model. Ca(2+) signals were investigated in vivo using Mn(2+)-enhanced MRI (MEMRI), and the downstream Ca(2+)-dependent signaling was investigated using phosphorylated cAMP response-element-binding (pCREB) immunohistology. The results showed that nociceptive stimulation led to (1) striatal CBV decreases, (2) Ca(2+) increases via the nigrostriatal pathway, and (3) substantial expression of pCREB in substantia nigra dopaminergic neurons and striatal neurons. Interestingly, the striatal negative fMRI response was abolished by blocking substantia nigra activity but was not affected by blocking the striatal activity. This suggests the importance of input activity other than output in triggering the negative CBV signals. These findings indicate that the striatal negative CBV fMRI signals are associated with Ca(2+) increases and Ca(2+)-dependent signaling along the nigrostriatal pathway. The obtained data reveal a new brain road map in response to nociceptive stimulation of hemodynamic changes in association with Ca(2+) signals within the dopaminergic system.

  16. The effect of fenugreek on nociceptive response in diabetic rats

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    Mehrdad Roghani

    2009-01-01

    Full Text Available   Abstract  Introduction: Diabetic rats display exaggerated hyperalgesic behavior in response to noxious stimuli that may resemble and model aspects of painful diabetic neuropathy in humans. This study was designed to investigate the effect of Trigonella foenum-graecum (TFG on formalin-induced nociceptive responses (standard formalin test in streptozotocin (STZ-induced diabetic rats.  Methods: For this purpose, STZ-diabetic rats received intraperitoneal injection of aqueous leaf extract of TFG (200 mg/kg every other day for a period of one month.  Results: It was found out that TFG treatment did cause a significant reduction in blood glucose in diabetic rats and TFG-treated diabetic rats exhibited a lower nociceptive score as compared to untreated-diabetic ones. Meanwhile, TFG treatment reduced the nociceptive score in both phases of the formalin test. In contrast, sodium salicylate as positive control only reduced this score in the second phase of the test.  Discussion: The results suggest therapeutic potential of aqueous extract of fenugreek for treating painful diabetic neuropathy. 

  17. Nociception at the diabetic foot, an uncharted territory

    Institute of Scientific and Technical Information of China (English)

    Ernst A Chantelau

    2015-01-01

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

  18. The zebrafish as a model for nociception studies.

    Science.gov (United States)

    Malafoglia, Valentina; Bryant, Bruce; Raffaeli, William; Giordano, Antonio; Bellipanni, Gianfranco

    2013-10-01

    Nociception is the sensory mechanism used to detect cues that can harm an organism. The understanding of the neural networks and molecular controls of the reception of pain remains an ongoing challenge for biologists. While we have made significant progress in identifying a number of molecules and pathways that are involved in transduction of noxious stimuli, from the skin through the sensory receptor cell and from this to the spinal cord on into the central nervous system, we still lack a clear understanding of the perceptual processes, the responses to pain and the regulation of pain perception. Mice and rat animal models have been extensively used for nociception studies. However, the study of pain and noiception in these organisms can be rather laborious, costly and time consuming. Conversely, the use of Drosophila and Caenorhabditis elegans may be affected by the large evolutionary distance between these animals and humans. We outline here the reasons why zebrafish presents a new and attractive model for studying pain reception and responses and the most interesting findings in the study of nociception that have been obtained using the zebrafish model.

  19. Chronic intrathecal cannulation enhances nociceptive responses in rats

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    Almeida F.R.C.

    2000-01-01

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

  20. The innervated free toe web flap for clitoris reconstruction.

    Science.gov (United States)

    Dabernig, Jörg; Shelley, Odhran P; Schaff, Jürgen

    2007-01-01

    Clitoris reconstruction is often used in transgender reassignment. Most techniques now reconstruct the clitoris using glans pedicled on the dorsal phallic neurovascular bundle. Other techniques of clitoris reconstruction re-shape retained elements of the proximal segment of the corpora cavernosa, as well as techniques mobilising local flaps. We are presenting a new technique for clitoris reconstruction using an innervated free web space flap. The operative technique and outcome are illustrated and discussed in this case report.

  1. ACETYL-L-CARNITINE AFFECTS THE ELECTRICAL ACTIVITY OF MECHANOSENSORY NEURONS IN HIRUDO MEDICINALIS GANGLIA

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    Giovanna Traina

    2017-04-01

    Full Text Available Was previously discovered that in the leech Hirudo medicinalis, acetyl-l-carnitine (ALC affects forms of non-associative learning, such as sensitization and dishabituation, due to nociceptive stimulation of the dorsal skin in the swim induction behavioural paradigm, likely through modulating the activity of the mechanosensory tactile (T neurons, which initiate swimming. Since was found that ALC impaired sensitization and dishabituation, both of which are mediated by the neurotransmitter serotonin, the present study analyzed how ALC may interfere with the sensitizing response. Was already found that ALC reduced the activity of nociceptive (N neurons, which modulate T cell activity through serotonergic mediation.

  2. Synaptic contact between median preoptic neurons and subfornical organ neurons projecting to the paraventricular hypothalamic nucleus.

    Science.gov (United States)

    Kawano, Hitoshi

    2017-04-01

    It is known that the median preoptic nucleus (POMe) sends dense projections to the subfornical organ (SFO). However, the functional significance of these projections have not been well discussed. In this electron microscopic study, we investigated the presence of synapses between POMe-derived axon terminals and SFO neurons that project to the paraventricular hypothalamic nucleus (PVN). After injection of a retrograde tracer, wheat germ agglutinin-conjugated horseradish peroxidase-colloidal gold complex, into the PVN, many labeled neurons were found in the SFO. In contrast, after injection of an anterograde tracer, biotinylated dextran amine, in the POMe, abundant labeled axon varicosities were observed in the SFO. Using electron microscopy, synapses were identified between retrogradely labeled dendrites and cell bodies, and anterogradely labeled axon terminals, indicating that POMe neurons innervate SFO neurons projecting to the PVN. The possibility that POMe neurons play multiple roles in the neuronal circuit responsible for vasopressin release and/or cardiovascular regulation is also discussed.

  3. Ovarian innervation develops before initiation of folliculogenesis in the rat.

    Science.gov (United States)

    Malamed, S; Gibney, J A; Ojeda, S R

    1992-10-01

    Sympathetic neurotransmitters have been shown to be present in the ovary of the rat during early postnatal development and to affect steroidogenesis before the ovary becomes responsive to gonadotropins, and before the first primordial follicles are formed. This study was undertaken to determine if development of the ovarian innervation is an event that antedates the initiation of folliculogenesis in the rat, Rattus norvegicus. Serial sections of postnatal ovaries revealed a negligible frequency of follicles 24 h after birth (about 1 primordial follicle per ovary). Twelve hours later there were about 500 follicles per ovary, a number that more than doubled to about 1300 during the subsequent 12 h, indicating that an explosive period of follicular differentiation occurs between the end of postnatal days 1 and 2. Electron microscopy demonstrated that before birth the ovaries are already innervated by fibers containing clear and dense-core vesicles. Immunohistochemistry performed on either fetal (day 19) or newborn (less than 15h after birth) ovaries showed the presence of catecholaminergic nerves, identified by their content of immunoreactive tyrosine hydroxylase (TH), the rate-limiting enzyme in catecholamine biosynthesis. While some of these fibers innervate blood vessels, others are associated with primordial ovarian cells, thereby suggesting their participation in non-vascular functions. Since prefollicular ovaries are insensitive to gonadotropins, the results suggest that the developing ovary becomes subjected to direct neurogenic influences before it acquires responsiveness to gonadotropins.

  4. [Density of the neurovegetative innervation of the uterus of rats].

    Science.gov (United States)

    Canon, E; Timmermans, L G

    1986-01-01

    Using the Karnovsky and Roots modified by E1 Badawi and Schenk's technic for the cholinergic innervation and with the method of Lindvall and Björklund modified by de la Torre and Surgeon for the adrenergic ones, we demonstrate the innervation of each tissular layer, in cervix, corpus and cornua of the uterus of the she-rat in pro-oestrus state. A statistic evaluation is established for the different areas. The density of cholinergic innervation is richer than the adrenergic one. The number of cholinergic fibers is maximum in the cervix. It decreases in corpus and cornua especially in the mucosal and sub-mucosal layers. The density of the muscular nervous network is predominant in the corpus versus the cervix. The number of adrenergic nerves is maximum in corpus it diminishes in the cervix and the cornua. In each region, the muscular adrenergic network domines over the other tissular layers. We confirm statistically morphometric non parametric observations of these other authors.

  5. GDE2 regulates subtype-specific motor neuron generation through inhibition of Notch signaling.

    Science.gov (United States)

    Sabharwal, Priyanka; Lee, Changhee; Park, Sungjin; Rao, Meenakshi; Sockanathan, Shanthini

    2011-09-22

    The specification of spinal interneuron and motor neuron identities initiates within progenitor cells, while motor neuron subtype diversification is regulated by hierarchical transcriptional programs implemented postmitotically. Here we find that mice lacking GDE2, a six-transmembrane protein that triggers motor neuron generation, exhibit selective losses of distinct motor neuron subtypes, specifically in defined subsets of limb-innervating motor pools that correlate with the loss of force-generating alpha motor neurons. Mechanistically, GDE2 is expressed by postmitotic motor neurons but utilizes extracellular glycerophosphodiester phosphodiesterase activity to induce motor neuron generation by inhibiting Notch signaling in neighboring motor neuron progenitors. Thus, neuronal GDE2 controls motor neuron subtype diversity through a non-cell-autonomous feedback mechanism that directly regulates progenitor cell differentiation, implying that subtype specification initiates within motor neuron progenitor populations prior to their differentiation into postmitotic motor neurons.

  6. Heterosynaptic long-term depression of craniofacial nociception: divergent effects on pain perception and blink reflex in man.

    Science.gov (United States)

    Yekta, Sareh Said; Lamp, Susanne; Ellrich, Jens

    2006-04-01

    Noxious low-frequency stimulation (LFS) of presynaptic nerve fibers induces long-term depression (LTD) of synaptic transmission. In vitro studies suggest a sole homosynaptic effect. Consequently, the present study addressed the hypothesis that LTD of craniofacial nociception in man is mediated by a homosynaptic mechanism. Nociceptive supraorbital afferents were excited by electric pulses via a concentric electrode in ten healthy volunteers. The electrically evoked bilateral blink reflex (BR) was recorded from both orbicularis oculi muscles by surface electrodes. The BR was evoked in blocks of ten electric stimuli each (0.1 Hz) with an interblock interval of 8 min. Conditioning noxious LFS (1 Hz, 20 min) was applied via concentric electrode either to the same site as BR test stimuli (ipsilateral) or to the corresponding contralateral forehead area (contralateral). LFS and test stimulus intensities corresponded to about threefold the pain threshold. After three baseline stimulus blocks, either conditioning ipsilateral or contralateral LFS were applied or stimulation was interrupted for 20 min as a control task. Afterwards, test stimulation blocks were continued for 40 min. Each volunteer participated in all three sessions on different days. Noxious LFS induced LTD of the BR independently from the side of conditioning stimulation. Pain perception decreased after ipsilateral LFS but not after contralateral LFS. The bilateral effect of noxious LFS on the BR provides evidence for heterosynaptic LTD based on bilateral projections of supraorbital nerve afferents onto spinal trigeminal nuclei. The divergent effect on pain perception may be due to a preferential contralateral projection of nociceptive afferents onto reflex interneurons but not onto trigeminothalamic projection neurons.

  7. 大鼠三叉神经本体感觉中枢通路二级神经元接受5-羟色胺能终末支配的电镜证明%ULTRASTRUCTURAL EVIDENCE OF SEROTON-INERGIC INNERVATION OF THE SECOND-ORDER NEURONS ON THE CENTRAL PATHWAY OF THE TRIGEMINAL PROPRIOCEPTION OF THE RAT

    Institute of Scientific and Technical Information of China (English)

    张富兴; 李金莲; 李继硕

    2002-01-01

    目的研究5-羟色胺(5-HT)样免疫反应纤维终末与大鼠三叉神经本体觉中枢通路二级神经元之间是否存在突触联系. 方法逆行束路追踪与免疫组织化学相结合的电镜双重标记技术. 结果将麦芽凝集素结合的辣根过氧化物酶(WGA-HRP)注入大鼠三叉神经感觉主核背内侧部(Vpdm)并进行5-HT免疫染色后,在三叉神经脊束核吻侧亚核背内侧部及其邻接的外侧网状结构(Vodm-LRF)中可见WGA-HRP逆行标记的神经元和5-HT样阳性轴突终末.电镜下观察到5-HT样阳性轴突终末与WGA-HRP标记的神经元之间有轴-体、轴-树突触联系,这些突触属对称或非对称型,但以对称型为主. 结论本研究为5-HT能终末可能对三叉神经本体觉信息的传递具有一定的调控作用提供了形态学依据.%Objective To investigate whether the serotonin(5-HT)-like immunoreactive axons synapse upon the second-order neurons on the central path way of the trigeminal proprioception in the rat. Methods Electron microscopic double-labeling of retrograde tract-tracing technique combined with immunohistochemistry. Results Following the injection of wheat germ agglutinin-horsera dish peroxidase (WGA-HRP) into the dorsomedial part of the principal sensory tr igeminal nucleus(Vpdm) of the rat and the immunostaining for 5-HT, there were n eurons retrogradely labeled by WGA-HRP and axon terminals with 5-HT-like immu noreactivity(5-HT-LI) in the dorsomedial part of the subnucleus oralis of the spinal trigeminal nucleus and its adjacent lateral reticular formation(Vodm-LRF ).At the electron microscopic level,the 5-HT-immunostained axonal profiles wer e observed to make synaptic contacts with the WGA-HRP-labeled neurons.Both the axon-somatic and axon-dendritic synapses were found.These synapses were mainly of symmetric type although the asymmetric ones were also seen.Conclusion The present results provided a morphologic basis for the serotoninergic terminals which

  8. Mediating roles of the vanilloid receptor TRPV1 in activation of rat primary afferent nociceptive neurons by formaldehyde%TRPV1介导甲醛激活初级传入伤害性感受器细胞的作用

    Institute of Scientific and Technical Information of China (English)

    田丽娟; 杜意如; 萧勇; 吕卓敏; 于耀清; 崔秀玉; 陈军

    2009-01-01

    flinches were strongly suppressed by CPZ in phase 1 but with phase 2 being significantly suppressed only during 25-55 min. It is therefore concluded that FA can directly activate a subpopulation of primary nociceptor cells and the FA-induced AP discharges are likely to contribute mainly to phase 1, but not phase 2 of the formalin-induced nociception. The activation of primary nociceptor cells by FA is likely to be mediated, at least in part, through TRPV1 and/or TRPA1 receptors.%福尔马林致痛模型是化学伤害性刺激引起急性和持续性痛常用的动物模型.本研究旨在细胞和整体水平上证明TRPV1受体是否参与甲醛溶液(甲醛是福尔马林溶液的主要成分)对初级伤害性感受器细胞的激活过程.运用电流钳记录的92个背根神经节细胞中,大约有34%的中、小细胞对甲醛溶液敏感,产生动作电位的发放,其产生动作电位的潜伏期是(367.34±32.96)s,并且单个动作电位复极化相具有伤害性感受器细胞的特征性,如动作电位间期较长、复极化相有"驼峰"以及较长的后超极化相.在同时给予FRPV1受体抑制剂Capsazepine(CPZ)时,甲醛溶液诱发背根神经节细胞产生的放电可以被阻断,但对细胞膜去极化不能完全阻断.在激光共聚焦钙成像中记录的160个背根神经节细胞中,有32%的细胞对甲醛溶液敏感,可以产生胞内钙离子浓度的升高,同时加入CPZ后,67%的这些甲醛敏感性细胞的胞内钙浓度升高可以被抑制.在电压钳状态下,甲醛溶液可以诱发背根神经节细胞产生内向电流,大约有41%的细胞对甲醛溶液敏感,实验证明甲醛溶液诱发产生内向电流的幅度呈剂量依赖.当同时给予CPZ时比TRPA1受体选择性抑制剂HC-030031抑制内向电流的幅度明显.利用行为学技术方法证明足底注射CPZ可以明显抑制福尔屿林溶液所致的第一相全程和第二相内仅第25~25 min的自发缩足反射.以上结果提示,甲醛溶液

  9. Dopamine control of pyramidal neuron activity in the primary motor cortex via D2 receptors

    Directory of Open Access Journals (Sweden)

    Clément eVitrac

    2014-02-01

    Full Text Available The primary motor cortex (M1 is involved in fine voluntary movements control. Previous studies have shown the existence of a dopamine (DA innervation in M1 of rats and monkeys that could directly modulate M1 neuronal activity. However, none of these studies have described the precise distribution of DA terminals within M1 functional region nor have quantified the density of this innervation. Moreover, the precise role of DA on pyramidal neuron activity still remains unclear due to conflicting results from previous studies regarding D2 effects on M1 pyramidal neurons.In this study we assessed in mice the neuroanatomical characteristics of DA innervation in M1 using unbiased stereological quantification of dopamine transporter-immunostained fibers. We demonstrated for the first time in mice that DA innervates the deep layers of M1 targeting preferentially the forelimb representation area of M1. To address the functional role of the DA innervation on M1 neuronal activity, we performed electrophysiological recordings of single neurons activity in vivo and pharmacologically modulated D2 receptors activity. Local D2 receptors activation by quinpirole enhanced pyramidal neurons spike firing rate without changes in spike firing pattern. Altogether, these results indicate that DA innervation in M1 can increase neuronal activity through D2 receptors activation and suggest a potential contribution to the modulation of fine forelimb movement. Given the demonstrated role for DA in fine motor skill learning in M1, our results suggest that altered D2 modulation of M1 activity may be involved in the pathophysiology of movement disorders associated with disturbed DA homeostasis.

  10. Neurogenic nitric oxide facilitates the central nociceptive transmission of migraine attacks

    Institute of Scientific and Technical Information of China (English)

    Hebo Wang; Huijun Qi; Shengyuan Yu; Sumian Yang; Ruozhuo Liu

    2011-01-01

    Recent studies have shown that nitric oxide (NO) can induce migraine attacks at three possible sites of action: nitroxidergic nerves, the vascular endothelium, and the central nervous system. Most previous studies have focused on the former two sites of action. Several experiments using exogenic NO donors have suggested that nitroglycerin may induce migraine via central mechanisms. However, few studies have investigated the source of the NO involved in the central mechanisms of migraine. The present study used a cat model of migraine to represent migraine attacks in humans. We performed immunochemical staining of successive frozen sections of the brainstem and upper cervical spinal cord, and then used c-Fos protein expression to label nerve cell activation. We observed the effects of Nω-nitro-L-arginine methyl ester (L-NAME), a non-selective nitric oxide synthase (NOS) inhibitor, and 7-nitroindozole (7-NI), a selective neuronal NOS inhibitor, on c-Fos and nNOS expression, which were induced by electrical stimulation to the dura mater near the superior sagittal sinus. The results demonstrated that c-Fos or nNOS immunoreactive cells was concentrated in the superficial layers (laminae I and II) of the spinal nucleus of trigeminal nerve. L-NAME and 7-NI pre-treatment significantly decreased c-Fos and neurogenic NOS expression; and there was a significant linear correlation between c-Fos and NOS expression (r= 0.858 2, P< 0.01). These findings suggest that neurogenic NO could facilitate migraine nociceptive transmission to second-order neurons of the trigeminal nerve. However, L-NAME and 7-NI may block the activation of neurons in the spinal nucleus of the trigeminal nerve by inhibiting NO synthesis, and thereby attenuate acute migraine attacks.

  11. Selective innervation of fast and slow muscle regions during early chick neuromuscular development.

    Science.gov (United States)

    Rafuse, V F; Milner, L D; Landmesser, L T

    1996-11-01

    The electrical properties of adult motoneurons are well matched to the contractile properties of the fast or slow muscle fibers that they innervate. How this precise matching occurs developmentally is not known. To investigate whether motoneurons exhibit selectivity in innervating discrete muscle regions, containing either fast or slow muscle fibers during early neuromuscular development, we caused embryonic chick hindlimb muscles to become innervated by segmentally inappropriate motoneurons. We used the in vitro spinal cord-hindlimb preparation to identify electrophysiologically the pools of foreign motoneurons innervating the posterior iliotibialis (pITIB), an all-fast muscle, and the iliofibularis (IFIB), a partitioned muscle containing discrete fast and slow regions. The results showed that the pITIB and the fast region of the IFIB were exclusively innervated by motoneurons that normally supply fast muscles. In contrast, the slow region of the IFIB was always innervated by motoneuron pools that normally supply slow muscles. Some experimental IFIB muscles lacked a fast region and were innervated solely by "slow" motoneurons. In addition, the intramuscular nerve branching patterns were always appropriate to the fast-slow nature of the muscle (region) innervated. The selective innervation was found early in the motoneuron death period, and we found no evidence that motoneurons grew into appropriate muscle regions, but failed to form functional contacts. Together, these results support the hypothesis that different classes of motoneurons exhibit molecular differences that allow them to project selectively to, and innervate, muscle fibers of the appropriate type during early neuromuscular development.

  12. The Dolognawmeter: A Novel Instrument and Assay to Quantify Nociception in Rodent Models of Orofacial Pain

    OpenAIRE

    Dolan, John C.; Lam, David K; Achdjian, Stacy H.; Schmidt, Brian L.

    2010-01-01

    Rodent pain models play an important role in understanding the mechanisms of nociception and have accelerated the search for new treatment approaches for pain. Creating an objective metric for orofacial nociception in these models presents significant technical obstacles. No animal assay accurately measures pain-induced orofacial dysfunction that is directly comparable to human orofacial dysfunction. We developed and validated a high throughput, objective, operant, nociceptive animal assay, a...

  13. The role of the ETS gene PEA3 in the development of motor and sensory neurons.

    Science.gov (United States)

    Ladle, David R; Frank, Eric

    2002-12-01

    The ETS family of transcription factors includes two members, ER81 and PEA3, which are expressed in groups of sensory and motor neurons supplying individual muscles. To investigate a possible role of these genes in determining sensory and/or motor neuron phenotype, we studied mice in which each of these genes was deleted. In contrast to the deletion of ER81, which blocks the formation of projections from muscle sensory neurons to motor neurons in the spinal cord, deletion of PEA3 causes no obvious effects on sensory neurons or on their synaptic connections with motor neurons. PEA3 does play a major role in the formation of some brachial motoneurons however. Motoneurons innervating the cutaneous maximus muscle, which are normally PEA3(+), fail to develop normally so that postnatally the muscle is innervated by few motoneurons and is severely atrophic. Other studies suggest that these motoneurons initially appear during development but fail to contact their normal muscle targets.

  14. Segregated cholinergic transmission modulates dopamine neurons integrated in distinct functional circuits.

    Science.gov (United States)

    Dautan, Daniel; Souza, Albert S; Huerta-Ocampo, Icnelia; Valencia, Miguel; Assous, Maxime; Witten, Ilana B; Deisseroth, Karl; Tepper, James M; Bolam, J Paul; Gerdjikov, Todor V; Mena-Segovia, Juan

    2016-08-01

    Dopamine neurons in the ventral tegmental area (VTA) receive cholinergic innervation from brainstem structures that are associated with either movement or reward. Whereas cholinergic neurons of the pedunculopontine nucleus (PPN) carry an associative/motor signal, those of the laterodorsal tegmental nucleus (LDT) convey limbic information. We used optogenetics and in vivo juxtacellular recording and labeling to examine the influence of brainstem cholinergic innervation of distinct neuronal subpopulations in the VTA. We found that LDT cholinergic axons selectively enhanced the bursting activity of mesolimbic dopamine neurons that were excited by aversive stimulation. In contrast, PPN cholinergic axons activated and changed the discharge properties of VTA neurons that were integrated in distinct functional circuits and were inhibited by aversive stimulation. Although both structures conveyed a reinforcing signal, they had opposite roles in locomotion. Our results demonstrate that two modes of cholinergic transmission operate in the VTA and segregate the neurons involved in different reward circuits.

  15. VGLUT2-dependent glutamatergic transmission in primary afferents is required for intact nociception in both acute and persistent pain modalities.

    Science.gov (United States)

    Rogoz, Katarzyna; Lagerström, Malin C; Dufour, Sylvie; Kullander, Klas

    2012-07-01

    Glutamate is an essential transmitter in pain pathways. However, its broad usage in the central and peripheral nervous system prevents us from designing efficient glutamate-based pain therapies without causing harmful side effects. The discovery of vesicular glutamate transporters (VGLUT1-3) has been a crucial step in describing specific glutamatergic neuronal subpopulations and glutamate-dependent pain pathways. To assess the role of VGLUT2-mediated glutamatergic contribution to pain transmission from the entire primary sensory population, we crossed our Vglut2(f/f) line with the Ht-Pa-Cre line. Such Vglut2-deficient mice showed significantly decreased, but not completely absent, acute nociceptive responses. The animals were less prone to develop an inflammatory-related state of pain and were, in the partial sciatic nerve ligation chronic pain model, much less hypersensitive to mechanical stimuli and did not develop cold allodynia or heat hyperalgesia. To take advantage of this neuropathic pain-resistant model, we analyzed Vglut2-dependent transcriptional changes in the dorsal spinal cord after nerve injury, which revealed several novel candidate target genes potentially relevant for the development of neuropathic pain therapeutics. Taken together, we conclude that VGLUT2 is a major mediator of nociception in primary afferents, implying that glutamate is the key somatosensory neurotransmitter.

  16. Estimation and identifiability of model parameters in human nociceptive processing using yes-no detection responses to electrocutaneous stimulation

    Directory of Open Access Journals (Sweden)

    Huan Yang

    2016-12-01

    Full Text Available Healthy or pathological states of nociceptive subsystems determine different stimulus-response relations measured from quantitative sensory testing. In turn, stimulus-responses measurements may be used to assess these states.In a recently developed computational model, six model parameters characterize activation of nerve endings and spinal neurons. However, both model nonlinearity and limited information in yes-no detection responses to electrocutaneous stimuli challenge to estimate model parameters. Here, we address the question whether and how one can overcome these difficulties for reliable parameter estimation. First, we fit the computational model to experimental stimulus-response pairs by maximizing the likelihood. To evaluate the balance between model fit and complexity, we evaluate the Bayesian Information Criterion. We find that the computational model is better than a conventional logistic model regarding the balance. Second, our theoretical analysis suggests to vary the pulse width among applied stimuli as a necessary condition to prevent structural non-identifiability. In addition, the numerically implemented profile likelihood approach reveals structural and practical non-identifiability. Our model-based approach with integration of psychophysical measurements can be useful for a reliable assessment of states of the nociceptive system.

  17. Withania somnifera (L.) Dunal root extract alleviates formalin-induced nociception in mice: involvement of the opioidergic system.

    Science.gov (United States)

    Orrù, Alessandro; Casu, Maria Antonietta; Tambaro, Simone; Marchese, Giorgio; Casu, Gianluca; Ruiu, Stefania

    2016-02-01

    Withania somnifera (L.) Dunal extracts (WSEs) may possess therapeutic perspectives in the treatment of inflammation and pain. We aimed to evaluate the antinociceptive property of a WSE in the formalin test and to investigate the involvement of several neurotransmitter systems in this effect. The time spent licking the formalin-injected paw was recorded in CD1 mice after pretreatment with increasing doses of WSE. Also, c-Fos spinal cord expression and the effects of different compounds were investigated under these experimental conditions. Finally, the efficacy of WSE was analyzed following an injection of glutamate. WSE reduced the antinociceptive response during the tonic but not the acute phase of the formalin test and decreased formalin-induced c-Fos expression in spinal neurons. These effects were antagonized by the opioid antagonist naltrexone, whereas GABA, cannabinoid, δ-opioid, and nitric oxide compounds were ineffective. The administration of WSE also reduced nociception and c-Fos expression induced by glutamate injection. These results showed that WSE is effective in assays of chemical-induced nociception, indicating that this plant has potential valuable properties for the treatment of specific painful conditions. The antinocicetive effects of WSE in the formalin test appeared to be specifically mediated by the opioidergic system, although the involvement of the glutamatergic system cannot be excluded.

  18. Development of rat tibia innervation: colocalization of autonomic nerve fiber markers with growth-associated protein 43.

    Science.gov (United States)

    Gajda, Mariusz; Litwin, Jan A; Tabarowski, Zbigniew; Zagólski, Olaf; Cichocki, Tadeusz; Timmermans, Jean-Pierre; Adriaensen, Dirk

    2010-01-01

    Development of autonomic innervation of the tibia was investigated in rat fetuses on gestational days (GD) 17-21 and in juvenile animals on postnatal days (PD) 1-28. Double immunofluorescence combined with confocal microscopy was applied to study colocalization of neuronal growth- associated protein 43 (GAP-43) and panneuronal marker protein gene product 9.5 (PGP) with markers of the autonomic nervous system: neuropeptide Y (NPY) and dopamine beta-hydroxylase (DbetaH) for adrenergic, as well as vasoactive intestinal polypeptide (VIP) and vesicular acetylcholine transporter (VAChT) for cholinergic fibers. The first GAP-43-immunoreactive (GAP-IR) nerve fibers were seen on GD17 in the perichondrium of the proximal epiphysis. Further GAP- and PGP-IR innervation appeared in the perichondrium/periosteum of the diaphysis and in the distal epiphysis (GD19), then in the bone marrow and in the intercondylar eminence (GD21). On PD1, NPY-IR and DbetaH-IR fibers appeared within the diaphyseal periosteum and on PD4 within the bone marrow. From PD14, GAP-43 immunoreactivity of NPY-positive fibers decreased. From PD7 on, NPY-IR fibers were observed in cartilage canals of both epiphyses and in the intercondylar eminence. In secondary ossification centers, NPY-IR fibers were seen from PD10, and in the bone marrow of the epiphyses from PD14. First VIP-IR and VAChT-IR fibers were observed on PD4 within the periosteum, bone marrow and patellar ligament. From PD10 on, VIP-positive fibers were seen in the intercondylar eminence, and from PD14 in secondary ossification centers. GAP-43 proved to be superior to PGP 9.5 as marker of growing nerve fibers, mostly due to its earlier appearance. The presence of specific nerve fibers may suggest possible involvement of autonomic innervation in regulation of bone development.

  19. Injection of adjuvant but not acidic saline into craniofacial muscle evokes nociceptive behaviors and neuropeptide expression.

    Science.gov (United States)

    Ambalavanar, R; Yallampalli, C; Yallampalli, U; Dessem, D

    2007-11-09

    Craniofacial muscle pain including muscular temporomandibular disorders accounts for a substantial portion of all pain perceived in the head and neck region. In spite of its high clinical prevalence, the mechanisms of chronic craniofacial muscle pain are not well understood. Injection of acidic saline into rodent hindlimb muscles produces pathologies which resemble muscular pathologies in chronic pain patients. Here we investigated whether analogous transformations occur following repeated injections of acidic saline into the rat masseter muscle. Injection of acidic saline (pH 4) into the masseter muscle transiently lowered i.m. pH to levels comparable to those reported for rodent hindlimb muscles. Nevertheless, repeated unilateral or bilateral injections of acidic saline (pH 4) into the masseter muscle failed to alter nociceptive behavioral responses as occurs in the hindlimb. Changing the pH of injected saline to pH 3.0 or 5.0 also did not evoke nocifensive behavior. Acid sensing ion channel 3 receptors, which are implicated in transformations following acidification of hindlimb muscles, were found on trigeminal ganglion muscle afferent neurons via combined neuronal tracing and immunocytochemistry. In contrast to the acidic saline, injection of complete Freund's adjuvant (CFA) into the masseter muscle induced mechanical allodynia for 3 weeks, thermal hyperalgesia for 1 week and an increase in the number of calcitonin gene-related peptide (CGRP)-immunoreactive muscle afferent neurons in the trigeminal ganglion. Although pH may alter CGRP release in primary afferent neurons, the number of CGRP-muscle afferent neurons did not change following i.m. injection of acidic saline. Further, there was no change in ganglionic iCGRP levels at 1, 4 or 12 days after i.m. injection of acidic saline. While these findings extend our earlier reports that CFA-induced muscle inflammation results in behavioral and neuropeptide changes they further suggest that i.m. acidification in

  20. Ionotropic Glutamate Receptor Expression in Preganglionic Neurons of the Rat Inferior Salivatory Nucleus

    OpenAIRE

    Kim, M.; Chiego, D.J.; Bradley, R.M.

    2007-01-01

    Glutamate receptor (GluR) subunit composition of inferior salivatory nucleus (ISN) neurons was studied by immunohistochemical staining of retrogradely labeled neurons. Preganglionic ISN neurons innervating the von Ebner or parotid salivary glands were labeled by application of a fluorescent tracer to the lingual-tonsilar branch of the glossopharyngeal nerve or the otic ganglion respectively. We used polyclonal antibodies to glutamate receptor subunits NR1, NR2A, NR2B, (NMDA receptor subunits)...

  1. The spatiotemporal development of innervation in spinal ligaments of chickens.

    Science.gov (United States)

    Jiang, H; Moreau, M; Greidanus, N; Bilo, J; Russell, G; Raso, J; Bagnall, K

    1996-08-01

    The development of the innervation of both central and lateral (intertransverse) spinal ligaments was investigated in chickens between the time of hatching and 13 wk of age. A total of 36 White Leghorn chickens in 4 groups of 9 at ages 0, 2, 7, and 13 wk were used. The spinal ligaments were dissected, serially sectioned and labelled with a monoclonal antibody against neurofilament protein and observed using either conventional fluorescence or confocal microscopy. Only a few nerve elements were found in the ligaments at hatching and these consisted simply of single nerve fibres and small nerve bundles. The number of nerve elements increased rapidly up to 7 wk of age when large nerve bundles and Ruffini corpuscles were also found. The number of nerve elements decreased between 7 and 13 wk birds when the ligaments had begun to ossify and the amount of collagenous ligamentous tissue was significantly reduced. The fluctuation in numbers of neural elements was due to changes in numbers of single nerve fibres and small nerve bundles rather than large nerve bundles and Ruffini corpuscles which remained constant. In contrast to this significant increase in numbers of nerve elements, the innervation density of the ligaments decreased because of the overwhelming increase of the ligament volume due to growth. There were no differences between ligaments on the left and right sides of the body, but there was an unequal distribution of the neural elements within the ligaments; most were found in the cranial third of the intertransverse ligaments. These results show that significant changes in innervation of spinal ligaments occur during development and reflect the possibility that damage to the ligaments during this time could produce significant and permanent damage, especially in relation to the maintenance of an erect spine.

  2. Nociceptive responses to thermal and mechanical stimulations in awake pigs

    DEFF Research Database (Denmark)

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

    2013-01-01

    animal studies in a large species require further examination. This manuscript describes the initial development of a porcine model of cutaneous nociception and focuses on interactions between the sensory modality, body size and the anatomical location of the stimulation site. METHODS: Pigs of different...... significantly lower pain thresholds (shorter latency to response) than large pigs to thermal and mechanical stimulations. Stimulations at the two anatomical locations elicited very distinct sets of behavioural responses, with different levels of sensitivity between the flank and the hind legs. Furthermore...

  3. Localization of motoneurons innervating individual abdominal muscles of the cat

    Science.gov (United States)

    Miller, Alan D.

    1987-01-01

    The paper presents the results of a systematic investigation of the innervation of the cat's individual abdominal muscles. The segmental distribution of the different motor pools was determined by using electrical microstimulation of the ventral horn to produce visible localized muscle twitches and by retrograde transport of horseradish peroxidase injected into individual muscles. The segmental distribution of each motor pool was as follows: rectus abdominis, T4-L3; external oblique, T6-L3; transverse abdominis, T9-L3; and internal oblique, T13-L3.

  4. Double innervations to the superior belly of omohyoid

    Directory of Open Access Journals (Sweden)

    Rao TR

    2008-12-01

    Full Text Available Awareness in the variations of infrahyoid muscles is useful guide for both in studies of human anatomy and in clinical practice today. The use of muscular flaps as a reconstructive tool requires a thorough anatomical knowledge of its blood supply and innervations. These muscles vary considerably in the extent of their development. The omohyoid is the most frequently absent muscle of this group. We present a rare case of double nerve supply to the superior belly of omohyoid, which was found during our routine anatomical dissection on the right side of the neck of a 55-year-old male cadaver.

  5. Disruption of cardiac cholinergic neurons enhances susceptibility to ventricular arrhythmias

    Science.gov (United States)

    Jungen, Christiane; Scherschel, Katharina; Eickholt, Christian; Kuklik, Pawel; Klatt, Niklas; Bork, Nadja; Salzbrunn, Tim; Alken, Fares; Angendohr, Stephan; Klene, Christiane; Mester, Janos; Klöcker, Nikolaj; Veldkamp, Marieke W.; Schumacher, Udo; Willems, Stephan; Nikolaev, Viacheslav O.; Meyer, Christian

    2017-01-01

    The parasympathetic nervous system plays an important role in the pathophysiology of atrial fibrillation. Catheter ablation, a minimally invasive procedure deactivating abnormal firing cardiac tissue, is increasingly becoming the therapy of choice for atrial fibrillation. This is inevitably associated with the obliteration of cardiac cholinergic neurons. However, the impact on ventricular electrophysiology is unclear. Here we show that cardiac cholinergic neurons modulate ventricular electrophysiology. Mechanical disruption or pharmacological blockade of parasympathetic innervation shortens ventricular refractory periods, increases the incidence of ventricular arrhythmia and decreases ventricular cAMP levels in murine hearts. Immunohistochemistry confirmed ventricular cholinergic innervation, revealing parasympathetic fibres running from the atria to the ventricles parallel to sympathetic fibres. In humans, catheter ablation of atrial fibrillation, which is accompanied by accidental parasympathetic and concomitant sympathetic denervation, raises the burden of premature ventricular complexes. In summary, our results demonstrate an influence of cardiac cholinergic neurons on the regulation of ventricular function and arrhythmogenesis. PMID:28128201

  6. Endomorphins suppress nociception-induced c-Fos and Zif/268 expression in the rat spinal dorsal horn.

    Science.gov (United States)

    Tateyama, Shingo; Ikeda, Tetsuya; Kosai, Kazuko; Nakamura, Tadashi; Kasaba, Toshiharu; Takasaki, Mayumi; Nishimori, Toshikazu

    2002-09-06

    We evaluated the potency of endomorphin-1 and -2 as endogenous ligands on c-Fos and Zif/268 expression in the spinal dorsal horn by formalin injection to the rat hind paw. Endomorphin-1, -2, or morphine was administered intrathecally or intracerebroventricularly 5 min before formalin injection (5%, 100 microl). All drugs produced marked reductions of formalin-induced c-Fos and Zif/268 immunoreactivity in laminae I and II, and laminae V and VI in the rat lumbar spinal cord. The reductions of Zif/268 expression by endomorphins were greater than those by morphine, while the reductions of c-Fos expression by endomorphins were smaller than those by morphine. These effects of endomorphins were attenuated by pretreatment with naloxone. These results indicate that endomorphin-1 and -2 act as endogenous ligands of mu-opioid receptor in neurons of the spinal dorsal horn and suppress the processing of nociceptive information in the central nervous system.

  7. Identification and quantification of neuropeptides in naïve mouse spinal cord using mass spectrometry reveals [des-Ser1]-cerebellin as a novel modulator of nociception.

    Science.gov (United States)

    Su, Jie; Sandor, Katalin; Sköld, Karl; Hökfelt, Tomas; Svensson, Camilla I; Kultima, Kim

    2014-07-01

    Neuropeptide transmitters involved in nociceptive processes are more likely to be expressed in the dorsal than the ventral horn of the spinal cord. This study was designed to examine the relative distribution of neuropeptides between the dorsal and ventral spinal cord in naïve mice using liquid chromatography, high-resolution mass spectrometry. We identified and relatively quantified 36 well-characterized full-length neuropeptides and an additional 168 not previously characterized peptides. By extraction with organic solvents we identified seven additional full-length neuropeptides. The peptide [des-Ser1]-cerebellin (desCER), originating from cerebellin precursor protein 1 (CBLN1), was predominantly expressed in the dorsal horn. Immunohistochemistry showed the presence of CBLN1 immunoreactivity with a punctate cytoplasmic pattern in neuronal cell bodies throughout the spinal gray matter. The signal was stronger in the dorsal compared to the ventral horn, with most CBLN1 positive cells present in outer laminae II/III, colocalizing with calbindin, a marker for excitatory interneurons. Intrathecal injection of desCER induced a dose-dependent mechanical hypersensitivity but not heat or cold hypersensitivity. This study provides evidence for involvement of desCER in nociception and provides a platform for continued exploration of involvement of novel neuropeptides in the regulation of nociceptive transmission. Neuropeptides involved in nociceptive processes are more likely to be expressed in the dorsal than the ventral horn of spinal cord. Well-characterized full-length neuropeptides as well as uncharacterized neuropeptides were quantified by mass spectrometry. The CBLN1-derived peptide [des-Ser1]-cerebellin (desCER) is predominantly expressed in the dorsal horn, and intrathecal injection of desCER induced a dose-dependent mechanical hypersensitivity.

  8. Alpha and gamma oscillation amplitudes synergistically predict the perception of forthcoming nociceptive stimuli.

    Science.gov (United States)

    Tu, Yiheng; Zhang, Zhiguo; Tan, Ao; Peng, Weiwei; Hung, Yeung Sam; Moayedi, Massieh; Iannetti, Gian Domenico; Hu, Li

    2016-02-01

    Ongoing fluctuations of intrinsic cortical networks determine the dynamic state of the brain, and influence the perception of forthcoming sensory inputs. The functional state of these networks is defined by the amplitude and phase of ongoing oscillations of neuronal populations at different frequencies. The contribution of functionally different cortical networks has yet to be elucidated, and only a clear dependence of sensory perception on prestimulus alpha oscillations has been clearly identified. Here, we combined electroencephalography (EEG) and functional magnetic resonance imaging (fMRI) in a large sample of healthy participants to investigate how ongoing fluctuations in the activity of different cortical networks affect the perception of subsequent nociceptive stimuli. We observed that prestimulus EEG oscillations in the alpha (at bilateral central regions) and gamma (at parietal regions) bands negatively modulated the perception of subsequent stimuli. Combining information about alpha and gamma oscillations predicted subsequent perception significantly more accurately than either measure alone. In a parallel experiment, we found that prestimulus fMRI activity also modulated the perception of subsequent stimuli: perceptual ratings were higher when the BOLD signal was higher in nodes of the sensorimotor network and lower in nodes of the default mode network. Similar to what observed in the EEG data, prediction accuracy was improved when the amplitude of prestimulus BOLD signals in both networks was combined. These findings provide a comprehensive physiological basis to the idea that dynamic changes in brain state determine forthcoming behavioral outcomes. Hum Brain Mapp 37:501-514, 2016. © 2015 Wiley Periodicals, Inc.

  9. Central and peripheral actions of the NSAID ketoprofen on spinal cord nociceptive reflexes.

    Science.gov (United States)

    Herrero, J F; Parrado, A; Cervero, F

    1997-10-01

    Ketoprofen is a non-steroidal antiinflammatory drug (NSAID) which provides effective analgesia in situations of pain provoked by tissue inflammation. However, the location of its analgesic effects, (peripheral tissues versus central nervous system), have not been clearly identified and separated. In the present study the effectiveness of ketoprofen was examined in two different types of experiments: (i) Open field behavioural tests in conscious rats, and (ii) spinal cord nociceptive reflexes (single motor units) activated by electrical and thermal stimulation in chloralose anaesthetised rats. The experiments were performed in rats with carrageenan-induced inflammation of one hindpaw, or of one knee joint. The administration of ketoprofen significantly inhibited the reduction of exploratory movements caused by inflammation in open field experiments. Ketoprofen was also effective in depressing reflex activity evoked by electrical and noxious thermal stimulation of the skin, either in inflamed tissue or in normal tissue of monoarthritic animals. It was also effective in the reduction of reflex wind-up; a phenomenon in which the activity of spinal cord neurones increases progressively with high frequency electrical stimulation. We therefore conclude that ketoprofen has central as well as peripheral analgesic activity.

  10. Identification of CNS neural circuitry involved in the innervation of C7 spinal nerve: a viral transsynaptic tracing study

    Institute of Scientific and Technical Information of China (English)

    WEI Hai-feng; CHEN Liang; GU Yu-dong

    2011-01-01

    Objective: Contralateral C7 spinal nerve transfer is a useful operation for the treatment of brachial plexus root avulsion. The recovery of the independent function at the ipsilateral side, however, depends on neural circuitry reorganization in the central nervous system (CNS).This study tried to locate the CNS neuronal elements involved in the innervation ofC7 spinal nerve.Method: Pseudorabies virus (PRV, TK/gG-,2 μl), which expressed green fluorescent protein (GFP), was injected into the left C7 spinal nerve in 20 adult Sprague Dawley rats.After rats survived for 6 h, 12 h, 24 h and 36 h, the C1-C7segments of the spinal cord and brain were processed using a polyclonal immunohistochemical antibody against PRV.Results: PRV-labeled neurons were found mainly in gray matter of the C1-C7 segments of the spinal cord and at the following structures of the brain: lateral vestibular nucleus, lateral paragigantocellular nucleus, A5 cells, red nucleus, primary and secondary motor cortexes, primary and secondary somatosensory cortexes. Although located bilaterally, the PRV-labeled neurons existed predominantly in the ipsilateral side of the spinal cord and the contralateral side of the brain at 6-12 h after injection (p.i.). The number of PRV-labeled neurons in the CNS was increasing with rat's survival time and the distribution of these neurons turned bilateral with no obvious dominance to either side at 24 h and 36 h (p.i.).Conclusion: By use of transsynaptic tracing technique with PRV, the anatomically connected set of neurons,which modulates the activity of C7 spinal nerve, is located successfully in the CNS.

  11. Differential effects in CGRPergic, nitrergic, and VIPergic myenteric innervation in diabetic rats supplemented with 2% L-glutamine

    Directory of Open Access Journals (Sweden)

    RENATA V.F. PEREIRA

    2016-01-01

    Full Text Available ABSTRACT The objective of this study was to investigate the effects of 2% L-glutamine supplementation on myenteric innervation in the ileum of diabetic rats, grouped as follows: normoglycemic (N; normoglycemic supplemented with L-glutamine (NG; diabetic (D; and diabetic supplemented with L-glutamine (DG. The ileums were subjected to immunohistochemical techniques to localize neurons immunoreactive to HuC/D protein (HuC/D-IR and neuronal nitric oxide synthase enzyme (nNOS-IR and to analyze varicosities immunoreactive to vasoactive intestinal polypeptide (VIP-IR and calcitonin gene-related peptide (CGRP-IR. L-Glutamine in the DG group (i prevented the increase in the cell body area of nNOS-IR neurons, (ii prevented the increase in the area of VIP-IR varicosities, (iii did not prevent the loss of HuC/D-IR and nNOS-IR neurons per ganglion, and (iv reduced the size of CGRP-IR varicosities. L-Glutamine in the NG group reduced (i the number of HuC/D-IR and nNOS-IR neurons per ganglion, (ii the cell body area of nNOS-IR neurons, and (iii the size of VIP-IR and CGRP-IR varicosities. 2% L-glutamine supplementation exerted differential neuroprotective effects in experimental diabetes neuropathy that depended on the type of neurotransmitter analyzed. However, the effects of this dose of L-glutamine on normoglycemic animals suggests there are additional actions of this beyond its antioxidant capacity.

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

    DEFF Research Database (Denmark)

    Rasmussen, Ditte B; Jensen, Katrine Fogsgaard; Røntved, Christine M.;

    2011-01-01

    Mastitis is a high incidence disease in dairy cows. The acute stage is considered painful and inflammation can lead to hyperalgesia and thereby contribute to decreased welfare. The aim of this study was to examine changes in nociceptive responses toward cutaneous nociceptive laser stimulation (NLS...

  13. Somatosensory and nociceptive changes in chronic post-stroke shoulder pain

    NARCIS (Netherlands)

    Roosink, M.; Renzenbrink, G.J.; Buitenweg, Jan R.; Van Dongen, R.T.M.; Geurts, A.C.H.; IJzerman, Maarten Joost; Engbersen, Johannes F.J.; Engelbersen, J.F.J.; Koopman, Hubertus F.J.M.; Kanger, Johannes S.

    2008-01-01

    Preliminary results from a cross-sectional study that investigated the relation between the presence of post-stroke shoulder pain and somatosensory and nociceptive changes are presented. The main finding is that both abnormal somatosensation and nociception are more frequently observed in stroke

  14. Nociception affects motor output: a review on sensory-motor interaction with focus on clinical implications.

    NARCIS (Netherlands)

    Nijs, J.; Daenen, L.; Cras, P.; Struyf, F.; Roussel, N.; Oostendorp, R.A.B.

    2012-01-01

    OBJECTIVES: Research has provided us with an increased understanding of nociception-motor interaction. Nociception-motor interaction is most often processed without conscious thoughts. Hence, in many cases neither patients nor clinicians are aware of the interaction. It is aimed at reviewing the sci

  15. Dependence of nociceptive detection thresholds on physiological parameters and capsaicin-induced neuroplasticity: a computational study

    NARCIS (Netherlands)

    Yang, Huan; Meijer, Hil G.E.; Doll, Robert J.; Buitenweg, Jan R.; Gils, van Stephan A.

    2016-01-01

    Physiological properties of peripheral and central nociceptive subsystems can be altered over time due to medical interventions. The effective change for the whole nociceptive system can be reflected in changes of psychophysical characteristics, e.g., detection thresholds. However, it is challenging

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

    African Journals Online (AJOL)

    produced a marked anti-nociceptive activity in mice, and pretreatment with naloxone did not reverse the anti-nociceptive ... cyclooxygenase-2 (COX-2) rabbit monoclonal. IgG and ... Table 1: Orthogonal experiment design (four factors and three levels). Factor. A .... Antibodies directed against β-actin were used to normalize ...

  17. Bidirectional modulation of hyperalgesia via the specific control of excitatory and inhibitory neuronal activity in the ACC

    OpenAIRE

    Kang, SukJae Joshua; Kwak, Chuljung; Lee, Jaejyun; Sim, Su-Eon; Shim, Jaehoon; Choi, Taehyuk; Graham L. Collingridge; Zhou, Min; Kaang, B-K

    2015-01-01

    Neurons in the anterior cingulate cortex (ACC) are assumed to play important roles in the perception of nociceptive signals and the associated emotional responses. However, the neuronal types within the ACC that mediate these functions are poorly understood. In the present study, we used optogenetic techniques to selectively modulate excitatory pyramidal neurons and inhibitory interneurons in the ACC and to assess their ability to modulate peripheral mechanical hypersensitivity in freely movi...

  18. Structural studies of innervation on nonpregnant rat uterus.

    Science.gov (United States)

    Garfield, R E

    1986-07-01

    Whole-mount preparations of the uterus and mesentery from nonpregnant rats were examined after staining with glyoxylic acid or acetylcholinesterase to demonstrate the innervation. Some uterine tissues were also evaluated by electron microscopy. Glyoxylic acid fluorescent nerves were present in the mesentery, mesometrium, and uterine wall exclusively around blood vessels. Acetylcholinesterase positive nerve fibers from Frankenhäuser's plexus (cervical ganglia) were associated with blood vessels and muscle in the uterine wall but not in the mesentery. Electron microscopy revealed nerve varicosities with granular vesicles associated with blood vessels and varicosities with agranular vesicles located near blood vessels and muscle cells. Treatment of animals for 3 days with 5- and 6-hydroxydopamine, respectively, increased granular size and damaged the varicosities with granular vesicles but did not change nerves with agranular vesicles or induce the presence of gap junctions. The results of this study suggest that blood vessels in the uterus are highly innervated by both adrenergic and other types of nerves that probably control blood flow. Nonadrenergic but not adrenergic nerves may also directly control myometrial contractility.

  19. [Microscopic innervation and vascularization of the tongue. General study].

    Science.gov (United States)

    Fuentes, A; Sanchiz, O

    1992-01-01

    Our study deals with 23 prenatal human tongues, and a comparative study was carried out on one neonatal tongue and a few human and animal postnatal tongues. Sagittal and coronal sections were stained with various techniques. After the 7th week, the development of the nerves and their relationships with the neighboring structures can be observed. There are very few capillaries making up the superficial vascular network under the epithelium. The vessels whose walls are beginning to develop include the future red blood cells with their basophilic nuclei. During the whole process of evolution, there is a tight correlation between the collagen fibers and the neighboring structures. The innervation and vascularization--the latter with changes in the vascular walls--progressively increase. A short time before birth, the nerve fibers include their characteristic components, except for the Schmidt-Lantermann fissures. A considerable innervation advances towards the papillae, and anterior and posterior nerve networks enter the papillae, whose connective tissue includes groups of corpuscles on serial sections.

  20. Ontogeny of innervation of rat and ovine fetal adrenals.

    Science.gov (United States)

    Engeland, W C; Wotus, C; Rose, J C

    1998-01-01

    The formation of adrenocortical zonation occurs in rats during late gestation. Since adult cortical function is modulated by neural mediators, it is possible that the development of differentiated function is dependent on cortical innervation. The goal of this study was to compare the pattern and timing of rodent and ovine adrenal innervation during late organogenesis by staining with antibodies directed against the neuropeptides vasoactive intestinal peptide (VIP), calcitonin gene-related peptide (CGRP) and neuropeptide tyrosine (NPY) and the catecholamine biosynthetic enzyme, tyrosine hydroxylase (TOH). Rat adrenals were collected from fetal days 17-21 (term=21 da