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Query: UMLS:C0030193 (pain)
 261,466 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Recent data support a role for nitric oxide (NO) in pain processing at the level of the spinal cord, possibly via regulation of neuropeptide release. The goal of this study was to determine whether capsaicin, which selectively activates primary afferent neurons and evokes neuropeptide release, acts in an NO-dependent manner. Our results indicate that capsaicin (1 microM)-evoked release of immunoreactive calcitonin gene-related peptide (iCGRP) is significantly reduced in the presence of the NO synthase inhibitor, L-NAME (10-400 nM; F(3,45)=68.38; P<0.001) and, the selective nNOS inhibitor, 3-bromo-7-nitroindazole (170-680 nM; F(5,48)=56.2; P<0. 01). D-NAME (200 nM) had no effect on capsaicin-evoked iCGRP release. Hemoglobin (an extracellular scavenger of NO; 3 mg/ml) significantly reduced the effect of capsaicin on the release of iCGRP (F(1,8)=9.12; P<0.05). The NOS substrate, L-arginine, effectively reversed the inhibitory effect of 3-bromo-7-nitroindazole on capsaicin-evoked iCGRP release. To determine whether the NO-mediated release was NMDA-driven, we superfused spinal cord slices with competitive and non-competitive NMDA antagonists in the presence and absence of capsaicin. MK-801 (0. 1-10 microM; F(4,33)=8.49; P<0.0001) and AP-5 (0.01-10 microM; F(4, 38)=3.34; P<0.05) reduced capsaicin-evoked iCGRP release. CNQX, an AMPA/kainate antagonist (10 nM-10 microM), significantly decreased capsaicin-evoked release of iCGRP (F(6,42)=8.76; P<0.01) in a dose-dependent fashion. Additionally, our results demonstrate that while capsaicin-evoked release is significantly reduced in the presence of LY-83583 (10 microM; F(2,18)=3.46; P<0.01; a cyclic GMP lowering agent), there is no effect of ODQ (a potent and selective inhibitor of guanylate cyclase). Moreover, the application of a cell permeable analog of cyclic GMP (8-bromo-cGMP; 0.01-1000 microM) is without effect on both basal and evoked iCGRP release. Finally, we observed no colocalization of immunoreactive neuronal NOS (nNOS) with CGRP in the dorsal horn. In summary, these data indicate that capsaicin evokes the release of iCGRP, in part, via the production of NO which enters the extracellular space prior to having an effect. Moreover, iCGRP and nNOS are produced in distinct populations of neurons within the dorsal horn. We conclude that capsaicin-evoked release involves the activation of the NMDA receptor but is also modified by the activation of AMPA or kainate receptors. Finally, these data suggest that while capsaicin-evoked iCGRP release is modified by NO, this release does not require the activation of guanylate cyclase and subsequent production of cyclic GMP.
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PMID:Capsaicin-evoked release of immunoreactive calcitonin gene-related peptide from the spinal cord is mediated by nitric oxide but not by cyclic GMP. 1076 Apr 83

Musculoskeletal pain is one of the most frequent symptoms for which medical assistance is sought. Yet, the majority of our knowledge regarding pain physiology is based on studies of cutaneous tissue. Comparatively little is known about activation of visceral, joint and perhaps least of all, musculoskeletal nociceptors although clinically-treated pain originates principally in these structures. Studies elucidating the mechanisms of muscle hyperalgesia have been hampered by the lack of an animal model that permits the evaluation of hypotheses using behavioral, biochemical, pharmacological, anatomical and molecular experimental approaches. Here we describe an animal model of muscle hyperalgesia we recently developed that permits such multidisciplinary investigation. This model employs the intramuscular injection of carrageenan, a chemical stimulus which evokes a well recognized model of cutaneous inflammation and is reported to activate muscle nociceptors. Intramuscular carrageenan evokes a time- and dose-dependent reduction in forelimb grip force that is anatomically specific. The carrageenan-evoked reduction in grip force is blocked by the mu-opioid agonist levorphanol in a dose-dependent, stereoselective and naltrexone-reversible manner. This behavioral dependent measure is also significantly reversed by agents used clinically to treat muscle pain, indomethacin and dexamethasone, as well as the non-competitive N-methyl-D-aspartate receptor antagonist MK801. Finally, evidence that reduction in grip force is in part mediated by small, unmyelinated afferents is provided by the demonstration that neonatal capsaicin treatment significantly reduced carrageenan-evoked behavioral hyperalgesia ( approximately 45% reduction) and reduced muscle content of immunoreactive CGRP ( approximately 60% reduction) relative to control levels. Collectively, these findings provide converging lines of evidence for the validity of this animal model to investigate mechanisms involved in the development of muscle hyperalgesia.
Pain 2000 Apr
PMID:A new animal model for assessing mechanisms and management of muscle hyperalgesia. 1078 7

The pain message originates peripherally from a great variety of substances either released from preformed stores or extemporaneously synthetized. They stimulate or sensitize nociceptors which are associated with the peripheral endings of sensitive protoneurones. Their central endings release many types of transmitters in the dorsal horn of medulla (substance P, NO, CGRP.). At this level their release, triggered by the firing rate, is modulated by the stimulation of various presynaptic receptors operated by transmitters produced by either interneurones (enkephalins) or medullar descending neurons (dopamine, norepinephrine, serotonine). These modulations correspond to the so-called gate control. The sensitive consecutive neurones which climb towards various brain areas are submitted to contradictory influences. Several of them enhance the pain perception (nociceptin, cholecystokinin, neuropeptide FF.) whereas several other reduce it (endorphines, neurotensin, neuromedin N, anandamide.).
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PMID:[Pain and its main transmitters]. 1079 Jun

Inhibition of proinflammatory cytokines reduces hyperalgesia in animal models of painful neuropathy. We set out to investigate the consequences of this treatment for nerve regeneration. Here we examined the sequels of epineurial application of neutralizing antibodies to tumor necrosis factor-alpha (TNF) in chronic constriction injury (CCI) of the sciatic nerve in C57/BL 6 mice. The mice were tested behaviorally for manifestations of thermal hyperalgesia and mechanical allodynia. Nerve regeneration was assessed by morphometry of myelinated nerve fibers in the sciatic nerve and of the epidermal innervation density in the glabrous skin of the hindpaws. Antibodies to TNF reduced thermal hyperalgesia and mechanical allodynia after CCI. Myelinated fiber density in the sciatic nerve was reduced to 30% of normal on day 7 after surgery, and reached 60% on day 45, with no difference between antibody-treated and untreated animals. Epidermal innervation density as shown by PGP 9.5 and CGRP immunohistochemistry was reduced to 25-47% at both time points after CCI, again without differences between antibody treated and untreated mice. Myelinated fiber density but not epidermal innervation density was correlated to thermal and mechanical withdrawal thresholds. We conclude that neutralization of endoneurial TNF attenuates pain related behavior but has no effect on nerve regeneration. Furthermore, the number of epidermal nerve fibers is not relevant to the magnitude of behavioral hyperalgesia in CCI.
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PMID:Effects of neutralizing antibodies to TNF-alpha on pain-related behavior and nerve regeneration in mice with chronic constriction injury. 1082 76

Thalidomide reduces thermal hyperalgesia and mechanical allodynia in chronic constrictive sciatic nerve injury (CCI). Since thalidomide mainly inhibits tumor necrosis factor alpha (TNF-alpha) synthesis with less well defined effects on other cytokines, we investigated the effect of the drug on the expression of the proinflammatory cytokines TNF-alpha, interleukin-1beta (IL-1beta) and interleukin 6 (IL-6), and of the anti-inflammatory cytokine interleukin-10 (IL-10) in the lesioned rat sciatic nerve. The increase of endoneurial TNF-alpha during the first week after CCI was reduced after thalidomide treatment, as shown with immunohistochemistry and enzyme-linked-immunosorbent assay. In contrast, endoneurial IL-1beta-immunoreactivity (IR) and IL-6-IR were not altered by thalidomide treatment, nor was macrophage influx. Recruitment of epineurial IL-10 immunoreactive macrophages as well as the recovery of injury-induced depletion of endoneurial IL-10-IR was enhanced by thalidomide treatment. To control for central plasticity as another factor for the effects of thalidomide, the spinal cord was analyzed for changes in neurotransmitters. The decrease in CGRP-IR and SP-IR in the dorsal horn of operated animals was not influenced by treatment. In contrast, the increase in met-enkephalin observed in the dorsal horn of operated animals was further enhanced in the thalidomide-treated animals. The study elucidates some of the complex alterations in CCI and its modulation by thalidomide, and provides further evidence for a possible therapeutic benefit of cytokine-modulating substances in the treatment of neuropathic pain.
Pain 2000 Dec 01
PMID:Thalidomide treatment in chronic constrictive neuropathy decreases endoneurial tumor necrosis factor-alpha, increases interleukin-10 and has long-term effects on spinal cord dorsal horn met-enkephalin. 1106 14

The study of the mechanisms of action of the triptan group of drugs has largely contributed to the progress made in the understanding of the physiopathological processes that are possibly responsible for migraine. In this context, two discoveries have been especially important: 1) these anti-migraine drugs are specifically recognized by three main types of serotonin receptors (5-HT1B, 5-HT1D, and 5-HT1F); and 2) these receptors are present in the meninges, where they are expressed by both smooth muscle cells and/or endothelial cells of the vascular wall and/or the perivascular trigeminal to be deleted axon terminals. These two findings have led to the most currently accepted physiopathogenic hypothesis, whereby the migraine attack would start with an excitation of the perivascular trigeminal to be deleted fibers, which would then trigger the release of vasoactive peptides (substance P, calcitonin gene-related peptide/CGRP) within the dura mater. Locally, i.e., in the dura mater in particular, these substances can provoke vasodilatation (CGRP) and plasmatic extravasation (substance P) with platelet lysis and mast cell degranulation, thereby leading to the release of algogenic substances that excite the neighboring trigeminal fibers, and this neurogenic inflammatory response can progressivelly extend to the meninges as a whole. This reaction subsequently reaches the bulbar and thalamic nuclei and then the sensory cortex, where it is integrated and expressed as migraine pain. The aim of this article was to report the main findings on endogenous substances (serotonin, peptides, nitric oxide [NO], etc.) which appear to play a key role in this physiopathogenic sequence.
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PMID:[Role of serotonin and other neuroactive molecules in the physiopathogenesis of migraine. Current hypotheses]. 1107 40

Migraine attacks can be provoked by administration of nitroglycerin, suggesting a role for nitric oxide (NO). The fact that release of the neuropeptide CGRP from trigeminal sensory nerves occurs during the pain phase of migraine and that NO can augment transmitter release prompted us to study CGRP release from the in situ dura mater in guinea pig skulls. Release of CGRP by capsaicin or by high potassium concentration was concentration-dependent and counteracted in calcium-free medium. The anti-migraine compound, sumatriptan, inhibited CGRP release via the 5-HT1-receptor. The NO donors, nitroglycerin, sodium nitroprusside and S-nitroso-N-acetylpenicillamine did not influence CGRP release, alone or together with the stimulants. We concluded that the skull preparation is well suited for scrutinizing CGRP release from dura mater. The fact that sumatriptan inhibits CGRP release as in migraine patients suggests a use for the present preparation in headache research.
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PMID:Release of calcitonin gene-related peptide (CGRP) from guinea pig dura mater in vitro is inhibited by sumatriptan but unaffected by nitric oxide. 1116 15

We tested the hypothesis that the decrease in spinal levels of SP and CGRP after peripheral nerve injury is related to neuropathic pain. We compared two groups of rats, both of which were subjected to unilateral transection of the inferior and superior caudal trunks between the S1 and S2 spinal nerves. One group exhibited well-developed neuropathic signs after the nerve injury, whereas the other group showed poorly developed signs despite the same nerve injury. The decrease in immunoreactivity of CGRP and SP in the S1 dorsal horn (injured segment) was not significantly different between the two groups. These results suggest that the decrease in spinal levels of CGRP and SP after peripheral nerve injury is not related to neuropathic pain.
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PMID:Decrease in spinal CGRP and substance P is not related to neuropathic pain in a rat model. 1120 Oct 82

The neuropeptide alpha CGRP (calcitonin gene-related peptide) is involved in the complex process of pain signaling, but the precise contribution of alpha CGRP remains unclear. Here we show that mice lacking alpha CGRP display an attenuated response to chemical pain and inflammation. Furthermore, alpha CGRP(-/-) mice do not show changes in heroin self-administration or morphine tolerance, but display a marked decrease in morphine withdrawal signs, suggesting an important contribution of alpha CGRP to opiate withdrawal.
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PMID:Altered neuroadaptation in opiate dependence and neurogenic inflammatory nociception in alpha CGRP-deficient mice. 1127 24

Animal models for human chronic pain syndromes have been developed and widely used for pain research. One of these neuropathic pain models by Kim and Chung (1992) has many advantages for operation and pain elicitation. In this neuropathic model we have examined the c-fos protein, substance P, CGRP immunoreactivity in dorsal root ganglia and dorsal horn. 50 Sprague-Dawley rats were used for this study. L5 and L6 spinal nerves were ligated tightly to produce the neuropathic pain model. After 2, 4, 8, 16, and 24 hours and 1 week of surgery, rats were anesthetized and sacrificed by perfusion. After confirmation of the roots transected by the surgery, the L5 and L6 dorsal root ganglions and spinal cord were removed and processed for immunohistochemistry. All tissue sections were immunohistochemically stained for substance P, CGRP and c-fos using the peroxidase-antiperoxidase (PAP) method. The number of immunostained substance P and CGRP dorsal root ganglion cells and c-fos immunoreactive dorsal horn cells were counted and analyzed statistically with Mann-Whitney U test. The results are as follows. The number of c-fos protein immunoreactive neurons in the superficial layer of dorsal horn were increased markedly 2 hours after operation, and gradually decreased to normal level 1 week after operation. The number of c-fos protein immunoreactive neurons in the deep layer of the dorsal horn gradually increased to a peak 24 hours after operation, then decreased to the normal level 1 week after operation. The number of substance P and CGRP immunoreactive L5 and L6 dorsal root ganglion neurons were decreased markedly 1 week after the pain model operation. In conclusion, after neuropathic pain model operation, c-fos proteins were immediately expressed in the superficial layer of spinal dorsal horn, thereafter c-fos proteins in the deep layer of spinal dorsal horn were expressed. CGRP and substance P immunoreactive neurons in DRG were decreased markedly 1 week after neuropathic pain model operation. These decrements do not coincide with the other chronic pain models, which show great increases in these pain transmitting substances. Therefore, the relationship between pain and c-fos, SP and CGRP should be investigated further.
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PMID:Studies on the changes of c-fos protein in spinal cord and neurotransmitter in dorsal root ganglion of the rat with an experimental peripheral neuropathy. 1129 99


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