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

Experimental glutamate and capsaicin-induced pain has not been described in tendon tissue despite the implications of addressing these receptors in pain management strategies. This study investigated pain induction and modulatory interactions by injecting glutamate (0.5 ml, 1 M) and capsaicin (0.5 ml, 5 microg, 33 microM) to human tendon tissue. Following the initial glutamate or capsaicin injection, a second injection of either glutamate (following capsaicin), capsaicin (following glutamate) or hypertonic saline (after both glutamate and capsaicin) was given. Twelve male volunteers participated. Subjects had four sequences of injections to tibialis anterior tendon over two sessions 1 week apart. Pain intensity responses were scored on a visual analogue scale (VAS). Pressure pain thresholds (PPTs) were assessed before, during and after pain induction. Capsaicin caused significantly higher peak pain scores compared to glutamate (P < 0.003) whilst glutamate pain was of significantly longer duration (P < 0.0003). Capsaicin following glutamate resulted in significantly higher average VAS scores 180-450 s after injection compared to capsaicin as primary injection (P < 0.05). PPTs were significantly reduced during capsaicin pain (72 +/- 5 and 80 +/- 6% of pre-pain values at the injection site and 2 cm proximal, P < 0.002). Following capsaicin, hypertonic saline and glutamate showed significant reductions in PPT at the same sites and to a similar degree compared to baseline (P < 0.002). The results indicate in tendon tissue a facilitation of response to capsaicin injection following glutamate injection. PPTs were only reliably reduced by capsaicin injection. These results emphasize the possible importance of peripheral glutamate receptor antagonists in pain management in musculoskeletal conditions.
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PMID:Glutamate and capsaicin-induced pain, hyperalgesia and modulatory interactions in human tendon tissue. 1913 65

Cytokines are pluripotent soluble proteins secreted by immune and glial cells and are key elements in the induction and maintenance of pain. They are categorized as pro-inflammatory cytokines, which are mostly algesic, and anti-inflammatory cytokines, which have analgesic properties. Progress has been made in understanding the mechanisms underlying the action of cytokines in pain. To date, several direct and indirect pathways are known that link cytokines with nociception or hyperalgesia. Cytokines may act via specific cytokine receptors inducing downstream signal transduction cascades, which then modulate the function of other receptors like the ionotropic glutamate receptor, the transient vanilloid receptors, or sodium channels. This receptor activation, either through amplification of the inflammatory reaction, or through direct modulation of ion channel currents, then results in pain sensation. Following up on results from animal experiments, cytokine profiles have recently been investigated in human pain states. An imbalance of pro- and anti-inflammatory cytokine expression may be of importance for individual pain susceptibility. Individual cytokine profiles may be of diagnostic importance in chronic pain states, and, in the future, might guide the choice of treatment.
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PMID:Mode of action of cytokines on nociceptive neurons. 1929 May 16

Although the postsynaptic events responsible for development of pathological pain have been intensively studied, the relative contribution of presynaptic neurotransmitters to the whole process remains less elucidated. In the present investigation, we sought to measure temporal changes in spinal release of both excitatory amino acids (EAAs, glutamate and aspartate) and inhibitory amino acids (IAAs, glycine, ?-aminobutyric acid and taurine) in response to peripheral inflammatory pain state. The results showed that following peripheral chemical insult induced by subcutaneous bee venom (BV) injection, there was an initial, parallel increase in spinal release of both EAAs and IAAs, however, the balance between them was gradually disrupted when pain persisted longer, with EAAs remaining at higher level but IAAs at a level below the baseline. Moreover, the EAAs-IAAs imbalance at the spinal level was dependent upon the ongoing activity from the peripheral injury site. Intrathecal blockade of ionotropic (NMDA and non-NMDA) and metabotropic (mGluRI, II, III) glutamate receptors, respectively, resulted in a differential inhibition of BV-induced different types of pain (persistent nociception vs. hyperalgesia, or thermal vs. mechanical hyperalgesia), implicating that spinal antagonism of any specific glutamate receptor subtype fails to block all types of pain-related behaviors. This result provides a new line of evidence emphasizing an importance of restoration of EAAs-IAAs balance at the spinal level to prevent persistence or chronicity of pain.
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PMID:Imbalance between excitatory and inhibitory amino acids at spinal level is associated with maintenance of persistent pain-related behaviors. 1941 28

Metabotropic glutamate receptor (mGluR) 2/3 is distributed in neurons and glial cells in many regions of the nervous system, but its role in nociceptive processing is unclear. In this study, we examined the mRNA expressions of mGluR2 and mGluR3, by real-time RT-PCR, in the spinal cord. We further investigated the possible involvement of mGluR2/3 and mechanisms underlying peripheral inflammatory pain induced by subcutaneous complete Freund's adjuvant (CFA) injection. We demonstrate that compared to the controls, the mRNA expression levels of mGluR2 and mGluR3 were significantly higher 4h after CFA injection. Functionally, blocking mGluR2/3 by their antagonist (2S)-2-amino-2-[(1S, 2S)-2-carboxycycloprop-1-yl]-3-(xanth-9-yl) propanoic acid (LY341495) alleviated the CFA-induced mechanical allodynia and the inhibitory effects were reversed by mGluR2/3 agonist (2R, 4R)-4-aminopyrrolidine-2,4-dicarboxylate ((2R, 4R)-APDC). In addition, a glial metabolism inhibitor dl-fluorocitric acid barium salt (fluorocitric acid) also inhibited the CFA-induced mechanical allodynia in a dose-dependent manner. Remarkably, simultaneous inhibition of mGluR2/3 and glial metabolism had synergistic effects. The co-administration of LY341495 and fluorocitric acid with minimal dosages produced significant more inhibition than the additive effects by the individual inhibitor alone. In summary, our data suggest that spinal mGluR2/3 contributes to the generation of mechanical allodynia induced by peripheral inflammation. We also suggest that involvement of mGluR2/3 in the communication between glial cells and neurons takes part in the processing of nociceptive information.
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PMID:Antinociceptive synergistic effect of spinal mGluR2/3 antagonist and glial cells inhibitor on peripheral inflammation-induced mechanical hypersensitivity. 1942 93

Metabotropic glutamate receptor subtype 5 (mGlu5) has been demonstrated to play a role in the modulation of numerous nociceptive modalities. When administered via peripheral, intrathecal, or systemic routes, mGlu5 antagonists have analgesic properties in a variety of preclinical pain models. Despite a wealth of data supporting the use of mGlu5 antagonists to treat pain, studies have been limited to preclinical animal models due to a lack of mGlu5 antagonists that are approved for use in humans. It has been demonstrated previously that fenobam [N-(3-chlorophenyl)-N'-(4,5-dihydro-1-methyl-4-oxo-1H-imidazole-2-yl)urea], an anxiolytic shown to be safe and effective in human trials, is a selective and potent noncompetitive antagonist of mGlu5 (J Pharmacol Exp Ther 315:711-721, 2005). Here, we report a series of studies aimed at testing whether fenobam, similar to the prototypical mGlu5 antagonist 2-methyl-6-(phenylethynyl)-pyridine (MPEP), has analgesic properties in mice. We show that fenobam reduces formalin-induced pain behaviors and relieves established inflammation-induced thermal hypersensitivity in mice. Similar results were seen with MPEP. Administration of fenobam resulted in an increase in locomotor activity in the open-field task but did not impair performance on the accelerating Rotarod. Analysis of brain and plasma fenobam levels indicated that fenobam is rapidly concentrated in brain after intraperitoneal administration in mice but is essentially cleared from circulation within 1 h after injection. Fenobam had no analgesic effect in mGlu5 knockout mice, whereas the prototypical antagonist MPEP retained significant analgesic efficacy in mGlu5 knockouts. These results demonstrate that fenobam is analgesic in mice and has an improved in vivo selectivity for mGlu5 over MPEP.
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PMID:The metabotropic glutamate receptor subtype 5 antagonist fenobam is analgesic and has improved in vivo selectivity compared with the prototypical antagonist 2-methyl-6-(phenylethynyl)-pyridine. 1951 68

Electrophysiological investigations of the spinal cord in animals have shown that pain sensitizes the central nervous system via glutamate receptor dependent long-term potentiation (LTP) related to an enhancement of pain perception. To expand these findings, we used functional magnetic resonance (fMRI), blood oxygen level dependent (BOLD) and perfusion imaging in combination with repeated electrical stimulation in humans. Specifically we monitored modulation of somatosensory processing during inhibition of excitatory transmission by ocular application of the glutamate receptor antagonist xenon. BOLD responses upon secondary stimulation increased in mid insular and in primary/secondary sensory cortices under placebo and decreased under xenon treatments. Xenon-induced decreases in regional perfusion were confined to stimulation responsive brain regions and correlated with time courses of xenon concentrations in the cranial blood. Moreover, effects of xenon on behavioral, fMRI and perfusion data scaled with stimulus intensity. The dependence of pain sensitization on sufficient pre-activation reflects a multistage process which is characteristic for glutamate receptor related processes of LTP. This study demonstrates how LTP related processes known from the cellular level can be investigated at the brain systems level.
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PMID:Xenon-induced changes in CNS sensitization to pain. 1970 72

The substantia gelatinosa (SG) of the trigeminal subnucleus caudalis (Vc) receives many thin-myelinated Adelta-fiber and unmyelinated C primary afferent fibers and has been implicated in the processing of nociceptive information. Somatostatin (SST) is a neuromodulator in the brain and spinal cord. A number of studies have demonstrated that SST can play a key role in pain modulation at the spinal cord level. However, there is little information available on functional SST receptor expression in the SG neurons of the Vc in mice. This study examined the direct membrane effects of SST and SST receptor type 2 agonist, seglitide (SEG) on the SG neurons of Vc in gramicidin perforated current clamp mode. In addition, SSTR2 mRNA expression was detected on the SG neurons using single cell RT-PCR in juvenile mice. Most SG neurons (37/68, 54%) were hyperpolarized after a bath application of SST. When SST was applied in stages, the second responses (83% of the first response) were less intense than those after the first application suggesting that SSTRs are desensitized by repeated application. The SST-induced hyperpolarizing response was maintained in the presence of TTX (Na(+) channel blocker), AP-5 (NMDA receptor antagonist), CNQX (non-NMDA glutamate receptor antagonist), picrotoxin (GABA(A) receptor antagonist) and strychnine (glycine receptor antagonist), respectively, suggesting that SST has direct effects on the postsynaptic SG neurons. SSTR2 mRNA was detected in 11 out of 28 (39%) SG neurons tested. The SST-induced hyperpolarizing effects were mimicked by SEG, a SSTR2 agonist. These results suggest that functional SSTR2 receptors are expressed on the SG neurons of Vc in juvenile mice and can be a potential target for modulating orofacial pain.
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PMID:Inhibitory effects of somatostatin on the substantia gelatinosa neurons of trigeminal subnucleus caudalis via somatostatin type 2 receptors in juvenile mice. 1978 64

The antinociceptive effects of honokiol and magnolol, two major bioactive constituents of the bark of Magnolia officinalis, were investigated on animal paw licking responses and thermal hyperalgesia induced by glutamate receptor agonists including glutamate, N-methyl-D-aspartate (NMDA), and metabotropic glutamate 5 receptor (mGluR5) activator (RS)-2-chloro-5-hydroxyphenylglycine (CHPG), as well as inflammatory mediators such as substance P and prostaglandin E2 (PGE2) in mice. The actions of honokiol and magnolol on glutamate-induced c-Fos expression in the spinal cord dorsal horn were also examined. Our data showed that honokiol and magnolol blocked glutamate-, substance P- and PGE2-induced inflammatory pain with similar potency and efficacy. Consistently, honokiol and magnolol significantly decreased glutamate-induced c-Fos protein expression in superficial (I-II) laminae of the L4-L5 lumbar dorsal horn. However, honokiol was more selective than magnolol for inhibition of NMDA-induced licking behavioral and thermal hyperalgesia. In contrast, magnolol was more potent to block CHPG-mediated thermal hyperalgesia. These results demonstrate that honokiol and magnolol effectively decreased the inflammatory pain. Furthermore, their different potency on inhibition of nociception provoked by NMDA receptor and mGluR5 activation should be considered.
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PMID:Antinociceptive actions of honokiol and magnolol on glutamatergic and inflammatory pain. 1983 97

Frequency-following responses (FFRs) are sustained potentials based on phase-locked neural activities elicited by low- to medium-frequency periodical sound waveforms. Human brainstem FFRs, which are able to encode some critical acoustic features of speech, can be unmasked by binaural processing. However, the underlying unmasking mechanisms have not previously been reported. In rats, most neurons in the inferior colliculus (IC) exhibit binaural responses which are affected by axonal projections from both the contralateral dorsal nucleus of the lateral lemniscus (DNLL) and the contralateral IC. The present study investigated whether the contralateral DNLL and the contralateral IC modulate binaural unmasking of FFRs recorded in the rat IC. The results show that IC FFRs to the rat pain call (chatter) were enhanced by local injection of the excitatory glutamate receptor antagonist kynurenic acid (KYNA) into the contralateral DNLL but were reduced by KYNA injection into the contralateral IC. Introducing a disparity between the interaural time difference (ITD) of the FFR-eliciting chatter and the ITD of the masking noise enhanced IC FFRs. Moreover, the ITD-disparity-induced FFR enhancement was weakened by injection of KYNA into either the contralateral DNLL or the contralateral IC when the ipsilateral chatter preceded the contralateral chatter. Thus, binaural hearing can improve IC FFRs against noise masking. More importantly, both inhibitory projections from the contralateral DNLL and excitatory projections from the contralateral IC modulate IC FFRs and play a role in forming binaural unmasking of IC FFRs.
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PMID:Two crossed axonal projections contribute to binaural unmasking of frequency-following responses in rat inferior colliculus. 1984 Jan 11

Inflammation causes sensitization of peripheral and central nociceptive neurons. Pharmacological modulation of the latter has successfully been used for clinical pain relief. In particular, inhibitors of the NMDA glutamate receptor such as ketamine and agonists at the mu-opioid receptor such as morphine are broadly used. Besides driving the propagation of pain signals, spinal mechanisms are also discussed to modulate inflammation in the periphery. Here, we tested the hypothesis that intrathecally applied ketamine or morphine not only reduce pain-related behavior, but also attenuate induction and maintenance of the inflammatory response in a model of chronic antigen-induced arthritis (AIA). Ketamine, morphine or vehicle was applied to the spinal cords of anesthesized animals with AIA. Swelling and histopathological changes were assessed after 6h (acute phase). Intrathecal catheters were implanted in another set of animals with AIA and substances were applied continuously. During the observation period of 21 days, inflammation and pain-related behavior were assessed. Ketamine and morphine significantly reduced arthritis severity as indicated by reduced joint swelling, but even more intriguingly by reduced infiltration with inflammatory cells and joint destruction in the acute and the chronic phase of arthritis. Morphine showed strong antinociceptive effects in the acute phase only, while the newly established effective dose for ketamine in a continuous application design reduced hyperalgesia in the acute and the chronic stage. In conclusion, both compounds exhibit anti-inflammatory effects during induction and maintenance of arthritis when applied intrathecally. These data thus propose a role of spinal NMDA- and opioid-receptors in the neuronal control of immune-mediated inflammation.
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PMID:Spinally applied ketamine or morphine attenuate peripheral inflammation and hyperalgesia in acute and chronic phases of experimental arthritis. 2000


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