Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0030193 (pain)
 261,466 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Intrathecal pretreatment with N-methyl-D-aspartate (NMDA) receptor antagonists blocks development of spinal sensitization in a number of pain models. In contrast, secondary mechanical allodynia evoked by thermal injury (52.5 degrees C for 45 s) applied to the hind paw of the rat is not blocked by intrathecal pretreatment with NMDA receptor antagonists. It is, however, blocked by antagonists to the non-NMDA, alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid/kainate (AMPA/KA) and calcium-permeable AMPA/KA receptors. These findings suggest a role for these receptors in the development of spinal sensitization. The present study used the same thermal injury model to assess the effects of the AMPA/KA receptor antagonist 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX) and specific calcium-permeable AMPA/KA receptor antagonists philanthotoxin (PHTx) and joro spider toxin (JST) when given as postinjury treatments. Intrathecal saline injection at 5 and 30 min postinjury had no effect on thermal injury-evoked allodynia as measured by calibrated von Frey filaments. In contrast, 36 nmol of CNQX given at either time point reversed allodynia. Intrathecal 13 nmol of PHTx or 9 nmol of JST (higher doses than that required for pretreatment) reversed allodynia at the 5-min time point, but neither drug was antiallodynic at the 30-min time point. Thus, secondary mechanical allodynia in this model is not maintained by calcium-permeable AMPA/KA receptors, but instead requires activation of calcium-impermeable AMPA/KA receptors. This finding supports a role for AMPA/KA receptor function in responses occurring during spinal sensitization.
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PMID:Calcium-permeable alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid/kainate receptors mediate development, but not maintenance, of secondary allodynia evoked by first-degree burn in the rat. 1500 1

Neuropathic pain is often resistant to opioids, so other medication classes, such as tricyclic antidepressants, anticonvulsants, and local anesthetics, are often used. Central sensitization, or pain 'wind-up', may perpetuate chronic neuropathic pain even when ongoing peripheral sensory input is absent. Wind-up is thought to cause allodynia, hyperalgesia, and hyperpathia. Receptors such as NMDA, AMPA, and M-glu have recently been identified for their role in central sensitization or pain 'wind-up'. Ketamine has been proposed recently for neuropathic pain secondary to its NMDA receptor activity. The current application as a topical gel stems from the theory that ketamine has peripheral action at both opioid and Na+-K+ channels. This case study involved 5 patients from 25 to 70 years old (3 RSD, 1 lumbar radiculopathy, 1 post-herpetic neuralgia). Dose used was determined by site and surface area of involvement and ranged from 0.093 mg/kg to 9.33 mg/kg. All five patients reported significant pain relief at initial application and wished to continue treatment. The average numerical analogue scale (NAS) score preapplication was 8.8. The average 15 minutes post application NAS was 1.6. Patients reported alterations in temperature sensation, feelings of relaxation and decreased tension in the area of application, and pain relief. Reduction in numerical pain scores postapplication of ketamine gel ranged from 53-100% using a 1-10 numerical pain intensity scale. No significant side effects were reported. Ketamine Gel may provide clinicians with a new option in the battle against chronic neuropathic pain. Until further information is available and larger trials can be conducted, we can only recommend this type of therapy for refractory cases in which all primary and secondary options have been exhausted.
Pain Med 2000 Mar
PMID:Topical ketamine gel: possible role in treating neuropathic pain. 1510 68

Lamina I of the spinal cord plays a key role in sensory transmission between afferent activity and the CNS. Studies have shown lamina I neurones to have distinct response properties compared to deep dorsal horn neurones, but little is known regarding excitatory amino acid mechanisms in their responses. Spinal electrophysiological recordings of lamina I neurones confirmed that the majority of these neurones (74%) are nociceptive specific (NS) in their responses, of which 18% can be termed polymodal nociceptive (HPC) (13% of the total population). The remainder (26%) were wide dynamic range. Lamina I neurones had smaller mechanical and heat-evoked responses compared to deeper dorsal horn neurones. The electrically evoked responses were also smaller, with a distinct lack of an NMDA-mediated 'wind-up' effect. NBQX (AMPA receptor antagonist, 0.5, 5, 50 microg/50 microl) produced dose-dependent inhibitions of the electrically evoked neuronal responses, but APV (NMDA receptor antagonist, 50, 100, 500 microg/50 microl) had minimal effects on their responses. These results implicate mainly AMPA receptors in the responses of lamina I neurones. Bicuculline (GABA(A) receptor antagonist, 0.5, 5, 50 microg/50 microl) demonstrated a role exerted by GABA(A) receptors in the control of A-delta fibre-mediated mechanical responses in lamina I. Overall, this study describes a high threshold, AMPA receptor possessing population of lamina I neurones, which seem to lack functional NMDA receptors, and are partially controlled by GABA(A) receptor activity.
Pain 2004 Mar
PMID:Electrophysiological characterisations of rat lamina I dorsal horn neurones and the involvement of excitatory amino acid receptors. 1510 10

The periaqueductal gray matter and the rostral ventromedial medulla (RVM), with its projections to the spinal dorsal horn, constitute the efferent channel of the 'descending pain-control system'. Noxious stimulation of a peripheral tissue causes more pain if this tissue is inflamed (primary hyperalgesia). In such cases, stimulation of neighboring but uninflamed tissues also becomes more painful (secondary hyperalgesia). In animal models of inflammation, the descending pain-control system sends down, simultaneously, inhibitory and facilitatory influences, but inhibition predominates for primary hyperalgesia while facilitation predominates for secondary hyperalgesia. Descending inhibition and facilitation during peripheral inflammation are due not only to previously existing descending modulation, but also to inflammation-induced changes in RVM which involve receptors for NMDA, AMPA, cholecystokinin and neurotensin, as well as synthesis of enkephalins and nitric oxide.
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PMID:To the descending pain-control system in rats, inflammation-induced primary and secondary hyperalgesia are two different things. 1513 34

1. Ingestion of a poisonous mushroom Clitocybe acromelalga is known to cause severe tactile pain (allodynia) in the extremities for a month and acromelic acid (ACRO), a kainate analogue isolated from the mushroom, produces selective damage of interneurons of the rat lower spinal cord when injected either systemically or intrathecally. Since ACRO has two isomers, ACRO-A and ACRO-B, here we examined their acute and late effects on induction of allodynia. 2. Intrathecal administration of ACRO-A and ACRO-B provoked marked allodynia by the first stimulus 5 min after injection, which lasted over the 50-min experimental period. Dose-dependency of the acute effect of ACRO-A on induction of allodynia showed a bell-shaped pattern from 50 ag x kg(-1) to 0.5 pg x kg(-1) and the maximum effect was observed at 50 fg x kg(-1). On the other hand, ACRO-B induced allodynia in a dose-dependent manner from 50 pg x kg(-1) to 50 ng x kg(-1). 3. N-methyl-d-aspartate (NMDA) receptor antagonists and Joro spider toxin, a Ca(2+)-permeable AMPA receptor antagonist, inhibited the allodynia induced by ACRO-A, but not by ACRO-B. However, other AMPA/kainate antagonists did not affect the allodynia induced by ACRO. 4. Whereas no neuronal damage was observed in the spinal cord in ACRO-A-treated mice, induction of allodynia by ACRO-A (50 fg x kg(-1)) and ACRO-B (50 ng x kg(-1)) was selectively lost 1 week after i.t. injection of a sublethal dose of ACRO-A (50 ng x kg(-1)) or ACRO-B (250 ng x kg(-1)). Higher doses of ACRO-A, however, could evoke allodynia dose-dependently from 50 pg x kg(-1) to 500 ng x kg(-1) in the ACRO-A-treated mice. The allodynia induced by ACRO-A (500 ng x kg(-1)) was not inhibited by Joro spider toxin or NMDA receptor antagonists. These properties of the late allodynia induced by ACRO-A were quite similar to those of the acute allodynia induced by ACRO-B. 5. ACRO-A could increase [Ca(2+)](i) in the deeper laminae, rather than in the superficial laminae, of the spinal cord. This increase was not blocked by the AMPA-preferring antagonist GYKI52466 and Joro spider toxin. 6. Taken together, these results demonstrate the stereospecificity of ACRO for the induction of allodynia and suggest the presence of a receptor specific to ACRO.
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PMID:Acute and late effects on induction of allodynia by acromelic acid, a mushroom poison related structurally to kainic acid. 1515 82

The effects of systemic administration of the novel AMPA/GluR5 selective receptor antagonist NS1209 in animal models of experimental pain have been tested and compared with the AMPA receptor antagonist NBQX and the opiate morphine. In the mouse hot plate test, NS1209 (3-30 mg/kg, s.c. and i.p.) and morphine (3-30 mg/kg, s.c.) significantly increased the nociceptive response latency, whereas NBQX (3-30 mg/kg, i.p.) was ineffective. In the rat formalin test, a model of persistent pain, NS1209 (3 and 6 mg/kg, i.p.) and morphine (0.5 and 3 mg/kg, s.c.) produced dose-dependent reductions in second phase nociceptive behaviours, although NBQX (10 and 20 mg/kg, i.p.) was without effect. In the chronic constriction injury model of neuropathic pain, NS1209 (3 and 6 mg/kg, i.p.), NBQX (10 and 20 mg/kg, i.p.) and morphine (3 and 6 mg/kg, s.c.) all reduced mechanical allodynia and hyperalgesia responses to von Frey hair and pin prick stimulation of the injured hindpaw. NS1209 and morphine also reduced cold hypersensitivity in response to ethyl chloride stimulation of the injured hindpaw. At the doses associated with anti-nociceptive actions, no effects on motor performance as determined by the rotarod test were observed for any of the drugs tested. Thus, systemic administration of NS1209 at non-ataxic doses has marked analgesic actions comparable to those of morphine in a range of animal models of experimental pain.
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PMID:Behavioural effects of the novel AMPA/GluR5 selective receptor antagonist NS1209 after systemic administration in animal models of experimental pain. 1527 24

To study the glutamatergic mechanisms underlying changes in excitability in the brain stem pain modulatory circuitry after injury, we examined GluR1 serine 831 phosphorylation in the rostral ventromedial medulla (RVM) after complete Freund's adjuvant-induced hindpaw inflammation. Western blots indicated a rapid and prolonged (30 min and 7 days post-inflammation) increase in phosphoserine 831 GluR1 protein levels in the RVM. The upregulated GluR1 phosphorylation was blocked by pretreatment, but not by post-treatment, with the local anesthetic, lidocaine, at the site of inflammation. The upregulation of phosphoserine 831 GluR1 was attenuated by pretreatment with chelerythrine, a selective PKC inhibitor, KN-93, a selective CaMKII inhibitor, and two NMDA receptor antagonists, MK-801 and APV. These findings provide new evidence linking in vivo AMPA receptor phosphorylation in the RVM pain modulatory circuitry to the enhanced descending pain modulation after inflammation.
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PMID:Changes in AMPA receptor phosphorylation in the rostral ventromedial medulla after inflammatory hyperalgesia in rats. 1527 47

Using a rat formalin-induced conditioned place avoidance (F-CPA) model and Fos immunohistochemistry, the present study observed the effect of N-methyl-D-aspartate (NMDA) and alpha-amino-3-hydroxy-5-methyl-isoxozole propionic acid/kainite (AMPA/KA) receptors on pain-related aversion. Adult Sprague-Dawley rats were implanted with cannula in the anterior cingulate cortex (ACC) or the lateral ventricle. Before (10 min) the injection of formalin into a hindpaw on days 2 and 4 of place-conditioning trials, vehicle (0.01 M PBS), the NMDA receptors antagonist, 2-amino-5-phosphonovalerate (AP5), or the AMPA/KA receptors antagonist, 6,7-dinitroquinoxaline-2,3-dione (DNQX), was injected through the cannula. F-CPA was effectively eliminated by both intracerebroventricular (icv) and intra-ACC microinjection of AP5. In contrast, the intra-ACC or icv injection of DNQX failed to alter the conditioning scores of F-CPA compared with vehicle control group (P >0.05). Intra-ACC or icv injection of AP5 or DNQX had no effect on formalin-induced acute nociceptive behaviors. Fos immunoreactivity in the ACC was activated by retrieval of pain-related aversion, and this activation was significantly suppressed by preadministration of AP5, but not DNQX (P <0.001). These results suggest that NMDA receptors in the ACC are preferentially involved in the processing of the affective dimension of pain.
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PMID:NMDA receptors in the anterior cingulate cortex mediate pain-related aversion. 1538 Apr 91

Molecular mechanisms underlying C-fiber stimulation-induced ERK (extracellular signal-regulated kinase) activation in dorsal horn neurons and its contribution to central sensitization have been investigated. In adult rat spinal slice preparations, activation of C-fiber primary afferents by a brief exposure of capsaicin produces an eightfold to 10-fold increase in ERK phosphorylation (pERK) in superficial dorsal horn neurons. The pERK induction is reduced by blockade of NMDA, AMPA/kainate, group I metabotropic glutamate receptor, neurokinin-1, and tyrosine receptor kinase receptors. The ERK activation produced by capsaicin is totally suppressed by inhibition of either protein kinase A (PKA) or PKC. PKA or PKC activators either alone or more effectively together induce pERK in superficial dorsal horn neurons. Inhibition of calcium calmodulin-dependent kinase (CaMK) has no effect, but pERK is reduced by inhibition of the tyrosine kinase Src. The induction of cAMP response element binding protein phosphorylation (pCREB) in spinal cord slices in response to C-fiber stimulation is suppressed by preventing ERK activation with the MAP kinase kinase inhibitor 2-(2-diamino-3-methoxyphenyl-4H-1-benzopyran-4-one (PD98059) and by PKA, PKC, and CaMK inhibitors. Similar signaling contributes to pERK induction after electrical stimulation of dorsal root C-fibers. Intraplantar injection of capsaicin in an intact animal increases expression of pCREB, c-Fos, and prodynorphin in the superficial dorsal horn, changes that are prevented by intrathecal injection of PD98059. Intrathecal PD98059 also attenuates capsaicin-induced secondary mechanical allodynia, a pain behavior reflecting hypersensitivity of dorsal horn neurons (central sensitization). We postulate that activation of ionotropic and metabotropic receptors by C-fiber nociceptor afferents activates ERK via both PKA and PKC, and that this contributes to central sensitization through post-translational and CREB-mediated transcriptional regulation in dorsal horn neurons.
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PMID:Ionotropic and metabotropic receptors, protein kinase A, protein kinase C, and Src contribute to C-fiber-induced ERK activation and cAMP response element-binding protein phosphorylation in dorsal horn neurons, leading to central sensitization. 1538 14

The role of Ca(2+)-permeable AMPA receptors in pain processing has not been extensively studied. In this issue of Neuron, Hartmann et al. show that altering the levels of these receptors has consequences for inflammatory pain hypersensitivity but not acute pain processing.
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PMID:AMPA receptors bring on the pain. 1554 12


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