Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: 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)

In intracranial structures unmyelinated C- and Adelta-fibers of the trigeminal nerve transmit pain stimuli from meninges to the trigeminal nucleus caudalis (Sp5C). Peripheral nerve endings surround meningeal vessels (the so-called trigeminovascular system) and contain vasoactive neuropeptides (calcitonin gene-related peptide, substance P and neurokinin A). Activation of the trigeminovascular system promotes a meningeal sterile inflammatory response through the release of neuropeptides by peripheral endings. Orthodromic conduction along trigeminovascular fibers transmits information centrally with induction of immediate early c-fos gene within post-synaptic Sp5C neurons, as a marker of neuronal activity within central nociceptive pathways. In laboratory animals the system is activated by either electrical stimulation of the TG, chemical stimulation of the meninges, electrical or mechanical stimulation of the superior sagittal sinus or by induction of cortical spreading depression. All these techniques induce c-fos within Sp5C and are used as a rodent/feline model of vascular headache in humans. Up-to-date there is evidence that at least ten receptors (5-HT(1B), 5-HT(1D), 5-HT(lF), 5-HT(2B), NK-1, GABA(A), NMDA, AMPA, class III metabotropic glutamate receptors, and opioids mu receptors) modulate c-fos expression within Sp5C. These receptors represent potential targets for anti-migraine drugs as shown by triptans (5-HT(1B/1D/1F)) and ergot alkaloids (5-HT(1A1B/1D/1F)). This review discusses the importance of c-fos expression within Sp5C as a marker of cephalic nociception, the different cephalic pain models that induce c-fos within Sp5C, the receptors involved and their potential role as targets for anti-migraine drugs.
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PMID:Receptor systems mediating c-fos expression within trigeminal nucleus caudalis in animal models of migraine. 1124 84

SIBIA and Novartis are investigating the use of excitatory amino acid agonists and antagonists for the metabotropic receptor and the ionotropic receptors AMPA and NMDA. Preliminary experiments indicate they may have potential in the treatment of epilepsy, stroke, anxiety, pain and neurodegenerative disease. Methylphenylethynylpyridine (MPEP) is the lead compound in the series [347212]. Other compounds in the series that arose from the collaboration were SIB-1893, and its equipotent analog, SIB-1757, both of which are subtype-selective, potent antagonists of mGluR5. Chemical derivation of SIB-1893 resulted in the discovery of MPEP, a selective, systemically active noncompetitive mGluR5 antagonist. Studies using these agents have yielded data to support the involvement of mGluR5 in inflammatory mechanical hyperalgesia [311829], [311828], [311823], [311880], [319655]. MPEP is the most potent of these compounds with an IC50 value of 12 nM for inhibition of quisqualate-stimulated phosphoinositide hydrolysis in recombinant human mGluR5a-expressing cells. MPEP exhibited no cross reactivity with mGluR1 and other mGluRs, or against representative NMDA, AMPA and kainate receptors up to concentrations of 100 microM. The compound, administered orally (100 mg/kg) produced a 70% reversal of mechanical hyperalgesia in the Freund's complete adjuvant model of inflammatory pain [319261]. By October 1999, investigations with SIB-1757 and SIB-1893 had been discontinued in favor of MPEP [347212].
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PMID:Methylphenylethynylpyridine (MPEP) Novartis. 1124 19

Spontaneous pain, allodynia and hyperalgesia are well known phenomena following peripheral nerve or tissue injury, and it is speculated that secondary hyperalgesia and allodynia, are generally thought to depend on a hyperexcitability (sensitization) of neurons in the dorsal horn. It is supposed that the sensitization may be due to various actions of neurotransmitters (SP, CGRP, excitatory amino acids) released from the primary afferent fibers. In this study, we examined effects of the iontophoretically applied SP and CGRP on the response to EAA receptor agonists (NMDA and non-NMDA) in the WDR dorsal horn neurones and see if the effects of SP or CGRP mimic the characteristic response pattern known in various pain models. The main results are summarized as follows: 1) SP specifically potentiated NMDA response. 2) CGRP non-specifically potentiated both NMDA and AMPA responses. Potentiation of NMDA response, however, was significantly greater than that of AMPA response. 3) 50% of SP applied cells and 15.8% of CGRP applied cells showed reciprocal changes(potentiation of NMDA response and suppression of AMPA response). These results are generally consistent with the sensitization characteristics in diverse pain models and suggests that the modulatory effects of SP and CGRP on NMDA and non-NMDA (AMPA) response are, at least in part, contribute to the development of sensitization in various pain models.
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PMID:Effects of iontophoretically applied substance P, calcitonin gene-related peptide on excitability of dorsal horn neurones in rats. 1129 4

Intraspinal injection of quisqualic acid, a mixed kainic acid/2-amino-3(3-hydroxy-5-methylisoxazol-4-yl)propionic acid and metabotropic glutamate receptor agonist, produces an excitotoxic injury that leads to the onset of both spontaneous and evoked pain behavior as well as changes in spinal and cortical expression of opioid peptide mRNA, preprodynorphin and preproenkephalin. What characteristics of the quisqualic acid-induced injury are attributable to activation of each receptor subtype is unknown. This study attempted to define the role of activation of the kainic acid/2-amino-3(3-hydroxy-5-methylisoxazol-4-yl)propionic acid (AMPA) and metabotropic glutamate receptor subtypes in the regulation of opioid peptide expression and the onset of spontaneous and evoked pain-related behavior following excitotoxic spinal cord injury by comparing quisqualic acid-induced changes with those created by co-injection of quisqualic acid and the kainic acid/AMPA antagonist, 2,3-dihydroxy-6-nitro-7-sulfamoylbenzo[f]quinoxaline, (NBQX) or the metabotropic antagonist, (RS)-1-aminoindan-1,5-dicarboxylic acid (AIDA). Therefore, 42 male Long-Evans adult rats were divided into seven treatment groups and received intraspinal microinjections of saline (sham), 0.5% dimethylsulphoxide (sham), quisqualic acid (1.2 microl, 125 mM), NBQX (1.2 microl, 60 microM), AIDA (1.2 microl, 250 microM), quisqualic acid/NBQX (1.2 microl, 125 mM/60 microM), or quisqualic acid/AIDA (1.2 microl, 125 mM/250 microM) directed at spinal levels thoracic 12-lumbar 2. Behavioral observations of spontaneous and evoked pain responses were completed following surgery. After a 10-day survival period, animals were killed and brain and spinal cord tissues were removed and processed for histologic analysis and in situ hybridization. Both AIDA and NBQX affected the quisqualic acid-induced total lesion volume but only AIDA caused a decrease in the percent tissue damage at the lesion epicenter. Preprodynorphin and preproenkephalin expression is increased in both spinal and cortical areas in quisqualic acid-injected animals versus sham-, NBQX or AIDA-injected animals. NBQX did not affect quisqualic acid-induced spinal or cortical expression of preprodynorphin or preproenkephalin except for a significant decrease in preproenkephalin expression in the spinal cord. In contrast, AIDA significantly decreases quisqualic acid-induced preprodynorphin and preproenkephalin expression within the spinal cord and cortex. AIDA, but not NBQX, significantly reduced the frequency of, and delayed the onset of, quisqualic acid-induced spontaneous pain-related behavior. From these data we suggest that both the kainic acid/AMPA and metabotropic glutamate receptor subtypes are involved in the induction of the excitotoxic cascade responsible for quisqualic acid-induced neuronal damage and changes in opioid peptide mRNA expression, while metabotropic glutamate receptors may play a more significant role in the onset of post-injury pain-related behavior.
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PMID:The role of kainic acid/AMPA and metabotropic glutamate receptors in the regulation of opioid mRNA expression and the onset of pain-related behavior following excitotoxic spinal cord injury. 1144 Aug 16

Lilly is developing the racemic compound LY-215490, a selective and competitive AMPA antagonist, as a potential treatment for cerebral infarction, cerebrovascular ischemia, epilepsy and as an analgesic [135089], [158980], [254029], [278691]. By January 2000, LY-293558 was undergoing phase II trials for pain [414000].
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PMID:LY-293558. Eli Lilly & Co. 1171 15

Despite the crucial role that prostaglandins (PGs) have in the sensitization of the central nervous system to pain, their cellular and molecular targets leading to increased pain perception have remained elusive. Here we investigated the effects of PGE(2) on fast synaptic transmission onto neurons in the rat spinal cord dorsal horn, the first site of synaptic integration in the pain pathway. We identified the inhibitory (strychnine-sensitive) glycine receptor as a specific target of PGE(2). PGE(2), but not PGF(2 alpha), PGD(2) or PGI(2), reduced inhibitory glycinergic synaptic transmission in low nanomolar concentrations, whereas GABAA, AMPA and NMDA receptor-mediated transmission remained unaffected. Inhibition of glycine receptors occurred via a postsynaptic mechanism involving the activation of EP2 receptors, cholera-toxin-sensitive G-proteins and cAMP-dependent protein kinase. Via this mechanism, PGE(2) may facilitate the transmission of nociceptive input through the spinal cord dorsal horn to higher brain areas where pain becomes conscious.
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PMID:PGE(2) selectively blocks inhibitory glycinergic neurotransmission onto rat superficial dorsal horn neurons. 1174 May 1

In order to clarify the functional role of glutamate receptors of the gracile nucleus neurons in rats with nerve injury-induced hyperalgesia, pharmacological, electrophysiological and in situ hybridization techniques were used in rats with chronic constriction nerve injury (CCI) of the sciatic nerve. A total of 54 wide dynamic range neurons were recorded from the gracile nucleus in the rats with CCI. Mechanical evoked responses were significantly depressed following application of AMPA receptor antagonist, CNQX, with noxious and non-noxious responses being similarly affected. AP-5, an NMDA receptor antagonist, induced depression of the pressure-evoked response only after application of the 1-microM concentration of this drug. The size of the receptive fields was significantly decreased after CNQX, but not MK-801 or AP-5, application. Afterdischarge was significantly depressed following the application of CNQX (1000 microM). The expression of ionotropic glutamate receptor subunit mRNAs in the gracile nucleus was studied using the in situ hybridization technique. The signals for NMDA subunits, NR2A, -2B and -2C, in the gracile nucleus neurons were not prominent, suggesting a low level expression of functional NMDA receptor complex. AMPA receptor subunits GluR1, -R2, -R3 and -R4 mRNAs were expressed in a large number of gracile nucleus neurons. These data are consistent with the pharmacological results that AMPA receptor antagonists depressed nociceptive neuronal activity, but NMDA receptor antagonists showed limited effects. These results suggest that the ionotropic glutamate receptors, i.e. the AMPA and NMDA receptors, are differentially involved in modulation of the wide dynamic range neuronal activity in the gracile nucleus following peripheral nerve injury.
Pain 2002 Jan
PMID:Involvement of glutamate receptors on hyperexcitability of wide dynamic range neurons in the gracile nucleus of the rats with experimental mononeuropathy. 1179 Apr 78

The recent literature on the antinociceptive action of ionotropic glutamate receptor antagonists is reviewed with special emphasis on their clinical potential. Actually the glutamatergic pathways descending from the brain stem into the spinal cord may generate analgesia. However, physiologically more important is that glutamate and aspartate are apparently the main neurotransmitters along the ascending nociceptive pathways in the spinal cord. Glutamate, aspartate and their receptors can be detected in particularly high concentrations in the dorsal root ganglia and the superficial laminae (I, II) of the spinal cord. In low doses glutamate receptor antagonists only slightly elevate the threshold of the physiological pain sensation. However, they suppress the process of pathological sensitisation i.e. lowering of the pain threshold seen upon excessive or lasting stimulation of C-fibre afferents, a process that takes place during inflammation or other kinds of tissue injury. At electrophysiological level antagonists of both the NMDA- and AMPA/kainate receptors inhibit wind up i.e. lasting activation of the polymodal, second-order sensory neurones in the deeper layers of the dorsal horn. During sensitisation the resting Mg(++) blockade of transmembrane Ca(++) channels is abolished, certain second messenger pathways are activated, the transcription of many genes is enhanced leading to overproduction of glutamate and other excitatory neurotransmitters and expression of Na(+) channels in the primary sensory neurones activated at lower level of depolarisation. This cascade of events leads to increased excitability of the pain pathways. NMDA antagonists are apparently more potent in experimental models of neuropathic pain, whereas AMPA antagonists are more effective in abolition of hyperalgesia seen during experimental inflammation. Clinically, of the previously known NMDA antagonists amantadine, dextromethorphan and ketamine have been tested, the latter extensively. Ketamine has been found quite active in certain cases of neuropathic pain and it reduced the opiate demand when used for postoperative analgesia. However, in other types of clinical pain their efficacy is less convincing. Not being registered there are no clinical data on the AMPA antagonists. There are, however, some investigational new drugs and some novel compounds in the stage of preclinical development which antagonise the AMPA receptors in competitive fashion or allosterically. Of the latter molecules 2,3-benzodiazepines are particularly promising.
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PMID:The role of ionotropic glutamate receptors in nociception with special regard to the AMPA binding sites. 1194 38

The spared nerve injury (SNI) model involves a lesion of two of the three terminal branches of the sciatic nerve (tibial and common peroneal nerves) leaving the sural nerve intact. The changes in pain-like sensation of the injured animals appear to correlate with a number of symptoms presented in human patients with neuropathic pain syndromes. In order to characterise the SNI model pharmacologically, reflex nociceptive responses to mechanical and cold stimulation were measured after systemic administration of morphine, mexiletine, gabapentin and the glutamate receptor antagonists, MK-801 and NS1209. We observed that injection of morphine (6 mg/kg, s.c.) in non-sedative doses significantly attenuated mechanical hypersensitivity in response to von Frey hair and pin prick stimulation and cold hypersensitivity in response to ethyl chloride. The sodium-channel blocker, mexiletine (37.5 mg/kg, i.p.), relieved both cold allodynia and mechanical hyperalgesia, but the most distinct and prolonged effect was observed on mechanical allodynia. Gabapentin (100 mg/kg, i.p.) significantly alleviated mechanical allodynia for at least 3h, while no significant effects were observed for either mechanical hyperalgesia or cold allodynia. In contrast, the NMDA receptor antagonist MK-801 (0.1 mg/kg, i.p.) and the AMPA receptor antagonist NS1209 (6 mg/kg, i.p.) did not relieve any of the pain-like behaviours of the SNI animals. The present study has shown that a variety of drugs with proven analgesic potency in other models of chronic pain, have differing analgesic profiles in the SNI model of neuropathic pain.
Pain 2002 Jul
PMID:Pharmacological characterisation of the spared nerve injury model of neuropathic pain. 1209 27

The oxazole derivative, irampanel, a non-competitive AMPA receptor antagonist, is under development by Boehringer Ingelheim for the potential treatment of stroke [329079]. Phase I/IIa trials for stroke had been initiated by July 2000 [374144]. Phase II trials were ongoing in April 2001 [407163]; in April 2002, however, the drug did not appear on the company's research and development pipeline [446554], and a company spokesperson declined to confirm its current status [450591]. The compound was also originally under investigation for other neurological disorders, including epilepsy and pain [329079], although by October 1999, development was only ongoing for stroke [346080].
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PMID:Irampanel Boehringer Ingelheim. 1213 11


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