title: Effects of a partial agonist and a full antagonist acting at the glycine site of the NMDA receptor on inflammation-induced mechanical hyperalgesia in rats.
abstract: 1. NMDA receptor antagonists have previously been shown to have antinociceptive effects in behavioural experiments, but controversy remains as to the role of NMDA receptors in mechanical hyperalgesia. We have studied the effects on mechanical nociceptive thresholds in rats with carrageenin-induced paw inflammation of L-687,414, a low efficacy partial agonist which acts as a functional antagonist at the glycine modulatory site of the NMDA receptor and of L-701,324, a structurally novel, highly selective, full antagonist at this site. 2. Mechanical thresholds were measured for both hind paws 1 h before and 3 h after carrageenin or saline was injected into 1 hind paw. Dose-response curves were constructed for each test compound in separate experiments, with test compound or vehicle being given i.p. 1 h before the final test. 3. Both compounds produced selective dose-dependent and statistically significant reversal of mechanical hyperalgesia, with minimum effective doses of 100 mg kg-1 L-687,414 and 3 mg kg-1 L-701,324. Neither L-687,414 nor L-701,324 affected the response threshold of the contralateral non-inflamed paw over the dose-range producing reversal of carrageenin-induced hyperalgesia. Neither compound had any effect on the paw oedema produced by carrageenin injection. 4. These results show that both a full antagonist and a low efficacy partial agonist at the glycine modulatory site of the NMDA receptor complex reverse inflammation-induced mechanical hyperalgesia, thus supporting the argument that maximal activation of the glycine site is required for transmission via NMDA receptors, and showing that NMDA receptor-mediated actions are important in mechanical hyperalgesia induced by inflammation.
authors.affiliation: Department of Pharmacology, Merck, Sharp & Dohme Research Laboratories, Harlow, Essex.
authors.forename: J M
authors.initials: JM
authors.lastname: Laird
authors.forename: G S
authors.initials: GS
authors.lastname: Mason
authors.forename: J
authors.initials: J
authors.lastname: Webb
authors.forename: R G
authors.initials: RG
authors.lastname: Hill
authors.forename: R J
authors.initials: RJ
authors.lastname: Hargreaves
mesh_terms: D000818:Animals; D001665:Binding Sites; D002351:Carrageenan; D018690:Excitatory Amino Acid Agonists / Q000494:pharmacology*; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology*; D005998:Glycine / Q000037:antagonists & inhibitors*; D006930:Hyperalgesia / Q000378:metabolism* / Q000473:pathology; D007249:Inflammation / Q000139:chemically induced / Q000378:metabolism; D008297:Male; D011760:Pyrrolidinones / Q000494:pharmacology*; D015363:Quinolones / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors / Q000378:metabolism*
chemical_list: D018690:Excitatory Amino Acid Agonists; D018691:Excitatory Amino Acid Antagonists; D011760:Pyrrolidinones; D015363:Quinolones; D016194:Receptors, N-Methyl-D-Aspartate; C084173:L 687414; D002351:Carrageenan; C094635:L 701324; D005998:Glycine