The glycine B receptor partial agonist, (+)-HA966, enhances induction of antinociception by RP 67580 and CP-99,994.
The tachykinin receptor antagonists (3aR,7aR)-7,7-diphenyl-2(1-imino-2-(2-methoxyphenyl/ethyl)++ +perhydroisoindole) (RP 67580) and (+)-(2S-3S)-3-(2-methoxybenzylamino)-2-phenylpiperidine (CP-99,994), which act selectively at neurokinin (NK)1 receptors, inhibited the early phase of formalin-induced pain in mice. Although (+)-(1-hydroxy-3-aminopyrrolidine-2-one) ((+)-HA966), a partial agonist at glycine B receptors, was inactive alone, it potentiated the actions of RP 67580 (but not its inactive stereoisomer, RP68651) and CP-99,994. In its presence, the dose-response curve for RP 67580 was dose-dependently shifted to the left. In contrast, (+)-HA966 did not modify the induction of ataxia by RP 67580 and CP-99,994. These data suggest that co-administration of partial agonists at glycine B receptors may improve the antinociceptive potency and 'therapeutic window' of tachykinin NK1 receptor antagonists.
Institut de Recherches Servier, Puteaux, France.
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Seguin
M J
MJ
Millan
D000700:Analgesics / Q000494:pharmacology*; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D005998:Glycine / Q000378:metabolism; D007211:Indoles / Q000494:pharmacology*; D054833:Isoindoles; D008297:Male; D051379:Mice; D010880:Piperidines / Q000494:pharmacology*; D011760:Pyrrolidinones / Q000494:pharmacology*; D018009:Receptors, Glycine / Q000187:drug effects; D018039:Receptors, Tachykinin / Q000037:antagonists & inhibitors
D000700:Analgesics; D007211:Indoles; D054833:Isoindoles; D010880:Piperidines; D011760:Pyrrolidinones; D018009:Receptors, Glycine; D018039:Receptors, Tachykinin; C071693:7,7-diphenyl-2-(1-imino-2-(2-methoxyphenyl)ethyl)perhydroisoindol-4-one; C080755:3-(2-methoxybenzylamino)-2-phenylpiperidine; C001369:1-hydroxy-3-amino-2-pyrrolidone; D005998:Glycine