Non-specific effects of the tachykinin NK1 receptor antagonist, CP-99,994, in antinociceptive tests in rat, mouse and gerbil.
We have examined the antinociceptive activity of the potent and selective tachykinin NK1 receptor antagonist, CP-99,994, and its less active enantiomer, CP-100,263, in a variety of models in rat, mouse and gerbil. Administered systemically to gerbil or mouse CP-99,994 but not CP-100,263 stereo selectively inhibited a caudally directed biting and scratching elicited by intrathecal administration of the tachykinin NK1 receptor agonist, GR73632. In contrast, both CP-99,994 (ED50 = 3 (1-6) mumol.kg-1 s.c.) and CP-100,263 (4 (2-10)), were equipotent at inhibiting acetylcholine-induced abdominal constrictions in mice. Similarly, both enantiomers were also equipotent in reducing formalin-induced licking in gerbil (CP-99,994 (10.1 (5.7-18.6)), CP-100,263 (13.8 (7.8-27.1)) and rat (100 mumol.kg-1 s.c.). Finally, in the spinalised, anaesthetised rat, CP-99,994 dose-dependently and significantly inhibited the flexion reflex evoked by noxious pinch (5.0 (3.3-7.5) mumol.kg-1 i.v.), whereas the less active enantiomer, CP-100,263, was without significant effect when tested up to 30 mumol.kg-1. Our results demonstrate that in the spinal cord, CP-99,994 exhibits a tachykinin NK1 receptor mediated antinociceptive action.
Smith
G
G
Glaxo Research and Development, Ware, Herts, UK.
Harrison
S
S
Bowers
J
J
Wiseman
J
J
Birch
P
P
D000700:Analgesics / Q000494:pharmacology*; D000818:Animals; D004305:Dose-Response Relationship, Drug; D005260:Female; D005849:Gerbillinae; D008297:Male; D051379:Mice; D064729:Neurokinin-1 Receptor Antagonists; D010880:Piperidines / Q000494:pharmacology*; D051381:Rats; D012018:Reflex / Q000187:drug effects; D013237:Stereoisomerism
D000700:Analgesics; D064729:Neurokinin-1 Receptor Antagonists; D010880:Piperidines; C080755:3-(2-methoxybenzylamino)-2-phenylpiperidine