Smith G, Harrison S, Bowers J, Wiseman J, Birch P
Glaxo Research and Development, Ware, Herts, UK.
Eur J Pharmacol. 1994 Dec 27;271(2-3):481-7. doi: 10.1016/0014-2999(94)90809-5.
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.
我们在大鼠、小鼠和沙鼠的多种模型中研究了强效选择性速激肽NK1受体拮抗剂CP-99,994及其活性较低的对映体CP-100,263的抗伤害感受活性。对沙鼠或小鼠全身给药时，CP-99,994而非CP-100,263能立体选择性地抑制鞘内注射速激肽NK1受体激动剂GR73632引起的尾部咬挠行为。相比之下，CP-99,994（ED50 = 3(1 - 6) μmol·kg-1皮下注射）和CP-100,263（4(2 - 10)）在抑制小鼠乙酰胆碱诱导的腹部收缩方面具有同等效力。同样，两种对映体在减少沙鼠（CP-99,994（10.1(5.7 - 18.6)），CP-100,263（13.8(7.8 - 27.1)））和大鼠（100 μmol·kg-1皮下注射）福尔马林诱导的舔舐行为方面也具有同等效力。最后，在脊髓麻醉的大鼠中，CP-99,994剂量依赖性且显著地抑制了有害夹捏诱发的屈曲反射（5.0(3.3 - 7.5) μmol·kg-1静脉注射），而活性较低的对映体CP-100,263在高达30 μmol·kg-1的测试剂量下无显著作用。我们的结果表明，在脊髓中，CP-99,994表现出速激肽NK1受体介导的抗伤害感受作用。
