Santos A R, Calixto J B
Department of Pharmacology, CCB, Universidade Federal de Santa Catarina, Florianópolis-SC, Brazil.
Neuropeptides. 1997 Aug;31(4):381-9. doi: 10.1016/s0143-4179(97)90075-5.
The intradermal (i.d.) injection of NK1 receptor antagonists GR 82334 and FK 888 (1-50 pmol/paw), in association with formalin, produced graded inhibition of the early but not the late phase of the formalin test. The NK2, SR 48968 and NK3 SR 142801 receptor antagonists (1-50 pmol/paw) were effective in inhibiting both phases of the formalin model. Co-injection of NK1, (FK 888, GR 82334), NK2 (SR 48968) or NK3 (SR 142801) receptor antagonists with capsaicin dose-dependently attenuated capsaicin-induced licking. In addition, all antagonists were more efficacious when compared with response in the formalin test. The antinociception caused by i.d. injection of the NK3 receptor antagonist SR 142801 against both phases of the formalin test, but not that of NK1 and NK2 receptor antagonists, was significantly reversed by intraperitoneal (i.p.) injection of naloxone (5 mg/kg). Intracerebroventricular (i.c.v.) injection of NK1, NK2 or NK3 receptor antagonists (15-500 pmol/site), all produced significant and dose-dependent inhibition of both phases of the formalin and capsaicin tests. With the exception of the response of SR 48968, which was equipotent in both models of nociception, FK 888, GR 82334 and SR 142801 were about 2-25-fold less potent at the ID50 level against the capsaicin-induced pain. The antinociception caused by i.c.v. injection of NK1, NK2 or NK3 receptor antagonists was reversed by i.p. injection of naloxone (5 mg/kg). These results indicate that tachykinin receptor antagonists, acting through NK1, NK2 and NK3 receptors, produce powerful antinociception when injected i.d. or by i.c.v. route against both formalin- and capsaicin-induced licking, being more efficacious against the latter model of nociception. The action of NK3 receptor antagonist given i.d. was mediated through an opioid mechanism sensitive to naloxone. However, when injected i.c.v., the antinociception caused by NK1, NK2 or NK3 receptor antagonists was largely reversed by naloxone when assessed in the formalin test, suggesting a distinct mechanism of action.
皮内（i.d.）注射NK1受体拮抗剂GR 82334和FK 888（1 - 50 pmol/爪），与福尔马林联合使用时，可对福尔马林试验的早期阶段产生分级抑制作用，但对晚期阶段无抑制作用。NK2受体拮抗剂SR 48968和NK3受体拮抗剂SR 142801（1 - 50 pmol/爪）可有效抑制福尔马林模型的两个阶段。将NK1（FK 888、GR 82334）、NK2（SR 48968）或NK3（SR 142801）受体拮抗剂与辣椒素共同注射，可剂量依赖性地减弱辣椒素诱导的舔舐行为。此外，与福尔马林试验中的反应相比，所有拮抗剂的效果都更好。腹腔内（i.p.）注射纳洛酮（5 mg/kg）可显著逆转皮内注射NK3受体拮抗剂SR 142801对福尔马林试验两个阶段所产生的抗伤害感受作用，但对NK1和NK2受体拮抗剂则无此作用。脑室内（i.c.v.）注射NK1、NK2或NK3受体拮抗剂（15 - 500 pmol/部位），均可对福尔马林试验和辣椒素试验的两个阶段产生显著的剂量依赖性抑制作用。除SR 48968在两种伤害感受模型中的作用相当外，FK 888、GR 82334和SR 142801在ID50水平对辣椒素诱导的疼痛的效力比对福尔马林试验的效力低约2 - 25倍。脑室内注射NK1、NK2或NK3受体拮抗剂所引起的抗伤害感受作用可被腹腔内注射纳洛酮（5 mg/kg）逆转。这些结果表明，速激肽受体拮抗剂通过NK1、NK2和NK3受体发挥作用，皮内注射或脑室内注射时，对福尔马林和辣椒素诱导的舔舐行为均产生强大的抗伤害感受作用，但对后者模型的伤害感受作用更有效。皮内注射NK3受体拮抗剂的作用是通过对纳洛酮敏感的阿片样物质机制介导的。然而，脑室内注射时，在福尔马林试验中评估发现，NK1、NK2或NK3受体拮抗剂所引起的抗伤害感受作用在很大程度上可被纳洛酮逆转，提示其作用机制不同。
