Sakurada S, Takeda S, Sato T, Hayashi T, Yuki M, Kutsuwa M, Tan-No K, Sakurada C, Kisara K, Sakurada T
Department of Physiology and Anatomy, Tohoku Pharmaceutical University, 4-4-1 Komatsushima, Aoba-ku, Sendai, Japan.
Eur J Pharmacol. 2000 Apr 28;395(2):107-12. doi: 10.1016/s0014-2999(00)00166-7.
To examine the role of mu-opioid receptor subtypes, we assessed the antinociceptive effect of H-Tyr-D-Arg-Phe-beta-Ala-OH (TAPA), an analogue of dermorphin N-terminal peptide in mice, using the tail-flick test. Intracerebroventricularly (i.c.v.) or intrathecally (i.t.) injected TAPA produced potent antinociception with tail-flick as a thermal noxious stimulus. The selective mu(1)-opioid receptor antagonist, naloxonazine (35 mg/kg, s.c.), or the selective mu-opioid receptor antagonist, beta-funaltrexamine, 24 h before testing antagonized the antinociceptive effect of i.t. or i.c.v. TAPA on the response to noxious stimuli. Pretreatment with beta-funaltrexamine completely antagonized the antinociception by both i.c.v. and i.t. administered TAPA and [D-Ala(2), Me-Phe(4), Gly(ol)(5)]enkephalin (DAMGO). Especially in the tail-flick test, pretreatment with naloxonazine produced a marked rightward displacement of the i.t. TAPA dose-response curve for antinociception. Though DAMGO is a highly selective mu-opioid receptor agonist, pretreatment with naloxonazine partially blocked the antinociceptive response to DAMGO after i.c.v., but not after i. t. injection. These results indicate that TAPA can act as a highly selective mu(1)-opioid receptor agonist (notable naloxonazine-sensitive receptor agonist) at not only the supraspinal level, but also the spinal level. These data also reveal different antinociceptive mechanisms for DAMGO and for TAPA.
为研究μ-阿片受体亚型的作用，我们使用甩尾试验评估了皮啡肽N端肽类似物H-Tyr-D-Arg-Phe-β-Ala-OH（TAPA）对小鼠的镇痛作用。脑室内（i.c.v.）或鞘内（i.t.）注射TAPA，以甩尾作为热伤害性刺激时，可产生强效镇痛作用。在测试前24小时，选择性μ(1)-阿片受体拮抗剂纳洛嗪（35 mg/kg，皮下注射）或选择性μ-阿片受体拮抗剂β-芬太尼可对抗i.t.或i.c.v. TAPA对伤害性刺激反应的镇痛作用。β-芬太尼预处理完全拮抗了i.c.v.和i.t.给予的TAPA及[D-Ala(2), Me-Phe(4), Gly(ol)(5)]脑啡肽（DAMGO）的镇痛作用。尤其是在甩尾试验中，纳洛嗪预处理使i.t. TAPA镇痛剂量反应曲线显著右移。虽然DAMGO是一种高度选择性的μ-阿片受体激动剂，但纳洛嗪预处理可部分阻断i.c.v.注射后对DAMGO的镇痛反应，而对i.t.注射后则无此作用。这些结果表明，TAPA不仅在脊髓上水平，而且在脊髓水平都可作为一种高度选择性的μ(1)-阿片受体激动剂（显著的纳洛嗪敏感受体激动剂）。这些数据还揭示了DAMGO和TAPA不同的镇痛机制。
