Sakurada S, Hayashi T, Yuhki M, Fujimura T, Murayama K, Yonezawa A, Sakurada C, Takeshita M, Zadina J E, Kastin A J, Sakurada T
Department of Physiology and Anatomy, Tohoku Pharmaceutical University, 4-4-1 Komatsushima, 981-8558, Sendai, Japan.
Brain Res. 2000 Oct 20;881(1):1-8. doi: 10.1016/s0006-8993(00)02770-0.
To determine the role of spinal mu-opioid receptor subtypes in antinociception induced by intrathecal (i.t.) injection of endomorphin-1 and -2, we assessed the effects of beta-funaltrexamine (a selective mu-opioid receptor antagonist) naloxonazine (a selective antagonist at the mu(1)-opioid receptor) and a novel receptor antagonist (3-methoxynaltrexone) using the paw-withdrawal test. Antinociception of i.t. endomorphins and [D-Ala(2), MePhe(4), Gly(ol)(5)]enkephalin (DAMGO) was completely reversed by pretreatment with beta-funaltrexamine (40 mg/kg s.c.). Pretreatment with a variety of doses of i.t. or s.c. naloxonazine 24 h before testing antagonized the antinociception of endomorphin-1, -2 and DAMGO. Judging from the ID(50) values of naloxonazine, the antinociceptive effect of endomorphin-2 was more sensitive to naloxonazine than that of endomorphin-1 or DAMGO. The selective morphine-6beta-glucuronide antagonist, 3-methoxynaltrexone, which blocked endomorphin-2-induced antinociception at each dose (0.25 mg/kg s.c. or 2.5 ng i.t.) that was inactive against DAMGO, did not affect endomorphin-1-induced antinociception but shifted the dose-response curve of endomorphin-2 3-fold to the right. These findings may be interpreted as indicative of the existence of a novel mu-opioid receptor subtype in spinal sites, where antinociception of morphine-6beta-glucuronide and endomorphin-2 are antagonized by 3-methoxynaltrexone. The present results suggest that endomorphin-1 and endomorphin-2 may produce antinociception through different subtypes of mu-opioid receptor.
为了确定脊髓μ-阿片受体亚型在鞘内注射内吗啡肽-1和-2诱导的抗伤害感受中的作用，我们使用足趾退缩试验评估了β-芬太尼环唑（一种选择性μ-阿片受体拮抗剂）、纳洛酮嗪（一种μ(1)-阿片受体选择性拮抗剂）和一种新型受体拮抗剂（3-甲氧基纳曲酮）的作用。鞘内注射内吗啡肽和[D-Ala(2), MePhe(4), Gly(ol)(5)]脑啡肽（DAMGO）的抗伤害感受被β-芬太尼环唑（40 mg/kg皮下注射）预处理完全逆转。在测试前24小时用不同剂量的鞘内或皮下纳洛酮嗪预处理可拮抗内吗啡肽-1、-2和DAMGO的抗伤害感受。从纳洛酮嗪的半数抑制剂量（ID(50)）值判断，内吗啡肽-2的抗伤害感受作用比内吗啡肽-1或DAMGO对纳洛酮嗪更敏感。选择性吗啡-6β-葡萄糖醛酸拮抗剂3-甲氧基纳曲酮在每个剂量（0.25 mg/kg皮下注射或2.5 ng鞘内注射）均阻断内吗啡肽-2诱导的抗伤害感受，而该剂量对DAMGO无作用，不影响内吗啡肽-1诱导的抗伤害感受，但使内吗啡肽-2的剂量-反应曲线右移3倍。这些发现可解释为表明脊髓部位存在一种新型μ-阿片受体亚型，其中吗啡-6β-葡萄糖醛酸和内吗啡肽-2的抗伤害感受被3-甲氧基纳曲酮拮抗。目前的结果表明，内吗啡肽-1和内吗啡肽-2可能通过不同亚型的μ-阿片受体产生抗伤害感受。
