Sakurada Shinobu, Hayashi Takafumi, Yuhki Masayuki, Fujimura Tsutomu, Murayama Kimie, Yonezawa Akihiko, Sakurada Chikai, Takeshita Mitsuhiro, Sato Takumi, Zadina James E, Kastin Abba J, Sakurada Tsukasa
Department of Physiology and Anatomy, Tohoku Pharmaceutical University, 4-4-1 Komatsushima, Sendai, Japan.
Peptides. 2002 May;23(5):895-901. doi: 10.1016/s0196-9781(02)00016-5.
To determine if different subtypes of mu-opioid receptors were involved in antinociception induced by endomorphin-1 and endomorphin-2, the effect of pretreatment with various mu-opioid receptor antagonists beta-funaltrexamine, naloxonazine and 3-methylnaltrexone on the inhibition of the paw-withdrawal induced by endomorphin-1 and endomorphin-2 given intracerebroventricularly (i.c.v.) were studied in ddY male mice. The inhibition of the paw-withdrawal induced by i.c.v. administration of endomorphin-1, endomorphin-2 or DAMGO was completely blocked by the pretreatment with a selective mu-opioid receptor antagonist beta-funaltrexamine (40 mg/kg), indicating that the antinociception induced by all these peptides are mediated by the stimulation of mu-opioid receptors. However, naloxonazine, a mu1-opioid receptor antagonist pretreated s.c. for 24h was more effective in blocking the antinociception induced by endomorphin-2, than by endomorphin-1 or DAMGO given i.c.v. Pretreatment with a selective morphine-6 beta-glucuronide blocker 3-methylnaltrexone 0.25mg/kg given s.c. for 25 min or co-administration of 3-methylnaltrexone 2.5 ng given i.c.v. effectively attenuated the antinociception induced by endomorphin-2 given i.c.v. and co-administration of 3-methylnaltrexone shifted the dose-response curves for endomorphin-2 induced antinociception to the right by 4-fold. The administration of 3-methylnaltrexone did not affect the antinociception induced by endomorphin-1 or DAMGO given i.c.v. Our results indicate that the antinociception induced by endomorphin-2 is mediated by the stimulation of subtypes of mu-opioid receptor, which is different from that of mu-opioid receptor subtype stimulation by endomorphin-1 and DAMGO.
为了确定不同亚型的μ-阿片受体是否参与内吗啡肽-1和内吗啡肽-2诱导的镇痛作用，我们研究了在ddY雄性小鼠中，预先给予各种μ-阿片受体拮抗剂β-氟纳曲胺、纳洛酮嗪和3-甲基纳曲酮对脑室内注射（i.c.v.）内吗啡肽-1和内吗啡肽-2诱导的爪部退缩抑制作用的影响。预先给予选择性μ-阿片受体拮抗剂β-氟纳曲胺（40 mg/kg）可完全阻断脑室内注射内吗啡肽-1、内吗啡肽-2或DAMGO诱导的爪部退缩抑制作用，这表明所有这些肽诱导的镇痛作用都是通过刺激μ-阿片受体介导的。然而，皮下注射μ1-阿片受体拮抗剂纳洛酮嗪24小时后，其对脑室内注射内吗啡肽-2诱导的镇痛作用的阻断效果比对脑室内注射内吗啡肽-1或DAMGO诱导的镇痛作用更有效。皮下注射0.25mg/kg选择性吗啡-6β-葡萄糖醛酸苷阻滞剂3-甲基纳曲酮25分钟，或脑室内共同注射2.5 ng 3-甲基纳曲酮，可有效减弱脑室内注射内吗啡肽-2诱导的镇痛作用，且共同注射3-甲基纳曲酮可使内吗啡肽-2诱导的镇痛作用的剂量-反应曲线右移4倍。注射3-甲基纳曲酮不影响脑室内注射内吗啡肽-1或DAMGO诱导的镇痛作用。我们的结果表明，内吗啡肽-2诱导的镇痛作用是由μ-阿片受体亚型的刺激介导的，这与内吗啡肽-1和DAMGO刺激μ-阿片受体亚型的情况不同。
