A Tyr-W-MIF-1 analog containing d-Pro² discriminates among antinociception in mice mediated by different classes of μ-opioid receptors

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• 作者：Daisuke Nakayama ; Chizuko Watanabe ; Hiroyuki Watanabe ; Hirokazu Mizoguchi ; Tsukasa Sakurada ; Shinobu Sakurada
• 关键词：d-Pro²-Tyr-W-MIF-1 ; Tyr-W-MIF-1 ; Antinociception ; Opioid receptor ; Supraspinal
• 刊名：European Journal of Pharmacology
• 出版年：2007
• 出版时间：1 June 2007
• 年：2007
• 卷：563
• 期：1-3
• 页码：109-116
• 全文大小：488 K

文摘

The antagonism by Tyr-d-Pro-Trp-Gly-NH₂ (d-Pro²-Tyr-W-MIF-1), a Tyr-Pro-Trp-Gly-NH₂ (Tyr-W-MIF-1) analog, of the antinociception induced by the μ-opioid receptor agonists Tyr-W-MIF-1, [d-Ala²,NMePhe⁴,Gly(ol)⁵]-enkephalin (DAMGO), Tyr-Pro-Trp-Phe-NH₂ (endomorphin-1), and Tyr-Pro-Phe-Phe-NH₂ (endomorphin-2) was studied with the mouse tail-flick test. d-Pro²-Tyr-W-MIF-1 (0.5–3 nmol) given intracerebroventricularly (i.c.v.) had no effect on the thermal nociceptive threshold. High doses of d-Pro²-Tyr-W-MIF-1 (4–16 nmol) administered i.c.v. produced antinociception with a low intrinsic activity of about 30 % of the maximal possible effect. d-Pro²-Tyr-W-MIF-1 (0.25–2 nmol) co-administered i.c.v. showed a dose-dependent attenuation of the antinociception induced by Tyr-W-MIF-1 or DAMGO without affecting endomorphin-2-induced antinociception. A 0.5 nmol dose of d-Pro²-Tyr-W-MIF-1 significantly attenuated Tyr-W-MIF-1-induced antinociception but not DAMGO- or endomorphin-1-induced antinociception. The highest dose (2 nmol) of d-Pro²-Tyr-W-MIF-1 almost completely attenuated Tyr-W-MIF-1-induced antinociception. However, that dose of d-Pro²-Tyr-W-MIF-1 significantly but not completely attenuated endomorphin-1 or DAMGO-induced antinociception, whereas the antinociception induced by endomorphin-2 was still not affected by d-Pro²-Tyr-W-MIF-1. Pretreatment i.c.v. with various doses of naloxonazine, a μ₁-opioid receptor antagonist, attenuated the antinociception induced by Tyr-W-MIF-1, endomorphin-1, endomorphin-2, or DAMGO. Judging from the ID₅₀ values for naloxonazine against the antinociception induced by the μ-opioid receptor agonists, the antinociceptive effect of Tyr-W-MIF-1 is extremely less sensitive to naloxonazine than that of endomorphin-1 or DAMGO. In contrast, endomorphin-2-induced antinociception is extremely sensitive to naloxonazine. The present results clearly suggest that d-Pro²-Tyr-W-MIF-1 is a selective antagonist for the μ₂-opioid receptor in the mouse brain. d-Pro²-Tyr-W-MIF-1 may also discriminate between Tyr-W-MIF-1-induced antinociception and the antinociception induced by endomorphin-1 or DAMGO, which both show a preference for the μ₂-opioid receptor in the brain.