A Tyr-W-MIF-1 Analog Containing D-Pro2 Acts as a Selective μ2-Opioid Receptor Antagonist in the Mouse
- Hiroyuki Watanabe,
- Daisuke Nakayama,
- Kanenori Ito,
- Chizuko Watanabe,
- Hirokazu Mizoguchi,
- Tsutomu Fujimura,
- Kimie Murayama,
- Shunsuke Kawamura,
- Takumi Sato,
- Chikai Sakurada,
- Tsukasa Sakurada and
- Shinobu Sakurada
- Department of Physiology and Anatomy, Tohoku Pharmaceutical University, Sendai, Japan (H.W., D.N., K.I., C.W., H.M., S.S.); Division of Biochemical Analysis, Central Laboratory of Medical Sciences, Juntendo University School of Medicine, Tokyo, Japan (T.F., K.M.); Educational Center for Pharmaceutical Sciences, Tohoku Pharmaceutical University, Sendai, Japan (S.K.); Department of Pharmacology, Nihon Pharmaceutical University, Saitama, Japan (T. Sat.); and Department of Biochemistry, Daiichi College of Pharmaceutical Sciences, Fukuoka, Japan (C.S., T. Sak.)
- Address correspondence to:
Dr. Shinobu Sakurada, Department of Physiology and Anatomy, Tohoku Pharmaceutical University, 4-4-1 Komatsushima, Aoba-ku, Sendai 981-8558, Japan. E-mail: s-sakura{at}tohoku-pharm.ac.jp
Abstract
The antagonistic properties of Tyr-d-Pro-Trp-Gly-NH2 (d-Pro2-Tyr-W-MIF-1), a Tyr-Pro-Trp-Gly-NH2(Tyr-W-MIF-1) analog, on the antinociception induced by the μ-opioid receptor agonists Tyr-W-MIF-1, [d-Ala2,N-Me-Phe4,Gly5-ol]-enkephalin (DAMGO), Tyr-Pro-Trp-Phe-NH2 (endomorphin-1), and Tyr-Pro-Phe-Phe-NH2 (endomorphin-2) were studied in the mouse paw-withdrawal test. d-Pro2-Tyr-W-MIF-1 injected intrathecally (i.t.) had no apparent effect on the thermal nociceptive threshold. d-Pro2-Tyr-W-MIF-1 (0.1–0.4 nmol) coadministered i.t. showed a dose-dependent attenuation of the antinociception induced by Tyr-W-MIF-1 without affecting endomorphin- or DAMGO-induced antinociception. However, higher doses of d-Pro2-Tyr-W-MIF-1 (0.8–1.2 nmol) significantly 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.t. 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 those 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 the selective antagonist to be identified for the μ2-opioid receptor in the mouse spinal cord. 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, all of which show a preference for the μ2-opioid receptor in the spinal cord.
Footnotes
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This work was supported by Grant-in-Aid for Scientific Research (C) KAK-ENHI 12672220 from the Japan Society for the Promotion of Science.
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doi:10.1124/jpet.104.075697.
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ABBREVIATIONS: MIF-1 melanocyte-stimulating hormone-release inhibiting factor-1; d-Pro2-endomorphin-1, Tyr-d-Pro-Trp-Phe-NH2; d-Pro2-endomorphin-2, Tyr-d-Pro-Phe-Phe-NH2; d-Pro2-Tyr-W-MIF-1, Tyr-d-Pro-Trp-Gly-NH2; endomorphin-1, Tyr-Pro-Trp-Phe-NH2; endomorphin-2, Tyr-Pro-Phe-Phe-NH2; Tyr-W-MIF-1, Tyr-Pro-Trp-Gly-NH2; DAMGO, [d-Ala2,N-Me-Phe4,Gly5-ol]-enkephalin; (–)-U-50,488, (–)-(trans)-3,4-dichloro-N-methyl-N-[2-(1-pyrrolidinyl)-cyclohexyl]benzeneacetamide; MPE, maximal possible effect; ACSF, artificial cerebrospinal fluid; ANOVA, analysis of variance; CI, confidence interval.
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- Received August 5, 2004.
- Revision received November 18, 2004.
- The American Society for Pharmacology and Experimental Therapeutics
