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NEUROPHARMACOLOGY

A Tyr-W-MIF-1 Analog Containing D-Pro² Acts as a Selective µ₂-Opioid Receptor Antagonist in the Mouse

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.)

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.

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