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

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.