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

Abstract The antagonism by Tyr- d -Pro-Trp-Gly-NH 2 ( d -Pro 2 -Tyr-W-MIF-1), a Tyr-Pro-Trp-Gly-NH 2 (Tyr-W-MIF-1) analog, of the antinociception induced by the μ-opioid receptor agonists Tyr-W-MIF-1, [ d -Ala 2 ,NMePhe 4 ,Gly(ol) 5 ]-enkephalin (DAMGO), Tyr-Pro-Trp-Phe-NH 2 (endomorphin-1), and Tyr-Pro-Phe-Phe-NH 2 (endomorphin-2) was studied with the mouse tail-flick test. d -Pro 2 -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 -Pro 2 -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 -Pro 2 -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 -Pro 2 -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 -Pro 2 -Tyr-W-MIF-1 almost completely attenuated Tyr-W-MIF-1-induced antinociception. However, that dose of d -Pro 2 -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 -Pro 2 -Tyr-W-MIF-1. Pretreatment i.c.v. with various doses of naloxonazine, a μ 1 -opioid receptor antagonist, attenuated the antinociception induced by Tyr-W-MIF-1, endomorphin-1, endomorphin-2, or DAMGO. Judging from the ID 50 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 -Pro 2 -Tyr-W-MIF-1 is a selective antagonist for the μ 2 -opioid receptor in the mouse brain. d -Pro 2 -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 μ 2 -opioid receptor in the brain.