title: A Tyr-W-MIF-1 analog containing D-Pro2 discriminates among antinociception in mice mediated by different classes of mu-opioid receptors.
abstract: 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 mu-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 mu1-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 mu-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 mu2-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 mu2-opioid receptor in the brain.
authors.affiliation: Department of Physiology and Anatomy, Tohoku Pharmaceutical University, 4-4-1 Komatsushima, Aoba-ku, Sendai 981-8558, Japan.
authors.forename: Daisuke
authors.initials: D
authors.lastname: Nakayama
authors.forename: Chizuko
authors.initials: C
authors.lastname: Watanabe
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Watanabe
authors.forename: Hirokazu
authors.initials: H
authors.lastname: Mizoguchi
authors.forename: Tsukasa
authors.initials: T
authors.lastname: Sakurada
authors.forename: Shinobu
authors.initials: S
authors.lastname: Sakurada
mesh_terms: D000701:Analgesics, Opioid / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D000818:Animals; D001921:Brain / Q000187:drug effects* / Q000378:metabolism; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D020875:Enkephalin, Ala(2)-MePhe(4)-Gly(5)- / Q000494:pharmacology; D006358:Hot Temperature; D007276:Injections, Intraventricular; D009075:MSH Release-Inhibiting Hormone / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D008297:Male; D051379:Mice; D009270:Naloxone / Q000031:analogs & derivatives / Q000494:pharmacology; D009292:Narcotic Antagonists / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D009842:Oligopeptides / Q000494:pharmacology; D010146:Pain / Q000378:metabolism / Q000503:physiopathology / Q000517:prevention & control*; D010147:Pain Measurement; D017288:Pain Threshold / Q000187:drug effects*; D011930:Reaction Time / Q000187:drug effects*; D017450:Receptors, Opioid, mu / Q000187:drug effects* / Q000378:metabolism; D013004:Somatostatin / Q000031:analogs & derivatives / Q000494:pharmacology; D013997:Time Factors
chemical_list: D000701:Analgesics, Opioid; D009292:Narcotic Antagonists; D009842:Oligopeptides; C404943:Oprm protein, mouse; D017450:Receptors, Opioid, mu; C105293:endomorphin 1; D020875:Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; C049352:phenylalanyl-cyclo(cysteinyltyrosyl-tryptophyl-ornithyl-threonyl-penicillamine)threoninamide; C077532:tyrosyl-prolyl-tryptophyl-glycinamide; D009270:Naloxone; C105294:endomorphin 2; D013004:Somatostatin; C034643:naloxonazine; D009075:MSH Release-Inhibiting Hormone