title: Blockade of mu-opioid receptor-mediated G-protein activation and antinociception by TRK-820 in mice.
abstract: The effects of kappa-opioid receptor agonists trans-3,4-dichloro-N-(2-(1-pyrollidinyl)-cyclohexyl) benzeneacetamide ((-)-U50,488H) and 17-cyclopropylmethyl-3,14beta-dihydroxy-4,5alpha-epoxy-6beta-[N-methyl-trans-3-(3-furyl)acrylamido]morphinan hydrochloride (TRK-820) on the G-protein activation and antinociception induced by the selective mu-opioid receptor agonist, [D-Ala(2),N-MePhe(4),Gly-ol(5)]enkephalin (DAMGO), were determined in mice. G-protein activation was measured by monitoring the guanosine-5'-O-(3-[35S]thio)triphosphate ([35S]GTPgammaS) binding in the mouse pons/medulla. DAMGO (10 microM) produced a marked increase of [35S]GTPgammaS binding to the mouse pons/medulla membrane. On the other hand, both TRK-820 and (-)-U50,488H produced small but significant increases of [35S]GTPgammaS binding to the mouse pons/medulla membrane. These increases by both TRK-820 and (-)-U50,488H were completely reversed by the selective kappa-opioid receptor antagonist, norbinaltorphimine. Under these same conditions, the DAMGO-induced increase of [35S]GTPgammaS binding was significantly attenuated by TRK-820 in a concentration-dependent manner, but not by (-)-U50,488H. In the tail-flick test, DAMGO (16 ng) given intracerebroventricularly (i.c.v.), produced a marked antinociception. The antinociception induced by DAMGO was dose-dependently blocked by co-treatment with TRK-820, but not (-)-U50,488H, in mice pretreated with norbinaltorphimine (5 microg, i.c.v.). The present results provide direct evidence for the antagonistic property of TRK-820 for mu-opioid receptors, in addition to the full agonistic property for kappa-opioid receptors.
authors.affiliation: Department of Anesthesiology, Medical College of Wisconsin, Medical Education Building, Room 462c, 8701 Watertown Plank Road, Milwaukee, WI 53226, USA.
authors.forename: Hirokazu
authors.initials: H
authors.lastname: Mizoguchi
authors.forename: Kuei-chun
authors.initials: KC
authors.lastname: Hung
authors.forename: Randy
authors.initials: R
authors.lastname: Leitermann
authors.forename: Minoru
authors.initials: M
authors.lastname: Narita
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Nagase
authors.forename: Tsutomu
authors.initials: T
authors.lastname: Suzuki
authors.forename: Leon F
authors.initials: LF
authors.lastname: Tseng
mesh_terms: D019900:3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer / Q000008:administration & dosage / Q000494:pharmacology; D000700:Analgesics / Q000008:administration & dosage / Q000494:pharmacology*; D000818:Animals; D004305:Dose-Response Relationship, Drug; D020875:Enkephalin, Ala(2)-MePhe(4)-Gly(5)- / Q000008:administration & dosage / Q000494:pharmacology; D019204:GTP-Binding Proteins / Q000378:metabolism*; D066298:In Vitro Techniques; D007276:Injections, Intraventricular; D008526:Medulla Oblongata / Q000378:metabolism; D051379:Mice; D009019:Morphinans / Q000494:pharmacology*; D009271:Naltrexone / Q000031:analogs & derivatives* / Q000494:pharmacology; D009292:Narcotic Antagonists / Q000494:pharmacology; D010147:Pain Measurement; D011149:Pons / Q000378:metabolism; D011869:Radioligand Assay; D017473:Receptors, Opioid, kappa / Q000819:agonists; D017450:Receptors, Opioid, mu / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D013141:Spiro Compounds / Q000494:pharmacology*
chemical_list: D000700:Analgesics; D009019:Morphinans; D009292:Narcotic Antagonists; D017473:Receptors, Opioid, kappa; D017450:Receptors, Opioid, mu; D013141:Spiro Compounds; D020875:Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; C111212:TRK 820; C051844:norbinaltorphimine; D009271:Naltrexone; D019900:3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; D019204:GTP-Binding Proteins