title: Selective antagonism by naloxonazine of antinociception by Tyr-D-Arg-Phe-beta-Ala, a novel dermorphin analogue with high affinity at mu-opioid receptors.
abstract: To examine the role of mu-opioid receptor subtypes, we assessed the antinociceptive effect of H-Tyr-D-Arg-Phe-beta-Ala-OH (TAPA), an analogue of dermorphin N-terminal peptide in mice, using the tail-flick test. Intracerebroventricularly (i.c.v.) or intrathecally (i.t.) injected TAPA produced potent antinociception with tail-flick as a thermal noxious stimulus. The selective mu(1)-opioid receptor antagonist, naloxonazine (35 mg/kg, s.c.), or the selective mu-opioid receptor antagonist, beta-funaltrexamine, 24 h before testing antagonized the antinociceptive effect of i.t. or i.c.v. TAPA on the response to noxious stimuli. Pretreatment with beta-funaltrexamine completely antagonized the antinociception by both i.c.v. and i.t. administered TAPA and [D-Ala(2), Me-Phe(4), Gly(ol)(5)]enkephalin (DAMGO). Especially in the tail-flick test, pretreatment with naloxonazine produced a marked rightward displacement of the i.t. TAPA dose-response curve for antinociception. Though DAMGO is a highly selective mu-opioid receptor agonist, pretreatment with naloxonazine partially blocked the antinociceptive response to DAMGO after i.c.v., but not after i. t. injection. These results indicate that TAPA can act as a highly selective mu(1)-opioid receptor agonist (notable naloxonazine-sensitive receptor agonist) at not only the supraspinal level, but also the spinal level. These data also reveal different antinociceptive mechanisms for DAMGO and for TAPA.
authors.affiliation: Department of Physiology and Anatomy, Tohoku Pharmaceutical University, 4-4-1 Komatsushima, Aoba-ku, Sendai, Japan. s-sakura@tohoku-pharm.ac.jp
authors.forename: S
authors.initials: S
authors.lastname: Sakurada
authors.forename: S
authors.initials: S
authors.lastname: Takeda
authors.forename: T
authors.initials: T
authors.lastname: Sato
authors.forename: T
authors.initials: T
authors.lastname: Hayashi
authors.forename: M
authors.initials: M
authors.lastname: Yuki
authors.forename: M
authors.initials: M
authors.lastname: Kutsuwa
authors.forename: K
authors.initials: K
authors.lastname: Tan-No
authors.forename: C
authors.initials: C
authors.lastname: Sakurada
authors.forename: K
authors.initials: K
authors.lastname: Kisara
authors.forename: T
authors.initials: T
authors.lastname: Sakurada
mesh_terms: D000700:Analgesics / Q000494:pharmacology*; D000701:Analgesics, Opioid / Q000494:pharmacology*; D000818:Animals; D004336:Drug Antagonism; D020875:Enkephalin, Ala(2)-MePhe(4)-Gly(5)- / Q000494:pharmacology; D007276:Injections, Intraventricular; D008297:Male; D051379:Mice; D009270:Naloxone / Q000031:analogs & derivatives* / Q000494:pharmacology; D009271:Naltrexone / Q000031:analogs & derivatives / Q000494:pharmacology; D009292:Narcotic Antagonists / Q000494:pharmacology; D009842:Oligopeptides / Q000737:chemistry / Q000494:pharmacology*; D018847:Opioid Peptides; D010147:Pain Measurement / Q000187:drug effects; D017450:Receptors, Opioid, mu / Q000187:drug effects / Q000378:metabolism*; D013997:Time Factors
chemical_list: D000700:Analgesics; D000701:Analgesics, Opioid; D009292:Narcotic Antagonists; D009842:Oligopeptides; D018847:Opioid Peptides; D017450:Receptors, Opioid, mu; D020875:Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; C102698:tyrosyl-arginyl-phenylalanyl-beta-alaninamide; C030058:dermorphin; D009270:Naloxone; D009271:Naltrexone; C024524:beta-funaltrexamine; C034643:naloxonazine