title: Potent in vivo antinociception and opioid receptor preference of the novel analogue [Dmt1]endomorphin-1.
abstract: [Dmt1]Endomorphin-1 is a novel analogue of the potent mu-opioid agonist endomorphin-1. Given the physiological role of endomorphin-1 in vivo, this compound was investigated to determine if the antinociception occurred through systemic, supraspinal or in a combination of both neuronal pathways. This compound exhibited a potent dose-dependent effect intracerebroventricularly in both spinal and supraspinal regions, and was blocked by opioid antagonist naloxone, which verified the involvement of opioid receptors. Specific opioid antagonists characterized the apparent receptor type: beta-funaltrexamine (mu1/mu2-irreversible antagonist) equally inhibited spinal- and central-mediated antinociception; on the other hand, naloxonazine (mu1-subtype) was ineffective in both neural pathways and naltrindole (delta-selective antagonist) partially (26%), though not significantly, blocked only the spinal-mediated antinociception. Therefore, spinal antinociception was primarily triggered by mu2-subtypes without involvement of mu1-opioid receptors; however, although a slight enhancement of antinociception by delta-receptors cannot be completely ruled out since functional bioactivity indicated mixed mu-agonism/delta-antagonism. In terms of the CNS action, [Dmt1]endomorphin-1 appears to act through mu2-opioid receptor subtypes.
authors.affiliation: Medicinal Chemistry Group, Laboratory of Pharmacology and Chemistry, National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709, USA. yunden@niehs.nih.gov
authors.forename: Yunden
authors.initials: Y
authors.lastname: Jinsmaa
authors.forename: Ewa
authors.initials: E
authors.lastname: Marczak
authors.forename: Yoshio
authors.initials: Y
authors.lastname: Fujita
authors.forename: Kimitaka
authors.initials: K
authors.lastname: Shiotani
authors.forename: Anna
authors.initials: A
authors.lastname: Miyazaki
authors.forename: Tingyou
authors.initials: T
authors.lastname: Li
authors.forename: Yuko
authors.initials: Y
authors.lastname: Tsuda
authors.forename: Akihiro
authors.initials: A
authors.lastname: Ambo
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Sasaki
authors.forename: Sharon D
authors.initials: SD
authors.lastname: Bryant
authors.forename: Yoshio
authors.initials: Y
authors.lastname: Okada
authors.forename: Lawrence H
authors.initials: LH
authors.lastname: Lazarus
mesh_terms: D000698:Analgesia; D000818:Animals; D001921:Brain / Q000502:physiology; D006168:Guinea Pigs; D007082:Ileum / Q000187:drug effects; D007276:Injections, Intraventricular; D008297:Male; D051379:Mice; D009270:Naloxone; D009271:Naltrexone / Q000031:analogs & derivatives / Q000494:pharmacology; D009842:Oligopeptides / Q000494:pharmacology*; D010146:Pain; D010147:Pain Measurement; D017465:Receptors, Opioid, delta / Q000187:drug effects*; D017450:Receptors, Opioid, mu / Q000187:drug effects*; D013116:Spinal Cord / Q000502:physiology; D013623:Tail; D014649:Vas Deferens / Q000187:drug effects
chemical_list: D009842:Oligopeptides; D017465:Receptors, Opioid, delta; D017450:Receptors, Opioid, mu; C105293:endomorphin 1; D009270:Naloxone; D009271:Naltrexone; C024524:beta-funaltrexamine; C055382:naltrindole