title: Role of mu 1-opiate receptors in supraspinal opiate analgesia: a microinjection study.
abstract: Microinjection of opiates into either the periaqueductual gray, locus coeruleus, nucleus raphe magnus, or nucleus reticularis gigantocellularis elicits a profound naloxone-sensitive analgesia. mu-Opioid receptors have been implicated in supraspinal analgesia and studies from our laboratory have demonstrated the importance of the mu 1-receptor subtype. In an effort to examine the receptor subtypes responsible for opioid analgesia in specific brain regions, we examined dose-response relationships and naloxonazine sensitivity of morphine and two enkephalin derivatives in the above 4 brain regions. Both morphine and [D-Ser2,Leu5]enkephalin-Thr6 (DSLET) were effective analgesics in all regions examined. The poor affinity of DSLET for mu 2-receptors and of morphine for delta-receptors, combined with their similar, high affinity for mu 1-receptors, implied a mu 1-mechanism of action. The mu 1-selective antagonist naloxonazine effectively blocked the analgesic responses of both compounds in all regions. [D-Pen2,D-Pen5]enkephalin (DPDPE), a potent delta-ligand which does not interact with mu 1-receptors, did not elicit analgesia in either the periaqueductal gray or locus coeruleus at any dose tested. These results suggest that opiates and opioid peptides produce analgesia in these 4 brain regions through mu 1-receptors. The inactivity of DPDPE argues against a role for delta-receptors and the similar analgesic potencies of morphine and DSLET makes a significant role for mu 2-receptors unlikely.
authors.affiliation: Cotzias Laboratory of Neuro-Oncology, Memorial Sloan-Kettering Cancer Center, New York, NY 10021.
authors.forename: R J
authors.initials: RJ
authors.lastname: Bodnar
authors.forename: C L
authors.initials: CL
authors.lastname: Williams
authors.forename: S J
authors.initials: SJ
authors.lastname: Lee
authors.forename: G W
authors.initials: GW
authors.lastname: Pasternak
mesh_terms: D000698:Analgesia; D000818:Animals; D001921:Brain / Q000187:drug effects / Q000502:physiology*; D002552:Cerebral Ventricles / Q000187:drug effects / Q000502:physiology*; D020881:Enkephalin, D-Penicillamine (2,5)-; D004743:Enkephalin, Leucine / Q000031:analogs & derivatives*; D004745:Enkephalins / Q000494:pharmacology; D007275:Injections, Intravenous; D007276:Injections, Intraventricular; D008297:Male; D008845:Microinjections; D009020:Morphine / Q000008:administration & dosage / Q000494:pharmacology*; D009842:Oligopeptides / Q000494:pharmacology; D009928:Organ Specificity; D051381:Rats; D011919:Rats, Inbred Strains; D011957:Receptors, Opioid / Q000187:drug effects / Q000502:physiology*; D017450:Receptors, Opioid, mu; D013116:Spinal Cord / Q000502:physiology
chemical_list: D004745:Enkephalins; D009842:Oligopeptides; D011957:Receptors, Opioid; D017450:Receptors, Opioid, mu; D004743:Enkephalin, Leucine; C034318:enkephalin, Ser(2), Leu(5), Thr(6)-; D009020:Morphine; D020881:Enkephalin, D-Penicillamine (2,5)-