title: Morphine can produce analgesia via spinal kappa opioid receptors in the absence of mu opioid receptors.
abstract: Previous studies have demonstrated the virtual lack of analgesia in mu opioid receptor knockout mice after systemic administration of morphine. Thus, it has been suggested that analgesic actions of morphine are produced via the mu opioid receptor, despite its ability to bind to kappa and delta receptors in vitro. However, it is not clear whether the results of these studies reflect the effect of morphine in the spinal cord. In the present study, we report study of the analgesic actions of spinally-administered morphine and other opioid receptor agonists in mu opioid receptor knockout and wild type mice. Morphine produced a dose-dependent antinociceptive effect in the tail flick test in the knockout mice, although higher doses were needed to produce antinociception than in wild type mice. The antinociceptive effect of morphine was completely blocked by naloxone (a non-selective opioid antagonist) and nor-binaltorphimine (nor-BNI, a selective kappa-opioid receptor antagonist), but not by naltrindole (a selective delta-opioid receptor antagonist). U-50,488H (a selective kappa-opioid receptor agonist) also produced a dose-dependent antinociceptive effect in knockout mice but presented lower analgesic potency in knockout mice than in wild type mice. Analgesic effects of [d-Pen2,d-Pen5]enkephalin (DPDPE, a selective delta-opioid receptor agonist) were observed in wild type mice but abolished in knockout mice. SNC80 (a selective delta-opioid receptor agonist) was not antinociceptive even in wild type mice. The present study demonstrated that morphine can produce thermal antinociception via the kappa opioid receptor in the spinal cord in the absence of the mu opioid receptor. Lower potency of U50,488H in mu opioid receptor knockout mice suggests interaction between kappa and mu opioid receptors at the spinal level.
authors.affiliation: Department of Autonomic Physiology, Chiba University Graduate School of Medicine, 1-8-1 Inohana, Chuo-ku, Chiba, Chiba-ken 260-8670, Japan.
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Yamada
authors.forename: Naohito
authors.initials: N
authors.lastname: Shimoyama
authors.forename: Ichiro
authors.initials: I
authors.lastname: Sora
authors.forename: George R
authors.initials: GR
authors.lastname: Uhl
authors.forename: Yasuichiro
authors.initials: Y
authors.lastname: Fukuda
authors.forename: Hideshige
authors.initials: H
authors.lastname: Moriya
authors.forename: Megumi
authors.initials: M
authors.lastname: Shimoyama
mesh_terms: D000701:Analgesics, Opioid / Q000494:pharmacology*; D000818:Animals; D004305:Dose-Response Relationship, Drug; D004361:Drug Tolerance / Q000235:genetics; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009020:Morphine / Q000494:pharmacology*; D009292:Narcotic Antagonists / Q000494:pharmacology; D010146:Pain / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D010147:Pain Measurement / Q000187:drug effects; D017288:Pain Threshold / Q000187:drug effects / Q000502:physiology; D011930:Reaction Time / Q000187:drug effects / Q000502:physiology; D020239:Receptor Cross-Talk / Q000502:physiology; D017465:Receptors, Opioid, delta / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism; D017473:Receptors, Opioid, kappa / Q000819:agonists* / Q000037:antagonists & inhibitors / Q000378:metabolism; D017450:Receptors, Opioid, mu / Q000235:genetics*; D013116:Spinal Cord / Q000187:drug effects* / Q000378:metabolism
chemical_list: D000701:Analgesics, Opioid; D009292:Narcotic Antagonists; D017465:Receptors, Opioid, delta; D017473:Receptors, Opioid, kappa; D017450:Receptors, Opioid, mu; D009020:Morphine