title: Kappa 3 receptors and levorphanol-induced analgesia.
abstract: Levorphanol is a widely used opiate analgesic. Although structurally related to morphine, levorphanol has high affinity for a number of receptor subtypes, including both kappa 1 and kappa 3. Prior reports had implicated a kappa component of levorphanol-induced antinociception. Evidence is now presented suggesting that levorphanol-induced analgesia is produced by a mixture of mu and kappa 3 mechanisms. Levorphanol was a potent analgesic in the tail-flick assay, when given systemically, spinally or supraspinally. Isobolographic analysis of the combined administration of levorphanol, spinally and supraspinally implied synergistic interactions. Naloxonazine reduced levorphanol-induced analgesia, implicating a role for mu1 receptors. The kappa 1 antagonist nor-binaltorphimine at a dose which reversed analgesia induced by U50,488H did not antagonize levorphanol-induced analgesia. Additional studies revealed no cross tolerance in either direction, between levorphanol with the kappa 1 analgesic U50,488H. Together, these results strongly argue against a role for kappa 1 receptors in levorphanol-induced analgesia. However, mice tolerant to the kappa 3 analgesic, naloxone benzoylhydrazone (NalBzoH), showed cross tolerance to levorphanol, implying a role of kappa 3 mechanisms in levorphanol-induced analgesia.
authors.affiliation: Cotzias Laboratory of Neuro-Oncology, Memorial Sloan-Kettering Cancer Center, New York, NY 10021.
authors.forename: L
authors.initials: L
authors.lastname: Tive
authors.forename: K
authors.initials: K
authors.lastname: Ginsberg
authors.forename: C G
authors.initials: CG
authors.lastname: Pick
authors.forename: G W
authors.initials: GW
authors.lastname: Pasternak
mesh_terms: D000698:Analgesia; D000700:Analgesics / Q000494:pharmacology; D000818:Animals; D004305:Dose-Response Relationship, Drug; D004361:Drug Tolerance; D007276:Injections, Intraventricular; D007981:Levorphanol / Q000494:pharmacology*; D008297:Male; D051379:Mice; D011930:Reaction Time / Q000187:drug effects; D017473:Receptors, Opioid, kappa / Q000037:antagonists & inhibitors / Q000187:drug effects*
chemical_list: D000700:Analgesics; D017473:Receptors, Opioid, kappa; D007981:Levorphanol