Nalbuphine, a mixed kappa 1 and kappa 3 analgesic in mice.
Nalbuphine is a mixed opioid agonist/antagonist analgesic. It labels mu receptors most potently where it acts as an antagonist. Nalbuphine is analgesic in the tail-flick assay after systemic (ED50, 41.8 mg/kg s.c.), i.c.v. (ED50, 21.3 micrograms) or intrathecal administration (ED50, 11.2 micrograms). Analgesia elicited by systemic nalbuphine was reversed by nor-binaltorphimine, but not by beta-funaltrexamine or naltrindole despite their ability to antagonize morphine and [D-Pen2,D-Pen5]enkephalin analgesia, respectively. This insensitivity toward beta-funaltrexamine and naltrindole argued strongly against either a mu or delta component of analgesia. Nor-binaltorphimine antagonized systemic nalbuphine analgesia over 10-fold more potently after intrathecal injection of the antagonist than after i.c.v. administration, implying a role for kappa 1 receptors at the spinal level. The presence of analgesic cross-tolerance between nalbuphine and both naloxone benzoylhydrazone and nalorphine indicated an analgesic role for kappa 3 receptors, which act supraspinally. Additional studies revealed synergistic interactions between spinal kappa 1 and supraspinal kappa 3 receptors when nalbuphine was given both intrathecally and i.c.v. In conclusion, these studies suggest that nalbuphine elicits analgesia through a complex interaction of supraspinal kappa 3 and spinal kappa 1 mechanisms.
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Cotzias Laboratory of Neuro-Oncology, Memorial Sloan-Kettering Cancer Center, New York, New York.
Paul
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Pasternak
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D000698:Analgesia; D000818:Animals; D004305:Dose-Response Relationship, Drug; D007278:Injections, Spinal; D008297:Male; D051379:Mice; D009266:Nalbuphine / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D009271:Naltrexone / Q000031:analogs & derivatives* / Q000494:pharmacology; D009292:Narcotic Antagonists / Q000494:pharmacology*; D011957:Receptors, Opioid / Q000187:drug effects*; D017473:Receptors, Opioid, kappa
D009292:Narcotic Antagonists; D011957:Receptors, Opioid; D017473:Receptors, Opioid, kappa; D009271:Naltrexone; C024524:beta-funaltrexamine; D009266:Nalbuphine