Nalbuphine, a mixed kappa 1 and kappa 3 analgesic in mice

CG Pick, D Paul and GW Pasternak

Cotzias Laboratory of Neuro-Oncology, Memorial Sloan-Kettering Cancer Center, New York, New York.

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.

Volume 262, Issue 3, pp. 1044-1050, 09/01/1992
Copyright © 1992 by American Society for Pharmacology and Experimental Therapeutics

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