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

J Pharmacol Exp Ther. 1992 Sep;262(3):1044-50.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Analgesia*
  • Animals
  • Dose-Response Relationship, Drug
  • Injections, Spinal
  • Male
  • Mice
  • Nalbuphine / antagonists & inhibitors
  • Nalbuphine / pharmacology*
  • Naltrexone / analogs & derivatives*
  • Naltrexone / pharmacology
  • Narcotic Antagonists / pharmacology*
  • Receptors, Opioid / drug effects*
  • Receptors, Opioid, kappa

Substances

  • Narcotic Antagonists
  • Receptors, Opioid
  • Receptors, Opioid, kappa
  • Naltrexone
  • beta-funaltrexamine
  • Nalbuphine