title: A subanalgesic dose of morphine eliminates nalbuphine anti-analgesia in postoperative pain.
abstract: The agonist-antagonist kappa-opioid nalbuphine administered for postoperative pain produces greater analgesia in females than in males. In fact, males administered nalbuphine (5 mg) experience pain greater than those receiving placebo, suggesting the existence of an anti-analgesic effect. These sexually dimorphic effects on postoperative pain can be eliminated by coadministration of a fixed ratio of the prototypical opioid receptor antagonist naloxone with nalbuphine, implying a role for opioid receptors in the anti-analgesic as well as analgesic effects of nalbuphine. In the present study, we further evaluated the role of opioid receptors in the sex-specific effects on pain produced by nalbuphine by coadministering a dose of morphine low enough that it does not produce analgesia. After extraction of bony impacted third molar teeth, nalbuphine (5 mg) was administered alone or in combination with either of 2 low doses of morphine (2 mg or 4 mg). Both doses of morphine reversed nalbuphine-induced anti-analgesia in males, but only the lower dose (2 mg) reached statistical significance. Neither dose affected nalbuphine-induced analgesia in females, and when administered alone in either males or females, morphine (2 mg) had no analgesic effect. Though not observed in females, the effect of morphine in males argues that, like naloxone, low-dose morphine may act as an anti-analgesia opioid receptor antagonist.
  
  
  CONCLUSIONS
  Previously, we reported that the nalbuphine produces both analgesic and anti-analgesic effects and that the opioid antagonist naloxone can enhance nalbuphine analgesia by selectively antagonizing the anti-analgesic effect. Here we show that morphine, given in a subanalgesic dose, reverses nalbuphine-induced anti-analgesia in males, perhaps by a similar mechanism.
authors.affiliation: Department of Oral and Maxillofacial Surgery, University of California, San Francisco, California 94143-0440, USA.
authors.forename: Robert W
authors.initials: RW
authors.lastname: Gear
authors.forename: Newton C
authors.initials: NC
authors.lastname: Gordon
authors.forename: Mehran
authors.initials: M
authors.lastname: Hossaini-Zadeh
authors.forename: Janice S
authors.initials: JS
authors.lastname: Lee
authors.forename: Christine
authors.initials: C
authors.lastname: Miaskowski
authors.forename: Steven M
authors.initials: SM
authors.lastname: Paul
authors.forename: Jon D
authors.initials: JD
authors.lastname: Levine
mesh_terms: D000293:Adolescent; D000328:Adult; D000701:Analgesics, Opioid / Q000009:adverse effects / Q000037:antagonists & inhibitors; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D004338:Drug Combinations; D004347:Drug Interactions / Q000502:physiology; D005260:Female; D006801:Humans; D008297:Male; D009020:Morphine / Q000008:administration & dosage*; D009266:Nalbuphine / Q000009:adverse effects* / Q000037:antagonists & inhibitors; D009292:Narcotic Antagonists / Q000009:adverse effects*; D010149:Postoperative Pain / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D011957:Receptors, Opioid / Q000187:drug effects* / Q000378:metabolism; D012727:Sex Characteristics; D012737:Sex Factors
chemical_list: D000701:Analgesics, Opioid; D004338:Drug Combinations; D009292:Narcotic Antagonists; D011957:Receptors, Opioid; D009020:Morphine; D009266:Nalbuphine