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NEUROPHARMACOLOGY

µ-Opioid Receptor Up-Regulation and Functional Supersensitivity Are Independent of Antagonist Efficacy

Department of Pharmaceutical Sciences, College of Pharmacy and Allied Health Professions, St. John's University, Queens, New York

Chronic opioid antagonist treatment up-regulates opioid receptors and produces functional supersensitivity. Although opioid antagonists vary from neutral to inverse, the role of antagonist efficacy in mediating the chronic effects of opioid antagonists is not known. In this study, the effects of two putative inverse agonists (naltrexone, naloxone) and a putative neutral antagonist (6-naltrexol) were examined. Initially, peak effect (40 min, naltrexone and naloxone; 70 min, 6-naltrexol) and relative potency to antagonize morphine analgesia were determined (relative potencies = 1, 2, and 16, 6-naltrexol, naloxone, and naltrexone, respectively). Next, mice were infused for 7 days with naloxone (0.1–10 mg/kg/day), naltrexone (10 or 15 mg s.c. pellet), or 6-naltrexol (0.2–20 mg/kg/day), and spinal µ-opioid receptor density was examined, or morphine analgesia dose-response studies were conducted. All antagonists up-regulated µ-opioid receptors (60–122%) and induced supersensitivity (1.8–2.0-fold increase in morphine potency). There were no differences in antagonist potency to produce up-regulation or supersensitivity. These data suggest that opioid antagonist-induced µ-opioid receptor up-regulation and supersensitivity require occupancy of the receptor and that antagonist efficacy is not critical. Finally, the ED₅₀ to precipitate withdrawal jumping was examined in morphine-dependent mice. Naltrexone, naloxone, and 6-naltrexol produced withdrawal jumping, although potencies relative to 6-naltrexol were 211, 96, and 1, respectively. Thus, antagonist potency to precipitate opioid withdrawal was related to inverse agonist efficacy. Overall, the estimated relative potency of the opioid antagonists was a function of the outcome measured, and inverse agonist activity was not required for µ-opioid receptor up-regulation and supersensitivity.

Address correspondence to: Dr. Byron C. Yoburn, Department of Pharmaceutical Sciences, College of Pharmacy and Allied Health Professions, St. John's University, 8000 Utopia Parkway, Queens, NY 11439. E-mail: yoburnb{at}stjohns.edu

This article has been cited by other articles:

				S. Sirohi, S. V. Dighe, P. A. Madia, and B. C. Yoburn The Relative Potency of Inverse Opioid Agonists and a Neutral Opioid Antagonist in Precipitated Withdrawal and Antagonism of Analgesia and Toxicity J. Pharmacol. Exp. Ther., August 1, 2009; 330(2): 513 - 519. [Abstract] [Full Text] [PDF]