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

Chronic opioid antagonist treatment up-regulates opioid recep-tors 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 antago-nist (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 -opioid receptor density was examined, or morphine analgesia dose