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

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 -opioid receptor density was examined, or morphine analgesia doseresponse studies were conducted. All antagonists up-regulated -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 -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 -opioid receptor up-regulation and supersensitivity. Receptor density regulation is a well documented phenomenon in the opioid system (e.g., Yoburn et al., 1986; Keith et al., 1996, 1998; Patel et al., 2002). Both opioid agonists and antagonists have been shown to regulate -opioid receptor density (Chakrabarti et al., 1997; Zaki et al., 2000; Rajashekara et al., 2003), and these changes can have an impact on the potency of opioid agonists (e.g., Stafford et al., 2001; Patel et al., 2003). The efficacy of an opioid agonist has been proposed to play an important role in -opioid receptor regulation (Patel et al., 2002; Pawar et al., 2007). For example, chronic treatment with high-efficacy agonists (e.g., etorphine, DAMGO) can induce internalization and down-regulation of -opioid receptors in vitro and in vivo (Duttaroy and Yoburn, 1995; Keith et al., 1998; Whistler and von Zastrow, 1998). Conversely, low-efficacy agonists (e.g., morphine, oxycodone) are less likely to produce either internalization or down-regulation (Keith et al., 1998; Pawar et al., 2007; however, see Haberstock-Debic et al., 2005). Chronic treatment with opioid antagonists (e.g., naltrexone, naloxone) has been shown to up-regulate -, -, and -opioid receptors (Yoburn et al., 1995; Lesscher et al., 2003; Patel et al., 2003) and increase the potency of opioid agonists (functional supersensitivity) (Yoburn and Inturrisi, 1988; Yoburn et al., 1989,