Opioid agonist efficacy predicts the magnitude of tolerance and the regulation of μ-opioid receptors and dynamin-2

Abstract

It has been proposed that opioid agonist efficacy may play a role in tolerance and the regulation of opioid receptor density. To address this issue, the present studies estimated the in vivo efficacy of three opioid agonists and then examined changes in spinal mu-opioid receptor density following chronic treatment in the mouse. In addition, tolerance and regulation of the trafficking protein dynamin-2 were determined. To evaluate efficacy, the method of irreversible receptor alkylation was employed and the efficacy parameter tau estimated. Mice were injected with the irreversible mu-opioid receptor antagonist clocinnamox (0.32-25.6 mg/kg, i.p), and 24 h later, the analgesic potency of s.c. morphine, oxycodone and etorphine were determined. Clocinnamox dose-dependently antagonized the analgesic effects of morphine, etorphine and oxycodone. The shift to the right of the dose-response curves was greater for morphine and oxycodone compared to etorphine and the highest dose of clocinnamox reduced the maximal effect of morphine and oxycodone, but not etorphine. The order of efficacy calculated from these results was etorphine>morphine>oxycodone. Other mice were infused for 7 days with oxycodone (10-150 mg/kg/day, s.c.) or etorphine (50-250 microg/kg/day, s.c.) and the analgesic potency of s.c. morphine determined. The low efficacy agonist (oxycodone) produced more tolerance than the high efficacy agonist (etorphine) at equi-effective infusion doses. In saturation binding experiments, the low efficacy opioid agonists (morphine, oxycodone) did not regulate the density of spinal mu-opioid receptors, while etorphine produced approximately 40% reduction in mu-opioid receptor density. Furthermore, etorphine increased spinal dynamin-2 abundance, while oxycodone did not produce any significant change in dynamin-2 abundance. Overall, these data indicate that high efficacy agonists produce less tolerance at equi-effective doses. Furthermore, increased efficacy was associated with mu-opioid receptor downregulation and dynamin-2 upregulation. Conversely, lower efficacy agonists produced more tolerance at equi-effective doses, but did not regulate mu-opioid receptor density or dynamin-2 abundance. Taken together, these studies indicate that agonist efficacy plays an important role in tolerance and regulation of receptors and trafficking proteins.

The Role of Amygdalar Mu-Opioid Receptors in Anxiety-Related Responses in Two Rat Models

“…We allowed a week before testing for postsurgical recovery, and to insure that this single injection of the weak partial agonist nalbuphine would not influence our results with MOR agonists or antagonists. Studies have shown that nalbuphine is a relatively weak partial agonist at MORs (Traynor et al, 2002), and that there is little change in MOR binding even after continuous 7-day exposure to more potent agonists in vivo (Pawar et al, 2007).…”

Agonist-Specific Regulation of μ-Opioid Receptor Desensitization and Recovery from Desensitization

“…It is widely speculated that differences in short-term MOR regulatory events underlie the profound agonist-selective differences observed in the development of tolerance in vivo (Whistler et al, 1999;Stafford et al, 2001;Walker and Young, 2001;Patel et al, 2002;Grecksch et al, 2006;Pawar et al, 2007). There is no consensus, however, on which elements of MOR regulation-signaling efficacy, desensitization, internalization, or resensitization-are most directly correlated with tolerance (Whistler et al, 1999;Bohn et al, 2000;Williams et al, 2001;Connor et al, 2004;von Zastrow, 2004;Bailey and Connor, 2005;Koch et al, 2005).…”

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

“…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 Keith et al, 1998;Whistler and von Zastrow, 1998).…”

“…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 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 Lesscher et al, 2003;Patel et al, 2003) and increase the potency of opioid agonists (functional supersensitivity) (Yoburn and Inturrisi, 1988;Yoburn et al, 1989Yoburn et al, , 1995.…”

“…It seemed likely that antagonist efficacy might determine up-regulation and supersensitivity given that previous studies indicate that agonist efficacy plays a role in -opioid receptor down-regulation and tolerance (e.g., Pawar et al, 2007). Although data indicate that antagonistinduced up-regulation and agonist-induced down-regulation are mechanistically distinct (e.g., Yoburn et al, 2004;Pawar et al, 2007), the evidence linking agonist efficacy, tolerance, and receptor regulation is compelling (Patel et al, 2002;Pawar et al, 2007), and some studies have suggested that antagonist efficacy may be important in up-regulation and supersensitivity (Morris and Millan, 1991;Milligan and Bond, 1997). Therefore, it seemed plausible that antagonist efficacy might have an impact on -opioid receptor up-regulation and functional supersensitivity.…”