Development of tolerance and sensitization to different opioid agonists in rats

Rationale: Despite numerous investigations, the mechanisms underlying the development of opioid tolerance are far from clear. However, several in vitro studies implicated a protective role of agonist-induced mu-opioid receptor endocytosis in the development of opioid tolerance. Moreover, we have recently demonstrated that the high-efficacy agonist etonitazene promotes rapid endocytosis of mu-opioid receptors, whereas the agonist morphine and the low-efficacy agonist buprenorphine fail to promote detectable receptor endocytosis in mu-opioid receptor expressing HEK293 cells. Objectives: The present study explored the effects of these opioids on the development of tolerance and sensitization in rats in vivo. Methods: The opioid effects were quantified using the hot plate, electric tail root stimulation, and the locomotor activity chamber in male Wistar rats. Dose-response curves were generated for each test drug. To induce tolerance, equieffective doses of etonitazene, morphine, and buprenorphine were administered daily for 29 days. Results: We found that chronic treatment with the noninternalizing drugs buprenorphine and morphine resulted in a greater development of tolerance than etonitazene. In addition, the sensitization to the locomotor stimulant effect was high after buprenorphine and morphine, but was lacking after chronic etonitazene application. Conclusion: The results support a role for the endocytotic potency of agonists in the development of tolerance and addiction during long-term opioid treatment.