buprenorphine and etonitazene

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 micro-opioid receptor endocytosis in the development of opioid tolerance. Moreover, we have recently demonstrated that the high-efficacy agonist etonitazene promotes rapid endocytosis of micro-opioid receptors, whereas the agonist morphine and the low-efficacy agonist buprenorphine fail to promote detectable receptor endocytosis in micro-opioid receptor expressing HEK293 cells.. The present study explored the effects of these opioids on the development of tolerance and sensitization in rats in vivo.. 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.. We found that chronic treatment with the non-internalizing 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.. The results support a role for the endocytotic potency of agonists in the development of tolerance and addiction during long-term opioid treatment.

Topics: Analgesics, Opioid; Animals; Behavior, Animal; Benzimidazoles; Buprenorphine; Dose-Response Relationship, Drug; Drug Tolerance; Electric Stimulation; Endocytosis; Hot Temperature; Hyperalgesia; Male; Morphine; Motor Activity; Rats; Rats, Wistar; Receptors, Opioid, mu

Repeated treatment experiments with high and low efficacy agonists provide critical insight into possible mechanisms underlying development of opioid tolerance.. Experiments in a tail-withdrawal assay tested the hypothesis that magnitude of tolerance to antinociceptive effects is inversely related to agonist relative efficacy in rats intermittently treated with etonitazene. morphine, or buprenorphine.. The antinociceptive effects of five mu opioid agonists were tested in male, Sprague-Dawley rats in a warm-water tail-withdrawal assay. To induce tolerance, escalating doses of the higher efficacy agonist etonitazene, the high efficacy agonist morphine, or the lower efficacy agonist buprenorphine were administered twice daily for 2-8 weeks.. Etonitazene, etorphine, morphine, buprenorphine, and GPA 1657 [(1)-beta-2'-hydroxy-2,9-dimethyl-5-phenyl-6,7-benzomorphan] produced dose-dependent increases in tail-withdrawal latency until 100% maximum possible effect (%MPE) was obtained. Treatment with escalating doses of etonitazene, morphine, or buprenorphine produced greater tolerance to the lower efficacy agonists buprenorphine and GPA 1657 than to the higher efficacy agonists etonitazene, etorphine, and morphine. Treatment with buprenorphine, a lower efficacy agonist, produced greater tolerance than did treatment with equivalent doses of the higher efficacy agonists morphine or etonitazene.. Taken together, these data suggest that magnitude of antinociceptive tolerance is inversely related to relative efficacy of mu agonists, with lower efficacy agonists being more susceptible to tolerance than are higher efficacy agonists under these intermittent dosing conditions.

Topics: Analgesics; Analgesics, Opioid; Animals; Benzimidazoles; Buprenorphine; Dose-Response Relationship, Drug; Drug Tolerance; Male; Morphine; Narcotics; Pain Measurement; Rats; Rats, Sprague-Dawley; Receptors, Opioid, mu