Differential tolerance to antinociceptive effects of mu opioids during repeated treatment with etonitazene, morphine, or buprenorphine in rats

Rationale: Repeated treatment experiments with high and low efficacy agonis ts provide critical insight into possible mechanisms underlying development of opioid tolerance. Objective: Experiments in a tail-withdrawal assay tes ted the hypothesis that magnitude of tolerance to antinociceptive effects i s inversely related to agonist relative efficacy in rats intermittently tre ated with etonitazene, morphine, or buprenorphine. Methods. The antinocicep tive effects of five mu opioid agonists were tested in male, Sprague-Dawley rats in a warm-water tail-withdrawal assay. To induce tolerance, escalatin g doses of the higher efficacy agonist etonitazene, the high efficacy agoni st morphine, or the lower efficacy agonist buprenorphine were administered twice daily for 2-8 weeks. Results: Etonitazene, etorphine, morphine, bupre norphine, and GPA 1657 [(1)-beta -2'-hydroxy-2,9-dimethyl-5-phenyl-6,7-benz omorphan] produced dose-dependent increases in tail-withdrawal latency unti l 100% maximum possible effect (%MPE) was obtained. Treatment with escalati ng doses of etonitazene, morphine, or buprenorphine produced greater tolera nce to the lower efficacy agonists buprenorphine and GPA 1657 than to the h igher efficacy agonists etonitazene, etorphine, and morphine. Treatment wit h buprenorphine, a lower efficacy agonist, produced greater tolerance than did treatment with equivalent doses of the higher efficacy agonists morphin e or etonitazene. Conclusions: Taken together, these data suggest that magn itude of antinociceptive tolerance is inversely related to relative efficac y of mu agonists, with lower efficacy agonists being more susceptible to to lerance than are higher efficacy agonists under these intermittent dosing c onditions.