PKC and PKA inhibitors reverse acute tolerance to low‐ and moderate‐ but not high‐efficacy mu‐opioid agonists

Abstract

The present study was designed to investigate possible differing mechanisms of tolerance to opioids of various efficacies. We, as well as others, have shown that the administration of highly selective inhibitors of protein kinase C (PKC) and A (PKA) completely reversed morphine antinociceptive tolerance in mice. We now have investigated whether these inhibitors reverse tolerance to other opioids of low and high efficacy. An 8‐hr model of acute tolerance was used in which the test opioid was administered repeatedly at a dose which yielded maximum antinociception in naïve mice. Animals were then challenged with increasing doses of the test opioid with and without the PKC and PKA inhibitors to construct a dose response curve. The 8‐hr tolerance to the low‐efficacy μ‐agonist meperidine and the moderate‐efficacy μ‐agonists, morphine and fentanyl was fully reversed by the PKC inhibitors Bisindolymaleimide I, and Gö6976 as well as the PKA inhibitor PKI 14‐22. However tolerance to DAMGO, a highly efficacious μ‐opioid agonist, was not reversed by injection of either the PKC inhibitor Gö6976 or the PKA inhibitor PKI 14‐22 suggesting that μ‐opioid receptor desensitization induced by high‐efficacy μ‐agonists is independent of PKC or PKA activation. It can be concluded that the mechanisms underlying μ‐opioid receptor desensitization may be determined by the agonist activating the receptor. Supported by DA01647 and DA020836.