TY - JOUR T1 - The Effect of PKC and GRK Inhibition on Tolerance Induced by μ-opioid Agonists of Different Efficacy JF - Journal of Pharmacology and Experimental Therapeutics JO - J Pharmacol Exp Ther DO - 10.1124/jpet.109.161455 SP - jpet.109.161455 AU - Lynn Christine Hull AU - Javier Llorente AU - Bichoy H Gabra AU - Forrest L Smith AU - Eamonn Kelly AU - Christopher Bailey AU - Graeme Henderson AU - William Dewey Y1 - 2009/01/01 UR - http://jpet.aspetjournals.org/content/early/2009/12/14/jpet.109.161455.abstract N2 - Differences in the mechanisms underlying tolerance and μ-opioid receptor desensitization resulting from exposure to opioid agonists of different efficacy have previously been suggested. The objective of this study was to determine the effects of PKC and GRK inhibition on antinociceptive tolerance in vivo to opioid agonists of different efficacy. A rapid (8-hr) tolerance-induction model was used where each opioid was repeatedly administered to naive mice. Animals were then challenged with the opioid following injection of a kinase inhibitor to determine its effects on the level of tolerance. Tolerance to meperidine, morphine or fentanyl was fully reversed by the PKC inhibitor Go6976. However, in vivo tolerance to [D-Ala2, N-Me-Phe4, Gly-ol5]-enkephalin (DAMGO) was not reversed by PKC inhibition. The novel small molecule GRK inhibitors, β-ARK1 and Ro 32-0432, did not reverse the tolerance to meperidine, fentanyl or morphine but did reverse the tolerance to DAMGO. To correlate GRK-dependent DAMGO-induced tolerance with μ-opioid receptor desensitization we used. in vitro whole cell patch clamp recording from mouse locus coeruleus neurons and observed that the GRK inhibitors reduced DAMGO-induced desensitization of μ-opioid receptors while the PKC inhibitor had no effect. These results suggest that tolerance induced by low- and moderate-efficacy μ-opioid receptor agonists is dependent on PKC while tolerance induced by the high-efficacy agonist, DAMGO, is dependent on GRK.The American Society for Pharmacology and Experimental Therapeutics ER -