Protein Kinase C Activation Enhances Morphine-Induced Rapid Desensitization of μ-Opioid Receptors in Mature Rat Locus Ceruleus Neurons

Abstract

Recent studies have shown that morphine, in contrast to other agonists at the μ-opioid receptor, causes very little rapid μ-opioid receptor desensitization or internalization in adult rat mammalian neurons, raising important questions about how morphine tolerance is induced. Here we show that morphine can indeed cause marked rapid desensitization of μ-opioid receptors in mature rat locus ceruleus neurons when protein kinase C is also activated. Thus, activation of Gq-coupled M₃ muscarinic receptors or application of a phorbol ester enhanced the desensitization of the μ-opioid receptor-evoked potassium current in rat locus ceruleus neurons. The enhancement of desensitization was reversible by the protein kinase C inhibitors chelerythrine and 2-[1-(3-dimethylaminopropyl)-1H-indol-3-yl]-3-(1H-indol-3-yl)-maleimide (GF109203X) and resulted from an effect at the level of the μ-opioid receptor rather than the potassium channel. This is the first finding that morphine can induce rapid μ-opioid receptor desensitization in adult rat neurons, and because reduced protein kinase C activity in vivo attenuates morphine tolerance, we propose that G-protein coupled receptor cross-talk and the level of protein kinase C activity may play critical roles in the desensitization of the μ-opioid receptor and could underlie the development of morphine tolerance.