Locus‐Specific Involvement of Anti‐Opioid Systems in Morphine Tolerance and Dependence

A bstract : Opioid tolerance and addiction could be discussed as two types of plasticity or counteradaptation, at the cellular level and through neuronal circuits. Cellular counteradaptation mechanisms include receptor desensitization through phosphorylation and endocytosis and through altered gene expression. The former mechanisms are related to the acute tolerance mechanisms, while the latter to chronic one. From current studies, it is known that various phosphorylation steps, such as protein kinase C (PKC) and G protein‐coupled receptor (GPCR) kinase (GRK) regulate endocytosis. Of interest is that there are some differences in the physiological roles between opioid receptor endocytosis and other GPCR ones. Endocytosis of the opioid receptor is conceived as a recycling and resensitization step rather than the desensitization step. PKC phosphorylation inhibits endocytosis (PKC hypothesis). Therefore the PKC inhibitor attenuates acute analgesic tolerance. The agonist, which shows high‐endocytosis stimulation, therefore makes less significant tolerance liability (RAVE hypothesis). Chronic tolerance is more likely related to the mechanisms through plastic modulation of neuronal circuits, where anti‐opioidergic neurons are involved. The knockout mice lacking the receptors for anti‐opioidergic nociceptin/orphanin FQ (N/OFQ) or glutamatergic neurons show weak or no morphine tolerance and dependence. As their gene expression or protein expression increases during chronic morphine treatments, we propose the hypothesis that the enhanced anti‐opioid system may cause a counteradaptation to show tolerance and dependence. By a novel electroporation technique to deliver the receptor into the brain of knockout mice, we succeeded in determining the specific locus for the site of anti‐opioid (through GluRε1 or NR2A) action. All these results suggest that enhanced anti‐opioid systems may contribute to the development of morphine tolerance and dependence, and their contributions could be brain locus specific.