A MITOGEN-ACTIVATED PROTEIN-KINASE PATHWAY IS REQUIRED FOR MU-OPIOID RECEPTOR DESENSITIZATION

The mu-opioid receptor mediates not only the beneficial painkilling ef fects of opiates like morphine but also the detrimental effects of chr onic exposure such as tolerance and dependence. Different studies have linked tolerance to opioid receptor desensitization. Agonist activati on of the mu-opioid receptor stimulates a mitogen-activated protein ki nase (MAPK) activity, but the functional significance of this pathway remains unclear. We have focused on the MAPK signaling cascade to stud y mu-opioid receptor desensitization. We report that inhibition of the MAPK pathway blocks desensitization of mu-opioid receptor signaling a s well as the loss of receptor density due to internalization. Our res ults suggest that a feedback signal emanating from the MAPK cascade is required for mu-opioid receptor desensitization.