Phosphatidylinositol‐3 kinase is distinctively required for µ‐, but not κ‐opioid receptor‐induced activation of c‐Jun N‐terminal kinase

Opioid receptors are the therapeutic targets of narcotic analgesics. All three types of opioid receptors (µ, δ and κ) are prototypical G i ‐coupled receptors with common signaling characteristics in their regulation of intracellular events. Nevertheless, numerous signaling processes are differentially regulated by the three receptors. We have recently demonstrated that stimulation of δ‐opioid receptor can up‐regulate the activity of the c‐Jun N‐terminal kinase (JNK) in a pertussis toxin‐sensitive manner (Kam et al . 2003; J. Neurochem . 84, 503–513). The present study revealed that the µ‐opioid receptor could stimulate JNK in both SH‐SY5Y cells and transfected COS‐7 cells. The mechanism by which the µ‐opioid receptor stimulated JNK was delineated with the use of specific inhibitors and dominant‐negative mutants of signaling intermediates. Activation of JNK by the µ‐opioid receptor was mediated through Gβγ, Src kinase, son‐of‐sevenless (Sos), Rac and Cdc42. Interestingly, unlike the δ‐opioid receptors, the µ‐opioid receptor required phosphatidylinositol‐3 kinase (PI3K) to activate JNK. The µ‐opioid receptor‐induced JNK activation was effectively inhibited by wortmannin or the coexpression of a dominant negative mutant of PI3Kγ. Like the δ‐opioid receptor, activation of JNK by the κ‐opioid receptor occurred in a PI3K‐independent manner. These studies revealed that the µ‐opioid receptor utilize a distinct mechanism to regulate JNK.