ABSTRACT
Oxidative stress following administration of morphine sulfate [MS] and related opioids involves activation of central nervous system opioid receptors coupled to depletion of the intracellular antioxidant gamma-glutamylcysteinylglycine [glutathione, GSH] in peripheral organs. Precise biochemical and molecular regulatory mechanisms underlying this novel central nervous system-peripheral organ physiological pathway remain to be fully elucidated. Employing a rodent model of MS-induced oxidative stress, we observed significant reduction in kidney GSH levels associated with induction of JNK and p38 mitogen-activated protein kinase [MAPK] activities, we monitored the effect of central MS administration on these biochemical parameters in kidney. We observed that p38 MAPK and JNK are inactive in kidney tissues. Following central MS administration, both p38 MAPK and JNK activities were significantly induced but were found to be temporally uncoupled. Pretreatment of rats with the GSH precursor N- acetylcysteine [NAC] prior to central MS administration resulted in inhibition of renal GSH depletion, and p38 MAPK activation. In contrast, JNK activation was potentiated by NAC pretreatment. The dependency of p38 MAPK [but not JNK] activation on intracellular GSH concentration indicates differential and potentially novel opioid regulation of transcriptional events in the kidney. We propose a model by which the p38 MAPK pathway is a specific sensor/effector of intracellular redox/GSH potential