Phosphorylation of neurogranin, protein kinase C, and Ca2+/calmodulin dependent protein kinase II in opioid tolerance and dependence.

Activation of Ca2+/calmodulin dependent protein kinase II (CaMKII) and protein kinase C (PKC) are hallmarks of opioid tolerance and dependence. It is not known if the actions of these two kinases are synchronized by a common mechanism in opioid tolerance and dependence. Neurogranin (Ng), through mechanisms such as phosphorylation, has been previously proposed to regulate the activities of these protein kinases. We examined the phosphorylation status of neurogranin in mice that were made tolerant to opioids by morphine (100 mg/kg, s.c.). Increase in phosphorylation of neurogranin was found both in brains and spinal cords of morphine-treated mice, as compared to the untreated baseline or saline-treated mice. The effect appeared to correlate with the changes in the activities of PKC and CaMKII, and with the development of opioid tolerance and dependence. We have found that neurogranin activity is regulated in opioid tolerance and dependence. Neurogranin may, therefore, provide a potential mechanism interacting with both CaMKII and PKC in opioid tolerance and dependence.