Regulation of extracellular signal-regulated kinases (ERKs) by naloxone-induced morphine withdrawal in the brain stress system

Our previous studies have shown that morphine withdrawal increases the hypothalamic–pituitary–adrenocortical axis activity, which is dependent on a hyperactivity of noradrenergic pathways (nucleus tractus solitarius-A₂) innervating the hypothalamic paraventricular nucleus. The extracellular signal-regulated kinase has been implicated in drug addiction, but its role in activation of paraventricular nucleus and nucleus tractus solitarius during morphine dependence remain poorly understood. We have determined the activation of extracellular signal-regulated kinase during morphine dependence and withdrawal as well as its involvement in morphine withdrawal-induced gene expression. We show that naloxone-induced morphine withdrawal activates extracellular signal-regulated kinases_1/2 and increases c-Fos expression in rat paraventricular nucleus and nucleus tractus solitarius-A₂ neurons. Activated extracellular signal-regulated kinases_1/2 was colocalized with c-Fos in both nuclei, and this response was blocked by SL327, a drug that prevents extracellular signal-regulated kinase activation. In the paraventricular nucleus from morphine-withdrawn rats, the number of neurons expressing CRF was increased. Immunohistochemical study showed a dramatic increase in c-Fos immunoreactivity within CRF-positive cells. These results suggest that extracellular signal-regulated kinases1/2 signaling pathway is necessary for morphine withdrawal-induced activation of brain areas associated with the stress system.