Neuropharmacology and AnalgesiaUp-regulation of Cav1.2 subunit via facilitating trafficking induced by Vps34 on morphine-induced place preference in mice

In the present study, we investigated the role of Vps34, a kinase classified into PI 3-kinase class III, in the brain of mouse after repeated in vivo treatment with morphine. The intracerebroventricular (i.c.v.) administration of nifedipine caused a dose-dependent inhibition of morphine-induced place preference. The protein levels of Vps34 in the frontal cortex including the cingulate cortex and the limbic forebrain including the nucleus accumbens significantly increased in morphine-induced place preference. I.c.v. administration of PI 3-kinase inhibitors such as wortmannin and LY294002 inhibited morphine-induced place preference in a dose-dependent manner. Cav1.2 protein level of L-type voltage-dependent calcium channels significantly increased in the frontal cortex and the limbic forebrain of the morphine psychologically dependent mice, which was significantly inhibited by PI 3-kinase inhibitors. Similar changes in the expression of Cav1.2 and Vps34 proteins are found in the primary culture of cerebral cortical neurons during short-term exposure to morphine. Under such conditions, facilitated translocation of Cav1.2 to the plasma membrane remarkably increased by the treatment of the cultured neurons with morphine when measuring protein level of Cav1.2, and such changes in Cav1.2 were also suppressed by PI 3-kinase inhibitors. These findings indicate a critical role of Vps34 in the up-regulation of Cav1.2 in the neuronal plasma membrane and the development of morphine-induced place preference.