Role of alpha2/delta subunit in the development of morphine-induced rewarding effect and behavioral sensitization

Previous data demonstrate that L-type voltage-gated calcium channel (VGCC) blockers, which bind to alpha(1) subunits of VGCC to suppress Ca(2+) entry into cells, inhibit the development of psychological dependence on drugs of abuse, suggesting the upregulation of L-type VGCC in the development of psychological dependence. However, there are few available data on changes of the auxiliary subunit alpha(2)/delta modifying L-type VGCC under such conditions. We therefore investigated here the role of alpha(2)/delta subunits of VGCCs in the brain of mouse after repeated treatment with morphine. The treatment with morphine increased alpha(2)/delta subunit expression in the frontal cortex and the limbic forebrain of mice showing rewarding effect and sensitization to hyperlocomotion by morphine. The morphine-induced behavioral sensitization and place preference were also suppressed by gabapentin, which binds to an exofacial epitope of the alpha(2)/delta auxiliary subunits of VGCCs. These findings indicate that the upregulation of alpha(2)/delta subunit as well as alpha(1) subunits of VGCC in the frontal cortex and the limbic forebrain plays a critical role in development of morphine-induced rewarding effect and behavioral sensitization following neuronal plasticity.