Role of α2/δ 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 α1 subunits of VGCC to suppress Ca2+ 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 α2/δ modifying L-type VGCC under such conditions. We therefore investigated here the role of α2/δ subunits of VGCCs in the brain of mouse after repeated treatment with morphine. The treatment with morphine increased α2/δ 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 α2/δ auxiliary subunits of VGCCs. These findings indicate that the upregulation of α2/δ subunit as well as α1 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.