Up-regulation of the G q/11α protein and protein kinase C during the development of sensitization to morphine-induced hyperlocomotion

Abstract

It has been recognized that protein kinase C (PKC) pathway is involved in the synaptic plasticity. The present study was then designed to examine the changes in G q/11α and G βγ subunits and PKC activity on sensitization to the morphine-induced hyperlocomotion. Repeated subcutaneous administration of morphine every 72 h produced sensitization to the morphine-induced hyperlocomotion. In morphine-sensitized mice, the protein level of G q/11α subunit in the limbic forebrain including the nucleus accumbens, but not in the lower midbrain containing the ventral tegmental area, was markedly increased, whereas the levels of G βγ subunit were not altered in either areas. Under these conditions, the levels of membrane-bound phosphorylated-PKC in the limbic forebrain was clearly up-regulated by intermittent morphine treatment. We also found the lack of changes in the level of the regulator of G protein signaling 4, which is a specific G q/11α-dependent GTPase activating protein, in the limbic forebrain obtained from morphine-sensitized mice. These results indicate that the up-regulation of membrane-bound PKC following intermittent morphine treatment results from the increase in levels of G q/11α protein. In order to investigate the direct involvement of PKC in the morphine-induced hyperlocomotion, the locomotion induced by acute morphine treatment in the presence or absence of a PKC inhibitor was measured. A specific PKC inhibitor Ro-32-0432 given intracerebroventricularly caused a dose-dependent inhibition of morphine-induced hyperlocomotion. These findings suggest that the up-regulation of G q/11α-dependent PKC activity in membranes of the limbic forebrain is implicated in the development of sensitization to morphine-induced hyperlocomotion in mice.