Up-regulation of the G(q/11alpha) protein and protein kinase C during the development of sensitization to morphine-induced hyperlocomotion.
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/11alpha) and G(betagamma) 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/11alpha) 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(betagamma) 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/11alpha)-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/11alpha) 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/11alpha)-dependent PKC activity in membranes of the limbic forebrain is implicated in the development of sensitization to morphine-induced hyperlocomotion in mice.
Narita
M
M
Department of Toxicology, School of Pharmacy, Hoshi University, 2-4-41 Ebara, Shinagawa-ku, Tokyo 142-8501, Japan.
Mizuo
K
K
Shibasaki
M
M
Narita
M
M
Suzuki
T
T
D000818:Animals; D004198:Disease Susceptibility; D004334:Drug Administration Schedule; D004789:Enzyme Activation / Q000502:physiology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D043802:GTP-Binding Protein alpha Subunits, Gq-G11; D020962:Heterotrimeric GTP-Binding Proteins / Q000378:metabolism*; D006948:Hyperkinesis / Q000139:chemically induced*; D007211:Indoles / Q000494:pharmacology; D008032:Limbic System / Q000378:metabolism; D008297:Male; D008636:Mesencephalon / Q000378:metabolism; D051379:Mice; D009020:Morphine / Q000008:administration & dosage; D009294:Narcotics / Q000008:administration & dosage; D016548:Prosencephalon / Q000378:metabolism; D020033:Protein Isoforms / Q000378:metabolism; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000378:metabolism*; D011758:Pyrroles / Q000494:pharmacology; D020710:RGS Proteins / Q000378:metabolism; D015854:Up-Regulation
D004791:Enzyme Inhibitors; D007211:Indoles; D009294:Narcotics; D020033:Protein Isoforms; D011758:Pyrroles; D020710:RGS Proteins; C085989:Ro 32-0432; C098799:RGS4 protein; D009020:Morphine; D011493:Protein Kinase C; D043802:GTP-Binding Protein alpha Subunits, Gq-G11; D020962:Heterotrimeric GTP-Binding Proteins