Enhanced μ-opioid responses in the spinal cord of mice lacking protein kinase Cγ isoform

The protein kinase C (PKC)gamma isoform is a major pool of the PKC family in the mammalian spinal cord. PKC gamma is distributed strategically in the superficial layers of the dorsal horn and, thus, may serve as an important biochemical substrate in sensory signal processing including pain. Here we report that mu -opioid receptor-mediated analgesia/antinociception and activation of G-proteins in the spinal cord are enhanced in PKC gamma knockout mice. In contrast, delta- and kappa -opioidergic and ORL-1 receptor-mediated activation of G-proteins in PKC gamma knockout mice was not altered significantly relative to the wildtype mice. Deletion of PKC gamma had no significant effect on the mRNA product of spinal mu -opioid receptors but caused an increase of maximal binding of the mu -opioid receptor agonist [H-3][D-Ala(2),N-Me-Phe(4),Gly(5)-ol] enkephalin in spinal cord membranes obtained from PKC gamma knockout mice. These findings suggest that deletion of PKC gamma genes protects the functional mu -opioid receptors from degradation by phosphorylation. More importantly the present data provide direct evidence that PKC gamma constitutes an essential pathway through which phosphorylation of mu -opioid receptors occurs.