Enhanced mu-opioid responses in the spinal cord of mice lacking protein kinase Cgamma isoform.
The protein kinase C (PKC)gamma isoform is a major pool of the PKC family in the mammalian spinal cord. PKCgamma 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 PKCgamma knockout mice. In contrast, delta- and kappa-opioidergic and ORL-1 receptor-mediated activation of G-proteins in PKCgamma knockout mice was not altered significantly relative to the wild-type mice. Deletion of PKCgamma 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 [3H][d-Ala(2),N-Me-Phe(4),Gly(5)-ol]enkephalin in spinal cord membranes obtained from PKCgamma knockout mice. These findings suggest that deletion of PKCgamma genes protects the functional mu-opioid receptors from degradation by phosphorylation. More importantly the present data provide direct evidence that PKCgamma constitutes an essential pathway through which phosphorylation of mu-opioid receptors occurs.
Department of Anesthesiology, Medical College of Wisconsin, Milwaukee, Wisconsin 53226, USA.
M
M
Narita
H
H
Mizoguchi
T
T
Suzuki
M
M
Narita
N J
NJ
Dun
S
S
Imai
Y
Y
Yajima
H
H
Nagase
T
T
Suzuki
L F
LF
Tseng
D000700:Analgesics / Q000494:pharmacology; D000818:Animals; D001483:Base Sequence; D017931:DNA Primers; D006868:Hydrolysis; D007527:Isoenzymes / Q000235:genetics / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011493:Protein Kinase C / Q000235:genetics / Q000502:physiology*; D017450:Receptors, Opioid, mu / Q000502:physiology*; D013116:Spinal Cord / Q000201:enzymology / Q000502:physiology*
D000700:Analgesics; D017931:DNA Primers; D007527:Isoenzymes; D017450:Receptors, Opioid, mu; C087857:protein kinase C gamma; D011493:Protein Kinase C