Genetic alteration of phospholipase C β3 expression modulates behavioral and cellular responses to μ opioids

Morphine and other CL opioids regulate a number of intracellular signaling pathways, including the one mediated by phospholipase C (PLC). By studying PLC beta 3-deficient mice, we have established a strong link between PLC and mu opioid-mediated responses at both the behavioral and cellular levels. Mice lacking PLC beta 3, when compared with the wild type, exhibited up to a 10-fold decrease in the ED50 value for morphine in producing antinociception. The reduced ED50 value was unlikely a result of changes in opioid receptor number or affinity because no differences were found in whole-brain B-max and K-d values for mu, kappa, and delta opioid receptors between wild-type and PLC beta 3-null mice. We also found that opioid regulation of voltage-sensitive Ca2+ channels in primary sensory neurons (dorsal root ganglion) was different between the two genotypes. Consistent with the behavioral findings, the specific mu agonist [D-Ala(2),(Me)Phe(4), Gly(ol)(5)]enkephalin (DAMGO) induced a greater whole-cell current reduction in a greater proportion of neurons isolated from the PLC beta 3-null mice than from the wild type. In addition, reconstitution of recombinant PLC protein back into PLC beta 3-deficient dorsal root ganglion neurons reduced DAMGO responses to those of wild-type neurons. In neurons of both genotypes, activation of protein kinase C with phorbol esters markedly reduced DAMGO-mediated Ca2+ current reduction. These data demonstrate that PLC beta 3 constitutes a significant pathway involved in negative modulation of In. opioid responses, perhaps via protein kinase C, and suggests the possibility that differences in opioid sensitivity among individuals could be, in part, because of genetic factors.