Genetic alteration of phospholipase C beta 3 expression modulates behavioral and cellular responses to mu 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 an d 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 antinocicept ion. The reduced ED50 value was unlikely a result of changes in opioid rece ptor 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-t ype and PLC beta 3-null mice. We also found that opioid regulation of volta ge-sensitive Ca2+ channels in primary sensory neurons (dorsal root ganglion ) was different between the two genotypes. Consistent with the behavioral f indings, the specific mu agonist [D-Ala(2),(Me)Phe(4), Gly(ol)(5)]enkephali n (DAMGO) induced a greater whole-cell current reduction in a greater propo rtion 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 th ose of wild-type neurons. In neurons of both genotypes, activation of prote in kinase C with phorbol esters markedly reduced DAMGO-mediated Ca2+ curren t reduction. These data demonstrate that PLC beta 3 constitutes a significa nt pathway involved in negative modulation of In. opioid responses, perhaps via protein kinase C, and suggests the possibility that differences in opi oid sensitivity among individuals could be, in part, because of genetic fac tors.