Genetic Alteration of Phospholipase C β 3 Expression Modulates Behavioral and Cellular Responses to μ Opioids

• Published in: Proceedings of the National Academy of Sciences - PNAS 1999-08, Vol.96 (18), p.10385-10390
• Main Authors: Xie, Wei, Samoriski, Gary M., McLaughlin, Jay P., Romoser, Valerie A., Smrcka, Alan, Hinkle, Patricia M., Bidlack, Jean M., Gross, Robert A., Jiang, Huiping, Wu, Dianqing
• Format: Article
• Language: English
• Subjects: Exons; Gene expression regulation; Genotypes; Mice; Morphine; Neurons; Opioid analgesics; Opioid receptors; opioids; Pretreatment; Receptors
• ISSN: 0027-8424
• DOI: 10.1073/pnas.96.18.10385

Morphine and other μ opioids regulate a number of intracellular signaling pathways, including the one mediated by phospholipase C (PLC). By studying PLC β 3- deficient mice, we have established a strong link between PLC and μ opioid-mediated responses at both the behavioral and cellular levels. Mice lacking PLC β 3, when compared with the wild type, exhibited up to a 10-fold decrease in the ED50value for morphine in producing antinociception. The reduced ED50value was unlikely a result of changes in opioid receptor number or affinity because no differences were found in whole-brain Bmaxand Kdvalues for μ , κ , and δ opioid receptors between wild-type and PLC β 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 μ agonist [D-Ala2, (Me)Phe4, Gly(ol)5] enkephalin (DAMGO) induced a greater whole-cell current reduction in a greater proportion of neurons isolated from the PLC β 3-null mice than from the wild type. In addition, reconstitution of recombinant PLC protein back into PLC β 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 β 3 constitutes a significant pathway involved in negative modulation of μ 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.