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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Genetic alteration of phospholipase C β3 expression modulates behavioral and cellular responses to μ opioids
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Genetic alteration of phospholipase C β3 expression modulates behavioral and cellular responses to μ opioids

机译：磷脂酶Cβ3表达的遗传改变可调节对μ阿片类药物的行为和细胞反应

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摘要

Morphine and other μ opioids regulate a number of intracellular signaling pathways, including the one mediated by phospholipase C (PLC). By studying PLC β3-def icient mice, we have established a strong link between PLC and μ opioid-mediated responses at both the behavioral and cellular levels. Mice lacking PLC β3, when compared with the wild type, exhibited up to a 10-fold decrease in the ED_(50) value for morphine in producing antinociception. The reduced ED_(50) 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 μ, κ, and δ opioid receptors between wild-type and PLC β3-null mice. We also found that opioid regulation of voltage-sensitive Ca~(2+) channels in primary sensory neurons (dorsal root ganglion) was different between the two genotypes. Consistent with the behavioral findings, the specific μ 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 β3-null mice than from the wild type. In addition, reconstitution of recombinant PLC protein back into PLC β3-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 Ca~(2+) current reduction. These data demonstrate that PLC β3 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.
机译：吗啡和其他μ阿片类药物调节许多细胞内信号传导途径，包括由磷脂酶C（PLC）介导的一种。通过研究PLCβ3缺陷小鼠，我们在行为和细胞水平上都建立了PLC与μ阿片样物质介导的反应之间的牢固联系。与野生型相比，缺乏PLCβ3的小鼠在产生抗伤害感受时，吗啡的ED_（50）值降低多达10倍。减少的ED_（50）值不太可能是阿片受体数量或亲和力变化的结果，因为野生型和PLC之间的全脑B_（max）和K_d值对μ，κ和δ类阿片受体没有差异。 β3无小鼠。我们还发现，两种基因型在初级感觉神经元（背根神经节）中的电压敏感Ca〜（2+）通道的阿片样物质调节是不同的。与行为研究结果一致，特定的μ激动剂[D-Ala〜2，（Me）Phe〜4，Gly（ol）〜5]脑啡肽（DAMGO）在更大比例的分离的神经元中诱导了更大的全细胞电流减少来自PLCβ3无小鼠的小鼠比来自野生型的小鼠更多。此外，重组PLC蛋白重新构建为PLCβ3缺陷型背根神经节神经元，减少了DAMGO对野生型神经元的反应。在两种基因型的神经元中，用佛波醇酯激活的蛋白激酶C明显减少了DAMGO介导的Ca〜（2+）电流减少。这些数据表明，PLCβ3构成了可能通过蛋白激酶C参与μ阿片样物质应答的负调节的重要途径，并暗示了个体之间阿片样物质敏感性差异的部分原因可能是由于遗传因素。

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