Differential Control of Opioid Antinociception to Thermal Stimuli in a Knock-In Mouse Expressing Regulator of G-Protein Signaling-Insensitive Gαo Protein
Differential Control of Opioid Antinociception to Thermal Stimuli in a Knock-In Mouse Expressing Regulator of G-Protein Signaling-Insensitive Gαo Protein
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DOI：
10.1523/jneurosci.5470-12.2013
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发表时间：
2013-03-06
影响因子：
5.3
通讯作者：
Traynor, John R.
中科院分区：
文献类型：
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作者：
Lamberts, Jennifer T.;Smith, Chelsea E.;Traynor, John R.
g蛋白信号调节因子（regulatory of G-protein signaling， RGS）通常作为g蛋白偶联受体信号的负调节因子。在体外，RGS蛋白已被证明可以抑制包括吗啡在内的阿片受体激动剂的信号传导。本研究的目的是评估内源性RGS蛋白在吗啡和其他阿片受体激动剂的抗痛觉作用中的作用。为此，研究人员对表达rgs不敏感（RGSi）突变体G α (o)蛋白G α (o) (G184S) （G α (o) RGSi）的敲入小鼠进行了吗啡或美沙酮抗痛觉作用的评估，以应对有害的热刺激。在热板和温水脱尾试验中，表达G α (o) RGSi亚基的小鼠表现出纳曲酮对基线潜伏期的敏感增强。在热板试验中，一种测量椎管上痛觉的方法，吗啡抗痛觉增加，这与阿片类药物抑制导水管周围灰质突触前GABA神经传递的能力增加有关。相比之下，吗啡或美沙酮产生的抗痛觉作用在尾断试验中减少，尾断试验是脊髓痛觉的一种测量方法。在表达G α (o) RGSi亚基的小鼠的全脑和脊髓匀浆中，G α (o)的表达有少量损失，并伴有基础G蛋白活性的降低。我们的研究结果有力地支持了RGS蛋白作为阿片样物质脊柱上抗痛觉通路的负调节因子的作用，同时也揭示了RGS蛋白作为阿片样物质脊柱抗痛觉通路的正调节因子的潜在新功能。
Regulator of G-protein signaling (RGS) proteins classically function as negative modulators of G-protein-coupled receptor signaling. In vitro, RGS proteins have been shown to inhibit signaling by agonists at the mu-opioid receptor, including morphine. The goal of the present study was to evaluate the contribution of endogenous RGS proteins to the antinociceptive effects of morphine and other opioid agonists. To do this, a knock-in mouse that expresses an RGS-insensitive (RGSi) mutant G alpha(o) protein, G alpha(o) (G184S) (G alpha(o) RGSi), was evaluated for morphine or methadone antinociception in response to noxious thermal stimuli. Mice expressing G alpha(o) RGSi subunits exhibited a naltrexone-sensitive enhancement of baseline latency in both the hot-plate and warm-water tail-withdrawal tests. In the hot-plate test, a measure of supraspinal nociception, morphine antinociception was increased, and this was associated with an increased ability of opioids to inhibit presynaptic GABA neurotransmission in the periaqueductal gray. In contrast, antinociception produced by either morphine or methadone was reduced in the tail-withdrawal test, a measure of spinal nociception. In whole-brain and spinal cord homogenates from mice expressing G alpha(o) RGSi subunits, there was a small loss of G alpha(o) expression and an accompanying decrease in basal G-protein activity. Our results strongly support a role for RGS proteins as negative regulators of opioid supraspinal antinociception and also reveal a potential novel function of RGS proteins as positive regulators of opioid spinal antinociceptive pathways.