Ligand-biased activation of extracellular signal-regulated kinase 1/2 leads to differences in opioid induced antinociception and tolerance.
Ligand-biased activation of extracellular signal-regulated kinase 1/2 leads to differences in opioid induced antinociception and tolerance.
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DOI：
10.1016/j.bbr.2015.10.032
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发表时间：
2016-02-01
影响因子：
2.7
通讯作者：
Morgan MM
中科院分区：
文献类型：
--
作者：
Bobeck EN;Ingram SL;Hermes SM;Aicher SA;Morgan MM
阿片类药物通过激活与μ-阿片受体（MOPr）相关的G蛋白信号传导产生抗伤害感受。然而，阿片样物质与MOPr的结合也激活β-arrestin信号传导。阿片类药物如DAMGO和芬太尼在激活这些信号级联的相对功效上不同，但这种差异信号传导的行为后果尚不清楚。本研究旨在探讨中脑导水管周围灰质（vlPAG）内G蛋白和内化依赖信号的行为学意义。通过给予百日咳毒素（PTX）阻断Gαi/o蛋白信号传导、给予动力蛋白显性负性抑制肽（dyn-DN）阻止内化或给予MEK抑制剂U 0126直接抑制ERK 1/2，来减弱通过将DAMGO显微注射到vlPAG中诱导的抗伤害感受。相比之下，给药PTX或U 0126并不改变vlPAG中微量注射芬太尼的抗伤害性效应，并且通过给药dyn-DN增强。vlPAG内微量注射DAMGO（芬太尼无此作用）可诱导ERK 1/2磷酸化，而给予dyn-DN可通过抑制受体内化而阻断ERK 1/2磷酸化，但不能通过抑制Gαi/o蛋白而阻断ERK 1/2磷酸化。ERK 1/2抑制也阻止了重复DAMGO显微注射耐受性的发展和表达，但对芬太尼耐受性没有影响。这些数据表明，MOPr内化后的ERK 1/2活化有助于一些（例如，DAMGO），但不是所有阿片类药物（例如，芬太尼），尽管这些激动剂在诱导β-抑制蛋白募集和内化方面具有已知的相似性。
Opioids produce antinociception by activation of G protein signaling linked to the mu-opioid receptor (MOPr). However, opioid binding to the MOPr also activates β-arrestin signaling. Opioids such as DAMGO and fentanyl differ in their relative efficacy for activation of these signaling cascades, but the behavioral consequences of this differential signaling are not known. The purpose of this study was to evaluate the behavioral significance of G protein and internalization dependent signaling within ventrolateral periaqueductal gray (vlPAG). Antinociception induced by microinjecting DAMGO into the vlPAG was attenuated by blocking Gαi/o protein signaling with administration of pertussis toxin (PTX), preventing internalization with administration of dynamin dominant-negative inhibitory peptide (dyn-DN) or direct inhibition of ERK1/2 with administration of the MEK inhibitor, U0126. In contrast, the antinociceptive effect of microinjecting fentanyl into the vlPAG was not altered by administration of PTX or U0126, and was enhanced by administration of dyn-DN. Microinjection of DAMGO, but not fentanyl, into the vlPAG induced phosphorylation of ERK1/2, which was blocked by inhibiting receptor internalization with administration of dyn-DN, but not by inhibition of Gαi/o proteins. ERK1/2 inhibition also prevented the development and expression of tolerance to repeated DAMGO microinjections, but had no effect on fentanyl tolerance. These data reveal that ERK1/2 activation following MOPr internalization contributes to the antinociceptive effect of some (e.g., DAMGO), but not all opioids (e.g., fentanyl) despite the known similarities for these agonists to induce β-arrestin recruitment and internalization.