β-Arrestin-2 knockout prevents development of cellular μ-opioid receptor tolerance but does not affect opioid-withdrawal-related adaptations in single PAG neurons
β-Arrestin-2 knockout prevents development of cellular μ-opioid receptor tolerance but does not affect opioid-withdrawal-related adaptations in single PAG neurons
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DOI：
10.1111/bph.12673
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发表时间：
2015-01-01
影响因子：
7.3
通讯作者：
Christie, M. J.
中科院分区：
文献类型：
--
作者：
Connor, M.;Bagley, E. E.;Christie, M. J.
背景和目的-arrestin-2 敲除小鼠对吗啡行为影响的耐受性减弱，但阿片类药物戒断基本上不受影响。已经在一些来自 -arrestin-2 敲除的神经元中研究了耐受的细胞机制，但尚未在导水管周围灰质 (PAG) 神经元的细胞水平上检查耐受和戒断机制，这对于中枢耐受和戒断现象至关重要。实验方法 - 阿片受体 (MOPr) 对电压门控钙通道电流 (I-Ca) 的抑制通过来自野生型和 -arrestin-2 的急性分离 PAG 神经元的膜片钳记录进行检查基因敲除小鼠长期接受吗啡（CMT）或媒介物治疗。使用脑切片中 PAG 神经元的穿孔贴片记录来确定阿片类药物戒断诱导的 GABA 转运蛋白 1 型 (GAT-1) 电流激活。关键结果 MOPr 对 PAG 神经元中 I-Ca 的抑制不受 -arrestin-2 缺失的影响。 CMT 损害了野生型小鼠 PAG 神经元中 MOPr 与 I-Ca 的偶联，但在 CMT -arrestin-2 敲除的神经元中没有观察到这种细胞耐受性。然而，-arrestin-2 基因敲除显示出与野生型 PAG 神经元相似的阿片类药物戒断诱导的 GAT-1 电流激活。 结论和意义在 -arrestin-2 基因敲除小鼠中，参与阿片类药物抗伤害作用的中枢神经元在长期吗啡后也无法产生对阿片类药物的细胞耐受。该结果还提供了第一个细胞生理学证据，证明阿片类药物戒断不会因 -arrestin-2 缺失而中断。然而，PAG 神经元对阿片类药物的基础敏感性未受影响，进一步证明基础 MOPr 敏感性的变化不能解释 -arrestin-2 敲除中报告的对吗啡的急性伤害性反应增强。 相关文章本文是“阿片类药物：功能选择性的新途径”主题部分的一部分。要查看本节中的其他文章，请访问
Background and PurposeTolerance to the behavioural effects of morphine is blunted in -arrestin-2 knockout mice, but opioid withdrawal is largely unaffected. The cellular mechanisms of tolerance have been studied in some neurons from -arrestin-2 knockouts, but tolerance and withdrawal mechanisms have not been examined at the cellular level in periaqueductal grey (PAG) neurons, which are crucial for central tolerance and withdrawal phenomena.Experimental Approach-Opioid receptor (MOPr) inhibition of voltage-gated calcium channel currents (I-Ca) was examined by patch-clamp recordings from acutely dissociated PAG neurons from wild-type and -arrestin-2 knockout mice treated chronically with morphine (CMT) or vehicle. Opioid withdrawal-induced activation of GABA transporter type 1 (GAT-1) currents was determined using perforated patch recordings from PAG neurons in brain slices.Key ResultsMOPr inhibition of I-Ca in PAG neurons was unaffected by -arrestin-2 deletion. CMT impaired coupling of MOPrs to I-Ca in PAG neurons from wild-type mice, but this cellular tolerance was not observed in neurons from CMT -arrestin-2 knockouts. However, -arrestin-2 knockouts displayed similar opioid-withdrawal-induced activation of GAT-1 currents as wild-type PAG neurons.Conclusions and ImplicationsIn -arrestin-2 knockout mice, the central neurons involved in the anti-nociceptive actions of opioids also fail to develop cellular tolerance to opioids following chronic morphine. The results also provide the first cellular physiological evidence that opioid withdrawal is not disrupted by -arrestin-2 deletion. However, the unaffected basal sensitivity to opioids in PAG neurons provides further evidence that changes in basal MOPr sensitivity cannot account for the enhanced acute nociceptive response to morphine reported in -arrestin-2 knockouts.Linked ArticlesThis article is part of a themed section on Opioids: New Pathways to Functional Selectivity. To view the other articles in this section visit