β-Arrestin-2 knockout prevents development of cellular μ-opioid receptor tolerance but does not affect opioid-withdrawal-related adaptations in single PAG neurons

被引：27

作者：

Connor, M. ^{[1
]}

Bagley, E. E. ^{[2
]}

Chieng, B. C. ^{[2
]}

Christie, M. J. ^{[2
]}

机构：

[1] Macquarie Univ, Australian Sch Adv Med, Sydney, NSW 2109, Australia

[2] Univ Sydney, Discipline Pharmacol, Sydney Med Sch, Sydney, NSW 2006, Australia

来源：

BRITISH JOURNAL OF PHARMACOLOGY | 2015年 / 172卷 / 02期

基金：

英国医学研究理事会;

关键词：

arrestins; morphine; -opioid receptor; opioid tolerance; opioid withdrawal; periaqueductal grey; ANTINOCICEPTIVE TOLERANCE; PERIAQUEDUCTAL GRAY; MORPHINE-TOLERANCE; MIDBRAIN NEURONS; GABA RELEASE; DESENSITIZATION; MICE; MODULATION; MECHANISMS; CURRENTS;

D O I：

10.1111/bph.12673

中图分类号：

R9 [药学];

学科分类号：

1007 ;

摘要：

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

引用

页码：492 / 500

页数：9

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