Department of Obstetrics and Gynecology, State University of New York, Downstate Medical Center, Brooklyn, New York 11203, USA.
J Pharmacol Exp Ther. 2012 Jan;340(1):56-63. doi: 10.1124/jpet.111.186874. Epub 2011 Oct 4.
We studied adaptations to acute precipitated opioid withdrawal of spinal μ-opioid receptor (MOR)-coupled regulation of the release of endomorphin 2 (EM2). The release of this highly MOR-selective endogenous opioid from opioid-naive spinal tissue of male rats is subjected to MOR-coupled positive as well as negative modulation via cholera toxin-sensitive G(s) and pertussis toxin-sensitive G(i)/G(o), respectively. The net effect of this concomitant bidirectional modulation is inhibitory. MOR-coupled pleiotropic regulation of EM2 release is retained in opioid-withdrawn spinal tissue of male rats, but the balance of MOR-coupled inhibitory and facilitatory regulation shifted such that facilitatory regulation predominates. Augmented coupling of MOR to G(s) is causally associated with this change. Strikingly, pleiotropic characteristics of MOR-coupled regulation of spinal EM2 release and adaptations thereof to opioid withdrawal are male-specific. In females, MOR-coupled regulation of EM2 release from opioid-naive and -withdrawn spinal tissue does not have a significant G(s)-coupled facilitatory component, and MOR-coupled inhibition of EM2 release persists unabated in withdrawn preparations. The male-specific adaptations to chronic morphine that shift the relative predominance of opposing dual G protein-coupled MOR pathways provides a mechanism for mitigating inhibitory MOR signaling without losing MOR-coupled feedback regulation. These adaptations enable using endogenous EM2 as a substitute for morphine that had been precipitously removed. The sexually dimorphic functionality and regulation of spinal EM2/MOR-coupled signaling suggest the clinical utility of using sex-specific treatments for addiction that harness the activity of endogenous opioids.
我们研究了急性诱发的阿片类药物戒断对脊髓 μ 型阿片受体（MOR）偶联调控内吗啡肽 2（EM2）释放的适应性。这种高度选择性的内源性阿片类物质从阿片类药物未处理的雄性大鼠脊髓组织中的释放受到 MOR 偶联的正向和负向调节，分别通过霍乱毒素敏感 G(s)和百日咳毒素敏感 G(i)/G(o)。这种伴随的双向调节的净效应是抑制性的。MOR 偶联对内吗啡肽 2 释放的多效性调节在雄性阿片类药物戒断的脊髓组织中得以保留，但 MOR 偶联的抑制和促进调节之间的平衡发生了变化，使得促进调节占主导地位。MOR 与 G(s)的偶联增强与这种变化有关。引人注目的是，MOR 偶联调节脊髓 EM2 释放的多效性特征及其对阿片类药物戒断的适应性是雄性特异性的。在雌性中，MOR 从阿片类药物未处理和处理的脊髓组织中调节 EM2 释放的偶联没有显著的 G(s)偶联促进成分，而在撤药制剂中，MOR 偶联对 EM2 释放的抑制作用仍然不变。慢性吗啡导致的雄性特异性适应性改变了相反的双重 G 蛋白偶联 MOR 途径的相对优势，为减轻抑制性 MOR 信号而不失 MOR 偶联反馈调节提供了一种机制。这些适应性使内源性 EM2 能够替代被突然去除的吗啡。脊髓 EM2/MOR 偶联信号的性别二态性功能和调节表明，使用针对特定性别的治疗方法来利用内源性阿片类药物治疗成瘾具有临床应用价值。
