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首页> 美国卫生研究院文献>other >THE ABSENCE OF ENDOGENOUS β-ENDORPHIN SELECTIVELY BLOCKS PHOSPHORYLATION AND DESENSITIZATION OF MU OPIOID RECEPTORS FOLLOWING PARTIAL SCIATIC NERVE LIGATION
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THE ABSENCE OF ENDOGENOUS β-ENDORPHIN SELECTIVELY BLOCKS PHOSPHORYLATION AND DESENSITIZATION OF MU OPIOID RECEPTORS FOLLOWING PARTIAL SCIATIC NERVE LIGATION

机译：局部坐骨神经结扎后内源性β-内啡肽选择性阻滞MU阿片受体的磷酸化和脱敏

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Phosphorylation of specific sites in the 2nd intracellular loop and in the C-terminal domain have previously been suggested to cause desensitization and internalization of the mu-opioid receptor (MOP-R). To assess sites of MOP-R phosphorylation in vivo, affinity-purified, phosphoselective antibodies were raised against either phosphothreonine-180 in the 2nd intracellular loop (MOR-P1) or the C-terminal domain of MOP-R containing phosphothreonine-370 and phosphoserine-375 (MOR-P2). We found that MOR-P2-immunoreactivity (IR) was significantly increased within the striatum of wild-type C57BL/6 mice after injection of the agonist fentanyl. Pretreatment with the antagonist naloxone blocked the fentanyl-induced increase. Furthermore, mutant mice lacking MOP-R showed only non-specific nuclear MOR-P2-IR before or after fentanyl treatment, confirming the specificity of the MOR-P2 antibodies. To assess whether MOP-R phosphorylation occurs following endogenous opioid release, we induced chronic neuropathic pain by partial sciatic nerve ligation (pSNL), which caused a significant increase in MOR-P2-IR in the striatum. pSNL also induced signs of mu opioid receptor tolerance demonstrated by a rightward shift in the morphine dose response in the tail withdrawal assay and by a reduction in morphine conditioned place preference (CPP). Mutant mice selectively lacking all forms of the β-endorphin peptides derived from the Pomc gene did not show increased MOR-P2-IR, decreased morphine antinociception, or reduced morphine CPP following pSNL. In contrast gene deletion of either proenkephalin or prodynorphin opioids did not block the effects of pSNL. These results suggest that neuropathic pain caused by pSNL in wild-type mice activates the release of the endogenous opioid β-endorphin, which subsequently induces MOP-R phosphorylation and opiate tolerance.
机译：先前已经提出了在第二 细胞内环和C-末端结构域中特定位点的磷酸化会引起μ阿片受体（MOP-R）的脱敏和内在化。为了评估MOP-R在体内的磷酸化位点，提出了亲和纯化的磷酸选择性抗体，其针对第二 细胞内环（MOR-P1）中的磷酸苏氨酸-180或MOP的C-末端结构域-R含有磷酸苏氨酸370和磷酸丝氨酸375（MOR-P2）。我们发现注射激动剂芬太尼后，野生型C57BL / 6小鼠的纹状体内MOR-P2-免疫反应性（IR）显着增加。用拮抗剂纳洛酮预处理可阻止芬太尼诱导的增加。此外，缺少MOP-R的突变小鼠在芬太尼处理之前或之后仅显示非特异性核MOR-P2-IR，证实了MOR-P2抗体的特异性。为了评估内源性阿片类药物释放后是否发生MOP-R磷酸化，我们通过部分坐骨神经结扎（pSNL）诱导了慢性神经性疼痛，这导致纹状体中MOR-P2-IR显着增加。 pSNL还诱导了μ阿片受体耐受性的迹象，这是通过尾巴撤回测定中吗啡剂量反应的右移和吗啡条件性位置偏爱（CPP）的降低证明的。选择性缺乏从Pomc基因衍生的所有形式的β-内啡肽的突变小鼠在pSNL后未显示MOR-P2-IR升高，吗啡抗伤害感受降低或吗啡CPP降低。相反，前脑啡肽或前强啡肽阿片样物质的基因缺失并未阻断pSNL的作用。这些结果表明，由pSNL在野生型小鼠中引起的神经性疼痛激活了内源性阿片类β-内啡肽的释放，随后诱导了MOP-R磷酸化和鸦片耐受。

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