Delta opioid receptor regulation of calcitonin gene-related peptide dynamics in the trigeminal complex.
Delta opioid receptor regulation of calcitonin gene-related peptide dynamics in the trigeminal complex.
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DOI：
10.1097/j.pain.0000000000002235
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发表时间：
2021-08-01
期刊：
影响因子：
7.4
通讯作者：
Pradhan AA
中科院分区：
文献类型：
--
作者：
Moye LS;Siegersma K;Dripps I;Witkowski W;Mangutov E;Wang D;Scherrer G;Pradhan AA
偏头痛非常普遍，是全球因致残而致残的第六大原因。专门针对偏头痛的治疗选择有限，而 δ 阿片受体 (DOP) 激动剂最近被认为是一种有前途的药物疗法。 DOP 调节偏头痛的机制目前尚不清楚。降钙素基因相关肽（CGRP）已被确定为内源性偏头痛触发因素，在偏头痛发生和易感性中发挥关键作用。本研究的目的是确定 DOP 激动剂对慢性偏头痛相关疼痛发展的行为影响，并研究三叉神经系统中 DOP 与 CGRP 和 CGRP 受体 (CGRPR) 的共表达。通过重复间歇性注射已知的人类偏头痛诱因硝酸甘油，在小鼠中诱发慢性偏头痛相关疼痛。慢性硝酸甘油会导致严重的慢性头痛，但通过 DOP 选择性激动剂 SNC80 的联合治疗可以预防这种情况。此外，在长期服用硝酸甘油后，观察到三叉神经节和三叉神经尾核中 CGRP 表达相应增加，但 SNC80 可阻断这种增加。此外，在慢性偏头痛模型后，这些头痛处理区域的 DOP 也上调。三叉神经节的免疫组织化学分析显示 DOP 与 CGRP 以及 CGRPR 的主要成分 RAMP1 共表达。在三叉神经尾核中，DOP 不与 CGRP 共表达，但与 RAMP1 和降钙素受体样受体高度共表达。这些结果表明，DOP 激动剂通过减弱 CGRP 释放和阻断 CGRPR 的伤害性信号传导来抑制偏头痛相关疼痛。
Migraine is highly prevalent and is the sixth leading cause worldwide for years lost to disability. Therapeutic options specifically targeting migraine are limited, and delta opioid receptor (DOP) agonists were recently identified as a promising pharmacotherapy. The mechanisms by which DOPs regulate migraine are currently unclear. Calcitonin gene–related peptide (CGRP) has been identified as an endogenous migraine trigger and plays a critical role in migraine initiation and susceptibility. The aim of this study was to determine the behavioral effects of DOP agonists on the development of chronic migraine–associated pain and to investigate DOP coexpression with CGRP and CGRP receptor (CGRPR) in the trigeminal system. Chronic migraine–associated pain was induced in mice through repeated intermittent injection of the known human migraine trigger, nitroglycerin. Chronic nitroglycerin resulted in severe chronic cephalic allodynia which was prevented with cotreatment of the DOP-selective agonist, SNC80. In addition, a corresponding increase in CGRP expression in the trigeminal ganglia and trigeminal nucleus caudalis was observed after chronic nitroglycerin, an augmentation that was blocked by SNC80. Moreover, DOP was also upregulated in these head pain-processing regions following the chronic migraine model. Immunohistochemical analysis of the trigeminal ganglia revealed coexpression of DOP with CGRP as well as with a primary component of the CGRPR, RAMP1. In the trigeminal nucleus caudalis, DOP was not coexpressed with CGRP but was highly coexpressed with RAMP1 and calcitonin receptor–like receptor. These results suggest that DOP agonists inhibit migraine-associated pain by attenuating CGRP release and blocking pronociceptive signaling of the CGRPR.
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