Leukocyte opioid receptors mediate analgesia via Ca2+-regulated release of opioid peptides
Leukocyte opioid receptors mediate analgesia via Ca2+-regulated release of opioid peptides
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DOI：
10.1016/j.bbi.2016.04.018
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发表时间：
2016-10-01
影响因子：
15.1
通讯作者：
Machelska, Halina
中科院分区：
文献类型：
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作者：
Celik, Melih Oe;Labuz, Dominika;Machelska, Halina
阿片类药物是最有效的止痛药。由于疼痛是由感觉传递驱动的，并且阿片样物质受体与抑制性G蛋白偶联，根据经典概念，阿片样物质通过激活神经元上的受体并阻断兴奋性介质（例如，P物质）。在这里，我们表明，镇痛可以介导免疫细胞中的阿片受体。我们提出，白细胞阿片受体的激活导致阿片肽甲硫氨酸脑啡肽、β-内啡肽和强啡肽A（1-17）的分泌，其随后作用于局部神经元受体，以缓解疼痛。在由坐骨神经慢性压迫性损伤诱导的神经性疼痛的小鼠模型中，在被表达阿片肽和受体的白细胞浸润的受损神经处注射δ-、μ-和x-阿片受体的外源性激动剂产生镇痛，如用von Frey细丝评估的。阿片肽的药理学或遗传失活以及白细胞耗竭可减弱镇痛作用。这种镇痛作用的降低通过野生型白细胞的转移而恢复，但不通过缺乏阿片受体的白细胞的转移。在体外，外源性阿片类物质触发从受损神经分离的野生型免疫细胞分泌阿片肽，通过阻断G α i/o或G β γ，（但不是气体）蛋白质，通过细胞内的螯合剂（但不是细胞外）Ca 2+，通过磷脂酶C（PLC）和肌醇1，4，5-三磷酸（IP 3）受体的阻断剂，并被蛋白激酶C抑制剂部分减弱。同样，白细胞耗竭诱导的外源性阿片类镇痛的减少通过转移用细胞外Ca 2+螯合剂预处理的离体免疫细胞而重新建立，但通过用细胞内Ca 2+螯合剂或Gai/o和Gpy蛋白的阻断剂预处理的白细胞而未改变。因此，离体阿片肽释放和体内镇痛都是由与G α 1/o-G β γ蛋白-PLC-IP 3受体-细胞内Ca 2+途径偶联的白细胞阿片受体介导的。我们的研究结果表明，免疫细胞中的阿片受体是控制病理性疼痛的重要靶点。(C)2016 Elsevier Inc. All rights reserved.
Opioids are the most powerful analgesics. As pain is driven by sensory transmission and opioid receptors couple to inhibitory G proteins, according to the classical concept, opioids alleviate pain by activating receptors on neurons and blocking the release of excitatory mediators (e.g., substance P). Here we show that analgesia can be mediated by opioid receptors in immune cells. We propose that activation of leukocyte opioid receptors leads to the secretion of opioid peptides Met-enkephalin, beta-endorphin and dynorphin A (1-17), which subsequently act at local neuronal receptors, to relieve pain. In a mouse model of neuropathic pain induced by a chronic constriction injury of the sciatic nerve, exogenous agonists of delta-, mu- and x-opioid receptors injected at the damaged nerve infiltrated by opioid peptide- and receptor expressing leukocytes, produced analgesia, as assessed with von Frey filaments. The analgesia was attenuated by pharmacological or genetic inactivation of opioid peptides, and by leukocyte depletion. This decrease in analgesia was restored by the transfer of wild-type, but not opioid receptor-lacking leukocytes. Ex vivo, exogenous opioids triggered secretion of opioid peptides from wild-type immune cells isolated from damaged nerves, which was diminished by blockade of G alpha i/o or G beta gamma (but not Gas) proteins, by chelator of intracellular (but not extracellular) Ca2+, by blockers of phospholipase C (PLC) and inositol 1,4,5-trisphosphate (IP3) receptors, and was partially attenuated by protein kinase C inhibitor. Similarly, the leukocyte depletion-induced decrease in exogenous opioid analgesia was re-established by transfer of immune cells ex vivo pretreated with extracellular Ca2+ chelator, but was unaltered by leukocytes pretreated with intracellular Ca2+ chelator or blockers of Gai/o and Gpy proteins. Thus, both ex vivo opioid peptide release and in vivo analgesia were mediated by leukocyte opioid receptors coupled to the G alpha i/o-G beta gamma protein-PLC-IP3 receptors-intracellular Ca2+ pathway. Our findings suggest that opioid receptors in immune cells are important targets for the control of pathological pain. (C) 2016 Elsevier Inc. All rights reserved.