CB2 cannabinoid receptor activation produces antinociception by stimulating peripheral release of endogenous opioids
CB2 cannabinoid receptor activation produces antinociception by stimulating peripheral release of endogenous opioids
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DOI：
10.1073/pnas.0409888102
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发表时间：
2005-02-22
影响因子：
11.1
通讯作者：
Malan, TP
中科院分区：
文献类型：
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作者：
Ibrahim, MM;Porreca, F;Malan, TP
CB2大麻素受体选择性激动剂是治疗疼痛的有希望的候选药物。CB2受体激活可抑制急性、炎症性和神经性疼痛反应，但不会引起中枢神经系统（CNS）的影响，这与正常CNS中缺乏CB2受体的情况一致。迄今为止，几乎没有关于CB2受体介导的疼痛反应抑制机制的信息。在这里，我们验证了CB2受体激活刺激角化细胞释放内源性阿片样物质β -内啡肽的假设，后者随后作用于初级传入神经元上的阿片样物质受体以抑制伤害感觉。当在大鼠的后爪处注射纳洛酮或抗内啡肽血清时，CB2受体选择性激动剂AM1241的抗痛觉作用被阻止，这表明-内啡肽是CB2受体介导的抗痛觉作用所必需的。此外，AM1241不抑制mu阿片受体缺陷小鼠的伤害感受。后爪注射-内啡肽足以产生抗伤害性。AM1241刺激大鼠皮肤组织和培养的人角质形成细胞释放β -内啡肽。这种刺激被AM630（一种CB2大麻素受体选择性拮抗剂）阻止，并且在CB2大麻素受体缺乏小鼠的皮肤中未观察到。这些数据表明，CB2受体激活刺激角化细胞释放β -内啡肽，其作用于局部神经元mu-阿片受体以抑制伤害感觉。支持这种可能性的是，在整个后爪表皮颗粒层中含有-内啡肽的角化细胞上检测到CB2免疫标记。这种机制允许在CB2受体存在的地方释放-内啡肽，从而导致阿片类药物作用的解剖特异性。
CB2 cannabinoid receptor-selective agonists are promising candidates for the treatment of pain. CB2 receptor activation inhibits acute, inflammatory, and neuropathic pain responses but does not cause central nervous system (CNS) effects, consistent with the lack of CB2 receptors in the normal CNS. To date, there has been virtually no information regarding the mechanism of CB2 receptor-mediated inhibition of pain responses. Here, we test the hypothesis that CB2 receptor activation stimulates release from keratinocytes of the endogenous opioid beta-endorphin, which then acts at opioid receptors on primary afferent neurons to inhibit nociception. The antinociceptive effects of the CB2 receptor-selective agonist AM1241 were prevented in rats when naloxone or antiserum to beta-endorphin was injected in the hindpaw where the noxious thermal stimulus was applied, suggesting that beta-endorphin is necessary for CB2 receptor-mediated anti nociception. Further, AM1241 did not inhibit nociception in mu-opioid receptor-deficient mice. Hindpaw injection of beta-endorphin was sufficient to produce anti nociception. AM1241 stimulated beta-endorphin release from rat skin tissue and from cultured human keratinocytes. This stimulation was prevented by AM630, a CB2 cannabinoid receptor-selective antagonist and was not observed in skin from CB2 cannabinoid receptor-deficient mice. These data suggest that CB2 receptor activation stimulates release from keratinocytes of beta-endorphin, which acts at local neuronal mu-opioid receptors to inhibit nociception. Supporting this possibility, CB2 immunolabeling was detected on beta-endorphin-containing keratinocytes in stratum granulosum throughout the epidermis of the hindpaw. This mechanism allows for the local release of beta-endorphin, where CB2 receptors are present, leading to anatomical specificity of opioid effects.