Epidermal adrenergic signaling contributes to inflammation and pain sensitization in a rat model of complex regional pain syndrome
Epidermal adrenergic signaling contributes to inflammation and pain sensitization in a rat model of complex regional pain syndrome
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DOI：
10.1016/j.pain.2013.03.033
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发表时间：
2013-08-01
期刊：
影响因子：
7.4
通讯作者：
Clark, J. David
中科院分区：
文献类型：
--
作者：
Li, Wenwu;Shi, Xiaoyou;Clark, J. David
在许多患者中，交感神经系统支持疼痛和复杂局部疼痛综合征（CRPS）的其他特征。越来越多的证据表明，白细胞介素(IL)-6也在CRPS中发挥作用，儿茶酚胺刺激几种组织中IL-6的产生。我们假设去甲肾上腺素通过角化细胞上表达的特异性肾上腺素能受体作用，刺激IL-6的产生，并导致大鼠胫骨骨折/铸造CRPS模型的伤害性致敏。我们的方法包括使用6-羟多巴胺或胍乙啶来消耗儿茶酚胺，以探索交感神经的作用。这两种药物都显著降低了伤害致敏性，并选择性地减少了皮肤中IL-6的产生。TB-2-081对IL-6信号的拮抗作用也降低了该模型的致敏性。利用大鼠角质形成细胞系进行的实验表明，β 2-肾上腺素能受体（β 2-AR）的表达水平相对较高。与IL-1 β、肿瘤坏死因子(TNF)- α或神经生长因子的表达相比，刺激该受体大大提高了IL-6的表达。对细胞的刺激也促进了丝裂原活化蛋白激酶P38、细胞外信号调节激酶和c-Jun氨基末端激酶的磷酸化。基于这些体外实验结果，我们回到动物实验，观察到选择性β 2-AR拮抗剂丁氧胺在CRPS模型中降低了伤害性致敏，局部注射选择性β 2-AR激动剂特布他林导致机械异常性疼痛和皮肤细胞中IL-6的产生。然而，IL-1 β、tnf - α或神经生长因子水平未见增加。这些数据表明，在CRPS中，交感神经末梢释放的去甲肾上腺素刺激表皮角质形成细胞上表达的β 2-ARs，导致局部IL-6产生，最终导致疼痛致敏。由爱思唯尔B.V.代表国际疼痛研究协会出版。
In many patients, the sympathetic nervous system supports pain and other features of complex regional pain syndrome (CRPS). Accumulating evidence suggests that interleukin (IL)-6 also plays a role in CRPS, and that catecholamines stimulate production of IL-6 in several tissues. We hypothesized that norepinephrine acting through specific adrenergic receptors expressed on keratinocytes stimulates the production of IL-6 and leads to nociceptive sensitization in a rat tibial fracture/cast model of CRPS. Our approach involved catecholamine depletion using 6-hydroxydopamine or, alternatively, guanethidine, to explore sympathetic contributions. Both agents substantially reduced nociceptive sensitization and selectively reduced the production of IL-6 in skin. Antagonism of IL-6 signaling using TB-2-081 also reduced sensitization in this model. Experiments using a rat keratinocyte cell line demonstrated relatively high levels of beta 2-adrenergic receptor (beta 2-AR) expression. Stimulation of this receptor greatly enhanced IL-6 expression when compared to the expression of IL-1 beta, tumor necrosis factor (TNF)-alpha, or nerve growth factor. Stimulation of the cells also promoted phosphorylation of the mitogen-activated protein kinases P38, extracellular signal-regulated kinase, and c-Jun amino-terminal kinase. Based on these in vitro results, we returned to animal testing and observed that the selective beta 2-AR antagonist butoxamine reduced nociceptive sensitization in the CRPS model, and that local injection of the selective beta 2-AR agonist terbutaline resulted in mechanical allodynia and the production of IL-6 in the cells of the skin. No increases in IL-1 beta, TNF-alpha, or nerve growth factor levels were seen, however. These data suggest that in CRPS, norepinephrine released from sympathetic nerve terminals stimulates beta 2-ARs expressed on epidermal keratinocytes, resulting in local IL-6 production, and ultimately, pain sensitization. Published by Elsevier B.V. on behalf of International Association for the Study of Pain.