Role of cholinergic signaling and its controlling regulatory genes in the pathophysiology of pain in fibromyalgia syndrome

纤维肌痛综合征（FMS）是一种常见的、使人衰弱的慢性广泛性疼痛疾病，经常伴有疲劳和睡眠障碍等其他症状，并具有很高的社会经济负担。FMS疼痛的病理生理学尚不完全清楚，缺乏客观的诊断生物标志物。在过去的几年里，有越来越多的证据表明，在FMS患者亚组中，小口径神经纤维的多维损伤可能导致FMS疼痛。此外，周围皮肤细胞，特别是角质形成细胞及其分泌产物在FMS疼痛病理生理学中的作用越来越受到重视。然而，角质形成细胞可能与表皮内伤害感受器相互作用并影响表皮内伤害感受器从而导致疼痛的机制尚不清楚。虽然本质上不是神经元的，但角质形成细胞能够产生乙酰胆碱，乙酰胆碱可以在与表皮内神经纤维（IENF）的串扰中充当传递物，并且取决于在这些神经纤维上表达的受体亚家族，可以诱导超敏或低敏。我们将调查是否有一个作用，胆碱能参与潜在的病理生理机制，在接口的角质形成细胞和IENF。我们推测，FMS患者与多维小神经纤维病理有疾病特异性的变化，其模式的胆碱能信号之间的IENF和角质形成细胞。此外，由于异常的胆碱能信号传导，当与健康对照的正常小神经纤维相比时，具有IENF病理的FMS患者将显示出修饰的全身和皮肤胆碱能基因和蛋白质特征。我们实验室的初步结果已经确定了FMS患者的这种变化。我们将使用最先进的分子诊断和干扰技术，包括转录组和microRNA分析，进一步验证我们的假设。我们的项目将有助于更好地了解角质形成细胞和IENF之间的相互作用，作为FMS疼痛的一个贡献者，并将为FMS和其他疼痛综合征的局部适用和靶向镇痛治疗开辟新的途径。

Fibromyalgia syndrome (FMS) is a frequent and debilitating chronic widespread pain condition that is regularly associated with additional symptoms like fatigue and sleep disturbance and has a high socioeconomic burden. The pathophysiology of pain in FMS is incompletely understood and objective diagnostic biomarkers are lacking. In the last few years there is increasing evidence for a multidimensional impairment of small calibre nerve fibers in subgroups of FMS patients which may contribute to FMS pain. Also, there is a growing appreciation for a role of the surrounding cutaneous cells, particularly keratinocytes, and their secretory products, on the pathophysiology of pain in FMS. However, the mechanisms by which keratinocytes may interact with and influence intraepidermal nociceptors, leading to pain, are unknown. Although not neuronal in nature, keratinocytes are able to produce acetylcholine, which may act as a transmitter in the cross-talk with intraepidermal nerve fibers (IENF), and depending on the receptor subfamily expressed on these nerve fibers, may induce hypersensitization or hyposensitization. We will investigate if there is a role for cholinergic involvement in potential pathophysiological mechanisms at the interface of keratinocytes and IENF. We hypothesize that FMS patients with multidimensional small nerve fiber pathology have disease-specific changes in their pattern of cholinergic signaling between IENF and keratinocytes. In addition, due to aberrant cholinergic signaling, FMS patients with IENF pathology would show a modified systemic and cutaneous cholinergic gene and protein signature when compared to normal small nerve fibers of healthy controls. Preliminary results in our laboratories have identified such changes in FMS patients. We will further test our hypotheses using state of the art molecular diagnostic and interference techniques including transcriptome and microRNA analyses. Our project will contribute to a better understanding of interactions between keratinocytes and IENF as one contributor to pain in FMS and will open new avenues for locally applicable and targeted analgesic treatment, both in FMS and other pain syndromes.