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)是一种频繁的、使人虚弱的慢性广泛性疼痛症状，经常与疲劳和睡眠障碍等额外症状相关，并有很高的社会经济负担。FMS疼痛的病理生理学机制尚不完全清楚，缺乏客观的诊断生物标志物。在过去的几年里，越来越多的证据表明，FMS患者亚组中的小口径神经纤维存在多维损伤，这可能与FMS疼痛有关。此外，人们越来越认识到周围皮肤细胞，特别是角质形成细胞及其分泌产物在FMS疼痛的病理生理学中所起的作用。然而，角质形成细胞可能与表皮内伤害性感受器相互作用并影响其导致疼痛的机制尚不清楚。虽然角质形成细胞本质上不是神经细胞，但它能产生乙酰胆碱，在与表皮内神经纤维(IENF)的串扰中发挥递质作用，并根据这些神经纤维上表达的受体亚家族的不同，可能导致过敏或减敏。我们将研究在角质形成细胞和IENF的界面上是否存在胆碱能参与潜在的病理生理机制。我们假设，具有多维小神经纤维病理的FMS患者在IENF和角质形成细胞之间的胆碱能信号模式中具有疾病特异性的变化。此外，由于胆碱能信号的异常，与健康对照组的正常小神经纤维相比，具有IENF病理的FMS患者的全身和皮肤胆碱能基因和蛋白信号会发生改变。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，将其作为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止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.