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

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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.