Characterisation of periorbital mechanical allodynia in the reserpine-induced fibromyalgia model in mice: The role of the Schwann cell TRPA1/NOX1 signalling pathway

Fibromyalgia (FM) is a complex and multifaceted condition characterized by a range of clinical symptoms, including widespread pain and a strong association with migraine headaches. Recent findings have underscored the role of oxidative stress and transient receptor potential ankyrin 1 (TRPA1) channel in migraine and FM. However, the precise mechanisms underlying the comorbidity between migraine and FM are unclear. Periorbital mechanical allodynia (PMA), which recapitulates one of the major symptoms of migraine, and the feed-forward mechanism driven by reactive oxygen species and TRPA1, were investigated in a reserpine-induced FM model in C57BL/6J mice, employing pharmacological interventions and genetic approaches. Reserpine-treated mice developed PMA (which was alleviated by antimigraine drugs) and increased endoneurial macrophages and oxidative stress markers in the trigeminal nerve tissues (neuroinflammation). These responses were absent upon macrophage depletion and by pharmacological inhibition or global genetic deletion of the TRPA1 channel. Furthermore, selective silencing of TRPA1 in Schwann cells attenuated both reserpine-induced PMA and neuroinflammation, while selective silencing of TRPA1 in sensory neurons reduced PMA but not neuroinflammation. In reserpine-treated mice, Schwann cell TRPA1 promoted NADPH oxidase 1-mediated reactive oxygen species generation and macrophage density increase in the mouse trigeminal nerve, which sustains PMA. Targeting TRPA1 channels in Schwann cells could offer a novel therapeutic strategy for FM-related headaches.