Behavioral and molecular characterization of various muscle-based surgical strategies for neuroma treatment in a peroneal nerve transection rat model

Chronic pain resulting from neuroma formation is a prevalent and challenging problem to treat. Clinical studies suggest (1) surgically intervening at the time of nerve injury rather than in a delayed fashion and (2) providing denervated muscle targets, such as vascularized denervated muscle targets (VDMTs), leads to greater pain resolution than innervated muscle targets (bury-in-muscle [BIM]), although the mechanisms underlying these benefits are unclear. We compared behavioral, histological, and transcriptional signatures associated with nerve transection, immediate VDMT (I-VDMT), BIM, and delayed/postneuroma VDMT (D-VDMT). Immediate VDMT most effectively reduced injury- or inflammation-associated signatures. Bioinformatic analysis predicted that MEF2C repression was associated with injury signaling, which was reversed in I-VDMT. BML-210, a small molecule inhibitor of HDAC4-MEF2C interactions, treatment reduced sensory hypersensitivity in rodent nerve injury models. This study elucidates the benefits of denervated muscle targets over innervated muscle targets and identifies pharmacologic interventions in HDAC4 protein interactions as treatment avenues for neuroma-related symptoms.