Efficacy of targeted muscle reinnervation is directly affected by timing of intervention in a neuropathic pain model

Purpose Targeted muscle reinnervation (TMR) coapts amputated nerves to small motor nerves to power a prosthetic limb. Additionally, clinical studies have shown TMR performed within 3 months of major limb amputation prevents or reduces phantom and residual limb pain. However, TMR delayed over 3 months is much less effective. We have previously shown that TMR performed 3 weeks following SNI returned pain behaviors to baseline. This study examined the effect of TMR performed at the time of TMR versus a delay of 12 weeks following SNI to determine whether this model reflects clinical findings. SNI was performed in male rats and interventions were applied at the time of SNI, 3 weeks, and 12 weeks following SNI. Pain behaviors were assessed with von Frey threshold, pin testing, dynamic brush testing and acetone testing prior to intervention and at 1, 3, 6, and 12 weeks following intervention. Simple neuroma excision (NE) was used as a control intervention. TMR performed immediately at the time of SNI prevented the development of a pain phenotype. Animals tested 3 and 12 weeks following SNI showed a robust pain phenotype: increased hyperalgesic responses, reduced Von Frey thresholds, and increased cold sensitivity. TMR at 3 weeks following SNI successfully reversed the pain behaviors to baseline. In contrast, if TMR or NE was delayed 12 weeks after SNI, the pain behaviors persisted. The neuropathic pain phenotype generated by SNI can be treated with TMR performed immediately and 3 weeks following development of a pain phenotype. In contrast, delayed TMR provides no relief of pain behaviors. This model closely corresponds to clinical experience in patients with limb amputation and will facilitate further understanding of the mechanisms behind TMR and how the intervention may be modified to help chronic amputation-related pain. Medical College of Wisconsin Neurosciences Research Center Plastic Surgery Foundation- American Association for Hand Surgery Pilot Grant 628811.