Foretinib Enhances Myelination of Neurons in vitro
Jose Lucas Zepeda, BS1, Gabriella Mraz, BS1, Elizabeth Roth, BS, MSN1 and Gwendolyn M.B. Hoben, M.D., Ph.D.2, 1Medical College of Wisconsin, Milwaukee, WI, 2Department of Surgery, Division of Plastic and Reconstructive Surgery, Medical College of Wisconsin, Milwaukee, WI
Neuropathic pain will affect upwards of 70% of all amputees. Surgical techniques to reroute amputated nerves to create an appropriate signal for a prosthesis have shown to also reduce amputation-related pain. Previously, we studied TMR in a rodent using the spared nerve injury model, preserving the hindlimb for standard pain behavior testing in the portion of the foot that remained innervated. Our aim is to expand to a full amputation model to study TMR and analgesia. This study evaluated a rat hindlimb amputation model in male and female rats to determine if it was effective to examine pain with and without TMR.
Ten male rats and twelve female rats were randomly split into two cohorts: amputation with immediate TMR (iTMR) and amputation-only. For iTMR the common peroneal, tibial, and sural branches were transected and coapted to the motor branches of the semimembranosus and bicep femoris. For the amputation-only cohort, the nerves were ligated, and a 4-5mm distal segment was removed. A full below the knee amputation was then performed in both groups. Baseline behavior testing pre-amputation was obtained. At two weeks and five weeks post-amputation, von Frey (mechanical hypersensitivity) and pin responses (hyperalgesia) were tested. Conditioned place preference (CPP) with gabapentin was completed at three weeks post-amputation. At five weeks post-amputation, acetone cold hypersensitivity and spontaneous pain measures were assessed.
Hyperalgesia measured at two weeks post-amputation showed the iTMR rats had an average noxious response of 10%, and amputation-only had an average noxious response of 46% (p<0.05). At four weeks post-amputation, iTMR rats had an average noxious response of 36%, while amputation-only rats had 48% noxious response (p<0.05). For acetone cold hypersensitivity, iTMR rats exhibited 30% noxious responses, while amputation-only exhibited 100% noxious responses (p<0.05). Rats with iTMR demonstrated an average of 19.2 seconds of guarding over a two-minute interval, and amputation-only rats averaged 28.9 seconds (p<0.05).
The pain behaviors of iTMR rats showed significantly greater analgesia, including reduced hyperalgesia, cold hypersensitivity, and spontaneous pain, compared to amputation only. However, the reinnervation of some of the ligated nerves in amputation-only rats may have resulted in the trend of improved pain behaviors over time. Our future work will aim to assess differences in motor versus sensory regeneration compared to different interventions and provide a more thorough characterization of the regenerative microenvironment at the coaptation sites.
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