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Attenuation of Molecular Markers and Neuropathic Pain Associated with Symptomatic Neuromas in Both Male and Female Rats with the Regenerative Peripheral Nerve Interface (RPNI)
Katherine L Burke, MD1; Jagienka H Timek, BS1; Amir Dehdashtian, MD, MPH1; Gabriela Cinotto, MD1; Erin Guy, BS1; Anna Riegger, BS1; Paul S Cederna, MD2; Stephen WP Kemp, PhD1
1University of Michigan, Ann Arbor, MI; 2Plastic Surgery, University of Michigan, Ann Arbor, MI

INTRODUCTION: In the United States, approximately two million people suffer from chronic pain from symptomatic neuromas following limb amputation leading to substantial physical disability and decreased quality of life among affected patients. Development of these neuromas triggers a cascade of immunological and molecular changes in nerve tissue, resulting in hypersensitivity and pain markers in both the peripheral and central nervous system. Furthermore, recent evidence has identified sexual dimorphic mechanisms of neuropathic pain, warranting a personalized approach to treatment. Regenerative peripheral nerve interfaces (RPNI) have been shown to attenuate both symptomatic neuroma development and chronic neuropathic pain when constructed prophylactically at the time of amputation. However, it is not known whether RPNIs attenuate the upregulation of neuroma induced molecular changes. This study investigates differences in pain-associated behaviors and molecular markers displayed by male and female rats in both neuroma and RPNI groups.
METHODS: Thirty-six F344 rats (n = 18/gender) were randomly assigned to one of three experimental groups (n=6/group): (1) neuroma; (2) RPNI treatment, and; (3) sham control. The proximal end of the tibial nerve was transected and either sutured to the surface of the biceps femoris to create a neuroma (Group 1) or wrapped in non-vascularized extensor digitorum longus (EDL) donor muscle from the contralateral side creating an RPNI (Group 2). Mechanical allodynia and neuroma site pain were assessed with the von Frey Test, while cold allodynia was assessed with the Acetone Test. Following surgery, animals were tested serially over an 8-week period. At the study endpoint, the RPNI, neuroma bulb, proximal nerve, L4-5 spinal cord segments, L4-5 DRGs of both sides, and control EDLs were harvested. These sections were immunostained for markers of neuroma and inflammation, including Nav1.7 sodium channels, beta-III tubulin, and microglia, to provide histological corollaries to observed pain behaviors.
RESULTS: The data indicate a significant attenuation of pain by the RPNI construct in both male and female animals in response to neuroma-site pain stimulation. Interestingly, the RPNI attenuated cold and heat allodynia to a significant degree in males, but not females. Significant differences in the upregulation and subsequent attenuation of neuroma induced molecular markers were seen between groups.
CONCLUSION: Together, these results support sex differences in pain attenuation following neuroma and RPNI treatment as reflected by both histological and behavioral assays. Furthermore, these findings suggest a need for a precision medicine-based approach to neuroma treatment based on sexual dimorphic differences.


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