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Regenerative Peripheral Nerve Interfaces (RPNI) Attenuate Neuropathic Pain And Molecular Markers Associated With Symptomatic Neuromas In Both Male And Female Rats
Jagienka H. Timek, BS, Erin Guy, BS, Amir Dehdashtian, MD, MPH, Anna Riegger, BS, Stephen Kemp, PhD, Paul Cederna, MD.
University of Michigan, Ann Arbor, MI, USA.

PURPOSE: Approximately 2 million people in the United States suffer from chronic peripheral nerve pain from symptomatic neuromas following limb amputation. 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. Unfortunately, no gold standard of care, either surgical or pharmacological, currently exists for treatment of neuropathic pain resulting from symptomatic neuromas. Furthermore, recent evidence suggests that sexual dimorphic mechanisms of neuropathic pain exist, warranting a personalized or precision-medicine approach to treatment. Regenerative peripheral nerve interfaces (RPNI) have been previously shown to attenuate both 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. The present study investigates differences in pain-associated behaviors and molecular markers displayed by male and female rats in both neuroma and RPNI groups.
METHODS: 36 F344 rats (n = 18/gender) were randomly assigned into one of three experimental groups (n=6/group): (1) neuroma; (2) RPNI treatment, and; (3) sham control. A neuroma was created in Group 1 by transecting the proximal end of the tibial nerve and suturing it to the surface of the biceps femoris in the right leg. RPNI group animals received the identical injury, but the proximal nerve ending was wrapped in non-vascularized extensor digitorum longus (EDL) donor muscle from the contralateral side. The site of injury in treatment and neuroma groups was superficially marked on the skin for direct access to the nerve for behavioral testing. 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, namely 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 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 data support sex differences in pain attenuation following neuroma and RPNI treatment as reflected by both histological and behavioral assays. Furthermore, these results suggest a need for a precision medicine-based approach to neuroma treatment based on sexual dimorphic differences.


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