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Regenerative Peripheral Nerve Interface (RPNI) treatment in rats alleviates chronic neuropathic pain hypersensitivity in a sexually dimorphic manner
Shelby Svientek, MD1, Nathan G Lawera, BSE2, Carrie A Kubiak, MD2, Theodore A Kung, MD3, Paul S Cederna, MD4 and Stephen WP Kemp, PhD2, (1)The University of Michigan, Ann Arbor, MI, (2)University of Michigan, Ann Arbor, MI, (3)Section of Plastic & Reconstructive Surgery, University of Michigan, Ann Arbor, MI, (4)Plastic Surgery, University of Michigan, Ann Arbor, MI

Introduction: Neuropathic pain is the most severely disabling type of chronic pain resulting from amputation, with associated US health care costs estimated to be greater than $600 billion annually. This type of pain is almost always resistant to opioid treatment. Currently, there is a fundamental gap in knowledge in understanding how to effectively treat neuropathic pain with non-opioid based strategies. Until this is solved, it will continue to lead to debilitating pain, an inability to perform daily activities of living, lack of meaningful employment, and an inability to wear prosthetic devices resulting in continued disability and poor quality of life. We have developed the Regenerative Peripheral Nerve Interface (RPNI) as a novel treatment strategy for the alleviation of neuropathic pain. RPNIs are constructed by surgically implanting the distal end of a transected nerve into an autogenous muscle graft. We assessed the ability of RPNIs to alleviate established chronic pain in both male and female rats.

Materials and Methods: 12 male and 12 female rats were randomly assigned into either a neuroma only group, or a neuroma + RPNI treatment group. At baseline, all animals were assessed in the following pain tests: (1) thigh von Frey (neuroma tenderness); (2) paw von Frey (tactile allodynia); (3) acetone test (cold allodynia), and; (4) Hargreaves test (thermal allodynia). All animals then underwent tibial neuroma surgery, and were serially assessed in behavioral pain measures for 2 months. At the 2 month timepoint, half of the animals received RPNI surgery, and the other half received sham surgery. Animals were then serially followed for an additional 2 months. At study endpoint, both spinal cord and dorsal root ganglion (DRG; L4/L5) were harvested for immunohistochemistry.

Results: All animals developed chronic pain hypersensitivity following neuroma creation. Following RPNI surgery, neuroma tenderness decreased drastically in both sexes. However, tactile allodynia (a surrogate marker of phantom limb pain) was attenuated in males to a much greater degree than in females. Female rats were also more sensitive to both cold and thermal allodynia. Reactive microgliosis was similar in both sexes, but the purinergic receptor P2X4 was upregulated exclusively in male rats.

Conclusions: Results show that RPNI surgery attenuates chronic neuroma pain in both sexes, although to a greater degree in male rats. Purinergic receptor upregulation is also specific to males. Taken together, these results demonstrate the existence of sexually dimorphic pain signaling in rats following neuroma and RPNI treatment.


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