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Attenuation Of Neuroma Induced Pain Hypersensitivity By Regenerative Peripheral Nerve Interfaces (rpnis) Is Sexually Dimorphic In Rats
Shelby Svientek, MD, Nathan G. Lawera, Jarred V. Brately, Theodore A. Kung, MD, Paul S. Cederna, MD, Stephen WP Kemp, PhD.
University of Michigan, Ann Arbor, MI, USA.

PURPOSE: Neuropathic pain is the most severely disabling type of chronic pain resulting from amputation, with associated health care costs in the US 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.
METHODS: Twenty-four rats (12 male, 12 female) 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 pain); (2) paw von Frey (tactile allodynia); (3) acetone test (cold allodynia), and; (4) Hargreaves test (thermal allodynia). Following baseline assessments, tibial neuromas were created in all animals, and they were then serially assessed in behavioral pain measures over a 2 month period. 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, spinal cord, dorsal root ganglion (DRG; L4/L5), neuroma bulbs, and proximal nerve were harvested for immunohistochemistry and histomorphometrical analysis.
RESULTS: All animals developed chronic pain hypersensitivity following neuroma creation. Following RPNI surgery, neuroma pain was significantly attenuated 3 weeks post-surgery 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.
CONCLUSION: 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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