American Society for Peripheral Nerve

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Neuropathic Pain Hypersensitivity From Terminal Neuromas is Sexually Dimorphic in Rats
Shelby Svientek, MD; Jason L. Kessler, BSc; Carrie A. Kubiak, MD; Scott W. Sabbagh, BS; Vincent Thieu, BSE; Brian P. Cleary, BS; Theodore A. Kung, MD; Paul S. Cederna, MD; Stephen WP Kemp, PhD
University of Michigan, Ann Arbor, MI

Introduction Symptomatic neuromas occur in approximately 30-40% of individuals following limb loss, often leading to excruciating neuropathic pain hypersensitivity. Recent literature indicates sex differences in pain signaling in mice following peripheral nerve injury. More specifically, microglia-neuron signaling in the spinal cord has been implicated as a key mediator of mechanical allodynia, although it is not known if this phenomenon is conserved in rats. The purpose of the present study was to investigate if sexual dimorphism in both pain behavior and central spinal mechanisms exist following surgical creation of terminal neuromas in rats.

Materials & Methods: A total of 23 rats (11 female and 12 male) were randomly assigned to either a tibial nerve neuroma group, or an uninjured control group. All animals underwent baseline functional pain and hypersensitivity testing. Following surgical intervention, rats were serially tested over 8 weeks for mechanical allodynia (von Frey), cold allodynia (Acetone test), and heat allodynia (Hargreaves test). At study endpoint, nerve and neuroma samples were harvested for histomorphometrical analysis. Spinal cord and dorsal root ganglion (DRG) samples were assessed for both microglia and T-cell immune mediated responses. These included P2X4 upregulation, p38 mitogen-activated protein kinas, and activation of the transcription factor IRF5.

Results: Both male and female rats with tibial neuromas displayed increased mechanical hypersensitivity in the von Frey test. Female rats required less force to generate a pain response in comparison to male rats in the control group; interestingly, the opposite held true in the tibial neuroma group. For cold allodynia, female rats demonstrated increased pain behavior for both control and neuroma groups. Sexual dimorphic responses did not occur for heat allodynia. Spinal mechanisms of neuroma induced hypersensitivity differed between males and females.

Conclusions: Previous experimental studies in mice have showed considerable differences in both the mediation and demonstration of pain hypersensitivity between sexes. This study confirms the existence of sexually dimorphic pain behavior and signaling in rats. Results from this study may lead to viable therapeutic targets for neuropathic pain in both sexes.

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