Sexually Dimorphic Pattern of Pain Mitigation Following Prophylactic Regenerative Peripheral Nerve Interface (RPNI) in a Rat Neuroma Model

Abstract

BACKGROUND: Treating neuroma pain is a clinical challenge. Identification of sex-specific nociceptive pathways allows a more individualized pain management. The Regenerative Peripheral Nerve Interface (RPNI) consists of a neurotized autologous free muscle using a severed peripheral nerve to provide physiological targets for the regenerating axons. OBJECTIVE: To evaluate prophylactic RPNI to prevent neuroma pain in male and female rats. METHODS: F344 rats of each sex were assigned to neuroma, prophylactic RPNI, or sham groups. Neuromas and RPNIs were created in both male and female rats. Weekly pain assessments including neuroma site pain and mechanical, cold, and thermal allodynia were performed for 8 weeks. Immunohistochemistry was used to evaluate macrophage infiltration and microglial expansion in the corresponding dorsal root ganglia and spinal cord segments. RESULTS: Prophylactic RPNI prevented neuroma pain in both sexes; however, female rats displayed delayed pain attenuation when compared with males. Cold allodynia and thermal allodynia were attenuated exclusively in males. Macrophage infiltration was mitigated in males, whereas females showed a reduced number of spinal cord microglia. CONCLUSION: Prophylactic RPNI can prevent neuroma site pain in both sexes. However, attenuation of both cold allodynia and thermal allodynia occurred in males exclusively, potentially because of their sexually dimorphic effect on pathological changes of the central nervous system.