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Prophylactic Regenerative Peripheral Nerve Interface (RPNI) Reveals Sexually Dimorphic Attenuation Of Neuropathic Pain In Rat'S Neuroma Model
Amir Dehdashtian, M.D., M.P.H, Shelby Svientek, M.D., Mary J. Risch, Daniel C. Ursu, M.D., PhD, Allison B. Vittert, Paul S. Cederna, M.D., Stephen WP Kemp, PhD.
University of Michigan, Ann Arbor, MI, USA.

PURPOSE: More than 185,000 people undergo amputations in the United States each year, and the total number of persons with amputations is expected to be nearly 3.6 million by 2050. Severing a nerve following amputation commonly leads to painful neuroma formation and hypersensitivity of both the central and peripheral nervous systems. Recent empirical evidence has shown that the underlying cellular and molecular mechanisms responsible for neuropathic pain are different between males and females. Potential preventions or treatments of symptomatic neuromas should therefore address sexual dimorphic mechanisms of pain hypersensitivity. The regenerative peripheral nerve interface (RPNI) is a surgically fabricated construct consisting of a residual peripheral nerve implanted into an autologous free muscle graft. Previous retrospective clinical studies in our lab have shown that RPNIs can both help treat neuroma pain and prevent neuroma recurrence. In the present study, we investigated the benefits of prophylactic RPNIs to attenuate central and peripheral pain hypersensitization in both male and female rats.METHODS: Thirty-six F344 rats (18 male, 18 female) were randomly assigned to one of three experimental groups (n=6/group): (1) neuroma with no treatment; (2) prophylactic RPNI, and; (3) sham surgery. Neuromas were created through transection of the tibial nerve at mid-thigh level. The proximal segment was relocated over the biceps femoris (BF) muscle and secured to the dermis with two epineural sutures. For the prophylactic RPNI groups, the transected tibial nerve was implanted into an autologous extensor digitorum longus (EDL) muscle. The RPNI construct was then placed inbetween the BF muscle and sutured to the sides. Serial behavioral tests were performed weekly for two months. Neuroma pain was assessed by five trials of five gentle tappings (similar to Tinel's test) on the skin overlying the neuroma using a single Von Frey filament (15.0 grams), and the percent of behavioral pain response was recorded. Mechanical allodynia was evaluated using the up-down Von Frey method at both the middle and lateral aspects of the hindlimb. Hypersensitivity to cold and thermal stimuli was assessed using the Acetone and Hargreaves tests, respectively. Finally, neuroma bulbs, RPNIs, tibial nerve, ipsilateral L4 and L5 dorsal root ganglions, and lumbar spinal cord were harvested for immunohistochemical and histomorphometrical analysis of microglia activity, adaptive immune cells, and nociceptive phenotype of nerves.
RESULTS: Our results demonstrate a significant effect of time on neuroma pain response in males (F(8, 8)= 52.19, p<0.001) and females (F(8, 8)= 24.66, p=<0.001). Prophylactic RPNIs not only prevented neuroma formation but also resulted in lower pain responses over time in both sexes (p<0.001 for each gender). Sexual dimorphic pain hypersensitivity was shown with females displaying significantly greater pain in the initial period following surgery, and a longer period before pain attenuation when compared to males (Figure 1).
CONCLUSION: Prophylactic implantation of RPNIs is associated with attenuation of symptomatic neuromas and the development of pain hypersensitivity in both males and females over time.


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