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Poorly Controlled Diabetes Is Associated with Decreased Neuroma Pain Following Peripheral Nerve Transection in a Rat Neuroma Model
Tiam M. Saffari, Varoon Phondge^*, Morgan Yun, Arianna Valenti, Bruno Pillari, Wan Jiao, Alex Wong, Edward Lee
Plastic Surgery, Rutgers NJMS, Newark, NJ

Introduction: Diabetes mellitus (DM) accounts for 80% of non-traumatic lower limb amputations, with up to 30% of amputees developing symptomatic neuromas. DM is suggested to attenuate symptomatic neuroma pain following nerve injury. The aim of this study was to evaluate the effect of poorly controlled diabetes with persistent hyperglycemia on neuroma-associated pain in a validated rat neuroma model.
Methods: Control and loosely controlled DM BB-Wistar (diabetic) rats (N=12/group) were used. A neuroma of the tibial nerve was surgically created. The tibial nerve was transected, transposed, and secured to the dermis of the thigh. Diabetic animals were maintained at a high glycemic range, between 300-450 mg/dL. Weekly assessments of thigh tap testing, von Frey testing, Hargreaves thermal nociception, and cold allodynia testing were performed. At 12 weeks, animals were sacrificed and dorsal root ganglia (DRG) were harvested and stained against neuropeptide Y (NPY), a marker for nerve injury-associated pain.
Results: Thigh tap and von Frey testing demonstrated significantly lower pain responses in diabetic animals (p < 0.0001), with differences observed at postoperative weeks 5-12 (p < 0.0001). No significant differences were found in cold allodynia. At week 4, Hargreaves thermal responses were significantly lower in diabetic animals compared to control (p<0.05). DRG NPY expression was significantly lower in diabetic animals (p = 0.001).
Conclusion: Poorly controlled diabetic rats with persistent hyperglycemia are associated with a significant attenuation of neuroma-associated pain. A decrease in DRG NPY expression suggests reduced neuronal activation in diabetic animals. These findings suggest that a hyperglycemic micro-environment may modify neuroma pain biology. Future studies are needed to evaluate how targeted muscle reinnervation (TMR) and regenerative peripheral nerve interfaces (RPNI) may alter neuroma pain outcomes in this diabetic rat neuroma model.
Figure 1: Results. (A) Von Frey and (B) Thigh tap testing were performed weekly for 12 weeks. Baseline measurements were obtained at week 0.
(C) Neuroma and (D) control images were stained for NPY (green) and DAPI (blue). (E) Quantification of NPY pixel density in DRG