Targeted Muscle Reinnervation in Rat Spared Nerve Injury Models Neuropathic Amputation-Related Pain Relief
Elizabeth L. Roth, B.S., Cheryl Stucky, Ph.D., Quinn Hogan, M.D. and Gwendolyn M.B. Hoben, M.D., Ph.D., Medical College of Wisconsin, Milwaukee, WI
Introduction: The success of targeted muscle reinnervation (TMR) in preventing or relieving amputation-related neuropathic pain has been well shown in clinical studies. However, many questions remain about the changes in pain pathways and neuronal regeneration induced by TMR. These questions are best answered in an animal model. Pre-clinical studies using amputation are problematic as limb sensation and stimulation-related pain behaviors cannot be tested, precluding validation of pain. We hypothesize TMR can be used to treat neuropathic pain that follows peripheral nerve transection in the spared nerve injury model, a robust, well-validated model of neuropathic pain. This model retains the limb and thus, allows for standard rodent pain behavior testing.
Materials and methods: Spared nerve injury was performed in male rats by unilaterally ligating the common peroneal and tibial nerves. After 3 weeks, the rats developed a robust and consistent neuropathic pain phenotype and two interventions were studied: 1. TMR: the neuromas were excised and the animals underwent coaptation of the common peroneal and tibial nerves to nerve branches to the biceps femoris; and 2. Neuroma Excision (NE): the neuromas were excised and the muscle branches divided but no coaptations were performed. The plantar skin in the sural distribution was tested with von Frey threshold, pin touch hyperalgesia, and hypersensitivity to dynamic mechanical stimulation (brush), acetone (cold), and heat (Hargreaves) to characterize pain behavior prior to intervention and at 1 and 3 weeks following intervention. The healthy contralateral limb was tested as an internal control.
Results: The spared nerve injury caused a robust pain phenotype with increased hyperalgesic responses, reduced von Frey thresholds, and increased cold sensitivity. One week after TMR, pain behaviors were significantly changed compared to pre-intervention pain measures, while pain measures did not change in the NE group. In the TMR group, hyperalgesia responses to pin were reduced 80% within 1 week following TMR but did not change significantly following NE. Von Frey thresholds returned to the baseline following TMR but remained significantly elevated in the NE group. There was also a trend to reduced cold hypersensitivity in the TMR group.
Conclusions: This rodent model mirrors the clinical results found in TMR and allows for measurement of allodynia, hyperalgesia, and sympathetic-related pain behavior changes. This model will allow for determining the underlying mechanisms at the dorsal root ganglion and axonal levels responsible for the clinical outcomes of TMR surgery.
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