Characterization of Chronic Pain and Hypersensitivity in Mixed, Motor, and Sensory Nerve Terminal Neuromas in Rats
Jason L. Kessler, BSc, Scott W. Sabbagh, BSc, Carrie A. Kubiak, MD, Jana Moon, BSc, Vincent Thieu, N/A, Brian P. Cleary, BSc, Paul S. Cederna, MD, Stephen W.P. Kemp, PhD.
University of Michigan Medical School, Ann Arbor, MI, USA.
PURPOSE: Approximately 185,000 amputations are performed annually in the United States. Symptomatic neuromas occur in approximately 30-40% of individuals after limb loss, and phantom limb pain affects 70-95% of these patients, often leading to excruciating pain and disability. Although pre-clinical animal studies have evaluated pain in different experimental models, it is not currently known whether different neuroma models lead to differences in pain hypersensitivity responses. The current study sought to characterize serial pain responses utilizing sensitive functional outcome measures from terminal mixed, motor, and sensory neuroma rat models.
METHODS: Prior to surgery, all rats underwent baseline pain sensitivity testing and were randomly assigned to one of three surgical groups of six rats each: (1) mixed nerve (tibial); (2) sensory nerve (sural), and; (3) motor nerve (femoral) neuromas. The distal nerve of each respective surgical group was isolated, transected, and transposed to a more superficial position in the hindlimb, creating neuromas that were accessible for sensitivity testing. Neuromas were created in the right hindlimb (experimental group) with the left hindlimb serving as a control. Functional pain outcome measures were performed serially for eight weeks and assessed mechanical allodynia (von Frey test), heat allodynia (Hargreaves test), and cold allodynia (Acetone test). Terminal outcome measures occurred at two months and consisted of histomorphometrical analysis of the nerve and histological assessment of the neuroma.
RESULTS: Both tibial and sural neuroma groups demonstrated increased mechanical sensitivity when the von Frey test was performed on the middle aspect of the hindpaw. However, only the tibial neuroma group displayed increased mechanical sensitivity when the test was performed on the lateral aspect of the hindpaw. von Frey assessment at the thigh level revealed decreased mechanical sensitivity at Week 1 post-surgery for all experimental groups. However, this decrease normalized to baseline and control levels during Week 2 post-surgery. Only the tibial neuroma group demonstrated an increase in thigh mechanical sensitivity at week 7 of testing. Cold allodynia assessed by the Acetone test revealed that only the tibial neuroma group displayed statistically significant hypersensitivity.
CONCLUSION: Of the three terminal neuroma models characterized in this study, only the tibial neuroma group demonstrated significant hypersensitivity to both mechanical and cold stimulation. Data from this study demonstrates that the tibial neuroma model is the most appropriate model for evaluating chronic behavioral pain responses following injury.
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