Analysis of Functional Regeneration in a Rat Model of Median Nerve Injury and Repair - Evaluation of Mechanical Allodynia and Gait Behavior
Jana Ritter, MD1, Cosima Prahm, Ph.D.1, Manuela Büttcher, DVM1, Thomas Wuttke, Dr. med.1, Adrien Daigeler, Prof. Dr.1, Johannes C. Heinzel, Dr. med.1,2 and Jonas Kolbenschlag, Prof. Dr. med.1, 1University of Tübingen, Tübingen, Germany, 2Austrian Cluster for Tissue Regeneration, Vienna, Austria
Introduction
Functional deficits after nerve injuries pose a major clinical problem. This highlights the importance of methods allowing comprehensive quantification of functional recovery in preclinical research. In the evaluation of sensory recovery after nerve injury, response to tactile stimulation can erroneously be allocated to regeneration of the injured nerve, disregarding the process of collateral spouting of adjacent uninjured nerves into the denervated skin. In the rat sciatic nerve model significant influence of collateral sprouting of intact nerves on the development of neuropathic pain could already be revealed. Our project aimed to analyze and correlate sensory and motor recovery and investigate the contribution of collateral nerve sprouting in a rat model of median nerve injury and repair.
Methods
Male Wistar rats (n=10) underwent transection and reconstruction of the median nerve with epineurial sutures in one forelimb. In the contralateral forelimb, 15mm of the median nerve were resected and the nerve stumps were coaptated to surrounding muscles to prevent regeneration. For 12 weeks after surgery, mechanical allodynia, grip strength and gait behavior were assessed weekly by means of the Von Frey Test, the Grasping Test and the CatWalk gait analysis system. To analyze the effects of collateral sprouting, Von Frey Monofilaments were applied to predefined test areas considering the sensory innervation of the forepaws: Medial and lateral areas selectively innervated by the median and ulnar nerve and the central area non-selectively innervated by both nerves.
Results
One week postoperatively, early mechanical allodynia was evident in the areas of the forepaw selectively innervated by the ulnar nerve and the overlapping area innervated by the median and ulnar nerves. Subsequently, mechanical allodynia developed in the areas of the paw innervated by the median nerve. This was associated with a significant decrease in grip strength and Print Area. From week 6, mechanical allodynia increased in the median nerve innervated territory, which was associated with regeneration of grip strength and Print Area. Mechanical allodynia persisted in all areas of the forepaws until week 12. The results of the functional tests correlated significantly and revealed a marked effect of nerve reconstruction on functional outcome.
Conclusion
Collateral sprouting of uninjured nerves and regeneration of the injured nerve contribute differently to sensory reinnervation after nerve injury. The use of functional tests to evaluate motor and sensory recovery provides profound insights into the interaction of these processes and adds to the understanding of the development and maintenance of neuropathic pain.
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