Differential effects of activity dependent treatments on axonal regeneration and neuropathic pain after peripheral nerve injury

Activity treatments are useful strategies to increase axonal regeneration and functional recovery after nerve lesions. They are thought to benefit neuropathy by enhancing neurotrophic factor expression. Nevertheless the effects on sensory function are still unclear. Since neurotrophic factors also play a fundamental role in peripheral and central sensitization, we studied the effects of acute electrical stimulation and early treadmill exercise on nerve regeneration and on neuropathic pain, and the relation with the expression of neurotrophins. After sciatic nerve section and suture repair, rats were subjected to electrical stimulation (ES) for 4h after injury, forced treadmill running (TR) for 5days, or both treatments combined. Sciatic nerve section induced hyperalgesia in the medial area of the plantar skin in the injured paw. TR and ES differently but positively reduced adjacent neuropathic pain before and after sciatic reinnervation. ES enhanced motor and sensory reinnervation, and combination with TR induced strong agonistic effects in relieving pain. The differential effects of these activity treatments were related to changes in neurotrophic factor mRNA levels in sensory and motor neurons. ES speeded up expression of BDNF and GDNF in DRG, and of BDNF and NT3 in the ventral horn. TR reduced the levels of pro-nociceptive factors such as BDNF, NGF and GDNF in DRG. Combination of ES and TR induced intermediate levels suggesting an optimal balancing of treatment effects. ► Activity-dependent therapies are useful to improve or recover lost functions after nerve lesions. ► Early electrical stimulation enhances nerve regeneration, motor and sensory reinnervation. ► Forced treadmill exercise reduced adjacent neuropathic pain before and after sciatic reinnervation. ► Combination of electrical stimulation with treadmill exercise induced agonistic effects in relieving neuropathic pain. ► Effects of activity treatments were related to changes in neurotrophic factor expression in sensory and motor neurons.