Transcutaneous Electrical Nerve Stimulation in Nerve Regeneration: A Systematic Review of In Vivo Animal Model Studies.

OBJECTIVE: Transcutaneous electrical nerve stimulation (TENS) is a noninvasive electrical stimulation therapy indicated for pain control that has been applied for the regeneration of nerves. This systematic review aimed to analyze the evidence on TENS effectiveness on nerve regeneration. MATERIALS AND METHODS: A systematic review was performed following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses criteria: PubMed/MEDLINE, Web of Science, ScienceDirect, and SciELO data bases. Primary research that evaluated TENS on nerve regeneration was considered. RESULTS: Several studies have investigated the use of TENS for pain treatment. A total of six animal studies analyzed TENS for nerve regeneration. The selected articles showed high quality (Animal Research: Reporting of In Vivo Experiments guidelines), with many unclear points related to bias opportunities (Systematic Review Center for Laboratory Animal Experimentation Risk of Bias tool). In general, TENS accelerated functional and motor recovery and increased axon quantity and diameter. More specifically, the application of low-frequency TENS resulted in a continuous basal lamina; a higher density of fibers with normal diameters, indicating normal myelination, showed signs of deterioration and delayed nerve regeneration. In contrast, the high-frequency TENS application stimulated motor regeneration and increased the diameter of the regenerated axons but revealed a small number of axons, demyelination, dark axoplasm, and an increase in the predisposition of neuropathic pain. CONCLUSIONS: Although there is some heterogeneous evidence in animal research, TENS seems to be a promising treatment for nerve injury that should be better explored. It is still necessary to improve the analysis of its application parameters, which can lead to the most satisfactory regeneration results and improve the understanding of its mechanisms on peripheral nerve regeneration.

Interleukin-4 mediates the analgesia produced by low-intensity exercise in mice with neuropathic pain.

Peripheral nerve injury (PNI) activates the immune system, resulting in increased proinflammatory cytokines at the site of injury and in the spinal cord dorsal horn. Exercise modulates the immune system promoting an anti-inflammatory phenotype of macrophages in uninjured muscle, and increases in anti-inflammatory cytokines can promote healing and analgesia. We proposed that PNI will decrease, and treadmill exercise will increase, release of anti-inflammatory cytokines at the site of injury and in the spinal cord. We show that 2 weeks of treadmill exercise improves neuropathic pain behaviors in mice: mechanical hyperalgesia, escape and avoidance behavior, and spontaneous locomotor activity. Peripheral nerve injury reduced anti-inflammatory cytokines (interleukin-4 [IL-4], IL-1ra, and IL-5) at the site of nerve injury and in the spinal dorsal horn, whereas exercise restored IL-4, IL-1ra, and IL-5 concentrations to preinjury levels. IL4 mice and mice treated with IL-4 antibody did not develop analgesia to treadmill exercise. Using immunohistochemical staining of the sciatic nerve, treadmill exercise increased the percentage of M2 macrophages (secretes anti-inflammatory cytokines) and decreased M1 macrophages (secretes proinflammatory cytokines) when compared with sedentary mice. The increased M2 and decreased M1 macrophages in exercised mice did not occur in IL-4 mice. In the spinal cord, PNI increased glial cell activation, brain-derived neurotrophic factor and ß-nerve growth factor levels, and decreased IL-4 and IL-1ra levels, whereas treadmill exercise suppressed glial cells activation (Glial Fibrillary Acidic Protein and Iba1 immunoreactivity), reduced brain-derived neurotrophic factor and ß-nerve growth factor, and increased IL-4, IL-1ra, and IL-5 concentrations. Our results suggest that IL-4 mediates the analgesia produced by low-intensity exercise by modulating peripheral and central neuroimmune responses in mice with neuropathic pain.