Mechanisms of Neuropathic Pain and Pain-Relieving Effects of Exercise Therapy in a Rat Neuropathic Pain Model.

Purpose: Pain disrupts the daily and social lives of patients with neuropathic pain. Effective treatment of neuropathic pain is difficult. Pharmacological treatments for neuropathic pain are limited, and 40-60% of patients do not achieve even partial relief of their pain. This study created a chronic constriction injury (CCI) model in rats to examine the effects of regular exercise on neuropathic pain relief, elucidate the mechanism, and determine the effects of neuropathic pain in the hippocampus. Methods: CCI model rats were randomly divided into exercise (Ex) and no exercise (No-Ex) groups. Normal rats (Normal group) were used as controls. The Ex group exercised on a treadmill at 20 m/min for 30 min, 5 days per week for 5 weeks post-CCI. The 50% pain response threshold was assessed by mechanical stimulation. Using immunohistochemistry, we examined activation of glial cells (microglia and astrocytes) by CCR2 and TRAF6 expression in the spinal cord dorsal horn and DCX and PROX1 expression in the hippocampal dentate gyrus. Results: The 50% pain response threshold was significantly lower in the Ex than in the No-Ex group at 5 weeks post-CCI, indicating pain relief. In the spinal cord dorsal horn, IBA1, CCR2, and TRAF6 expression was markedly lower in the Ex group than in the No-Ex group at 3 weeks post-CCI. IBA1, GFAP, CCR2, and TRAF6 expression was markedly lower in the Ex group than in the No-Ex group at 5 weeks post-CCI. In the hippocampus, DCX, but not PROX1, expression was significantly higher in the Ex group than in the No-Ex group at 3 weeks post-CCI. At 5 weeks post-CCI, both DCX and PROX1 expression was markedly increased in the Ex group compared to the No-Ex group. Conclusion: Our findings suggest that regular exercise can improve the neuropathic pain-induced neurogenic dysfunction in the hippocampal dentate gyrus.