Transcranial Direct Current Stimulation Alleviates the Chronic Pain of Osteoarthritis by Modulating NMDA Receptors in Midbrain Periaqueductal Gray in Rats

Purpose: Osteoarthritis (OA) is the most common cause to lead to chronic pain. Transcranial direct current stimulation (tDCS) has been widely used to treat nerve disorders and chronic pain. The benefits of tDCS for chronic pain are apparent, but its analgesic mechanism is still unclear. This study observed the analgesic effects of tDCS on OA-induced chronic pain and the changes of NMDA receptor levels in PAG after tDCS treatment in rats to explore the analgesic mechanism of tDCS. Methods: After establishing chronic pain by injecting monosodium iodoacetate (MIA) into the rat ankle joint, the rats received tDCS for 14 consecutive days (20 min/day). Before tDCS treatment, Ifenprodil (the selective antagonist of NMDAR2B) was given to rats in different ways: intracerebroventricular (i.c.v.) injection or intraperitoneal (i.p.) injection. The Von Frey and hot plate tests were applied to assess the pain-related behaviors at different time points. The expression level of NMDAR2B was evaluated in midbrain periaqueductal gray (PAG) by Western blot. In addition, NMDAR2B and c-Fos were observed by the Immunohistochemistry staining after tDCS treatment. Results: The mechanical allodynia and thermal hyperalgesia were produced after MIA injection. However, tDCS treatment reverted the mechanical allodynia and thermal hyperalgesia. Moreover, tDCS treatment significantly increased the expression of NMDAR2B and the proportion of positive stained cells of NMDAR2B. Besides that, the tDCS treatment also decreased the proportion of positive stained cells of c-Fos in PAG. However, these changes did not occur in the rats given the Ifenprodil (i.c.v.). Conclusion: These results indicate that tDCS may increase the expression of NMDA receptors in PAG and strengthen the NMDA receptors-mediated antinociception to alleviate OA-induced chronic pain in rats.