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

Abstract

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.

Transcranial direct current stimulation attenuates the chronic pain of osteoarthritis in rats via the top-down modulation

“…More and more studies believed that tDCS could be effective in the direct contact area of the electrode and play a role in the distance 38,39 . In our previous study, we chose M1 as the stimulation site of tDCS and observed the changes of NMDA receptor in periaqueductal gray (PAG) 24 . It is believed that the stimulation of tDCS in M1 region can activate contiguous regions such as PAG.…”

“…This exogenous stimulus may use similar pathways involved in the top-down modulation found across sensory systems 23 . In our previous study, we demonstrated that tDCS can alleviate OA-induced chronic pain in rats by modulating the expression of NMDA receptors in PAG to play an analgesic role 24 . However, whether the analgesic effect of tDCS can work in the spinal cord by top-down modulation is still unclear.…”

Effects of tDCS on Foot Biomechanics: A Narrative Review and Clinical Applications

“…Relevant animal experiments also partially confirmed the findings. Researchers established a chronic pain model by injecting a drug into the ankle joint of the rat and found that tDCS effectively restored mechanical allodynia and thermal hyperalgesia and its effects lasted two weeks [ 55 ].…”

Mechanisms of transcranial direct current stimulation (tDCS) for pain in patients with fibromyalgia syndrome

“…Transcranial direct current stimulation can induce neuroplasticity in a manner dependent on N-methyl-D-aspartate receptors (NMDARs) ( Liebetanz et al, 2002 ; Nitsche et al, 2003 ), which can regulate signaling pathways by allowing positively charged ions, such as calcium, to enter the cell and strengthen the synapse. Research also discovered that tDCS increased the amount of NMDA receptors and subsequently enhanced pain-related responses in animals ( Li et al, 2022a , b ). This suggests tDCS enhances NMDAR-mediated synaptic plasticity by increasing neuronal membrane NMDAR density, heightening synaptic responsiveness crucial to modulating pain.…”