5-HT₇ Receptor Is Involved in Electroacupuncture Inhibition of Chronic Pain in the Spinal Cord

Knee osteoarthritis (KOA) is a common and disabling condition characterized by attacks of pain around the joints, and it is a typical disease that develops chronic pain. Previous studies have proved that 5-HT₁, 5-HT₂, and 5-HT₃ receptors in the spinal cord are involved in electroacupuncture (EA) analgesia. The 5-HT₇ receptor plays antinociceptive role in the spinal cord. However, it is unclear whether the 5-HT₇ receptor is involved in EA analgesia. The 5-HT₇ receptor is a stimulatory G-protein (Gs)-coupled receptor that activates adenylyl cyclase (AC) to stimulate cyclic adenosine monophosphate (cAMP) formation, which in turn activates protein kinase A (PKA). In the present study, we found that EA significantly increased the tactile threshold and the expression of the 5-HT₇ receptor in the dorsal spinal cord. Intrathecal injection of 5-HT₇ receptor agonist AS-19 mimicked the analgesic effect of EA, while a selective 5-HT₇ receptor antagonist reversed this effect. Moreover, intrathecal injection of AC and PKA antagonists prior to EA intervention prevented its anti-allodynic effect. In addition, GABA_A receptor antagonist bicuculline administered (intrathecal, i.t.) prior to EA intervention blocked the EA effect on pain hypersensitivity. Our data suggest that the spinal 5-HT₇ receptor activates GABAergic neurons through the Gs–cAMP–PKA pathway and participates in EA-mediated inhibition of chronic pain in a mouse model of KOA.