Electroacupuncture Relieves Nerve Injury–Induced Pain Hypersensitivity via the Inhibition of Spinal P2X7 Receptor–Positive Microglia

BACKGROUND: Electroacupuncture (EA) has therapeutic effects on neuropathic pain induced by nerve injury; however, the underlying mechanisms remain unclear. In this study, we examined whether EA treatment relieves pain hypersensitivity via the down-regulation of spinal P2X7 receptor–positive (P2X7R+) microglia-mediated overexpression of interleukin (IL)-1β and/or IL-18. METHODS: Male Sprague-Dawley rats underwent chronic constriction injury (CCI) or 3′-O-(4-benzoylbenzoyl) adenosine 5′-triphosphate (BzATP) intrathecal injection. Von Frey and Hargreaves tests were performed to evaluate the effect of EA on pain hypersensitivity. The spinal P2X7R, IL-1β, and IL-18 expression levels were determined by real-time polymerase chain reaction, Western blot analysis, immunofluorescence staining, and enzyme-linked immunosorbent assay. The selective P2X7R antagonist A-438079 was used to examine the P2X7R+ microglia–dependent release of IL-1β and IL-18. Primary cultures were subsequently used to assess the P2X7R+ microglia–induced IL-1β and IL-18 release. RESULTS: EA treatment significantly improved the pain thresholds and inhibited spinal P2X7R+ microglia activation induced by CCI or BzATP administration, which was accompanied by the suppression of spinal IL-1β and IL-18 overexpression. Moreover, A-438079 also improved pain thresholds and suppressed overexpression of IL-1β in the CCI- and BzATP-injected rats. The analysis of cultured microglia further demonstrated that A-438079 markedly decreased BzATP-induced IL-1β release. CONCLUSIONS: EA treatment relieves nerve injury-induced tactile allodynia and thermal hyperalgesia via the inhibition of P2X7R+ microglia–mediated IL-1β overexpression.

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