Research Article| Volume 22, ISSUE 8, P968-980, August 2021

P2X4R Contributes to Central Disinhibition Via TNF-α/TNFR1/GABAaR Pathway in Post-stroke Pain Rats


      • Central poststroke pain rats exhibited increased TNF-α and reduced surface GABAaR levels.
      • P2X4 receptor inhibition attenuated central poststroke pain through TNF-α/TNFR1-GABAaR signaling.
      • TNF-α antagonist etanercept reversed the endocytosis of surface GABAaR.
      • TNF-α decreased surface GABAaR via activation of TNFR1.


      Central post-stroke pain (CPSP) is a disabling condition in stroke patients. It is a type of neuropathic pain for which the mechanism and relevant drug pathways remain unknown. Inflammatory response and central disinhibition have been suggested recently. Our previous research has shown targeting P2X4 receptors (P2X4R) may be effective in the treatment of CPSP, but the downstream pathway of the P2X4R has not been studied. In this study, we found the increase in tumor necrosis factor alpha (TNF-α) level and endocytosis of surface gamma-aminobutyric acid a receptors (GABAaR) in CPSP, and these effects were inhibited by blocking P2X4R. Furthermore, antagonizing TNF-α can increase surface GABAaR expression and mechanical pain threshold. Meanwhile, knocking down TNFR1 but not TNFR2 reversed the endocytosis of surface GABAaR and alleviated mechanical allodynia. Thus, the neuropathic pain was mediated, in part, through P2X4R/TNF-α/TNFR1/GABAaR signaling, which was induced after stroke.


      P2X4R regulates the pathophysiological mechanism of CPSP through central disinhibition mediated by TNF-α/TNFR1. Our results suggest that modulation of P2X4R-TNF-α/TNFR1-GABAaR signaling could provide a new therapeutic strategy to treat CPSP.

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