Highlights
- •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.
Abstract
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.
Perspective
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.
Key words
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Article info
Publication history
Published online: March 04, 2021
Accepted:
February 21,
2021
Received in revised form:
February 8,
2021
Received:
December 4,
2020
Footnotes
Supported by National Key R&D Program of China (2017YFC0110304); National Science Foundation of China (No.81701309, 81803553); Key R & D program of Jiangsu Province (Social Development) (key project-clinical frontier technology) (BE2019666); Key Medical Talents Program for Youth in Jiangsu (QNRC2016729) and Clinical Key Diseases Diagnosis and Treatment Technology Special Project in Suzhou (LCZX201702).
Conflict of interest: All authors declared there were no conflict of interests involved.
Identification
Copyright
© 2021 by United States Association for the Study of Pain, Inc.
