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P2X4 receptors mediate PGE2 release by tissue‐resident macrophages and initiate inflammatory pain
Author(s) -
Ulmann Lauriane,
Hirbec Hélène,
Rassendren François
Publication year - 2010
Publication title -
the embo journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 7.484
H-Index - 392
eISSN - 1460-2075
pISSN - 0261-4189
DOI - 10.1038/emboj.2010.126
Subject(s) - inflammation , prostaglandin e2 receptor , mediator , prostaglandin e2 , sensitization , biology , receptor , prostaglandin , pharmacology , immunology , microbiology and biotechnology , endocrinology , biochemistry , agonist
Prostaglandin E2 (PGE2) is a key mediator of inflammation and contributes to pain hypersensitivity by promoting sensory neurons hyperexcitability. PGE2 synthesis results from activation of a multi‐step enzymatic cascade that includes cyclooxygenases (COXs), the main targets of non‐steroidal anti‐inflammatory drugs (NSAIDs). Although NSAIDs are widely prescribed to reduce inflammatory symptoms such as swelling and pain, associated harmful side effects restrict their long‐term use. Therefore, finding new drugs that limit PG production represents an important therapeutic issue. In response to peripheral inflammatory challenges, mice lacking the ATP‐gated P2X4 channel (P2X4R) do not develop pain hypersensitivity and show a complete absence of inflammatory PGE2 in tissue exudates. In resting conditions, tissue‐resident macrophages constitutively express P2X4R. Stimulating P2X4R in macrophages triggers calcium influx and p38 MAPK phosphorylation, resulting in cytosolic PLA2 (cPLA2) activation and COX‐dependent release of PGE2. In naive animals, pain hypersensitivity was elicited by transfer into the paw of ATP‐primed macrophages from wild type, but not P2X4R‐deficient mice. Thus, P2X4Rs are specifically involved in inflammatory‐mediated PGE2 production and might therefore represent useful therapeutic targets.