P2X receptors-mediated cytosolic phospholipase A2 activation in primary afferent sensory neurons contributes to neuropathic pain |
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Authors: | Tsuda Makoto Hasegawa Shigeo Inoue Kazuhide |
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Institution: | Department of Molecular and System Pharmacology, Graduate School of Pharmaceutical Sciences, Kyushu University, Higashi, Fukuoka, Japan |
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Abstract: | Activation of P2X3 and P2X2/3 receptors (P2X3R/P2X2/3R), ionotropic ATP receptor subtypes, in primary sensory neurons is involved in neuropathic pain, a debilitating chronic pain that occurs after peripheral nerve injury. However, the underlying mechanisms remain unknown. We investigated the role of cytosolic phospholipase A2 (cPLA2) as a downstream molecule that mediates the P2X3R/P2X2/3R-dependent neuropathic pain. We found that applying ATP to cultured dorsal root ganglion (DRG) neurons increased the level of Ser505-phosphorylated cPLA2 and caused translocation of Ser505-phosphorylated cPLA2 to the plasma membrane. The ATP-induced cPLA2 activation was inhibited by a selective antagonist of P2X3R/P2X2/3R and by a selective inhibitor of cPLA2. In the DRG in vivo , the number of cPLA2-activated neurons was strikingly increased after peripheral nerve injury but not after peripheral inflammation produced by complete Freund's adjuvant. Pharmacological blockade of P2X3R/P2X2/3R reversed the nerve injury-induced cPLA2 activation in DRG neurons. Moreover, administering the cPLA2 inhibitor near the DRG suppressed nerve injury-induced tactile allodynia, a hallmark of neuropathic pain. Our results suggest that P2X3R/P2X2/3R-dependent cPLA2 activity in primary sensory neurons is a key event in neuropathic pain and that cPLA2 might be a potential target for treating neuropathic pain. |
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Keywords: | cytosolic phospholipase A2 neuropathic pain P2X receptor primary afferent sensory neurons |
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