5,6-EET Is Released upon Neuronal Activity and Induces Mechanical Pain Hypersensitivity via TRPA1 on Central Afferent Terminals

Marco Sisignano, Chul-Kyu Park, Carlo Angioni, Dong Dong Zhang, Christian von Hehn, Enrique J. Cobos, Nader Ghasemlou, Zhen-Zhong Xu, Vigneswara Kumaran, Ruirui Lu, Andrew Grant, Michael J. M. Fischer, Achim Schmidtko, Peter Reeh, Ru-Rong Ji, Clifford J. Woolf, Gerd Geisslinger, Klaus Scholich, Christian Brenneis

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97 Citations (Scopus)

Abstract

Epoxyeicosatrienoic acids (EETs) are cytochrome P450-epoxygenase-derived metabolites of arachidonic acid that act as endogenous signaling molecules in multiple biological systems. Here we have investigated the specific contribution of 5,6-EET to transient receptor potential (TRP) channel activation in nociceptor neurons and its consequence for nociceptive processing. We found that, during capsaicin-induced nociception, 5,6-EET levels increased in dorsal root ganglia (DRGs) and the dorsal spinal cord, and 5,6-EET is released from activated sensory neurons in vitro. 5,6-EET potently induced a calcium flux (100 nM) in cultured DRG neurons that was completely abolished when TRPA1 was deleted or inhibited. In spinal cord slices, 5,6-EET dose dependently enhanced the frequency, but not the amplitude, of spontaneous EPSCs (sEPSCs) in lamina II neurons that also responded to mustard oil (allyl isothiocyanate), indicating a presynaptic action. Furthermore, 5,6-EET-induced enhancement of sEPSC frequency was abolished in TRPA1-null mice, suggesting that 5,6-EET presynaptically facilitated spinal cord synaptic transmission by TRPA1. Finally, in vivo intrathecal injection of 5,6-EET caused mechanical allodynia in wild-type but not TRPA1-null mice. We conclude that 5,6-EET is synthesized on the acute activation of nociceptors and can produce mechanical hypersensitivity via TRPA1 at central afferent terminals in the spinal cord.

Original languageEnglish
Pages (from-to)6364-6372
Number of pages9
JournalJournal of Neuroscience
Volume32
Issue number18
DOIs
Publication statusPublished - 2 May 2012

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