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

2012; Society for Neuroscience; Volume: 32; Issue: 18 Linguagem: Inglês

10.1523/jneurosci.5793-11.2012

1529-2401

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 W. Reeh, Ru‐Rong Ji, Clifford J. Woolf, Gerd Geißlinger, Klaus Scholich, Christian Brenneis,

Pain Mechanisms and Treatments

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.