title: 5,6-EET is released upon neuronal activity and induces mechanical pain hypersensitivity via TRPA1 on central afferent terminals.
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.
authors.affiliation: Institute of Clinical Pharmacology, Pharmazentrum Frankfurt/Center for Drug Research, Development and Safety (ZAFES), University Hospital, Goethe-University, D-60590 Frankfurt am Main, Germany.
authors.forename: Marco
authors.initials: M
authors.lastname: Sisignano
authors.forename: Chul-Kyu
authors.initials: CK
authors.lastname: Park
authors.forename: Carlo
authors.initials: C
authors.lastname: Angioni
authors.forename: Dong Dong
authors.initials: DD
authors.lastname: Zhang
authors.forename: Christian
authors.initials: C
authors.lastname: von Hehn
authors.forename: Enrique J
authors.initials: EJ
authors.lastname: Cobos
authors.forename: Nader
authors.initials: N
authors.lastname: Ghasemlou
authors.forename: Zhen-Zhong
authors.initials: ZZ
authors.lastname: Xu
authors.forename: Vigneswara
authors.initials: V
authors.lastname: Kumaran
authors.forename: Ruirui
authors.initials: R
authors.lastname: Lu
authors.forename: Andrew
authors.initials: A
authors.lastname: Grant
authors.forename: Michael J M
authors.initials: MJ
authors.lastname: Fischer
authors.forename: Achim
authors.initials: A
authors.lastname: Schmidtko
authors.forename: Peter
authors.initials: P
authors.lastname: Reeh
authors.forename: Ru-Rong
authors.initials: RR
authors.lastname: Ji
authors.forename: Clifford J
authors.initials: CJ
authors.lastname: Woolf
authors.forename: Gerd
authors.initials: G
authors.lastname: Geisslinger
authors.forename: Klaus
authors.initials: K
authors.lastname: Scholich
authors.forename: Christian
authors.initials: C
authors.lastname: Brenneis
mesh_terms: D015126:8,11,14-Eicosatrienoic Acid / Q000031:analogs & derivatives* / Q000378:metabolism; D000200:Action Potentials / Q000502:physiology*; D000344:Afferent Pathways / Q000503:physiopathology*; D000818:Animals; D002478:Cells, Cultured; D006930:Hyperalgesia / Q000503:physiopathology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011984:Sensory Receptor Cells / Q000378:metabolism*
chemical_list: C040776:5,6-epoxy-8,11,14-eicosatrienoic acid; D015126:8,11,14-Eicosatrienoic Acid