title: Soluble epoxide hydrolase limits mechanical hyperalgesia during inflammation.
abstract: BACKGROUND
  Cytochrome-P450 (CYP450) epoxygenases metabolise arachidonic acid (AA) into four different biologically active epoxyeicosatrienoic acid (EET) regioisomers. Three of the EETs (i.e., 8,9-, 11,12- and 14,15-EET) are rapidly hydrolysed by the enzyme soluble epoxide hydrolase (sEH). Here, we investigated the role of sEH in nociceptive processing during peripheral inflammation.
  
  
  RESULTS
  In dorsal root ganglia (DRG), we found that sEH is expressed in medium and large diameter neurofilament 200-positive neurons. Isolated DRG-neurons from sEH(-/-) mice showed higher EET and lower DHET levels. Upon AA stimulation, the largest changes in EET levels occurred in culture media, indicating both that cell associated EET concentrations quickly reach saturation and EET-hydrolyzing activity mostly effects extracellular EET signaling. In vivo, DRGs from sEH-deficient mice exhibited elevated 8,9-, 11,12- and 14,15-EET-levels. Interestingly, EET levels did not increase at the site of zymosan-induced inflammation. Cellular imaging experiments revealed direct calcium flux responses to 8,9-EET in a subpopulation of nociceptors. In addition, 8,9-EET sensitized AITC-induced calcium increases in DRG neurons and AITC-induced calcitonin gene related peptide (CGRP) release from sciatic nerve axons, indicating that 8,9-EET sensitizes TRPA1-expressing neurons, which are known to contribute to mechanical hyperalgesia. Supporting this, sEH(-/-) mice showed increased nociceptive responses to mechanical stimulation during zymosan-induced inflammation and 8,9-EET injection reduced mechanical thresholds in naive mice.
  
  
  CONCLUSIONS
  Our results show that the sEH can regulate mechanical hyperalgesia during inflammation by inactivating 8,9-EET, which sensitizes TRPA1-expressing nociceptors. Therefore we suggest that influencing the CYP450 pathway, which is actually highly considered to treat cardiovascular diseases, may cause pain side effects.
authors.affiliation: Pharmazentrum Frankfurt/ZAFES, Institute of Clinical Pharmacology, Johann Wolfgang Goethe-University, Frankfurt, Germany. Christian.Brenneis@childrens.harvard.edu
authors.forename: Christian
authors.initials: C
authors.lastname: Brenneis
authors.forename: Marco
authors.initials: M
authors.lastname: Sisignano
authors.forename: Ovidiu
authors.initials: O
authors.lastname: Coste
authors.forename: Kai
authors.initials: K
authors.lastname: Altenrath
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Fischer
authors.forename: Carlo
authors.initials: C
authors.lastname: Angioni
authors.forename: Ingrid
authors.initials: I
authors.lastname: Fleming
authors.forename: Ralf P
authors.initials: RP
authors.lastname: Brandes
authors.forename: Peter W
authors.initials: PW
authors.lastname: Reeh
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
mesh_terms: D015126:8,11,14-Eicosatrienoic Acid / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D015153:Blotting, Western; D015740:Calcitonin Gene-Related Peptide / Q000378:metabolism; D002118:Calcium / Q000378:metabolism; D002478:Cells, Cultured; D002853:Chromatography, Liquid; D004851:Epoxide Hydrolases / Q000235:genetics / Q000378:metabolism*; D005727:Ganglia, Spinal / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D006930:Hyperalgesia / Q000235:genetics / Q000378:metabolism*; D007150:Immunohistochemistry; D007249:Inflammation / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D000074025:TRPA1 Cation Channel; D053719:Tandem Mass Spectrometry; D050051:Transient Receptor Potential Channels / Q000378:metabolism
chemical_list: D000074025:TRPA1 Cation Channel; D050051:Transient Receptor Potential Channels; C475685:Trpa1 protein, mouse; C050715:8,9-epoxyeicosatrienoic acid; D004851:Epoxide Hydrolases; D015126:8,11,14-Eicosatrienoic Acid; D015740:Calcitonin Gene-Related Peptide; D002118:Calcium