Soluble epoxide hydrolase limits mechanical hyperalgesia during inflammation

Molecular Pain

Klaus Scholich²  Gerd Geisslinger²  Clifford J Woolf³  Peter W Reeh⁶  Ralf P Brandes⁵  Ingrid Fleming⁴  Carlo Angioni²  Michael J Fischer¹  Kai Altenrath²  Ovidiu Coste²  Marco Sisignano²  Christian Brenneis³ 

[1]Department of Pharmacology, University of Cambridge, Cambridge, UK

[2]Pharmazentrum Frankfurt/ZAFES, Institute of Clinical Pharmacology, Johann Wolfgang Goethe-University, Frankfurt, Germany

[3]F. M. Kirby Neurobiology Center, Department of Neurology, Children's Hospital Boston, Boston, MA, USA

[4]Institute for Vascular Signalling, ZAFES, Faculty of Medicine, Johann Wolfgang Goethe-University, Frankfurt, Germany

[5]Institute for Cardiovascular Physiology, ZAFES, Faculty of Medicine, Johann Wolfgang Goethe-University, Frankfurt, Germany

[6]Department of Physiology and Pathophysiology, Friedrich-Alexander-University Erlangen-Nürnberg, Erlangen, Germany

关键词: hyperalgesia;    TRPA1;    nociceptors;    CYP450;    EET;    sEH;   

Others  :  865703
DOI  :  10.1186/1744-8069-7-78

 received in 2011-06-14, accepted in 2011-10-04,  发布年份 2011

【 摘 要 】

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.

Conclusion

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.

【 授权许可】

   
2011 Brenneis et al; licensee BioMed Central Ltd.

【 图 表 】

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