title: Systemic desensitization through TRPA1 channels by capsazepine and mustard oil - a novel strategy against inflammation and pain.
abstract: We demonstrate a novel dual strategy against inflammation and pain through body-wide desensitization of nociceptors via TRPA1. Attenuation of experimental colitis by capsazepine (CPZ) has long been attributed to its antagonistic action on TRPV1 and associated inhibition of neurogenic inflammation. In contrast, we found that CPZ exerts its anti-inflammatory effects via profound desensitization of TRPA1. Micromolar CPZ induced calcium influx in isolated dorsal root ganglion (DRG) neurons from wild-type (WT) but not TRPA1-deficient mice. CPZ-induced calcium transients in human TRPA1-expressing HEK293t cells were blocked by the selective TRPA1 antagonists HC 030031 and A967079 and involved three cysteine residues in the N-terminal domain. Intriguingly, both colonic enemas and drinking water with CPZ led to profound systemic hypoalgesia in WT and TRPV1(-/-) but not TRPA1(-/-) mice. These findings may guide the development of a novel class of disease-modifying drugs with anti-inflammatory and anti-nociceptive effects.
authors.affiliation: Institute of Physiology and Pathophysiology, Friedrich-Alexander-Universität Erlangen-Nürnberg, Universitätsstr. 17, 91054 Erlangen, Germany.
authors.forename: Katrin
authors.initials: K
authors.lastname: Kistner
authors.affiliation: Institute of Physiology and Pathophysiology, Friedrich-Alexander-Universität Erlangen-Nürnberg, Universitätsstr. 17, 91054 Erlangen, Germany.
authors.forename: Norbert
authors.initials: N
authors.lastname: Siklosi
authors.affiliation: University of Bucharest Department of Physiology, Faculty of Biology, Splaiul Independentei 91-95, 050095 Bucharest, Romania.
authors.forename: Alexandru
authors.initials: A
authors.lastname: Babes
authors.affiliation: Institute of Physiology and Pathophysiology, Friedrich-Alexander-Universität Erlangen-Nürnberg, Universitätsstr. 17, 91054 Erlangen, Germany.|Department of Medicine 1, Universitätsklinikum Erlangen, Ulmenweg 18, 91054 Erlangen, Germany.
authors.forename: Mohammad
authors.initials: M
authors.lastname: Khalil
authors.affiliation: University of Bucharest Department of Physiology, Faculty of Biology, Splaiul Independentei 91-95, 050095 Bucharest, Romania.
authors.forename: Tudor
authors.initials: T
authors.lastname: Selescu
authors.affiliation: Department of Anaesthesiology, Universitätsklinikum Erlangen, Krankenhausstr. 12, 91054 Erlangen, Germany.
authors.forename: Katharina
authors.initials: K
authors.lastname: Zimmermann
authors.affiliation: Department of Medicine 1, Universitätsklinikum Erlangen, Ulmenweg 18, 91054 Erlangen, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Wirtz
authors.affiliation: Department of Medicine 1, Universitätsklinikum Erlangen, Ulmenweg 18, 91054 Erlangen, Germany.
authors.forename: Christoph
authors.initials: C
authors.lastname: Becker
authors.affiliation: Department of Medicine 1, Universitätsklinikum Erlangen, Ulmenweg 18, 91054 Erlangen, Germany.
authors.forename: Markus F
authors.initials: MF
authors.lastname: Neurath
authors.affiliation: Institute of Physiology and Pathophysiology, Friedrich-Alexander-Universität Erlangen-Nürnberg, Universitätsstr. 17, 91054 Erlangen, Germany.
authors.forename: Peter W
authors.initials: PW
authors.lastname: Reeh
authors.affiliation: Department of Medicine 1, Universitätsklinikum Erlangen, Ulmenweg 18, 91054 Erlangen, Germany.
authors.forename: Matthias A
authors.initials: MA
authors.lastname: Engel
mesh_terms: D000083:Acetanilides / Q000494:pharmacology; D000700:Analgesics / Q000494:pharmacology*; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D020013:Calcium Signaling / Q000187:drug effects*; D002211:Capsaicin / Q000031:analogs & derivatives* / Q000494:pharmacology; D057809:HEK293 Cells; D006801:Humans; D007249:Inflammation / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D009149:Mustard Plant; D010091:Oximes / Q000494:pharmacology; D010146:Pain / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D010938:Plant Oils / Q000494:pharmacology*; D011687:Purines / Q000494:pharmacology; D000074025:TRPA1 Cation Channel / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*
chemical_list: C552888:2-(1,3-dimethyl-2,6-dioxo-1,2,3,6-tetrahydro-7H-purin-7-yl)-N-(4-isopropylphenyl)acetamide; C560402:A 967079; D000083:Acetanilides; D000700:Analgesics; D000893:Anti-Inflammatory Agents; D010091:Oximes; D010938:Plant Oils; D011687:Purines; D000074025:TRPA1 Cation Channel; C473350:TRPA1 protein, human; C475685:Trpa1 protein, mouse; C071423:capsazepine; D002211:Capsaicin; C027793:mustard oil