title: Transient receptor potential ankyrin-1 has a major role in mediating visceral pain in mice.
abstract: The excitatory ion channel transient receptor potential ankyrin-1 (TRPA1) is prominently expressed by primary afferent neurons and is a mediator of inflammatory pain. Inflammatory agents can directly activate [e.g., hydroxynonenal (HNE), prostaglandin metabolites] or indirectly sensitize [e.g., agonists of protease-activated receptor (PAR(2))] TRPA1 to induce somatic pain and hyperalgesia. However, the contribution of TRPA1 to visceral pain is unknown. We investigated the role of TRPA1 in visceral hyperalgesia by measuring abdominal visceromotor responses (VMR) to colorectal distention (CRD) after intracolonic administration of TRPA1 agonists [mustard oil (MO), HNE], sensitizing agents [PAR(2) activating peptide (PAR(2)-AP)], and the inflammatory agent trinitrobenzene sulfonic acid (TNBS) in trpa1(+/+) and trpa1(-/-) mice. Sensory neurons innervating the colon, identified by retrograde tracing, coexpressed immunoreactive TRPA1, calcitonin gene-related peptide, and substance P, expressed TRPA1 mRNA and responded to MO with depolarizing currents. Intracolonic MO and HNE increased VMR to CRD and induced immunoreactive c-fos in spinal neurons in trpa1+/+ but not in trpa1(-/-) mice. Intracolonic PAR(2)-AP induced mechanical hyperalgesia in trpa1+/+ but not in trpa1(-/-) mice. TNBS-induced colitis increased in VMR to CRD and induced c-fos in spinal neurons in trpa1(+/+) but not in trpa1(-/-) mice. Thus TRPA1 is expressed by colonic primary afferent neurons. Direct activation of TRPA1 causes visceral hyperalgesia, and TRPA1 mediates PAR(2)-induced hyperalgesia. TRPA1 deletion markedly reduces colitis-induced mechanical hyperalgesia in the colon. Our results suggest that TRPA1 has a major role in visceral nociception and may be a therapeutic target for colonic inflammatory pain.
authors.affiliation: Department of Surgery, University of California, San Francisco, California, USA.
authors.forename: Fiore
authors.initials: F
authors.lastname: Cattaruzza
authors.forename: Ian
authors.initials: I
authors.lastname: Spreadbury
authors.forename: Marcela
authors.initials: M
authors.lastname: Miranda-Morales
authors.forename: Eileen F
authors.initials: EF
authors.lastname: Grady
authors.forename: Stephen
authors.initials: S
authors.lastname: Vanner
authors.forename: Nigel W
authors.initials: NW
authors.lastname: Bunnett
mesh_terms: D000447:Aldehydes / Q000494:pharmacology; D000818:Animals; D015740:Calcitonin Gene-Related Peptide / Q000378:metabolism; D003092:Colitis / Q000139:chemically induced / Q000503:physiopathology*; D003106:Colon / Q000294:innervation / Q000502:physiology; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology; D004525:Efferent Pathways / Q000502:physiology; D005260:Female; D006930:Hyperalgesia / Q000139:chemically induced / Q000503:physiopathology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009149:Mustard Plant; D009619:Nociceptors / Q000187:drug effects / Q000502:physiology; D010146:Pain / Q000139:chemically induced / Q000503:physiopathology*; D010938:Plant Oils / Q000494:pharmacology; D011247:Pregnancy; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D044464:Receptor, PAR-2 / Q000819:agonists / Q000378:metabolism; D013116:Spinal Cord / Q000502:physiology; D013373:Substance P / Q000378:metabolism; D000074025:TRPA1 Cation Channel; D050051:Transient Receptor Potential Channels / Q000819:agonists / Q000235:genetics / Q000378:metabolism*; D017833:Visceral Afferents / Q000187:drug effects / Q000502:physiology*
chemical_list: D000447:Aldehydes; D015853:Cysteine Proteinase Inhibitors; D010938:Plant Oils; D016760:Proto-Oncogene Proteins c-fos; D012333:RNA, Messenger; D044464:Receptor, PAR-2; D000074025:TRPA1 Cation Channel; D050051:Transient Receptor Potential Channels; C475685:Trpa1 protein, mouse; D013373:Substance P; D015740:Calcitonin Gene-Related Peptide; C027576:4-hydroxy-2-nonenal; C027793:mustard oil