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Research Article

Transient Receptor Potential Ankyrin-1 has a Major Role in Mediating Visceral Pain in Mice

¹University of California-San Francisco ²Hotel Dieu Hospital, Kingston, Ontario, Canada ³Hotel Dieu Hospital

Submitted 11 June 2009 ; revision received 20 October 2009 ; accepted in final form 20 October 2009

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 [PAR₂]) 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 (PAR₂ activating peptide [PAR₂ -AP]) and the inflammatory agent trinitrobenzene sulfonic acid (TNBS) in trpa1^+/+ and trpa1^-/- mice. Sensory neurons innervating the colon, identified by retrograde tracing, co-expressed 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 PAR₂-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 PAR₂-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.

pain; protease-activated receptors; TRP channels; sensory nerves