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.

Protease-Activated Receptors as Therapeutic Targets in Visceral Pain

“…Direct activation of TRPV4 or TRPA1 causes somatic and visceral hypersensitivity to mechanical stimuli [38,[66][67][68]. Moreover, TRPV4 and TRPA1 mediate PAR 2 -induced somatic and visceral hyperalgesia in vivo [38,[66][67][68]. For TRPV4, the interaction between this receptor and PAR 2 was confirmed by the fact that direct responses of splanchnic colonic afferents to PAR 2 activation were totally lost in TRPV4-deficient mice [70].…”

“…Studies on the interactions of PARs and channels such as the TRP family could be the challenges and opportunities of future research in molecular mechanism of PARs-regulated inflammatory pain. PAR 2 is also co-expressed with other members of the TRP family in sensory neurons such as TRPV4 [65,66] and TRPA1 [67,68]. In sensory neurons, PAR 2 activation potentiates the response of those cells to agonists of TRPA1 [68] or TRPV4 [66].…”

“…In sensory neurons, the increased TRPA1 sensitivity is due to activation of PLC, which releases TRPA1 from PIP2 inhibition [68]. Direct activation of TRPV4 or TRPA1 causes somatic and visceral hypersensitivity to mechanical stimuli [38,[66][67][68]. Moreover, TRPV4 and TRPA1 mediate PAR 2 -induced somatic and visceral hyperalgesia in vivo [38,[66][67][68].…”

“…Authors suggest that the strong interaction between TRPV4 and PAR 2 in sensory neurons projecting from the colon is due to a tight co-localization, whereas TRPA1 and PAR 2 are localized in different cellular microdomains, rendering this channel inaccessible to products of PAR 2 activation [71]. Thus, the electrophysiological recordings from splanchnic afferents did not reveal that PAR 2 sensitizes TRPA1 [71] but the behavioral studies of awake animals showed sensitization [67]. In a very recent study, authors demonstrated a functional coupling between PAR 2 and TRPV4 [72].…”

Extrinsic primary afferent signalling in the gut

“…123,125 TRPA1 is the third TRP channel known to have a key role in setting the sensitivity of vascular afferents. It might also mediate PAR2-evoked sensitization in the gut 126 and/or bradykininmediated hypersensitivity. 127 TRPA1 is directly mechanosensitive in gastrointestinal afferents and interacts with TrpV1.…”