Both TRPA1 and
purinergic P2X receptors have been proposed as potential targets for the treatment of
visceral pain. We found that the intracolonic administration of a low dose mustard oil (0.5%), a well-known TRPA1 agonist, produced nociceptive responses and abdominal wall referred
mechanical hyperalgesia, without inducing apparent tissue damage. Both nociceptive responses and referred
hyperalgesia were abolished by the ablation of TRPV1-expressing neurons (and the consequent ablation of TRPA1+ nociceptors) by
resiniferatoxin (RTX) treatment, and by the TRPA1 antagonist AP18. However, a higher dose of mustard oil (2.5%) damaged the colonic epithelium and induced pERK activation in the spinal cord, and these processes were clearly independent of TRPV1-expressing neurons ablated by RTX. This higher dose of mustard oil induced nociceptive responses and referred
mechanical hyperalgesia which were insensitive or only slightly sensitive to
resiniferatoxin or AP18, but were markedly reduced by the P2X antagonist
TNP-ATP, which is known to inhibit nociceptive actions induced by
ATP released from injured tissues. In conclusion, whereas a low dose of intracolonic mustard oil induces
visceral pain in a manner fully dependent on TRPA1 actions, when a high dose of this chemical
irritant is used,
visceral pain becomes mostly independent of TRPA1 activation but clearly enhanced by
ATP purportedly released by the damaged colonic epithelium. Therefore, TRPA1 inhibition is not sufficient to substantially decrease
visceral pain during tissue injury, whereas purinergic antagonism appears to be a more effective strategy.