Differential Contribution of TRPA1, TRPV4 and TRPM8 to Colonic Nociception in Mice

Background Various transient receptor potential (TRP) channels in sensory neurons contribute to the transduction of mechanical stimuli in the colon. Recently, even the cold-sensing menthol receptor TRPM(melastatin) 8 was suggested to be involved in murine colonic mechanonociception. Methods To analyze the roles of TRPM8, TRPA1 and TRPV4 in distension-induced colonic nociception and pain, TRP-deficient mice and selective pharmacological blockers in wild-type mice (WT) were used. Visceromotor responses (VMR) to colorectal distension (CRD) in vivo were recorded and distension/pressure-induced CGRP release from the isolated murine colon ex vivo was measured by EIA. Results Distension-induced colonic CGRP release was markedly reduced in TRPA1(-/-) and TRPV4(-/-) mice at 90/150 mmHg compared to WT. In TRPM8-deficient mice the reduction was only distinct at 150 mmHg. Exposure to selective pharmacological antagonists (HC030031, 100 mu M; RN1734, 10 mu M; AMTB, 10 mu M) showed corresponding effects. The unselective TRP blocker ruthenium red (RR, 10 mu M) was as efficient in inhibiting distension-induced CGRP release as the unselective antagonists of mechanogated DEG/ENaC (amiloride, 100 mu M) and stretch-activated channels (gadolinium, 50 mu M). VMR to CRD revealed prominent deficits over the whole pressure range (up to 90 mmHg) in TRPA1(-/-) and TRPV4(-/-) but not TRPM8(-/-) mice; the drug effects of the TRP antagonists were again highly consistent with the results from mice lacking the respective TRP receptor gene. Conclusions TRPA1 and TRPV4 mediate colonic distension pain and CGRP release and appear to govern a wide and congruent dynamic range of distensions. The role of TRPM8 seems to be confined to signaling extreme noxious distension, at least in the healthy colon.