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Differential Contribution of TRPA1, TRPV4 and TRPM8 to Colonic Nociception in Mice.
PLoS One. 2015; 10(7):e0128242.Plos

Abstract

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 mechano-nociception.

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 μM; RN1734, 10 μM; AMTB, 10 μM) showed corresponding effects. The unselective TRP blocker ruthenium red (RR, 10 μM) was as efficient in inhibiting distension-induced CGRP release as the unselective antagonists of mechanogated DEG/ENaC (amiloride, 100 μM) and stretch-activated channels (gadolinium, 50 μM). 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.

Authors+Show Affiliations

Institute of Physiology and Pathophysiology, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany.Institute of Physiology and Pathophysiology, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany.Department of Medicine 1, Universitätsklinikum Erlangen, Erlangen, Germany.Department of Medicine 1, Universitätsklinikum Erlangen, Erlangen, Germany.Institute of Physiology and Pathophysiology, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany.Department of Medicine 1, Universitätsklinikum Erlangen, Erlangen, Germany.

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

26207981

Citation

Mueller-Tribbensee, Sonja M., et al. "Differential Contribution of TRPA1, TRPV4 and TRPM8 to Colonic Nociception in Mice." PloS One, vol. 10, no. 7, 2015, pp. e0128242.
Mueller-Tribbensee SM, Karna M, Khalil M, et al. Differential Contribution of TRPA1, TRPV4 and TRPM8 to Colonic Nociception in Mice. PLoS One. 2015;10(7):e0128242.
Mueller-Tribbensee, S. M., Karna, M., Khalil, M., Neurath, M. F., Reeh, P. W., & Engel, M. A. (2015). Differential Contribution of TRPA1, TRPV4 and TRPM8 to Colonic Nociception in Mice. PloS One, 10(7), e0128242. https://doi.org/10.1371/journal.pone.0128242
Mueller-Tribbensee SM, et al. Differential Contribution of TRPA1, TRPV4 and TRPM8 to Colonic Nociception in Mice. PLoS One. 2015;10(7):e0128242. PubMed PMID: 26207981.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Differential Contribution of TRPA1, TRPV4 and TRPM8 to Colonic Nociception in Mice. AU - Mueller-Tribbensee,Sonja M, AU - Karna,Manoj, AU - Khalil,Mohammad, AU - Neurath,Markus F, AU - Reeh,Peter W, AU - Engel,Matthias A, Y1 - 2015/07/24/ PY - 2014/12/01/received PY - 2015/04/23/accepted PY - 2015/7/25/entrez PY - 2015/7/25/pubmed PY - 2016/5/3/medline SP - e0128242 EP - e0128242 JF - PloS one JO - PLoS One VL - 10 IS - 7 N2 - 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 mechano-nociception. 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 μM; RN1734, 10 μM; AMTB, 10 μM) showed corresponding effects. The unselective TRP blocker ruthenium red (RR, 10 μM) was as efficient in inhibiting distension-induced CGRP release as the unselective antagonists of mechanogated DEG/ENaC (amiloride, 100 μM) and stretch-activated channels (gadolinium, 50 μM). 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. SN - 1932-6203 UR - https://www.unboundmedicine.com/medline/citation/26207981/Differential_Contribution_of_TRPA1_TRPV4_and_TRPM8_to_Colonic_Nociception_in_Mice_ L2 - https://dx.plos.org/10.1371/journal.pone.0128242 DB - PRIME DP - Unbound Medicine ER -