title: Differential Contribution of TRPA1, TRPV4 and TRPM8 to Colonic Nociception in Mice.
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.affiliation: Institute of Physiology and Pathophysiology, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany.
authors.forename: Sonja M
authors.initials: SM
authors.lastname: Mueller-Tribbensee
authors.affiliation: Institute of Physiology and Pathophysiology, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany.
authors.forename: Manoj
authors.initials: M
authors.lastname: Karna
authors.affiliation: Department of Medicine 1, Universitätsklinikum Erlangen, Erlangen, Germany.
authors.forename: Mohammad
authors.initials: M
authors.lastname: Khalil
authors.affiliation: Department of Medicine 1, Universitätsklinikum Erlangen, Erlangen, Germany.
authors.forename: Markus F
authors.initials: MF
authors.lastname: Neurath
authors.affiliation: Institute of Physiology and Pathophysiology, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany.
authors.forename: Peter W
authors.initials: PW
authors.lastname: Reeh
authors.affiliation: Department of Medicine 1, Universitätsklinikum Erlangen, Erlangen, Germany.
authors.forename: Matthias A
authors.initials: MA
authors.lastname: Engel
mesh_terms: D000083:Acetanilides / Q000494:pharmacology; D000818:Animals; D001549:Benzamides / Q000494:pharmacology; D015740:Calcitonin Gene-Related Peptide / Q000378:metabolism; D003106:Colon / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology; D005260:Female; D008297:Male; D008465:Mechanoreceptors / Q000502:physiology; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D059225:Nociception / Q000502:physiology*; D059226:Nociceptive Pain / Q000503:physiopathology; D011687:Purines / Q000494:pharmacology; D012430:Ruthenium Red / Q000494:pharmacology; D013449:Sulfonamides / Q000494:pharmacology; D000074025:TRPA1 Cation Channel; D050053:TRPM Cation Channels / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*; D050916:TRPV Cation Channels / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*; D013876:Thiophenes / Q000494:pharmacology; D050051:Transient Receptor Potential Channels / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*
chemical_list: C552888:2-(1,3-dimethyl-2,6-dioxo-1,2,3,6-tetrahydro-7H-purin-7-yl)-N-(4-isopropylphenyl)acetamide; D000083:Acetanilides; D001549:Benzamides; C532415:N-(3-aminopropyl)-2-(((3-methylphenyl) methyl)oxy)-N-(2-thienylmethyl)benzamide hydrochloride salt; D011687:Purines; C544743:RN 1734; D013449:Sulfonamides; D000074025:TRPA1 Cation Channel; D050053:TRPM Cation Channels; C492297:TRPM8 protein, mouse; D050916:TRPV Cation Channels; D013876:Thiophenes; D050051:Transient Receptor Potential Channels; C475685:Trpa1 protein, mouse; C486576:Trpv4 protein, mouse; D012430:Ruthenium Red; D015740:Calcitonin Gene-Related Peptide