title: The proximodistal aggravation of colitis depends on substance P released from TRPV1-expressing sensory neurons.
abstract: BACKGROUND
  Transient receptor potential vanilloid type-1 (TRPV1)-expressing sensory neurons release neuropeptides such as substance P (SP) and calcitonin gene-related peptide (CGRP), which play a crucial role in the pathomechanism of experimental colitis. We investigated whether innervation density and neuropeptide release were responsible for the proximodistal aggravation of murine dextran-sulfate-sodium-salt (DSS) colitis.
  
  
  METHODS
  Whole mount TRPV1/CGRP immunostained mouse colon preparations were semiquantitatively analyzed. TRPV1 activation by capsaicin and acidic solution (pH 5.1) induced colonic CGRP/SP release, measured by EIA. Single cell quantitative PCR was employed to measure TRPV1 expression levels in DiI-labeled colonic dorsal root ganglion (DRG) neurons. The proximodistal gradient of DSS colitis severity was investigated in WT, CGRP(-/-), SP(-/-), and resiniferatoxin (RTX)-desensitized mice, employing mouse endoscopy, histology, and body weight measurement.
  
  
  RESULTS
  TRPV1/CGRP-positive nerve fiber density was increased in the distal colon wall. CGRP/SP release induced by TRPV1 activation from the distal colon was greater than that from the proximal colon. This gradient further increased in colitis. TRPV1 gene expression increased in colonic DRGs projecting to the distal, compared to that in colonic DRGs projecting to the proximal colon, and was further enhanced during colitis. In contrast to WT and CGRP(-/-) mice, SP(-/-) and RTX-desensitized mice showed amelioration of DSS colitis accompanied by a loss of the proximodistal gradient of inflammation.
  
  
  CONCLUSIONS
  The spatial correlation among increased colonic innervation density, TRPV1 receptor expression, stimulated SP release, and colitis severity suggested that TRPV1/SP-expressing sensory neurons should be considered as a therapeutic target in human ulcerative colitis.
authors.affiliation: Institute of Physiology and Pathophysiology, Friedrich-Alexander-Universität Erlangen-Nürnberg, Universitätsstr. 17, 91054 Erlangen, Germany. engel@physiologie1.uni-erlangen.de
authors.forename: Matthias A
authors.initials: MA
authors.lastname: Engel
authors.forename: Mohammad
authors.initials: M
authors.lastname: Khalil
authors.forename: Sonja M
authors.initials: SM
authors.lastname: Mueller-Tribbensee
authors.forename: Christoph
authors.initials: C
authors.lastname: Becker
authors.forename: Winfried L
authors.initials: WL
authors.lastname: Neuhuber
authors.forename: Markus F
authors.initials: MF
authors.lastname: Neurath
authors.forename: Peter W
authors.initials: PW
authors.lastname: Reeh
mesh_terms: D000818:Animals; D015740:Calcitonin Gene-Related Peptide / Q000235:genetics; D003092:Colitis / Q000503:physiopathology*; D016264:Dextran Sulfate / Q000633:toxicity; D004195:Disease Models, Animal; D005786:Gene Expression Regulation; D007249:Inflammation / Q000503:physiopathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D020133:Reverse Transcriptase Polymerase Chain Reaction; D011984:Sensory Receptor Cells / Q000378:metabolism*; D012720:Severity of Illness Index; D013373:Substance P / Q000235:genetics / Q000378:metabolism*; D050916:TRPV Cation Channels / Q000378:metabolism*
chemical_list: D050916:TRPV Cation Channels; C493921:TRPV1 protein, mouse; D013373:Substance P; D016264:Dextran Sulfate; D015740:Calcitonin Gene-Related Peptide
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