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Transient receptor potential vanilloid 4 mediates protease activated receptor 2-induced sensitization of colonic afferent nerves and visceral hyperalgesia.

Publication ,  Journal Article
Sipe, WEB; Brierley, SM; Martin, CM; Phillis, BD; Cruz, FB; Grady, EF; Liedtke, W; Cohen, DM; Vanner, S; Blackshaw, LA; Bunnett, NW
Published in: Am J Physiol Gastrointest Liver Physiol
May 2008

Protease-activated receptor (PAR(2)) is expressed by nociceptive neurons and activated during inflammation by proteases from mast cells, the intestinal lumen, and the circulation. Agonists of PAR(2) cause hyperexcitability of intestinal sensory neurons and hyperalgesia to distensive stimuli by unknown mechanisms. We evaluated the role of the transient receptor potential vanilloid 4 (TRPV4) in PAR(2)-induced mechanical hyperalgesia of the mouse colon. Colonic sensory neurons, identified by retrograde tracing, expressed immunoreactive TRPV4, PAR(2), and calcitonin gene-related peptide and are thus implicated in nociception. To assess nociception, visceromotor responses (VMR) to colorectal distension (CRD) were measured by electromyography of abdominal muscles. In TRPV4(+/+) mice, intraluminal PAR(2) activating peptide (PAR(2)-AP) exacerbated VMR to graded CRD from 6-24 h, indicative of mechanical hyperalgesia. PAR(2)-induced hyperalgesia was not observed in TRPV4(-/-) mice. PAR(2)-AP evoked discharge of action potentials from colonic afferent neurons in TRPV4(+/+) mice, but not from TRPV4(-/-) mice. The TRPV4 agonists 5',6'-epoxyeicosatrienoic acid and 4alpha-phorbol 12,13-didecanoate stimulated discharge of action potentials in colonic afferent fibers and enhanced current responses recorded from retrogradely labeled colonic dorsal root ganglia neurons, confirming expression of functional TRPV4. PAR(2)-AP enhanced these responses, indicating sensitization of TRPV4. Thus TRPV4 is expressed by primary spinal afferent neurons innervating the colon. Activation of PAR(2) increases currents in these neurons, evokes discharge of action potentials from colonic afferent fibers, and induces mechanical hyperalgesia. These responses require the presence of functional TRPV4. Therefore, TRPV4 is required for PAR(2)-induced mechanical hyperalgesia and excitation of colonic afferent neurons.

Duke Scholars

Published In

Am J Physiol Gastrointest Liver Physiol

DOI

ISSN

0193-1857

Publication Date

May 2008

Volume

294

Issue

5

Start / End Page

G1288 / G1298

Location

United States

Related Subject Headings

  • Viscera
  • TRPC Cation Channels
  • Serous Membrane
  • Ruthenium Red
  • Receptor, PAR-2
  • Rats, Sprague-Dawley
  • Rats
  • Phorbol Esters
  • Nociceptors
  • Neurons, Afferent
 

Citation

APA
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MLA
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Sipe, W. E. B., Brierley, S. M., Martin, C. M., Phillis, B. D., Cruz, F. B., Grady, E. F., … Bunnett, N. W. (2008). Transient receptor potential vanilloid 4 mediates protease activated receptor 2-induced sensitization of colonic afferent nerves and visceral hyperalgesia. Am J Physiol Gastrointest Liver Physiol, 294(5), G1288–G1298. https://doi.org/10.1152/ajpgi.00002.2008
Sipe, Walter E. B., Stuart M. Brierley, Christopher M. Martin, Benjamin D. Phillis, Francisco Bautista Cruz, Eileen F. Grady, Wolfgang Liedtke, et al. “Transient receptor potential vanilloid 4 mediates protease activated receptor 2-induced sensitization of colonic afferent nerves and visceral hyperalgesia.Am J Physiol Gastrointest Liver Physiol 294, no. 5 (May 2008): G1288–98. https://doi.org/10.1152/ajpgi.00002.2008.
Sipe WEB, Brierley SM, Martin CM, Phillis BD, Cruz FB, Grady EF, et al. Transient receptor potential vanilloid 4 mediates protease activated receptor 2-induced sensitization of colonic afferent nerves and visceral hyperalgesia. Am J Physiol Gastrointest Liver Physiol. 2008 May;294(5):G1288–98.
Sipe, Walter E. B., et al. “Transient receptor potential vanilloid 4 mediates protease activated receptor 2-induced sensitization of colonic afferent nerves and visceral hyperalgesia.Am J Physiol Gastrointest Liver Physiol, vol. 294, no. 5, May 2008, pp. G1288–98. Pubmed, doi:10.1152/ajpgi.00002.2008.
Sipe WEB, Brierley SM, Martin CM, Phillis BD, Cruz FB, Grady EF, Liedtke W, Cohen DM, Vanner S, Blackshaw LA, Bunnett NW. Transient receptor potential vanilloid 4 mediates protease activated receptor 2-induced sensitization of colonic afferent nerves and visceral hyperalgesia. Am J Physiol Gastrointest Liver Physiol. 2008 May;294(5):G1288–G1298.

Published In

Am J Physiol Gastrointest Liver Physiol

DOI

ISSN

0193-1857

Publication Date

May 2008

Volume

294

Issue

5

Start / End Page

G1288 / G1298

Location

United States

Related Subject Headings

  • Viscera
  • TRPC Cation Channels
  • Serous Membrane
  • Ruthenium Red
  • Receptor, PAR-2
  • Rats, Sprague-Dawley
  • Rats
  • Phorbol Esters
  • Nociceptors
  • Neurons, Afferent