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

Walter E.B. Sipe, Stuart M. Brierley, Christopher M. Martin, Benjamin D. Phillis, Francisco Bautista Cruz, Eileen F. Grady, Wolfgang Liedtke, David M. Cohen, Stephen Vanner, L. Ashley Blackshaw, Nigel W. Bunnett

Research output: Contribution to journalArticlepeer-review

118 Scopus citations


Protease-activated receptor (PAR2) is expressed by nociceptive neurons and activated during inflammation by proteases from mast cells, the intestinal lumen, and the circulation. Agonists of PAR2 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 PAR2-induced mechanical hyperalgesia of the mouse colon. Colonic sensory neurons, identified by retrograde tracing, expressed immunoreactive TRPV4, PAR2, and calcitonin generelated 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 PAR2 activating peptide (PAR2-AP) exacerbated VMR to graded CRD from 6-24 h, indicative of mechanical hyperalgesia. PAR2-induced hyperalgesia was not observed in TRPV4-/- mice. PAR2-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 4α-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. PAR2-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 PAR2-induced mechanical hyperalgesia and excitation of colonic afferent neurons.

Original languageEnglish (US)
Pages (from-to)G1288-G1298
JournalAmerican Journal of Physiology - Gastrointestinal and Liver Physiology
Issue number5
StatePublished - May 2008
Externally publishedYes


  • Protease-activated receptors
  • Proteases
  • Transient receptor potential channels
  • Visceral pain

ASJC Scopus subject areas

  • Physiology
  • Hepatology
  • Gastroenterology
  • Physiology (medical)


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