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1 Pediatrics, UCSF, San Francisco, California, United States
2 Gastroenterology and Hepatology, Royal Adelaide Hospital, Adelaide, South Australia, Australia
3 Gastroenterology, Queen's University, Kingston, Canada
4 Surgery, UCSF, San Francisco, California, United States
5 Medicine and Neurobiology, Duke University, Durham, North Carolina, United States
6 Portland V.A. Medical Center, Portland, OR, 97239, Portland, Oregon, United States
7 G.I. Division, Hotel Dieu Hospital, Kingston, Canada
8 Nerve Gut Research Laboratory, Royal Adelaide Hospital, Adelaide, South Australia, Australia; , Australia
9 Surgery and Physiology, University of California-San Francisco, San Francisco, California, United States
* To whom correspondence should be addressed. E-mail: nigel.bunnett{at}ucsf.edu.
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 gene-related peptide, and are thus implicated in nociception. To assess nociception, visceromotor responses (VMR) to colorectal distention (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 4
-phorbol 12,13-didecanoate stimulated discharge of action potentials in colonic afferent fibers and enhanced current responses recorded from retrogradely-labeled colonic DRG 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 PAR2 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.
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