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

Departments of ¹Pediatrics, ²Surgery, and ³Physiology, University of California, San Francisco, California; ⁴Nerve Gut Research Laboratory, Department of Gastroenterology and Hepatology, Hanson Institute, Royal Adelaide Hospital, and the Disciplines of ⁵Medicine and ⁶Physiology, School of Molecular and Biomedical Sciences, The University of Adelaide, Adelaide, Australia; ⁷Gastrointestinal Diseases Research Unit, Division of Gastroenterology, Queen's University, Kingston, Ontario, Canada; ⁸Department of Medicine and Neurobiology, Duke University Medical Centre, Durham, North Carolina; and ⁹Portland Veterans Affairs Medical Center, Portland, Oregon

Submitted 2 January 2008 ; accepted in final form 28 February 2008

ABSTRACT

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 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 4-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 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.

visceral pain; proteases; protease-activated receptors; transient receptor potential channels

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