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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.AJ

Abstract

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.

Authors+Show Affiliations

Department of Pediatrics, University of California San Francisco, San Francisco, CA 94143-0660, USA.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

18325985

Citation

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." American Journal of Physiology. Gastrointestinal and Liver Physiology, vol. 294, no. 5, 2008, pp. G1288-98.
Sipe WE, Brierley SM, Martin CM, 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;294(5):G1288-98.
Sipe, W. E., Brierley, S. M., Martin, C. M., Phillis, B. D., Cruz, F. B., Grady, E. F., Liedtke, W., Cohen, D. M., Vanner, S., Blackshaw, L. A., & Bunnett, N. W. (2008). Transient receptor potential vanilloid 4 mediates protease activated receptor 2-induced sensitization of colonic afferent nerves and visceral hyperalgesia. American Journal of Physiology. Gastrointestinal and Liver Physiology, 294(5), G1288-98. https://doi.org/10.1152/ajpgi.00002.2008
Sipe WE, 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;294(5):G1288-98. PubMed PMID: 18325985.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Transient receptor potential vanilloid 4 mediates protease activated receptor 2-induced sensitization of colonic afferent nerves and visceral hyperalgesia. AU - Sipe,Walter E B, AU - Brierley,Stuart M, AU - Martin,Christopher M, AU - Phillis,Benjamin D, AU - Cruz,Francisco Bautista, AU - Grady,Eileen F, AU - Liedtke,Wolfgang, AU - Cohen,David M, AU - Vanner,Stephen, AU - Blackshaw,L Ashley, AU - Bunnett,Nigel W, Y1 - 2008/03/06/ PY - 2008/3/8/pubmed PY - 2008/7/1/medline PY - 2008/3/8/entrez SP - G1288 EP - 98 JF - American journal of physiology. Gastrointestinal and liver physiology JO - Am J Physiol Gastrointest Liver Physiol VL - 294 IS - 5 N2 - 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. SN - 0193-1857 UR - https://www.unboundmedicine.com/medline/citation/18325985/Transient_receptor_potential_vanilloid_4_mediates_protease_activated_receptor_2_induced_sensitization_of_colonic_afferent_nerves_and_visceral_hyperalgesia_ L2 - https://journals.physiology.org/doi/10.1152/ajpgi.00002.2008?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub=pubmed DB - PRIME DP - Unbound Medicine ER -