Protease‐activated receptor‐4 (PAR4): a role as inhibitor of visceral pain and hypersensitivity
Abstract
Abstract Protease‐activated receptor‐4 (PAR 4) belongs to the family of receptors activated by the proteolytic cleavage of their extracellular N‐terminal domain and the subsequent binding of the newly released N‐terminus. While largely expressed in the colon, the role of PAR 4 in gut functions has not been defined. We have investigated the effects of PAR 4 agonist on colonic sensations and sensory neuron signalling, and its role in visceral pain. We observed that a single administration of the PAR 4 agonist peptide (AYPGKF‐NH 2), but not the control peptide (YAPGKF‐NH 2) into the colon lumen of mice significantly reduced the visceromotor response to colorectal distension at different pressures of distension. Further, intracolonic administration of the PAR 4 agonist, but not the control peptide, was able to significantly inhibit PAR 2 agonist‐ and transcient receptor potential vanilloid‐4 (TRPV4) agonist‐induced allodynia and hyperalgesia in response to colorectal distension. Protease‐activated receptor‐4 was detected in sensory neurons projecting from the colon, and isolated from the dorsal root ganglia, where it co‐expressed with PAR 2 and TRPV4. In total sensory neurons, PAR 4 agonist exposure inhibited free intracellular calcium mobilization induced by the pro‐nociceptive agonists of PAR 2 and TRPV4. Finally, PAR 4‐deficient mice experienced increased pain behaviour in response to intracolonic administration of mustard oil, compared with wild‐type littermates. These results show that PAR 4 agonists modulate colonic nociceptive response, inhibit colonic hypersensitivity and primary afferent responses to pro‐nociceptive mediators. Endogenous activation of PAR 4 also plays a major role in controlling visceral pain. These results identify PAR 4 as a previously unknown modulator of visceral nociception.
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PAR-4 activation suppresses the excitability of colonic nociceptors in vitro and in vivo.
“PAR-4 activation suppresses the excitability of colonic nociceptors in vitro,157 and in vivo.158”
From The emerging roles of bacterial proteases in intestinal diseases (2023) · cites this paper as [158]
Activation of PAR-4 has opposite effects on nociceptor activation to PAR-2 activation in rodents.
“Importantly, activation of PAR-4 has opposite effects on nociceptor activation to PAR-2 activation in rodents.”
From The emerging roles of bacterial proteases in intestinal diseases (2023) · cites this paper as [158]
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- Authors
- Augé, C., Balz‐hara, D., Steinhoff, M., Vergnolle, N., & Cenac, N.
- Affiliations
- Université Toulouse III - Paul Sabatier (FR)
- University of Münster (DE)
- Corresponding author
- Vergnolle, N.
- Venue
- Neurogastroenterology & Motility
- Publisher
- Wiley
- Published
- 2009-10-02
- Volume
- 21
- Issue
- 11
- Pages
- 1189
- ISSN
- 1350-1925 (ISSN-L)
- 1365-2982
- OpenAlex
- W2151257438
- Cited by
- 99
- References
- 33
- Citations by year
- 2026: 1 · 2025: 2 · 2024: 2 · 2023: 3 · 2022: 3 · 2021: 5 · 2020: 2 · 2019: 3 · 2018: 6 · 2017: 8 · 2016: 7 · 2015: 6 · 2014: 6 · 2013: 4 · 2012: 11
- FWCI
- 9.06
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Neurogastroenterology & Motility (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Fondation Bettencourt Schueller
- Topics
- Health Sciences › Medicine › Physiology › Pain Mechanisms and Treatments
- Life Sciences › Neuroscience › Sensory Systems › Ion Channels and Receptors
- Health Sciences › Medicine › Hematology › Blood Coagulation and Thrombosis Mechanisms
- Keywords
- PAR4, visceral pain, colonic hypersensitivity, colorectal distension, allodynia, hyperalgesia, PAR2, TRPV4, sensory neurons, dorsal root ganglia, calcium mobilization, mustard oil, visceral nociception
- MeSH terms
- Animals, Behavior, Animal, Catheterization, Ganglia, Spinal, Hyperalgesia, Male, Mice, Inbred C57BL, Mustard Plant, Neurons, Afferent, Oligopeptides, Pain, Plant Oils, Sensory Receptor Cells, Visceral Afferents, Receptors, Thrombin, TRPV Cation Channels, Mice
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