ArticleThe Journal of neuroscience : the official journal of the Society for Neuroscience2004
Protease-activated receptor 2 sensitizes the capsaicin receptor transient receptor potential vanilloid receptor 1 to induce hyperalgesia.
Article in The Journal of neuroscience : the official journal of the Society for Neuroscience, 2004. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 182 papers, 2 of them syntheses that pooled it.
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Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
182 citing papers in PubMed, 2 syntheses or guidelines pooled it, 407 citations in OpenAlex.
- A systematic review and meta-analysis reveals enrichment of pro-inflammatory and bacterial immunity-modulating taxa in oral squamous cell carcinoma.Frontiers in immunology · 2026Pooled it
- Capsaicin: A Two-Decade Systematic Review of Global Research Output and Recent Advances Against Human Cancer.Frontiers in oncology · 2022Pooled it
- Effect of Intradermal Morphine on Histaminergic and Non-Histaminergic Itch: A Randomised, Single-Blinded, Human Study.Experimental dermatology · 2025Trial
- Trial
- Roles of Interleukin-31 in Allergen-Driven Cough: Linking Protease-Activated Receptor-2 Activation and Vagal Ganglion Sensitization in a Dermatophagoides farinae-Induced Asthma Model.Brain and behavior · 2026Article
- The Mast Cell-PAR2-TRP Axis: A Convergent Mechanism for Visceral Hypersensitivity Independent of Divergent Motility in IBS.Biomolecules · 2026Review
- Modulation of Nociceptive Ion Channels by Protease-Activated Receptor-2 in Inflammatory Pain: Molecular Mechanisms and Therapeutic Potential.International journal of molecular sciences · 2026Review
- Endosomal MrGPRX1 signaling sensitizes TRPV1 to enhance itch.Frontiers in molecular neuroscience · 2026Article
- Reviewing the Peripheral and Central Mechanisms of Visceral Hypersensitivity in Intestinal Disorders.International journal of medical sciences · 2026Review
- Neuro-immune-epithelial pathways involving substance P may contribute to mucosal pathology in gastro-oesophageal reflux disease.Frontiers in immunology · 2026Article
- Endosomal MrGPRX1 signaling sensitizes TRPV1 to enhance itch.bioRxiv : the preprint server for biology · 2025Article
- Neuroimmune interactions: The bridge between inflammatory bowel disease and the gut microbiota.Clinical and translational medicine · 2025Review
- Efficacy of MEDI0618, a pH-dependent monoclonal antibody targeting PAR2, in preclinical models of migraine.Brain : a journal of neurology · 2025Article
- Neuromodulators in Acute and Chronic Cough in Children: An Update from the Literature.International journal of molecular sciences · 2024Review
- Mast cell modulation: A novel therapeutic strategy for abdominal pain in irritable bowel syndrome.Cell reports. Medicine · 2024Review
- Update on the Role of β2AR and TRPV1 in Respiratory Diseases.International journal of molecular sciences · 2024Review
- Article
- Mast cell-sensory neuron crosstalk in allergic diseases.The Journal of allergy and clinical immunology · 2024Review
- Update on protease-activated receptor 2 in inflammatory and autoimmune dermatological diseases.Frontiers in immunology · 2024Review
- A mast cell-thermoregulatory neuron circuit axis regulates hypothermia in anaphylaxis.Science immunology · 2023Article
122 more citing papers are in PubMed but not listed here.
Corrections and comments
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Authors and funding
13 authors at 5 institutions in 5 countries.
Funding
Abstract
Inflammatory proteases (mast cell tryptase and trypsins) cleave protease-activated receptor 2 (PAR2) on spinal afferent neurons and cause persistent inflammation and hyperalgesia by unknown mechanisms. We determined whether transient receptor potential vanilloid receptor 1 (TRPV1), a cation channel activated by capsaicin, protons, and noxious heat, mediates PAR2-induced hyperalgesia. PAR2 was coexpressed with TRPV1 in small- to medium-diameter neurons of the dorsal root ganglia (DRG), as determined by immunofluorescence. PAR2 agonists increased intracellular [Ca2+] ([Ca2+]i) in these neurons in culture, and PAR2-responsive neurons also responded to the TRPV1 agonist capsaicin, confirming coexpression of PAR2 and TRPV1. PAR2 agonists potentiated capsaicin-induced increases in [Ca2+]i in TRPV1-transfected human embryonic kidney (HEK) cells and DRG neurons and potentiated capsaicin-induced currents in DRG neurons. Inhibitors of phospholipase C and protein kinase C (PKC) suppressed PAR2-induced sensitization of TRPV1-mediated changes in [Ca2+]i and TRPV1 currents. Activation of PAR2 or PKC induced phosphorylation of TRPV1 in HEK cells, suggesting a direct regulation of the channel. Intraplantar injection of a PAR2 agonist caused persistent thermal hyperalgesia that was prevented by antagonism or deletion of TRPV1. Coinjection of nonhyperalgesic doses of PAR2 agonist and capsaicin induced hyperalgesia that was inhibited by deletion of TRPV1 or antagonism of PKC. PAR2 activation also potentiated capsaicin-induced release of substance P and calcitonin gene-related peptide from superfused segments of the dorsal horn of the spinal cord, where they mediate hyperalgesia. We have identified a novel mechanism by which proteases that activate PAR2 sensitize TRPV1 through PKC. Antagonism of PAR2, TRPV1, or PKC may abrogate protease-induced thermal hyperalgesia.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.