title: Stimulation of proteinase-activated receptor 2 excites jejunal afferent nerves in anaesthetised rats.
abstract: Proteinase-activated receptor 2 (PAR2) is a receptor for mast cell tryptase and trypsins and might participate in brain-gut communication. However, evidence that PAR2 activation can lead to afferent impulse generation is lacking. To address this issue, we examined the sensitivity of jejunal afferent nerves to a hexapeptide agonist of PAR2, SLIGRL-NH2, and the modulation of the resulting response to treatment with drugs and vagotomy. Multiunit recordings of jejunal afferent activity were made using extracellular recording techniques in anaesthetised male rats. SLIGRL-NH2 (0.001-1 mg kg-1, I.V.) increased jejunal afferent firing and intrajejunal pressure. The reverse peptide sequence (1 mg kg-1, I.V.), which does not stimulate PAR2, was inactive. Naproxen (10 mg kg-1, I.V.), but not a cocktail of omega-conotoxins GVIA and SVIB (each at 25 mug kg-1, I.V.), curtailed both the afferent response and the intrajejunal pressure rise elicited by the PAR2 agonist. Although neither treatment modulated the peak magnitude of the afferent firing, they each altered the intestinal motor response, unmasking an initial inhibitory component. Nifedipine (1 mg kg-1, I.V.) reduced the peak magnitude of the afferent nerve discharge and abolished the initial rise in intrajejunal pressure produced by SLIGRL-NH2. Vagotomy did not significantly influence the magnitude of the afferent response to the PAR2 agonist, which involves a contribution from capsaicin-sensitive fibres. In conclusion, intravenous administration of SLIGRL-NH2 evokes complex activation of predominantly spinally projecting extrinsic intestinal afferent nerves, an effect that involves both direct and indirect mechanisms.
authors.affiliation: Department of Biomedical Science, Alfred Denny Building, University of Sheffield, Western Bank, Sheffield S10 2TN, UK.
authors.forename: Anthony J
authors.initials: AJ
authors.lastname: Kirkup
authors.forename: Wen
authors.initials: W
authors.lastname: Jiang
authors.forename: Nigel W
authors.initials: NW
authors.lastname: Bunnett
authors.forename: David
authors.initials: D
authors.lastname: Grundy
mesh_terms: D000758:Anesthesia; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology; D001794:Blood Pressure / Q000187:drug effects; D002121:Calcium Channel Blockers / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D006339:Heart Rate / Q000187:drug effects; D007583:Jejunum / Q000294:innervation*; D008297:Male; D008643:Mesentery / Q000294:innervation; D009046:Motor Neurons / Q000187:drug effects; D009288:Naproxen / Q000494:pharmacology; D009412:Nerve Fibers / Q000502:physiology; D009475:Neurons, Afferent / Q000502:physiology*; D051381:Rats; D017208:Rats, Wistar; D044464:Receptor, PAR-2 / Q000819:agonists / Q000502:physiology*; D013268:Stimulation, Chemical; D013373:Substance P / Q000378:metabolism; D009435:Synaptic Transmission / Q000502:physiology; D014628:Vagotomy; D020960:omega-Conotoxins / Q000494:pharmacology
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D002121:Calcium Channel Blockers; D044464:Receptor, PAR-2; D020960:omega-Conotoxins; D013373:Substance P; D009288:Naproxen