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TRPV1 and TRPM8 antagonists reduce cystitis-induced bladder hypersensitivity via inhibition of different sensitised classes of bladder afferents in guinea pigs

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dc.contributor.authorRamsay, S.
dc.contributor.authorKeightley, L.
dc.contributor.authorBrookes, S.
dc.contributor.authorZagorodnyuk, V.
dc.date.issued2023
dc.descriptionPublished June 2023
dc.description.abstractInterstitial cystitis (=painful bladder syndrome) is a chronic bladder syndrome characterised by pelvic and bladder pain, urinary frequency and urgency, and nocturia. Transient receptor potential (TRP) channels are an attractive target in reducing the pain associated with interstitial cystitis. The current study aims to determine the efficacy of combination of TRP vanilloid 1 (TRPV1) and TRP melastatin 8 (TRPM8) channel inhibition in reducing the pain associated with experimental cystitis in guinea pigs. A novel animal model of non-ulcerative interstitial cystitis has been developed using protamine sulfate/zymosan in female guinea pigs. Continuous voiding cystometry was performed in conscious guinea pigs. Ex vivo "close-to-target" single unit extracellular recordings were made from fine branches of pelvic nerves entering the guinea pig bladder. Visceromotor responses in vivo were used to determine the effects of TRP channel antagonists on cystitis-induced bladder hypersensitivity. Protamine sulfate/zymosan treatment evoked mild inflammation in the bladder and increased micturition frequency in conscious animals. In cystitis, high threshold muscular afferents were sensitised via up-regulation of TRPV1 channels, high threshold muscular-mucosal afferents were sensitised via TRPM8 channels, and mucosal afferents by both. Visceromotor responses evoked by noxious bladder distension were significantly enhanced in cystitis and were returned to control levels upon administration of combination of low doses of TRPV1 and TRPM8 antagonists. The data demonstrates the therapeutic promises of combination of TRPV1 and TRPM8 antagonists for treatment of bladder hypersensitivity in cystitis.
dc.description.statementofresponsibilityStewart Ramsay, Lauren Keightley, Simon Brookes, Vladimir Zagorodnyuk
dc.identifier.citationBritish Journal of Pharmacology, 2023; 180(11):1482-1499
dc.identifier.doi10.1111/bph.16017
dc.identifier.issn0007-1188
dc.identifier.issn1476-5381
dc.identifier.orcidRamsay, S. [0000-0003-2068-3868]
dc.identifier.urihttps://hdl.handle.net/2440/137363
dc.language.isoen
dc.publisherWiley
dc.relation.granthttp://purl.org/au-research/grants/nhmrc/1184546
dc.rights© 2022 British Pharmacological Society
dc.source.urihttps://doi.org/10.1111/bph.16017
dc.subjectbladder afferents
dc.subjectbladder hypersensitivity
dc.subjectcystitis
dc.subjectTRPM8 channels
dc.subjectTRPV1 channels
dc.subjectvisceromotor responses
dc.titleTRPV1 and TRPM8 antagonists reduce cystitis-induced bladder hypersensitivity via inhibition of different sensitised classes of bladder afferents in guinea pigs
dc.typeJournal article
pubs.publication-statusPublished

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