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A combination of peripherally restricted CB₁ and CB₂ cannabinoid receptor agonists reduces bladder afferent sensitisation in cystitis

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dc.contributor.authorRamsay, S.
dc.contributor.authorYew, W.P.
dc.contributor.authorBrookes, S.
dc.contributor.authorZagorodnyuk, V.
dc.date.issued2024
dc.description.abstractCannabinoid agonists can potentially ameliorate lower urinary tract symptoms (LUTS), including pain associated with interstitial cystitis/bladder pain syndrome (IC/BPS). This study aims to determine the contributions of the cannabinoid 1 receptors (CB1Rs) and CB2Rs in regulating the activity of different functional classes of afferents, comparing normal healthy bladder with bladders from guinea pigs with protamine/zymosan-induced cystitis. The mechanosensitivity of different functional afferent classes was determined by ex vivo single-unit extracellular recordings. Peripherally restricted CB1R preferential agonists, ACEA and PrNMI and peripherally restricted CB2R selective agonists, 4Q3C and olorinab all reduced the mechanosensitivity of mucosal bladder afferents. The potency and efficacy of these synthetic cannabinoid agonists were significantly increased in cystitis compared to controls. Combined application of CB1R agonists, ACEA or PrNMI with the CB2R agonist, 4Q3C produced additive inhibitory effects. ACEA and PrNMI also inhibited the stretch-induced firing of high-threshold muscular bladder afferents in animals with cystitis. In contrast, low- and high-threshold muscular-mucosal bladder afferents were unaffected by the CB1R and CB2R agonists in control and cystitis. Our data indicated that peripherally restricted CB1R and CB2R agonists effectively reduce the sensitisation of probable nociceptive afferents in the bladder in cystitis. The findings also suggest a potential benefit of simultaneously targeting both the CB1Rs and CB2Rs to ameliorate LUTS in cystitis.
dc.description.statementofresponsibilityStewart Ramsay, Wai Ping Yew, Simon Brookes, Vladimir Zagorodnyuk
dc.identifier.citationEuropean Journal of Pharmacology, 2024; 985:177078-1-177078-10
dc.identifier.doi10.1016/j.ejphar.2024.177078
dc.identifier.issn0014-2999
dc.identifier.issn0014-2999
dc.identifier.orcidRamsay, S. [0000-0003-2068-3868]
dc.identifier.urihttps://hdl.handle.net/2440/143745
dc.language.isoen
dc.publisherElsevier
dc.relation.granthttp://purl.org/au-research/grants/nhmrc/1184546
dc.rights© 2024 The Authors. Published by Elsevier B.V. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
dc.source.urihttps://doi.org/10.1016/j.ejphar.2024.177078
dc.subjectCB1 and CB2 cannabinoid receptors; Peripherally restricted cannabinoid agonists; Bladder afferents; Cystitis
dc.titleA combination of peripherally restricted CB₁ and CB₂ cannabinoid receptor agonists reduces bladder afferent sensitisation in cystitis
dc.title.alternativeA combination of peripherally restricted CB1 and CB2 cannabinoid receptor agonists reduces bladder afferent sensitisation in cystitis
dc.typeJournal article
pubs.publication-statusPublished

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