Fatty acid amide hydrolase inhibition normalises bladder function and reduces pain through normalising the anandamide/palmitoylethanolamine ratio in the inflamed bladder of rats
Fatty acid amide hydrolase inhibition may be used to control bladder function and pain by modulating endocannabinoid levels in cystitis. We studied the effect of the peripherally restricted fatty acid amide hydrolase inhibitor URB937 in bladder reflex activity and bladder pain using the lipopolysaccharide model of cystitis. We also correlated the URB937’s effects with tissue levels of the endocannabinoids anandamide and palmitoylethanolamine. URB937 did not change the reflex activity of normal bladders. In inflamed bladders, URB937 had a U-shaped dose–response curve; following an initial cannabinoid receptor type 1-mediated reduction in pain responses and normalisation of bladder reflex activity, URB937 gradually increased both pain responses and bladder reflex activity through the transient receptor potential ion channel subfamily V member 1. Chronic cystitis increased the tissue levels of anandamide and decreased those of palmitoylethanolamine. At the dose that normalised bladder reflex activity and decreased pain responses, URB937 normalised the levels of anandamide and palmitoylethanolamine in the bladder. At high doses that induced excitatory effects, URB937 apparently did not change anandamide and palmitoylethanolamine levels, which therefore were in the range of the inflamed bladder. Fatty acid amide hydrolase inhibition results in complex changes in bladder endocannabinoid levels. The therapeutic effect of fatty acid amide hydrolase inhibitors is not related to increase in anandamide levels but rather a normalisation of the anandamide and palmitoylethanolamine level ratio.
KeywordsAnandamide CB1 FAAH TRPV1 URB937
AC was supported by Fundação para a Ciência e Tecnologia (FCT) fellowship SFRH/BPD/68716/2010. RO is supported by NORTE2020 fellowship NORTE-08-5369-FSE-000026.
AC, RM and RO performed the experiments. TM and IN performed the endocannabinoid quantification. AC was responsible for the data analysis. AC, IN and FC were responsible for the work concept. All the authors contributed to manuscript writing.
- Aizawa N, Gandaglia G, Hedlund P, Fujimura T, Fukuhara H, Montorsi F, Homma Y, Igawa Y (2016) URB937, a peripherally restricted inhibitor for fatty acid amide hydrolase, reduces prostaglandin E2-induced bladder overactivity and hyperactivity of bladder mechano-afferent nerve fibres in rats. BJU Int 117:821–828. https://doi.org/10.1111/bju.13223 CrossRefPubMedGoogle Scholar
- Charrua A, Cruz CD, Jansen D, Rozenberg B, Heesakkers J, Cruz F (2015) Co-administration of transient receptor potential vanilloid 4 (TRPV4) and TRPV1 antagonists potentiate the effect of each drug in a rat model of cystitis. BJU Int 115:452–460. https://doi.org/10.1111/bju.12861 CrossRefPubMedGoogle Scholar
- Clapper JR, Moreno-Sanz G, Russo R, Guijarro A, Vacondio F, Duranti A, Tontini A, Sanchini S, Sciolino NR, Spradley JM, Hohmann AG, Calignano A, Mor M, Tarzia G, Piomelli D (2010) Anandamide suppresses pain initiation through a peripheral endocannabinoid mechanism. Nat Neurosci 13:1265–1270. https://doi.org/10.1038/nn.2632 CrossRefPubMedPubMedCentralGoogle Scholar
- Dinis P, Charrua A, Avelino A, et al (2004) Anandamide-evoked activation of vanilloid receptor 1 contributes to the development of bladder hyperreflexia and nociceptive transmission to spinal dorsal horn neurons in cystitis. J Neurosci 24: doi: https://doi.org/10.1523/JNEUROSCI.2657-04.2004 CrossRefGoogle Scholar
- Lever IJ, Robinson M, Cibelli M, Paule C, Santha P, Yee L, Hunt SP, Cravatt BF, Elphick MR, Nagy I, Rice ASC (2009) Localization of the endocannabinoid-degrading enzyme fatty acid amide hydrolase in rat dorsal root ganglion cells and its regulation after peripheral nerve injury. J Neurosci 29:3766–3780. https://doi.org/10.1523/jneurosci.4071-08.2009 CrossRefPubMedPubMedCentralGoogle Scholar
- Mahmud A, Santha P, Paule CC, Nagy I (2009) Cannabinoid 1 receptor activation inhibits transient receptor potential vanilloid type 1 receptor-mediated cationic influx into rat cultured primary sensory neurons. Neuroscience 162:1202–1211. https://doi.org/10.1016/j.neuroscience.2009.05.024 CrossRefPubMedGoogle Scholar
- Quarta C, Bellocchio L, Mancini G, Mazza R, Cervino C, Braulke LJ, Fekete C, Latorre R, Nanni C, Bucci M, Clemens LE, Heldmaier G, Watanabe M, Leste-Lassere T, Maitre M, Tedesco L, Fanelli F, Reuss S, Klaus S, Srivastava RK, Monory K, Valerio A, Grandis A, de Giorgio R, Pasquali R, Nisoli E, Cota D, Lutz B, Marsicano G, Pagotto U (2010) CB(1) signaling in forebrain and sympathetic neurons is a key determinant of endocannabinoid actions on energy balance. Cell Metab 11:273–285. https://doi.org/10.1016/j.cmet.2010.02.015 CrossRefPubMedGoogle Scholar
- Starowicz K, Makuch W, Korostynski M, Malek N, Slezak M, Zychowska M, Petrosino S, de Petrocellis L, Cristino L, Przewlocka B, di Marzo V (2013) Full inhibition of spinal FAAH leads to TRPV1-mediated analgesic effects in neuropathic rats and possible lipoxygenase-mediated remodeling of anandamide metabolism. PLoS One 8:e60040. https://doi.org/10.1371/journal.pone.0060040 CrossRefPubMedPubMedCentralGoogle Scholar
- Varga A, Jenes A, Marczylo TH, Sousa-Valente J, Chen J, Austin J, Selvarajah S, Piscitelli F, Andreou AP, Taylor AH, Kyle F, Yaqoob M, Brain S, White JPM, Csernoch L, di Marzo V, Buluwela L, Nagy I (2014) Anandamide produced by Ca(2+)-insensitive enzymes induces excitation in primary sensory neurons. Pflugers Arch 466:1421–1435. https://doi.org/10.1007/s00424-013-1360-7 CrossRefPubMedGoogle Scholar
- Veress G, Meszar Z, Muszil D, Avelino A, Matesz K, Mackie K, Nagy I (2013) Characterisation of cannabinoid 1 receptor expression in the perikarya, and peripheral and spinal processes of primary sensory neurons. Brain Struct Funct 218:733–750. https://doi.org/10.1007/s00429-012-0425-2 CrossRefPubMedGoogle Scholar