Fatty acid amide hydrolase inhibition normalises bladder function and reduces pain through normalising the anandamide/palmitoylethanolamine ratio in the inflamed bladder of rats

Ana Charrua*, Rita Matos, Raquel Oliveira, Timothy Marczylo, Istvan Nagy, Francisco Cruz

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

2 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)263-272
Number of pages10
JournalNaunyn-Schmiedeberg's Archives of Pharmacology
Volume393
Issue number2
DOIs
Publication statusPublished - 1 Feb 2020

Bibliographical note

Funding Information:
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.

Funding Information:
AC was supported by Funda??o para a Ci?ncia e Tecnologia (FCT) fellowship SFRH/BPD/68716/2010. RO is supported by NORTE2020 fellowship NORTE-08-5369-FSE-000026.

Publisher Copyright:
© 2019, Springer-Verlag GmbH Germany, part of Springer Nature.

Keywords

  • Anandamide
  • CB1
  • FAAH
  • TRPV1
  • URB937

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