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

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.

Authors+Show Affiliations

Departamento de Biomedicina-Unidade de Biologia Experimental, Faculdade de Medicina da Universidade do Porto, Rua Dr. Plácido da Costa, 91, 4200, Porto, Portugal. anacharr@gmail.com. I3S-Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Porto, Portugal. anacharr@gmail.com. IBMC-Instituto de Biologia Molecular e Celular, Universidade do Porto, Porto, Portugal. anacharr@gmail.com.Departamento de Biomedicina-Unidade de Biologia Experimental, Faculdade de Medicina da Universidade do Porto, Rua Dr. Plácido da Costa, 91, 4200, Porto, Portugal. I3S-Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Porto, Portugal. IBMC-Instituto de Biologia Molecular e Celular, Universidade do Porto, Porto, Portugal. IPATIMUP-Instituto de Patologia e Imunologia Molecular da Universidade do Porto, Porto, Portugal.Departamento de Biomedicina-Unidade de Biologia Experimental, Faculdade de Medicina da Universidade do Porto, Rua Dr. Plácido da Costa, 91, 4200, Porto, Portugal. I3S-Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Porto, Portugal. IBMC-Instituto de Biologia Molecular e Celular, Universidade do Porto, Porto, Portugal.Toxicology Department, Public Health England, Chilton, UK.Department of Surgery & Cancer, Faculty of Medicine, Imperial College London, London, UK.I3S-Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Porto, Portugal. IBMC-Instituto de Biologia Molecular e Celular, Universidade do Porto, Porto, Portugal. Departamento de Urologia, Hospital S. João, Porto, Portugal.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

31522241

Citation

Charrua, Ana, et al. "Fatty Acid Amide Hydrolase Inhibition Normalises Bladder Function and Reduces Pain Through Normalising the Anandamide/palmitoylethanolamine Ratio in the Inflamed Bladder of Rats." Naunyn-Schmiedeberg's Archives of Pharmacology, 2019.
Charrua A, Matos R, Oliveira R, et al. Fatty acid amide hydrolase inhibition normalises bladder function and reduces pain through normalising the anandamide/palmitoylethanolamine ratio in the inflamed bladder of rats. Naunyn Schmiedebergs Arch Pharmacol. 2019.
Charrua, A., Matos, R., Oliveira, R., Marczylo, T., Nagy, I., & Cruz, F. (2019). Fatty acid amide hydrolase inhibition normalises bladder function and reduces pain through normalising the anandamide/palmitoylethanolamine ratio in the inflamed bladder of rats. Naunyn-Schmiedeberg's Archives of Pharmacology, doi:10.1007/s00210-019-01729-9.
Charrua A, et al. Fatty Acid Amide Hydrolase Inhibition Normalises Bladder Function and Reduces Pain Through Normalising the Anandamide/palmitoylethanolamine Ratio in the Inflamed Bladder of Rats. Naunyn Schmiedebergs Arch Pharmacol. 2019 Sep 15; PubMed PMID: 31522241.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Fatty acid amide hydrolase inhibition normalises bladder function and reduces pain through normalising the anandamide/palmitoylethanolamine ratio in the inflamed bladder of rats. AU - Charrua,Ana, AU - Matos,Rita, AU - Oliveira,Raquel, AU - Marczylo,Tim, AU - Nagy,Istvan, AU - Cruz,Francisco, Y1 - 2019/09/15/ PY - 2019/06/13/received PY - 2019/09/06/accepted PY - 2019/9/16/entrez PY - 2019/9/16/pubmed PY - 2019/9/16/medline KW - Anandamide KW - CB1 KW - FAAH KW - TRPV1 KW - URB937 JF - Naunyn-Schmiedeberg's archives of pharmacology JO - Naunyn Schmiedebergs Arch. Pharmacol. N2 - 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. SN - 1432-1912 UR - https://www.unboundmedicine.com/medline/citation/31522241/Fatty_acid_amide_hydrolase_inhibition_normalises_bladder_function_and_reduces_pain_through_normalising_the_anandamide/palmitoylethanolamine_ratio_in_the_inflamed_bladder_of_rats L2 - https://dx.doi.org/10.1007/s00210-019-01729-9 DB - PRIME DP - Unbound Medicine ER -