title: Inhibition of peripheral FAAH depresses activities of bladder mechanosensitive nerve fibers of the rat.
abstract: OBJECTIVE
  FAAH degrades endocannabinoids and fatty acid amides. FAAH inhibition reduces micturition frequency and counteracts bladder overactivity in rats. We studied the effects of the peripherally active selective FAAH inhibitor URB937, and the CB1 and CB2 receptor antagonists rimonabant and SR144528, respectively, on single unit afferent activity of primary bladder afferents in rats.
  
  
  METHODS
  Female Sprague Dawley® rats were anesthetized. Single unit afferent activity of Aδ or C-fibers from the L6 dorsal roots was recorded during bladder filling before and after URB937 administration with or without rimonabant or SR144528. Drugs (1 mg/kg) were given intravenously. FAAH, CB1 and CB2 expression, and expression of the sensory marker CGRP in the L6 dorsal root ganglion were compared by immunofluorescence.
  
  
  RESULTS
  A total of 102 single afferent fibers (48 Aδ and 54 C-fibers) were isolated from 57 rats. URB937 decreased single unit afferent activity of C-fibers to a mean ± SEM of 78% ± 9% and of Aδ-fibers to a mean of 67% ± 7% while increasing bladder compliance to a mean of 116% ± 3%. The effects of URB937 on single unit afferent activity and bladder compliance were counteracted by rimonabant or SR144528. Rimonabant increased single unit afferent activity of each fiber type but SR144528 affected only Aδ-fiber activity. CGRP positive L6 dorsal root ganglion neurons showed strong FAAH, CB1 and CB2 staining.
  
  
  CONCLUSIONS
  To our knowledge we report for the first time that inhibiting peripheral FAAH depresses the Aδ and C-fiber activity of primary bladder afferents via CB1 and CB2 receptors. CB antagonists alone exerted facilitatory effects on single unit afferent activity during bladder filling in rats. The endocannabinoid system may be involved in physiological control of micturition as regulators of afferent signals.
authors.affiliation: Department of Continence Medicine, University of Tokyo Graduate School of Medicine, Tokyo, Japan.
authors.forename: Naoki
authors.initials: N
authors.lastname: Aizawa
authors.affiliation: Urological Research Institute, San Raffaele University, Milan, Italy; Department of Clinical Pharmacology, Linköping University, Linköping, Sweden. Electronic address: petter.hedlund@liu.se.
authors.forename: Petter
authors.initials: P
authors.lastname: Hedlund
authors.affiliation: Department of Urology, Ludwig-Maximilians-University, Munich, Germany.
authors.forename: Claudius
authors.initials: C
authors.lastname: Füllhase
authors.affiliation: Department of Continence Medicine, University of Tokyo Graduate School of Medicine, Tokyo, Japan.
authors.forename: Hiroki
authors.initials: H
authors.lastname: Ito
authors.affiliation: Department of Urology, University of Tokyo Graduate School of Medicine, Tokyo, Japan.
authors.forename: Yukio
authors.initials: Y
authors.lastname: Homma
authors.affiliation: Department of Continence Medicine, University of Tokyo Graduate School of Medicine, Tokyo, Japan. Electronic address: yigawa-jua@umin.ac.jp.
authors.forename: Yasuhiko
authors.initials: Y
authors.lastname: Igawa
mesh_terms: D000581:Amidohydrolases / Q000037:antagonists & inhibitors* / Q000502:physiology*; D000818:Animals; D001892:Camphanes / Q000494:pharmacology*; D063387:Cannabinoid Receptor Antagonists / Q000494:pharmacology*; D002186:Cannabinoids / Q000494:pharmacology*; D005260:Female; D009412:Nerve Fibers / Q000187:drug effects* / Q000502:physiology*; D010880:Piperidines / Q000494:pharmacology*; D011720:Pyrazoles / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D000077285:Rimonabant; D001743:Urinary Bladder / Q000187:drug effects* / Q000294:innervation / Q000502:physiology*; D000099252:Fatty Acid Amide Hydrolases
chemical_list: D000581:Amidohydrolases; D001892:Camphanes; D063387:Cannabinoid Receptor Antagonists; D002186:Cannabinoids; D010880:Piperidines; D011720:Pyrazoles; D000077285:Rimonabant; D000099252:Fatty Acid Amide Hydrolases; C110630:SR 144528; C552918:URB937
keywords: afferent; cannabinoid; endocannabinoids; nerves; receptors; urinary bladder; urination