Inhibition of peripheral FAAH depresses activities of bladder mechanosensitive nerve fibers of the rat

Naoki Aizawa; Petter Hedlund; Claudius Füllhase; Hiroki Ito; Yukio Homma; Yasuhiko Igawa

doi:10.1016/j.juro.2014.04.008

Inhibition of peripheral FAAH depresses activities of bladder mechanosensitive nerve fibers of the rat

J Urol. 2014 Sep;192(3):956-63. doi: 10.1016/j.juro.2014.04.008. Epub 2014 Apr 16.

Authors

Naoki Aizawa¹, Petter Hedlund², Claudius Füllhase³, Hiroki Ito¹, Yukio Homma⁴, Yasuhiko Igawa⁵

Affiliations

¹ Department of Continence Medicine, University of Tokyo Graduate School of Medicine, Tokyo, Japan.
² Urological Research Institute, San Raffaele University, Milan, Italy; Department of Clinical Pharmacology, Linköping University, Linköping, Sweden. Electronic address: petter.hedlund@liu.se.
³ Department of Urology, Ludwig-Maximilians-University, Munich, Germany.
⁴ Department of Urology, University of Tokyo Graduate School of Medicine, Tokyo, Japan.
⁵ Department of Continence Medicine, University of Tokyo Graduate School of Medicine, Tokyo, Japan. Electronic address: yigawa-jua@umin.ac.jp.

PMID: 24746881
DOI: 10.1016/j.juro.2014.04.008

Abstract

Purpose: 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.

Materials and 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.

Keywords: afferent; cannabinoid; endocannabinoids; nerves; receptors; urinary bladder; urination.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Amidohydrolases / antagonists & inhibitors*
Amidohydrolases / physiology*
Animals
Camphanes / pharmacology*
Cannabinoid Receptor Antagonists / pharmacology*
Cannabinoids / pharmacology*
Female
Nerve Fibers / drug effects*
Nerve Fibers / physiology*
Piperidines / pharmacology*
Pyrazoles / pharmacology*
Rats
Rats, Sprague-Dawley
Rimonabant
Urinary Bladder / drug effects*
Urinary Bladder / innervation
Urinary Bladder / physiology*

Substances

Camphanes
Cannabinoid Receptor Antagonists
Cannabinoids
Piperidines
Pyrazoles
SR 144528
URB937
Amidohydrolases
fatty-acid amide hydrolase
Rimonabant