FAAH Inhibitor Improves Function of Inflamed Bladders by Modulation of Anandamide and Palmitoylethanolamide

Introduction: We aim to study the effect of fatty acid amide hydrolase (FAAH) blockade on bladder hyperactivity and on fatty acid amides levels during cystitis. Material and Methods: Cystitis was induced in female Wistar rats using 5 mg/mL lipopolysaccharide (LPS). Control group were intravesical instilled with saline. LPS and control groups received intravenously (caudal vein) during cystometry: URB 937 (URB; FAAH antagonist) in doses of 0.007, 0.07, 0.7 and 7 mg/kg (cumulative, with 10 minutes interval). Using the maximal effective dose of URB (0.7 mg/kg, see below) animals received 10 uM MJ15 (CB1 receptor antagonist) or 0.3 mg SR144528 /kg (SR; CB2 receptor antagonist). At dose of 7 mg/kg, animals receive 1.4 μg SB366791/kg (SB; TRPV1 antagonist). Control and inflamed (without and with 0.7 and 7 mg/kg URB) group were euthanized and the bladder was harvested for the determination of anandamide (AEA) and palmitoylethanolamide (PEA) by mass spectrometry. Results: Frequency of control was not changed by URB treatment at any dose. LPS increase bladder frequency. 0.007 mg and 0.07 mg URB decrease bladder frequency of LPS-inflamed rats. 0.7 URB reversed LPS-induced bladder hyperactivity. At 7 mg, URB was unable to reverse or reduce LPS-induced bladder hyperactivity. The administration of CB1, CB2 and TRPV1 antagonists did not change the frequency of voiding contractions of naive animals. CB1 antagonist reversed the effect of 0.7 URB while TRPV1 antagonist reduced the effect of 7 URB. AEA levels increase during inflammation. Treating LPS-inflamed animals with 0.7 mg URB brought AEA levels to control levels. Treating LPS-inflamed animals with 7 mg URB did not change AEA levels, compared to LPS-inflamed animals. PEA levels decrease during inflammation. Treating LPS-inflamed animals with 0.7 mg URB brought AEA levels to control levels. Treating LPS-inflamed animals with 7 mg URB, decreased PEA levels to values similar to the ones observed in LPS- -inflamed animals. Conclusion: During cystitis, the FAAH inhibitor raises the levels of PEA and reverses the urinary frequency by a CB1 receptor- mediated mechanism. When used in very high doses, the FAAH antagonist raises the levels of AEA and increases the urinary frequency by a TRPV1-dependent mechanism. Therefore, the choice of FAAH inhibitor dosage to be used in the clinics should consider the putative effects over the endocannabinoid levels in the system.