Synergy between Enzyme Inhibitors of Fatty Acid Amide Hydrolase and Cyclooxygenase in Visceral Nociception

Abstract

The present study investigated whether inhibition of fatty acid amide hydrolase (FAAH), the enzyme responsible for anandamide catabolism, produces antinociception in the acetic acidinduced abdominal stretching model of visceral nociception. Genetic deletion or pharmacological inhibition of FAAH reduced acetic acid-induced abdominal stretching. Transgenic mice that express FAAH exclusively in the nervous system displayed the antinociceptive phenotype, indicating the involvement of peripheral fatty acid amides. The cannabinoid receptor 1 (CB 1 ) receptor antagonist, rimonabant, but not the cannabinoid receptor 2 (CB 2 ) receptor antagonist, SR144528, blocked the antinociceptive phenotype of FAAH(Ϫ/Ϫ) mice and the analgesic effects of URB597 (3Ј-carbamoyl-biphenyl-3-ylcyclohexylcarbamate) or OL-135 (1-oxo-1[5-(2-pyridyl)-2-yl]-7-phenyl heptane), respective irreversible and reversible FAAH inhibitors, administered to C57BL/6 mice. The opioid receptor antagonist, naltrexone, did not block the analgesic effects of either FAAH inhibitor. URB597, ED 50 [95% confidence interval (CI) ϭ 2.1 (1.5-2.9) mg/kg], and the nonselective cyclooxygenase inhibitor, diclofenac sodium [ED 50 (95% CI) ϭ 9.8 (8.2-11.7) mg/kg], dose-dependently inhibited acetic acid-induced abdominal stretching. Combinations of URB597 and diclofenac yielded synergistic analgesic interactions according to isobolographic analysis. It is important that FAAH(Ϫ/Ϫ) mice and URB597-treated mice displayed significant reductions in the severity of gastric irritation caused by diclofenac. URB597 lost its gastroprotective effects in CB 1 (Ϫ/Ϫ) mice, whereas it maintained its efficacy in CB 2 (Ϫ/Ϫ) mice, indicating a CB 1 mechanism of action. Taken together, the results of the present study suggest that FAAH represents a promising target for the treatment of visceral pain, and a combination of FAAH inhibitors and NSAIDs may have great utility to treat visceral pain, with reduced gastric toxicity.Visceral pain is a major cause of consulting in gastroenterology and the principal symptom of functional bowel disorders. This symptom is often associated with gut hypersensitivity to distension. The endogenous cannabinoid system possesses attractive targets for drugs that could potentially treat visceral and other types of pain. These targets include cannabinoid (i.e., CB 1 and CB 2 ) receptors and fatty acid amide hydrolase (FAAH), the enzyme responsible for degradation of the endogenous cannabinoid, anandamide, and other fatty acid amides (Walker and Hohmann, 2005). Directacting cannabinoid receptor agonists, such as ⌬ 9 -tetrahydrocannabinol (THC), the primary psychoactive constituent of Cannabis sativa, and the irreversible FAAH inhibitor URB597 inhibited visceral nociception, as assessed in the phenyl-p-quinone model (Haller et al., 2006). The antinociceptive effects of both of these compounds were blocked by the CB 1 receptor antagonist, rimonabant, indicating a CB 1 receptor mechanism of action.Although direct-acting cannabinoid receptor agonists possess analg...

Inhibition of Monoacylglycerol Lipase Attenuates Nonsteroidal Anti-Inflammatory Drug-Induced Gastric Hemorrhages in Mice

“…These findings, coupled with the synergistic antinociceptive interactions between the NSAIDs and FAAH inhibition (Fowler et al, 2009;Naidu et al, 2009), support the idea that FAAH and MAGL are promising targets for the development of analgesic therapeutics that not only lack adverse gastrointestinal side effects, but also protect against NSAID-induced gastric ulcers.…”

“…The experimental procedure was based on published reports (Sá nchez et al, 2002;Naidu et al, 2009). Mice were weighed, then food-deprived for 24 h with free access to water.…”

Repeated Low-Dose Administration of the Monoacylglycerol Lipase Inhibitor JZL184 Retains Cannabinoid Receptor Type 1–Mediated Antinociceptive and Gastroprotective Effects

“…It is well established that elevation of either AEA or 2-AG, via inhibition of their respective catabolic enzymes, fatty acid amide hydrolase (FAAH) or monoacylglycerol lipase (MAGL), produces analgesic and anti-inflammatory effects in vivo (Schlosburg et al, 2009b). For example, FAAH inhibition attenuates neuropathic pain (Jhaveri et al, 2006;Russo et al, 2007;Kinsey et al, 2009;Clapper et al, 2010), inflammatory pain (Booker et al, 2011), collagen-induced arthritis (Kinsey et al, 2011a), and gastric ulceration (Naidu et al, 2009;Sasso et al, 2012), as well as elicits anxiolytic-like behavioral effects (Patel and Hillard, 2006;Naidu et al, 2007) in rodents. Similarly, the selective MAGL inhibitor 4-nitrophenyl 4-(dibenzo [d] [1,3]dioxol-5-yl(hydroxy)methyl)piperidine-1-carboxylate (JZL184) attenuates nociception in neuropathic (Kinsey et al, 2009) and inflammatory (Ghosh et al, 2012) pain models.…”

Endogenous Cannabinoid System and Its Role in Gastrointestinal Tract: Review

“…[52][53][54]58 FAAH ve MAGL inhibisyonu ile analjezik etki görülürken, santral depresan yan etkinin görülmediği ve bu deneklerde bağımlılık oluşmaması, FAAH ve MAGL inhibisyonunun yeni bir terapötik hedef olabileceğini düşündürmüştür.…”