Although FAAH suppression can elicit significant effects under some instances in which consequential procedural modifications are made, the present results indicate that the pharmacological inhibition or genetic deletion of FAAH is ineffective in standard mouse models of emotional reactivity. It remains to be established whether the effects of FAAH inhibition in these modified tasks are predictive of their efficacy in treating emotional disorders.

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...

Alzheimer’s disease is a complex and multifactorial neurodegenerative disease. Central administration of colchicine, a microtubule-disrupting agent, causes loss of cholinergic neurons and cognitive dysfunction that is associated with excessive free radical generation. The present study was aimed at evaluating the effects of trans-resveratrol in the prevention of colchicine-induced cognitive impairment and oxidative stress in rats. Intracerebroventricular administration of colchicine (15 µg/5 µl) induced impaired cognitive functions in both the Morris water maze task and the elevated plus-maze task. Chronic treatment with resveratrol (10 and 20 mg/kg, p.o.) for a period of 25 days, beginning 4 days prior to colchicine injection, significantly improved the colchicine-induced cognitive impairment. Intracerebroventricular colchicine injection resulted in free radical generation characterized by alterations in oxidative stress markers with a significant increase in malondialdehyde (MDA) and nitrite levels and depletion of reduced glutathione (GSH) activity in the rat brains. It also showed a significant decrease in acetylcholinesterase activity. Besides improving cognitive dysfunction, chronic administration of resveratrol significantly reduced the elevated MDA and nitrite levels and restored the depleted GSH and acetylcholinesterase activity. Results of the present study indicated that trans-resveratrol has a neuroprotective role against colchicine-induced cognitive impairment and associated oxidative stress.

Although cannabinoids are efficacious in laboratory animal models of inflammatory pain, their established cannabimimetic actions diminish enthusiasm for their therapeutic development. Conversely, fatty acid amide hydrolase (FAAH), the chief catabolic enzyme regulating the endogenous cannabinoid N-arachidonoylethanolamine (anandamide), has emerged as an attractive target for treating pain and other conditions. Here, we tested WIN 55212 and CB 1 mechanisms of action. However, the transient receptor potential vanilloid type 1 antagonist capsazepine did not affect either the antihyperalgesic or antiedematous effects of URB597. Finally, URB597 attenuated levels of the proinflammatory cytokines interleukin-1␤ and tumor necrosis factor ␣ in LPS-treated paws. These findings demonstrate that simultaneous elevations in non-neuronal and neuronal endocannabinoid signaling are possible through inhibition of a single enzymatic target, thereby offering a potentially powerful strategy for treating chronic inflammatory pain syndromes that operate at multiple levels of anatomical integration.Increased pain sensitivity is one of the most common and debilitating symptoms of inflammatory disorders and is caused by various mediators, including neuropeptides, eicosanoids, and cytokines (Dray and Bevan, 1993). Cannabis extracts and cannabinoid receptor agonists have long been known to elicit analgesic and anti-inflammatory actions (Sofia et al., 1973); however, the therapeutic utility of these drugs has been greatly limited by the occurrence of psychotropic side effects. The endogenous cannabinoid (endocannabinoid) system, consisting of naturally occurring ligands (e.g., anandamide) and 2-arachidonoyl glycerol (2-AG), enzymes regulating ligand biosynthesis and degradation, and two cloned cannabinoid receptors (i.e., CB 1 and CB 2 ) (Jhaveri et al., 2007;Ahn et al., 2008), provides multiple targets for the development of new pharmacological approaches for

Huntington's disease is a progressive, degenerative disease characterized by abnormal body movements called chorea, and a reduction of various mental abilities. 3-Nitropropionic acid, an inhibitor of complex II of the electron transport chain, causes Huntington's disease-like symptoms in rodents. Recently, it has been reported that oxidative stress, which is one of the pathological hallmarks of various neurodegenerative disorders, also plays an important role in the pathogenesis of Huntington's disease. The present study was designed to investigate effects of resveratrol, an antioxidant with cyclooxygenase I inhibitory activity, in the 3-nitropropionic acid-induced model of Huntington's disease. Intraperitoneal administration of 3-nitropropionic acid (20 mg/kg for 4 days) caused significant loss of body weight, a decline in motor function (locomotor activity, movement pattern and vacuous chewing movements) and poor retention of memory. Repeated treatment with resveratrol (5 and 10 mg/kg, orally), once daily for a period of 8 days beginning 4 days prior to 3-nitropropionic acid administration, significantly improved the 3-nitropropionic acid-induced motor and cognitive impairment. Biochemical analysis revealed that systemic 3-nitropropionic acid administration significantly increased lipid peroxidation, nitrite levels, and depleted reduced glutathione levels, and decreased succinate dehydrogenase activity in the brains of rats. The results of the present study indicate that resveratrol (5 and 10 mg/kg, orally) significantly reversed 3-nitropropionic acid-induced motor and cognitive impairment, and that the beneficial effects of resveratrol might be attributed to its antioxidant activity.