urb-597 and Vomiting

The gastric myoelectric activity (GMA) is the electrical pacesetter potential, which drives gastric motility. Cannabinoids have broad-spectrum antiemetic and antinauseant activity. Paradoxically, they inhibit intestinal peristalsis and reduce gastric motility but their effect on GMA remains unknown.. Ferrets were surgically implanted with radiotelemetry transmitters to record GMA, body temperature and heart rate. The effect of WIN 55,212-2 (1 mg kg(-1), i.p.), an agonist at the cannabinoid type 1 and 2 receptors was examined in conscious, unrestrained ferrets. WIN 55,212-2 was also compared to the anandamide upregulator URB 597 (5 mg kg(-1), i.p.) for a potential to modulate the emetic response and behavioral changes induced by apomorphine (0.25 mg kg(-1), s.c.).. WIN 55,212-2 decreased GMA frequency (8.1 ± 0.4 cpm, compared to 9.6 ± 0.1 cpm in vehicle-treated animals, n = 6, P < 0.01). Apomorphine induced 9.0 ± 1.6 emetic episodes, WIN 55,212-2 inhibited the emetic response (3.3 ± 1.0 episodes, n = 6, P < 0.05) but URB 597 had no effect (9.0 ± 1.5 episodes). Apomorphine-induced hyperactivity in vehicle-treated animals (6.5 ± 3.6-16.6 ± 4.9 active behavior counts, n = 6, P < 0.01), which was reduced by WIN 55,212-2 (5.0 ± 1.5 counts, n = 6, P < 0.05).. WIN 55,212-2 demonstrated clear antiemetic efficacy, which extends the broad-spectrum antiemetic efficacy of cannabinoids to dopamine receptor agonists in the ferret. Our results, however, suggest a more limited spectrum of action for URB 597. WIN 55,212-2 decreased the frequency of the antral electrical pacemaker, which reveals new insights into the mechanism regulating the decrease in motility induced by cannabinoids.

Topics: Amidohydrolases; Animals; Apomorphine; Benzamides; Biological Clocks; Body Temperature; Cannabinoids; Carbamates; Emetics; Female; Ferrets; Heart Rate; Myoelectric Complex, Migrating; Receptor, Cannabinoid, CB1; Receptor, Cannabinoid, CB2; Telemetry; Vomiting

Considerable evidence implicates the endocannabinoid system as a neuromodulator of nausea and vomiting. The action of anandamide (AEA) can be prolonged by inhibiting its degradation, through the use of URB597 (URB), a Fatty Acid Amide Hydrolase (FAAH) enzyme inhibitor. Here we present evidence that the FAAH inhibitor, URB, interferes with cisplatin- and nicotine-induced vomiting in the Suncus murinus. In Experiment 1, shrews were injected with URB (0.9 mg/kg) or vehicle 120 min prior to the behavioral testing. They received a second injection of AEA (5 mg/kg) or vehicle 15 min prior to being injected with cisplatin (20 mg/kg) or saline and the number of vomiting episodes were counted for 60 min. In Experiment 2, shrews were injected with vehicle or URB (0.9 mg/kg) 120 min prior to receiving an injection of nicotine (5 mg/kg) or saline and the number of vomiting episodes were counted for 15 min. Experiment 3 evaluated the potential of the CB(1) antagonist, SR141716, to reverse the effect of URB on nicotine-induced vomiting. URB attenuated vomiting produced by cisplatin and nicotine and the combination of URB+AEA suppressed vomiting produced by cisplatin. The effect of URB on nicotine-induced vomiting was reversed by SR141716. These data suggest that the EC system plays a tonic role in the regulation of toxin-induced vomiting.

Topics: Amidohydrolases; Animals; Arachidonic Acids; Benzamides; Carbamates; Cisplatin; Drug Interactions; Endocannabinoids; Female; Male; Nicotine; Piperidines; Polyunsaturated Alkamides; Pyrazoles; Receptor, Cannabinoid, CB1; Rimonabant; Shrews; Vomiting

The endogenous cannabinoid system plays a vital role in the control of nausea and emesis. Because of the rapid breakdown and hydrolysis of endocannabinoids, such as anandamide, the therapeutic effects may be enhanced by prolonging their duration of action.. The present experiment evaluated the potential of various doses of URB597, a fatty acid amide hydrolase (FAAH) inhibitor, alone and in combination with systemic administration of anandamide to modulate the establishment of lithium-induced conditioned taste reactivity responses in rats.. In experiment 1, on the conditioning day, rats first received an injection of 0.3 mg/kg URB597, 0.15 mg/kg URB597, or vehicle and then received a second injection of anandamide (5 mg/kg) or vehicle, before a 3-min exposure of 0.1% saccharin by intraoral infusion. Immediately after the saccharin exposure, the rats were injected with lithium chloride. On each of three test days, rats received a 3-min intraoral infusion of saccharin solution, and the taste reactivity responses were videotaped and monitored. In experiment 2, the effects of pretreatment with the CB(1) antagonist, AM-251, on URB597 and anandamide-induced suppressed aversion was evaluated.. Administration of URB597 alone and in combination with anandamide reduced active rejection reactions elicited by a LiCl-paired saccharin solution; both effects were reversed by pretreatment with AM-251, suggesting that they were CB(1) receptor mediated.. The results suggest that prolonging the action of anandamide by pretreatment with the FAAH inhibitor, URB597, suppresses lithium-induced nausea in the rat.

Topics: Amidohydrolases; Animals; Arachidonic Acids; Association Learning; Avoidance Learning; Benzamides; Carbamates; Conditioning, Classical; Dose-Response Relationship, Drug; Endocannabinoids; Injections, Intraperitoneal; Lithium Chloride; Male; Nausea; Piperidines; Polyunsaturated Alkamides; Pyrazoles; Rats; Rats, Long-Evans; Receptor, Cannabinoid, CB1; Vomiting

The chemotherapeutic agent cisplatin may produce emesis via release of several neurotransmitters such as serotonin (5-HT), substance P and/or dopamine as well as production of prostaglandins (PGs). Administration of synthetic 2-arachidonoylglycerol (2-AG) but not of anandamide, which are two putative endocannabinoids, causes vomiting via its downstream metabolites such as arachidonic acid (AA) and PGs in the least shrew (Cryptotis parva). We report here that cisplatin (0, 5, 10 and 20 mg/kg, i.p.) causes dose- and time-dependent increases in brain tissue levels of 2-AG but not anandamide in this vomiting species. Concomitantly, intestinal tissue levels of both endocannabinoids are relatively reduced. Selective inhibitors [arachidonoyl-serotonin (AA-5-HT) and URB597, 0-5 and 0-10 mg/kg, i.p.] of one of the major endocannabinoid metabolic enzymes, the intracellular fatty acid amide hydrolase (FAAH), do not significantly prevent vomiting produced by emetic doses of i.p.-administered 2-AG, cisplatin or the dopamine receptor agonist apomorphine. At large doses (10 and 20 mg/kg, respectively), both FAAH inhibitors caused emesis per se. Administration of one selective uptake inhibitor of endocannabinoids, OMDM1 (0-5 mg/kg, i.p.), also did not significantly prevent emesis by the direct and indirect emetic stimuli, and likewise caused emesis by itself at a high (10 mg/kg) dose. However, another selective uptake inhibitor, VDM11, did not produce significant emesis per se and prevented emesis caused by apomorphine. Both the corticosteroid dexamethasone, and the cyclooxygenase inhibitor indomethacin, reduced vomiting produced by cisplatin. These data: (a) provide the first evidence that cisplatin causes a selective increase in 2-AG levels in the brain, and (b) support the established notion that 2-AG may produce some of its effects, including emesis, via downstream metabolites produced independently of FAAH.

Topics: Analysis of Variance; Animals; Apomorphine; Arachidonic Acids; Benzamides; Benzyl Compounds; Brain; Carbamates; Cisplatin; Dopamine Agonists; Dose-Response Relationship, Drug; Drug Interactions; Endocannabinoids; Female; Glycerides; Intestinal Mucosa; Intestines; Male; Radiation-Sensitizing Agents; Serotonin; Shrews; Time Factors; Vomiting