am-404 and Hypothermia

Previous findings showed that inhibitors of fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL), degrading enzymes of anandamide (2-AEA) and 2-arachidonoylglycerol (2-AG), reduced the nonsteroidal anti-inflammatory drug-induced gastric lesions. The present study aimed to investigate: i./whether central or peripheral mechanism play a major role in the gastroprotective effect of inhibitors of FAAH, MAGL and AEA uptake, ii./which peripheral mechanism(s) may play a role in mucosal protective effect of FAAH, MAGL and uptake inhibitors.. Gastric mucosal damage was induced by acidified ethanol. Gastric motility was measured in anesthetized rats. Catalepsy and the body temperature were also evaluated. Mucosal calcitonin gene-related peptide (CGRP), somatostatin concentrations and superoxide dismutase (SOD) activity were measured. The compounds were injected intraperitoneally (i.p.) or intracerebroventricularly (i.c.v.).. 1. URB 597, JZL184 (inhibitors of FAAH and MAGL) and AM 404 (inhibitor of AEA uptake) decreased the mucosal lesions significantly given either i.c.v. or i.p. 2. URB 937, the peripherally restricted FAAH inhibitor failed to exert significant action injected i.p. 3. Ethanol-induced decreased levels of mucosal CGRP and somatostatin were reversed by URB 597, JZL 184 and AM 404, the decreased SOD activity was elevated significantly by URB 597 and JZL 184. 4. Neither compounds given i.c.v. influenced gastric motility, elicited catalepsy, or hypothermia.. Elevation of central endocannabinoid levels by blocking their degradation or uptake via stimulation of mucosal defensive mechanisms resulted in gastroprotective action against ethanol-induced mucosal injury. These findings might suggest that central endocannabinoid system may play a role in gastric mucosal defense and maintenance of mucosal integrity.

Topics: Analysis of Variance; Animals; Arachidonic Acids; Benzamides; Benzodioxoles; Calcitonin Gene-Related Peptide; Carbamates; Catalepsy; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Administration Routes; Endocannabinoids; Ethanol; Gastric Mucosa; Gastrointestinal Motility; Hypothermia; Male; Piperidines; Rats; Rats, Wistar; Somatostatin; Stomach Diseases; Superoxide Dismutase

In recent years, there has been increasing interest in hypothermia induced by paracetamol for therapeutic purposes, which, in some instances, has been reported as a side effect. Understanding the mechanism by which paracetamol induces hypothermia is therefore an important question. In this study, we investigated whether the novel metabolite of paracetamol, N-(4-hydroxyphenyl)arachidonylamide (AM404), which activates the cannabinoid (CB) and transient receptor potential vanilloid-1 (TRPV1) systems, mediates the paracetamol-induced hypothermia. The hypothermic response to 300 mg/kg paracetamol in CB(1) receptor (CB(1)R) and TRPV1 knockout mice was compared to wild-type mice. Hypothermia induced by paracetamol was also investigated in animals pretreated with the CB(1)R or TRPV1 antagonist 1-(2,4-dichlorophenyl)-5-(4-iodophenyl)-4-methyl-N-1-piperdinyl-1H-pyrazole-3-carboxamide trifluoroacetate salt (AM251) or 4'-chloro-3-methoxycinnamanilide (SB366791), respectively. In CB(1)R or TRPV1 knockout mice, paracetamol induced hypothermia to the same extent as in wild-type mice. In addition, in C57BL/6 mice pretreated with AM251 or SB366791, paracetamol induced hypothermia to the same extent as in control mice. AM404 failed to induce hypothermia at pharmacological doses. Inhibition of fatty acid amide hydrolase (FAAH), which is involved in the metabolism of paracetamol to AM404, did not prevent the development of hypothermia with paracetamol. Paracetamol also induced hypothermia in FAAH knockout mice to the same extent as wild-type mice. We conclude that paracetamol induces hypothermia independent of cannabinoids and TRPV1 and that AM404 does not mediate this response. In addition, potential therapeutic value of combinational drug-induced hypothermia is supported by experimental evidence.

Topics: Acetaminophen; Amidohydrolases; Anilides; Animals; Arachidonic Acids; Cannabinoids; Cinnamates; Hypothermia; Hypothermia, Induced; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Piperidines; Pyrazoles; Receptor, Cannabinoid, CB1; TRPV Cation Channels

The endocannabinoid system mediates in the pharmacological actions of ethanol and genetic studies link endocannabinoid signaling to alcoholism. Drugs activating cannabinoid CB1 receptors have been found to promote alcohol consumption but their effects on self-administration of alcohol are less clear because of the interference with motor performance. To avoid this problem, a novel pharmacological approach to the study of the contribution of the cannabinoid system in alcoholism may be to use drugs that locally amplify the effects of alcohol on endogenous cannabinoids. In the present study we addressed this model by studying the effects of the anandamide transport inhibitor N-(4-hydroxyphenyl) arachidonoyl-ethanolamide (AM404) on both ethanol self-administration and reinstatement of alcohol-seeking behavior in rats. The results show that AM404 significantly reduced ethanol self-administration in a dose-dependent manner but failed to modify reinstatement for lever pressing induced by the stimulus associated with alcohol. This effect was not due to a motor depressant effect and was not related to a decrease in general motivational state, as it was not effective in other reward paradigms such as lever pressing for a saccharin solution. The mechanism of action of AM404 does not involve cannabinoid CB1 receptors as the CB1-selective antagonist SR141716A did not block the reduction of ethanol self-administration induced by the anandamide uptake blocker. Moreover, 3-(1,1-dimethylheptyl)-(-)-11-hydroxy-delta 8-tetrahydrocannabinol (HU-210), a classical cannabinoid receptor agonist, did not affect ethanol self-administration. The effects of AM404 are not mediated by either vanilloid VR1 receptors or cannabinoid CB2 receptors because it is not antagonized by either the VR1 receptor antagonist capsazepine or the CB2 antagonist AM630. These results indicate that AM404 may be considered as an innovative approach to reduce alcohol consumption.

Topics: Alcohol Drinking; Animals; Arachidonic Acids; Capsaicin; Central Nervous System Depressants; Conditioning, Operant; Depression, Chemical; Endocannabinoids; Ethanol; Extinction, Psychological; Hypothermia; Male; Motor Activity; Polyunsaturated Alkamides; Rats; Rats, Wistar; Receptor, Cannabinoid, CB1; Receptor, Cannabinoid, CB2; Reinforcement, Psychology; Saccharin; Self Administration; TRPV Cation Channels

AM 404 inhibits endocannabinoid uptake and enhances the cannabinoid CB(1)-mediated effects of endogenous cannabinoids. Accumulating evidence also suggests that AM 404 acts at sites other than the endocannabinoid system. One site is the transient receptor potential vanilloid 1 cation channel (TRPV1). A useful endpoint for discriminating between TRPV1- or CB(1)-mediated effects of AM 404 is hypothermia. This is because TRPV1 or CB(1) receptor activation produces a significant hypothermia in rats. The present study investigated the effects of AM 404 (1, 5, 10 and 20 mg/kg, i.p.) on body temperature in rats and the involvement of TRPV1 and CB(1) receptors in the effects of AM 404. Doses of 10 and 20 mg/kg of AM 404 produced significant hypothermia. Pre-treatment with capsazepine (30 mg/kg, i.p.) blocked the hypothermia caused by 10 and 20 mg/kg of AM 404. Pre-treatment with SB 366791 (2 mg/kg, i.p.), a new TRPV1 antagonist, also abolished the hypothermia evoked by AM 404 (20 mg/kg, i.p.). In contrast, pre-treatment with SR 141716A (Rimonabant), a CB(1) antagonist, or AA-5-HT, a fatty acid amide hydrolase (FAAH) blocker, did not affect AM 404-evoked hypothermia. The present data demonstrate that AM 404 evokes a significant hypothermia in rats that is dependent on TRPV1 receptor activation.

Topics: Amidohydrolases; Anilides; Animals; Arachidonic Acids; Body Temperature; Capsaicin; Cinnamates; Endocannabinoids; Hypothermia; Male; Piperidines; Polyunsaturated Alkamides; Pyrazoles; Rats; Rats, Sprague-Dawley; Receptor, Cannabinoid, CB1; Rimonabant; TRPV Cation Channels