urb-597 and Acute-Disease

Endocannabinoid signalling has been reported as an important neurochemical mechanism involved in responses to stress. Previous studies provided evidence of endocannabinoid release in the bed nucleus of the stria terminalis (BNST) during aversive stimuli. Nevertheless, a possible involvement of this neurochemical mechanism in stress responses has never been evaluated. Therefore, in the present study we investigated the involvement of BNST endocannabinoid neurotransmission, acting via local CB1 receptors, in the cardiovascular responses to acute restraint stress in rats.. The selective CB1 receptor antagonist AM251 (1, 30 and 100 pmol 100 nL(-1) ) and/or the fatty acid amide hydrolase (FAAH) enzyme inhibitor URB597 (30 pmol 100 nL(-1) ) or the monoacylglycerol lipase (MAGL) enzyme inhibitor JZL184 (30 pmol 100 nL(-1) ) was microinjected into the BNST before the acute restraint stress.. Microinjection of AM251 into the BNST enhanced the tachycardia caused by restraint stress, without affecting the increase in arterial pressure and the sympathetic-mediated cutaneous vasoconstrictor response. Conversely, the increased endogenous levels of AEA in the BNST evoked by local treatment with the FAAH enzyme inhibitor URB597 decreased restraint-evoked tachycardia. Inhibition of the hydrolysis of 2-arachidonoylglycerol (2-AG) in the BNST by local microinjection of the MAGL enzyme inhibitor JZL184 also decreased the HR response. These effects of URB597 and JZL184 were abolished by BNST pretreatment with AM251.. These findings indicate an involvement of BNST endocannabinoid neurotransmission, acting via CB1 receptors, in cardiovascular adjustments during emotional stress, which may be mediated by the local release of either AEA or 2-AG.

Topics: Acute Disease; Animals; Benzamides; Benzodioxoles; Carbamates; Cardiovascular System; Dose-Response Relationship, Drug; Endocannabinoids; Male; Piperidines; Pyrazoles; Rats; Rats, Wistar; Restraint, Physical; Septal Nuclei; Stress, Psychological; Structure-Activity Relationship; Synaptic Transmission

Fatty acid amide hydrolase (FAAH) inhibition elevates anandamide (AEA), which acts on cannabinoid (CB1 and CB2) receptors, as well as N-palmitoylethanolamide (PEA) and N-oleoylethanolamine (OEA), which act on peroxisome proliferator-activated receptor alpha (PPARα). Here, we determine the mechanism of action of FAAH inhibition on acute and anticipatory nausea (AN).. We compared the effectiveness and mechanism of action of two FAAH inhibitors, URB597 and PF-3845, to reduce acute nausea and AN in rodent models of conditioned gaping.. For assessment of acute nausea, rats were pretreated with vehicle (VEH), URB597 (0.3 and 10 mg/kg, experiment 1a) or PF-3845 (10 mg/kg, experiment 1b) 120 min prior to a saccharin-lithium chloride (LiCl) pairing. To assess the CB1 receptor or PPARα mediation of the effect of PF-3845 on acute nausea, rats were also pretreated with rimonabant or MK886, respectively. For assessment of AN, following four pairings of a novel context with LiCl, rats received a pretreatment of VEH, URB597 (0.3 mg/kg, experiment 2a), or PF-3845 (10, 20 mg/kg, experiment 2b) 120 min prior to placement in the AN context. To assess the CB1 receptor or PPARα mediation of the effect, rats were also pretreated with rimonabant or MK886, respectively.. PF-3845 (10 mg/kg, but not URB597 0.3 or 10 mg/kg) suppressed acute nausea via PPARα, but not CB1 receptors. URB597 (0.3 and 10 mg/kg) or PF-3845 (10 and 20 mg/kg) reduced AN via CB1 receptors, but not PPARα.. FAAH inhibition reduces acute nausea and AN through PPARα and CB1 receptor mediated effects, respectively.

Topics: Acute Disease; Amidohydrolases; Animals; Anticipation, Psychological; Benzamides; Carbamates; Male; Nausea; Piperidines; PPAR alpha; Pyridines; Rats; Rats, Sprague-Dawley; Receptor, Cannabinoid, CB1

During the progression of rheumatoid arthritis (RA), there are frequent but intermittent flares in which the joint becomes acutely inflamed and painful. Although a number of drug therapies are currently used to treat RA, their effectiveness is variable and side effects are common. Endocannabinoids have the potential to ameliorate joint pain and inflammation, but these beneficial effects are limited by their rapid degradation. One enzyme responsible for endocannabinoid breakdown is fatty acid amide hydrolase (FAAH). The present study examined whether URB597, a potent and selective FAAH inhibitor, could alter inflammation and pain in a mouse model of acute synovitis.. Acute joint inflammation was induced in male C57BL/6 mice by intra-articular injection of 2% kaolin/2% carrageenan. After 24 hr, articular leukocyte kinetics and blood flow were used as measures of inflammation, while hindlimb weight bearing and von Frey hair algesiometry were used as measures of joint pain. The effects of local URB597 administration were then determined in the presence or absence of either the cannabinoid (CB)1 receptor antagonist AM251, or the CB2 receptor antagonist AM630.. URB597 decreased leukocyte rolling and adhesion, as well as inflammation-induced hyperaemia. However, these effects were only apparent at low doses and the effects of URB597 were absent at higher doses. In addition to the anti-inflammatory effects of URB597, fatty acid amide hydrolase (FAAH) inhibition improved both hindlimb weight bearing and von Frey hair withdrawal thresholds. The anti-inflammatory effects of URB597 on leukocyte rolling and vascular perfusion were blocked by both CB1 and CB2 antagonism, while the effect on leukocyte adherence was independent of cannabinoid receptor activation. The analgesic effects of URB597 were CB1 mediated.. These results suggest that the endocannabinoid system of the joint can be harnessed to decrease acute inflammatory reactions and the concomitant pain associated with these episodes.

Topics: Acute Disease; Amidohydrolases; Animals; Arthralgia; Benzamides; Carbamates; Carrageenan; Endocannabinoids; Hindlimb; Hyperalgesia; Indoles; Inflammation; Kaolin; Knee Joint; Male; Mice, Inbred C57BL; Piperidines; Pyrazoles; Receptor, Cannabinoid, CB1; Receptor, Cannabinoid, CB2; Synovitis; Weight-Bearing

The anticonvulsant activities of cannabinoid compounds have been shown in various models of seizure and epilepsy. At least, part of antiseizure effects of cannabinoid compounds is mediated through calcium (Ca(2+)) channels. The L-type Ca(2+) channels have been shown to be important in various epilepsy models. However, there is no data regarding the role of L-type Ca(2+) channels in protective action of cannabinoids on acute and chronic models of seizure. In this study, the effects of cannabinoid compounds and L-type Ca(2+) channels blockers, either alone or in combination were investigated using acute model of pentylenetetrazole (PTZ)-induced seizure in mice and chronic model electrical kindling of amygdala in rats. Pretreatment of mice with both cannabinoid CB1 receptor agonist arachidonyl-2'-chloroethylamide (ACEA) and endocannabinoid degradating enzyme inhibitor cyclohexylcarbamic acid 3'-carbamoyl-biphenyl-3-yl ester (URB597) produced a protective effect against PTZ-induced seizure. Administration of various doses of the two L-type Ca(2+) channel blockers verapamil and diltiazem did not alter PTZ-induced seizure threshold. However, co-administration of verapamil and either ACEA or URB597 attenuated the protective effect of cannabinoid compounds against PTZ-induced seizure. Also, pretreatment of mice with diltiazem blocked the anticonvulsant activity of both ACEA and URB597. Moreover, (R)-(+)-[2,3-dihydro-5-methyl-3[(4-morpholinyl)methyl]pyrrolo[1,2,3-de]-1,4-benzoxazinyl]-(1-naphthalenyl) methanone mesylate (WIN55,212-2), the non-selective cannabinoid CB1 and CB2 receptor agonist showed anticonvulsant effect in amygdala-kindled rats. However, co-administration of WIN55,212-2 and verapamil attenuated the protective properties of WIN55,212-2. Our results showed that the anticonvulsant activity of cannabinoid compounds is mediated, at least in part, by L-type Ca(2+) channels in these two models of convulsion and epilepsy.

Topics: Acute Disease; Animals; Anticonvulsants; Benzamides; Benzoxazines; Calcium Channels, L-Type; Cannabinoids; Carbamates; Chronic Disease; Diltiazem; Disease Models, Animal; Kindling, Neurologic; Male; Mice; Morpholines; Naphthalenes; Rats; Rats, Wistar; Seizures; Verapamil

Evidence shows that the endocannabinoid system modulates the addictive properties of nicotine. In the present study, we hypothesized that spontaneous withdrawal resulting from removal of chronically implanted transdermal nicotine patches is regulated by the endocannabinoid system. A 7-day nicotine dependence procedure (5.2 mg/rat/day) elicited occurrence of reliable nicotine abstinence symptoms in Wistar rats. Somatic and affective withdrawal signs were observed at 16 and 34 hours following removal of nicotine patches, respectively. Further behavioral manifestations including decrease in locomotor activity and increased weight gain also occurred during withdrawal. Expression of spontaneous nicotine withdrawal was accompanied by fluctuation in levels of the endocannabinoid anandamide (AEA) in several brain structures including the amygdala, the hippocampus, the hypothalamus and the prefrontal cortex. Conversely, levels of 2-arachidonoyl-sn-glycerol were not significantly altered. Pharmacological inhibition of fatty acid amide hydrolase (FAAH), the enzyme responsible for the intracellular degradation of AEA, by URB597 (0.1 and 0.3 mg/kg, i.p.), reduced withdrawal-induced anxiety as assessed by the elevated plus maze test and the shock-probe defensive burying paradigm, but did not prevent the occurrence of somatic signs. Together, the results indicate that pharmacological strategies aimed at enhancing endocannabinoid signaling may offer therapeutic advantages to treat the negative affective state produced by nicotine withdrawal, which is critical for the maintenance of tobacco use.

Topics: Acute Disease; Amidohydrolases; Animals; Anxiety; Arachidonic Acids; Benzamides; Brain; Cannabinoid Receptor Modulators; Carbamates; Cotinine; Endocannabinoids; Glycerides; Implants, Experimental; Locomotion; Male; Maze Learning; Nicotine; Polyunsaturated Alkamides; Rats; Rats, Wistar; Substance Withdrawal Syndrome; Tobacco Use Cessation Devices; Weight Gain

The cardiovascular effects of cannabinoids can be influenced by anaesthesia and can differ in chronic hypertension, but the extent to which they are influenced by acute hypertension in conscious animals has not been determined.. We examined cardiovascular responses to intravenous administration of anandamide and the synthetic cannabinoid, (R)-(+)-[2,3-dihydro-5-methyl-3-(4-morpholinylmethyl)pyrrolo[1,2,3-de]-1,4-benzoxazin-6-yl]-1-naphthalenylmethanone (WIN55212-2), in conscious male Wistar rats made acutely hypertensive by infusion of angiotensin II (AII) and arginine vasopressin (AVP). Rats were chronically instrumented for measurement of arterial blood pressure and vascular conductances in the renal, mesenteric and hindquarters beds.. Anandamide dose-dependently decreased the mean arterial blood pressure of rats made hypertensive by AII-AVP infusion, but not normotensive rats. Interestingly, acute hypertension also revealed a hypotensive response to WIN55212-2, which caused hypertension in normotensive animals. The enhanced depressor effects of the cannabinoids in acute hypertension were associated with increased vasodilatation in hindquarters, renal and mesenteric vascular beds. Treatment with URB597, which inhibits anandamide degradation by fatty acid amide hydrolase, potentiated the depressor and mesenteric vasodilator responses to anandamide. Furthermore, haemodynamic responses to WIN55212-2, but not to anandamide, were attenuated by the CB(1) receptor antagonist, AM251 [N-(piperidin-1-yl)-5-(4-iodophenyl)-1-(2,4-dichlorophen yl)-4-methyl-1H-pyrazole-3-carboxamide].. These results broadly support the literature showing that the cardiovascular effects of cannabinoids can be exaggerated in hypertension, but highlight the involvement of non-CB(1) receptor-mediated mechanisms in the actions of anandamide.

Topics: Acute Disease; Amidohydrolases; Animals; Arachidonic Acids; Benzamides; Benzoxazines; Blood Pressure; Cannabinoids; Carbamates; Consciousness; Endocannabinoids; Hindlimb; Hypertension; Infusions, Intravenous; Injections, Intravenous; Male; Morpholines; Naphthalenes; Piperidines; Polyunsaturated Alkamides; Pyrazoles; Rats; Rats, Wistar; Receptor, Cannabinoid, CB1; Renal Circulation; Splanchnic Circulation; Vascular Resistance; Vasodilation