am-630 and arachidonyl-2-chloroethylamide

Recurrent panic attacks, comprising emotional and cardiovascular aversive responses, are common features in panic disorder, a subtype of anxiety disorder. The underlying brain circuitry includes nuclei of the hypothalamus, such as the dorsomedial hypothalamus (DMH). The endocannabinoid system has been proposed to modulate several biological processes in the hypothalamus. Thus, we tested the hypothesis that hypothalamic endocannabinoid signalling controls aversive responses in an animal model of panic attacks. Local infusion of NMDA into the DMH of rats induced panic-like behaviour. This effect was prevented by local, but not intraperitoneal, injection of a 2-arachidonoylglycerol (2-AG) hydrolysis inhibitor (MAGL inhibitor, URB602). The anandamide hydrolysis inhibitor (FAAH inhibitor), URB597, was ineffective. The anti-aversive action of URB602 was reversed by CB

Topics: Animals; Arachidonic Acids; Benzamides; Biphenyl Compounds; Blood Pressure; Cannabinoids; Carbamates; Corticosterone; Dorsomedial Hypothalamic Nucleus; Endocannabinoids; Indoles; Male; Microinjections; N-Methylaspartate; Panic Disorder; Piperidines; Pyrazoles; Rats

Chronic alcohol consumption is a critical contributing factor to ischemic stroke, as it enhances ischemia-induced glutamate release, leading to more severe excitotoxicity and brain damage. But the neural mechanisms underlying this phenomenon are poorly understood.. We evaluated the effects of chronic alcohol exposure on the modulation of ischemia-induced glutamate release via CB1 and CB2 cannabinoid receptors during middle cerebral artery occlusion, using in vivo microdialysis coupled with high-performance liquid chromatography, in alcohol-naïve rats or rats after 1 or 30 days of withdrawal from chronic ethanol intake (6% v/v for 14 days).. Intra-dorsal hippocampus (DH) infusions of ACEA or JWH133, selective CB1 or CB2 receptor agonists, respectively, decreased glutamate release in the DH in alcohol-naïve rats in a dose-dependent manner. Such an effect was reversed by co-infusions of SR141716A or AM630, selective CB1 or CB2 receptor antagonists, respectively. After 30 days, but not 1 day of withdrawal, ischemia induced an enhancement in glutamate release in the DH, as compared with non-alcohol-treated control group. Intra-DH infusions of JWH133, but not ACEA, inhibited ischemia-induced glutamate release in the DH after 30 days of withdrawal. Finally, 1 day of withdrawal did not alter the protein level of CB1 or CB2 receptors in the DH, as compared to non-alcohol-treated control rats. Whereas 30 days of withdrawal robustly decreased the protein level of CB1 receptors, but failed to alter the protein level of CB2 receptors, in the DH, as compared to non-alcohol-treated control rats.. Together, these findings suggest that loss of expression/function of CB1 receptors, but not CB2 receptors in the DH, is correlated with the enhancement of ischemia-induced glutamate release after prolonged alcohol withdrawal.

Topics: Animals; Arachidonic Acids; Cannabinoids; Dose-Response Relationship, Drug; Ethanol; Glutamic Acid; Hippocampus; Indoles; Infarction, Middle Cerebral Artery; Ischemia; Male; Piperidines; Pyrazoles; Rats; Receptor, Cannabinoid, CB1; Receptor, Cannabinoid, CB2; Rimonabant

Transcriptional dysregulation is a major pathological feature of Huntington's disease (HD). The goal of this study was to understand how p65/RelA co-regulated genes, specifically those of the cytokine and endocannabinoid systems, were affected in HD. p65/RelA levels were lower in human HD tissue and R6/2 HD mice, as were the levels of the type 1 cannabinoid receptor (CB1), IL-1β, IL-8, CCL5, GM-CSF, MIP-1β, and TNFα, all of which may be regulated by p65/RelA. Activation of p65/RelA restored CB1 and CCL5 expression in STHdh cell models of HD. Therefore, p65/RelA activation may normalize the expression of some genes in HD.

Topics: Adult; Age Factors; Aged; Amidohydrolases; Animals; Arachidonic Acids; Cannabinoids; Cells, Cultured; Corpus Striatum; Cytokines; Disease Models, Animal; Endocannabinoids; Enzyme Inhibitors; Female; Gene Expression Regulation; Humans; Huntingtin Protein; Huntington Disease; Indoles; Male; Mice; Mice, Inbred C57BL; Mice, Transgenic; Middle Aged; Nerve Tissue Proteins; Neurons; NF-kappa B; Nuclear Proteins; Receptor, Cannabinoid, CB1; Transcription Factor RelA; Trinucleotide Repeats; Young Adult

Intestinal hyperpermeability, impaired peritoneal macrophages (PMs) phagocytosis, and bacterial translocation (BT), resulting in increased systemic and local infection/inflammation such as spontaneous bacterial peritonitis (SBP) together with increased tumor necrosis factor-α (TNFα) levels, are all implicated in the pathogenesis of cirrhosis-related complications. Manipulation of the cannabinoid receptors (CB1R and CB2R), which are expressed on the gut mucosa and PMs, has been reported to modulate intestinal inflammation and systemic inflammatory cytokine release. Our study aims to explore the effects of chronic CB1R/CB2R agonist/antagonist treatments on relevant abnormalities in cirrhotic ascitic rats.. Vehicle, archidonyl-2-chloroethylamide (ACEA, CB1R agonist), JWH133 (CB2R agonist), and AM630 (CB2R antagonist) were given to thioacetamide (TAA) and common bile duct ligation (BDL) cirrhotic rats with ascites for two weeks and various measurement were performed.. Compared to sham rats, CB2Rs were downregulated in cirrhotic rat intestines and PMs. The two-week JWH133 treatment significantly decreased systemic/intestinal oxidative stress, TNFα and inflammatory mediators, infection, intestinal mucosal damage and hyperpermeability; the JWH133 treatment also decreased bacterial overgrowth/adhesion, BT and SBP, upregulated intestinal tight junctions and downregulated the PM TNFα receptor/NFκBp65 protein expression in cirrhotic rats. Acute and chronic JWH133 treatment corrected the TNFα-induced suppression of phagocytosis of cirrhotic rat PMs, which then could be reversed by concomitant AM630 treatment.. Our study suggests that CB2R agonists have the potential to treat BT and various relevant abnormalities through inhibition of systemic/intestinal oxidative stress, inflammatory cytokines and TNFα release in cirrhosis. Overall, the chronic CB2R agonist treatment affects multiple approach mechanisms, and its direct effect on the hyperdynamic circulation is only minor.

Topics: Animals; Arachidonic Acids; Ascites; Bacterial Infections; Bacterial Translocation; Cannabinoids; Cytokines; Hep G2 Cells; Humans; Indoles; Inflammation Mediators; Intestinal Mucosa; Liver Circulation; Liver Cirrhosis, Experimental; Macrophages, Peritoneal; Oxidative Stress; Peritonitis; Phagocytosis; Rats; Receptor, Cannabinoid, CB1; Receptor, Cannabinoid, CB2; RNA, Messenger

Pain associated with musculoskeletal disorders can be difficult to control and the incorporation of new approaches for its treatment is an interesting challenge. Activation of cannabinoid (CB) receptors decreases nociceptive transmission in acute, inflammatory and neuropathic pain states; however, although the use of cannabis derivatives has been recently accepted as a useful alternative for the treatment of spasticity and pain in patients with multiple sclerosis, the effects of CB receptor agonists in muscular pain have hardly been studied.. Here, we characterized the antinociceptive effect of non selective and selective CB agonists by systemic and local administration, in two muscular models of pain, masseter and gastrocnemius, induced by hypertonic saline (HS) injection. Drugs used were: the non-selective agonist WIN 55,212-2 and two selective agonists, ACEA (CB 1) and JWH 015 (CB 2); AM 251 (CB 1) and AM 630 (CB 2) were used as selective antagonists.. In the masseter pain model, both systemic (intraperitoneal) and local (intramuscular) administration of CB 1 and CB 2 agonists reduced the nociceptive behaviour induced by HS, whereas in the gastrocnemius model the local administration was more effective than systemic.. Our results provide evidence that both, CB 1 and CB 2 receptors can contribute to muscular antinociception and, interestingly, suggest that the local administration of CB agonists could be a new and useful pharmacological strategy in the treatment of muscular pain, avoiding adverse effects induced by systemic administration.

Topics: Animals; Arachidonic Acids; Behavior, Animal; Benzoxazines; Cannabinoid Receptor Agonists; Cannabinoid Receptor Antagonists; Indoles; Male; Morpholines; Motor Activity; Musculoskeletal Pain; Naphthalenes; Pain Measurement; Piperidines; Pyrazoles; Rats; Rats, Wistar; Treatment Outcome

The endogenous cannabinoid system participates in oligodendrocyte progenitor differentiation in vitro. To determine the effect of synthetic cannabinoids on oligodendrocyte differentiation, we exposed differentiating cultures of oligodendrocytes with cannabinoid CB(1), CB(2) and CB(1)/CB(2) receptor agonists and antagonists. The response of the PI3K/Akt and the mammalian target of rapamycin (mTOR) signalling pathways were studied as effectors of cannabinoid activity.. Purified oligodendrocyte progenitor cells (OPC) obtained from primary mixed glial cell cultures were treated for 48 h with CB(1), CB(2) and CB(1) /CB(2) receptor agonists (ACEA, JWH133 and HU210, respectively) in the presence or absence of the antagonists AM281 (CB(1) receptor) and AM630 (CB(2) receptor). Moreover, inhibitors of the phosphatidylinositol 3-kinase (PI3K)/Akt and mTOR pathways (LY294002 and rapamycin, respectively) were used to study the involvement of these pathways on cannabinoid-induced OPC maturation.. ACEA, JWH133 and HU-210 enhanced OPC differentiation as assessed by the expression of stage specific antigens and myelin basic protein (MBP). Moreover, this effect was blocked by the CB receptor antagonists. ACEA, JWH133 and HU210 induced a time-dependent phosphorylation of Akt and mTOR, whereas the inhibitors of PI3K/Akt (LY294002) or of mTOR (rapamycin) reversed the effects of HU-210 on oligodendrocyte differentiation and kinase activation.. Activation of cannabinoid CB(1) or CB(2) receptors with selective agonists accelerated oligodendrocyte differentiation through the mTOR and Akt signalling pathways.

Topics: Animals; Arachidonic Acids; Cannabinoids; Cell Differentiation; Cells, Cultured; Chromones; Dronabinol; Enzyme Activators; Indoles; Morpholines; Myelin Proteins; Oligodendroglia; Oncogene Protein v-akt; Phosphatidylinositol 3-Kinases; Phosphoinositide-3 Kinase Inhibitors; Phosphorylation; Pyrazoles; Rats; Rats, Wistar; Receptor, Cannabinoid, CB1; Receptor, Cannabinoid, CB2; Signal Transduction; Sirolimus; Stem Cells; TOR Serine-Threonine Kinases

The purpose of the present study was to examine whether cannabinoid receptor agonists influence spontaneous contractile activity of longitudinal muscle in mouse ileum in vitro. Isolated segments of mouse ileum displayed spontaneous contractions with an amplitude and frequency of about 300 mg and 30 cpm, respectively. The endocannabinoid anandamide (1-100 microM), the selective cannabinoid CB(1) receptor agonist, ACEA (0.1 microM-10 microM), but not the selective cannabinoid CB(2) receptor agonist, JWH 133 (0.1 microM-10 microM), reduced in a concentration-dependent manner the spontaneous mechanical activity. The inhibitory effect consisted in a decrease of the mean amplitude of longitudinal spontaneous contractions, without changes in the resting tone. The inhibitory effect induced by cannabinoids was significantly antagonized by the selective cannabinoid CB(1) receptor antagonist, SR141716A (0.1 microM), but not by the selective cannabinoid CB(2) receptor antagonist, AM630 (0.1 microM). None of the cannabinoid antagonists, at the concentration used, did affect the spontaneous mechanical activity. The ACEA-induced reduction of spontaneous contractions was almost abolished by tetrodotoxin, atropine or apamin and it was unaffected by hexamethonium or N(omega)-nitro-l-arginine methyl ester (l-NAME), inhibitor of nitric oxide synthase. The myogenic contractions evoked by carbachol were not affected by ACEA. In conclusion, the present results suggest that activation of neural cannabinoid CB(1) receptors may play a role in the control of spontaneous mechanical activity through inhibition of acetylcholine release from cholinergic nerve. Activation of small conductance Ca(2+)-dependent K(+) channels is involved in this action.

Topics: Animals; Apamin; Arachidonic Acids; Atropine; Cannabinoid Receptor Modulators; Cannabinoids; Dose-Response Relationship, Drug; Endocannabinoids; Hexamethonium; Ileum; In Vitro Techniques; Indoles; Male; Mice; Mice, Inbred C57BL; Muscle Contraction; Muscle, Smooth; NG-Nitroarginine Methyl Ester; Piperidines; Polyunsaturated Alkamides; Pyrazoles; Receptor, Cannabinoid, CB1; Receptor, Cannabinoid, CB2; Rimonabant; Tetrodotoxin

It is well accepted that endogenous cannabinoids and CB1 receptors are involved in the regulation of smooth muscle contractility and intestinal motility, through a mechanism mainly related to reduction of acetylcholine release from cholinergic nerve endings. Because, few data exist on a possible modulatory action of the cannabinoid agents on the non-adrenergic non-cholinergic (NANC) excitatory and inhibitory neurotransmission, the aim of the present study was to investigate the effects of cannabinoid drugs on the NANC responses elicited by electrical field stimulation (EFS) in the circular muscle of mouse proximal colon. Colonic contractions were monitored as changes in endoluminal pressure. In NANC conditions, EFS evoked TTX-sensitive responses, characterized by a relaxation, nitrergic in origin, followed by a contraction. The EFS-evoked contraction was significantly reduced by SR48968, NK2 receptor antagonist, and abolished by co-administration of SR48968 and SR140333, NK1 receptor antagonist, suggesting that it was due to release of tachykinins. The cannabinoid receptor synthetic agonist, WIN55,212-2, the putative endogenous ligand, anandamide, the selective CB1 receptor agonist ACEA, but not the selective CB2 receptor agonist JWH-015, produced a concentration-dependent reduction of the NANC contractile responses, without affecting the NANC relaxation. ACEA or anandamide did not modify the contractions induced by exogenous [beta-Ala(8)]-NKA(4-10), agonist of NK2 receptors. The selective antagonist of CB1 receptors, SR141716A, per se failed to affect the EFS-evoked responses, but antagonized the inhibitory effects of WIN55,212-2, anandamide and ACEA on NANC contractile responses. AM630, CB2 receptor antagonist, did not modify the inhibitory effects of WIN55,212-2 or anandamide. URB597, inhibitor of the fatty acid amide hydrolase, enzyme which catalyze the hydrolysis of anandamide, was without any effect on the NANC evoked responses. We conclude that the activation of prejunctional CB1 receptors produces inhibition of NANC contractile responses in mouse colonic preparations. However, endogenous ligands do not seem to modulate tonically the NANC transmission in mouse colon.

Topics: Animals; Arachidonic Acids; Benzoxazines; Cannabinoid Receptor Modulators; Cannabinoids; Colon; Dose-Response Relationship, Drug; Electric Stimulation; Endocannabinoids; Enteric Nervous System; Excitatory Postsynaptic Potentials; Gastrointestinal Motility; In Vitro Techniques; Indoles; Inhibitory Postsynaptic Potentials; Mice; Mice, Inbred C57BL; Morpholines; Naphthalenes; Neuromuscular Junction; Piperidines; Polyunsaturated Alkamides; Pyrazoles; Receptor, Cannabinoid, CB1; Receptor, Cannabinoid, CB2; Receptors, Tachykinin; Rimonabant; Synaptic Transmission; Tachykinins

While most of the studies concerning the role of cannabinoids on gastric motility have focused the attention on the gastric emptying in in vivo animal models, there is little information about the cannabinoid peripheral influence in the stomach. In addition, the functional features of CB2 receptors in the gastrointestinal tract have been poorly characterized. The purpose of the present study was to investigate the effects of cannabinoid drugs on the excitatory cholinergic and inhibitory non-adrenergic non-cholinergic (NANC) neurotransmission in mouse isolated gastric preparations. Intraluminal pressure from isolated whole stomach was recorded and mechanical responses induced by electrical field stimulation (EFS) were analyzed in different experimental conditions. EFS (0.5ms duration, supramaximal voltage, in trains of 5s, 2-16Hz) caused a cholinergic contraction, which was abolished by atropine or tetrodotoxin (TTX). The cannabinoid receptor agonist, WIN 55,212-2, the endogenous ligand, anandamide, the selective CB1 receptor agonist ACEA, and the selective CB2 receptor agonists, JWH015 and JWH133, produced a concentration-dependent reduction of the EFS-evoked cholinergic contractions. SR141716A, CB1 receptor antagonist, significantly attenuated the inhibitory effects induced by WIN 55,212-2, anandamide or ACEA, without affecting those caused by JWH133. AM630, CB2 receptor antagonist, reduced the inhibitory effects induced by WIN 55,212-2, anandamide, JWH015 or JWH133, without affecting those caused by ACEA. The joint application of SR141716A and AM630 was able of fully preventing the WIN 55,212-2 and anandamide actions. The cannabinoid antagonists failed per se to affect the neurally evoked responses. Cannabinoids did not modify the contractions produced by exogenous carbachol. In the presence of atropine and guanethidine (NANC conditions) EFS-induced TTX-sensitive relaxation consisting in an early and rapid component followed by a second slow phase, which were unaffected by cannabinoid drugs. In conclusion, the present results suggest that cannabinoids play a prejunctional modulatory role on the cholinergic excitatory transmission without affecting the NANC inhibitory transmission. In addition, this study provides experimental evidence that also the activation of CB2 receptors is able to reduce cholinergic neurotransmission in the mouse stomach.

Topics: Animals; Arachidonic Acids; Benzoxazines; Cannabinoid Receptor Modulators; Cannabinoids; Cholinergic Fibers; Electric Stimulation; Endocannabinoids; Excitatory Postsynaptic Potentials; Gastrointestinal Motility; In Vitro Techniques; Indoles; Inhibitory Postsynaptic Potentials; Male; Mice; Mice, Inbred C57BL; Morpholines; Naphthalenes; Neuromuscular Junction; Piperidines; Polyunsaturated Alkamides; Pyrazoles; Receptor, Cannabinoid, CB1; Receptor, Cannabinoid, CB2; Receptors, Presynaptic; Rimonabant; Stomach; Synaptic Transmission