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Beta-caryophyllene (BCP), a cannabinoid 2 ([CB.sub.2]) receptor agonist has recently been found to have cardioprotective activity as an anti-inflammatory and antioxidant molecule. L-arginine (LA), a nitric oxide (NO) donor, is a potential regulator of cardiovascular function. Considering the role of [CB.sub.2] receptor activation and NO regulation in cardiovascular diseases, the combination of BCP with LA may be a possible treatment of diabetic cardiomyopathy (DCM). Hence, we investigated the efficacy of the novel combination of BCP with LA on cardiovascular inflammation and oxidative stress in diabetic rats. DCM was induced by streptozotocin (55 mg/kg) in Sprague-Dawley rats intraperitoneally. BCP, LA, and BCP with LA were administered to diabetic rats for 4 weeks. After completion of the study, hemodynamic parameters, biochemical parameters, and inflammatory cytokine levels were analyzed. Also, oxidative stress parameters, nuclear factor kappa beta (NF-[kappa][beta]) expression, and histopathology in cardiac tissues were estimated. The combination of BCP (200 mg/kg) with LA (200 mg/kg) significantly normalized the hemodynamic parameters and decreased the glucose, cardiac markers, interleukin-6, and tumor necrosis factor-alpha levels. Treatment of BCP and LA showed a significant decrease in oxidative stress and down-regulated the cardiac expression of NF- [kappa][beta]. Thus, the combination of BCP with LA improves cardiac functions by attenuating inflammation through NF- [kappa][beta] inhibition in DCM. Key words: beta-caryophyllene, L-arginine, diabetic cardiomyopathy, NF-[kappa][beta] inhibition, streptozotocin. Recemment, on a montre que le beta caryophyllene (BCP), un agoniste des recepteurs cannabinoides de type 2 ([CB.sub.2]), dispose d'une activite cardioprotectrice comme molecule anti-inflammatoire et anti-oxydante. La L- arginine (LA), un donneur d'oxyde nitrique (NO), est un agent de regulation potentiel du fonctionnement cardiovasculaire. Etant donne le role de l'activation des recepteurs [CB.sub.2] et de la regulation du NO dans les maladies cardiovasculaires, l'association de BCP avec de la LA pourrait constituer un traitement eventuel contre la cardiomyopathie diabetique (CMD). Par consequent, nous avons etudie l'efficacite de la nouvelle association du BCP avec la LA sur l'inflammation et le stress oxydatif cardiovasculaires chez des rats diabetiques. Nous avons provoque la CMD a l'aide de streptozotocine (55 mg/kg) administree par voie intraperitoneale chez des rats SD. Nous avons administre le BCP, la LA et le BCP avec la LA pendant 4 semaines chez des rats diabetiques. Une fois l'etude terminee, nous avons analyse les parametres hemodynamiques et biochimiques, de meme que les taux de cytokines inflammatoires. Nous avons aussi estime les parametres du stress oxydatif, l'expression du NF-[kappa][beta] et l'histopathologie des tissus cardiaques. L'association du BCP (200 mg/kg) avec la LA (200 mg/kg) entrainait une stabilisation des parametres hemodynamiques et la diminution des taux de glucose, de marqueurs cardiaques, d'IL-6 et de TNF-[alpha] de facon notable. L'administration de BCP et de LA a entraine une diminution marquee du stress oxydatif, avec une regulation a la baisse de l'expression du NF-[kappa][beta] dans le coeur. Par consequent, l'association du BCP avec la LA permet d'ameliorer certains aspects du fonctionnement du coeur en attenuant l'inflammation par l'intermediaire de l'inhibition du NF-[kappa][beta] dans la CMD. Mots-cles: beta caryophyllene, L-arginine, cardiomyopathie diabetique, inhibition du NF-[kappa][beta], streptozotocine., 1. Introduction According to the International Diabetes Federation, approximately 12%-32% of patients with diabetes have suffered from diabetic cardiomyopathy (DCM), a major cause of mortality, and these patients have a [...]

Consciousness can be defined by two major attributes: awareness of environment and self, and arousal, which reflects the level of awareness. The return of arousal after general anesthesia presents an experimental tool for probing the neural mechanisms that control consciousness. Here we have identified that systemic or intracerebral injection of the cannabinoid [CB.sub.1] receptor ([CB.sub.1]R) antagonist AM281 into the dorsomedial nucleus of the hypothalamus (DMH)--but not the adjacent perifornical area (Pef) or the ventrolateral preoptic nucleus of the hypothalamus (VLPO)--accelerates arousal in mice recovering from general anesthesia. Anesthetics selectively activated endocannabinoid (eCB) signaling at DMH glutamatergic but not GABAergic synapses, leading to suppression of both glutamatergic DMH-Pef and GABAergic DMH-VLPO projections. Deletion of CB1R from widespread cerebral cortical or prefrontal cortical (PFC) glutamatergic neurons, including those innervating the DMH, mimicked the arousal-accelerating effects of AM281. In contrast, CB1R deletion from brain GABAergic neurons or hypothalamic glutamatergic neurons did not affect recovery time from anesthesia. Inactivation of PFC-DMH, DMHVLPO, or DMH-Pef projections blocked AM281-accelerated arousal, whereas activation of these projections mimicked the effects of AM281. We propose that decreased eCB signaling at glutamatergic terminals of the PFC-DMH projection accelerates arousal from general anesthesia through enhancement of the excitatory DMH-Pef projection, the inhibitory DMH-VLPO projection, or both., Introduction Consciousness is an essential human attribute (1), but the neural mechanism controlling consciousness remains unknown (2, 3). Consciousness consists of two major components: arousal (i.e., the level of consciousness) [...]

Despite previous findings on the effects of cannabinoid and vanilloid systems on learning and memory, the effects of the combined stimulation of these 2 systems on learning and memory have not been studied. Therefore, in this study, we tested the interactive effects of cannabinoid and vanilloid systems on learning and memory in rats by using passive avoidance learning (PAL) tests. Forty male Wistar rats were divided into the following 4 groups: (1) control (DMSO+saline), (2) WIN55,212-2, (3) capsaicin, and (4) WIN55,212-2 + capsaicin. On test day, capsaicin, a vanilloid receptor type 1 (TRPV1) agonist, or WIN55,212-2, a cannabinoid receptor ([CB.sub.1]/[CB.sub.2]) agonist, or both substances were injected intraperitoneally. Compared to the control group, the group treated with capsaicin (TRPV1 agonist) had better scores in the PAL acquisition and retention test, whereas treatment with WIN55,212-2 ([CB.sub.1]/[CB.sub.2] agonist) decreased the test scores. Capsaicin partly reduced the effects of WIN55,212-2 on PAL and memory. We conclude that the acute administration of a TRPV1 agonist improves the rats' cognitive performance in PAL tasks and that a vanilloid-related mechanism may underlie the agonistic effect of WIN55,212-2 on learning and memory. Key words: cannabinoid, vanilloid, TRPV1, passive avoidance test, learning, memory, WIN55,212-2, capsaicin. En depit de resultats obtenus anterieurement sur les effets des systemes cannabinoide et vanilloide sur l'apprentissage et la memoire, les effets de la stimulation de ces deux systemes combines n'ont pas ete etudies sur l'apprentissage et la memoire. Par consequent, dans les presents travaux, nous avons etudie l'interaction des effets des systemes cannabinoide et vanilloide sur l'apprentissage et la memoire chez le rat a l'aide de tests d'apprentissage par evitement passif (AEP). Nous avons reparti 40 rats Wistar males dans les quatre groupes suivants : (1) temoin (DMSO + solution saline), (2) WIN55,212-2, (3) capsaicine et (4) WIN55,212-2 + capsaicine. Le jour de l'evaluation, nous avons injecte par voie intraperitoneale de la capsaicine (un agoniste du TRPV1 [recepteur vanilloide de type 1]), du WIN55,212-2 (un agoniste des recepteurs cannabinoides [CB.sub.1] et [CB.sub.2]) ou les deux substances a la fois. Sur le plan de l'acquisition et de la retention, les animaux exposes a la capsaicine (agoniste du TRPV1) obtenaient de meilleures notes aux tests d'AEP que ceux du groupe temoin. Par contre, les notes diminuaient avec le WIN55,212-2 (agoniste des recepteurs [CB.sub.1] et [CB.sub.2]). La capsaicine entrainait une diminution partielle des effets du WIN55,212-2 sur le plan de l'AEP et de la memoire. Nous en arrivons a la conclusion que l'administration aigue d'un agoniste du TRPV1 permet d'ameliorer les performances cognitives des rats dans les taches d'AEP et qu'un mecanisme lie aux recepteurs vanilloides pourrait soustendre les effets agonistes du WIN55,212-2 sur l'apprentissage et la memoire. [Traduit par la Redaction] Mots-cles : cannabinoide, vanilloide, TRPV1, test d'evitement passif, apprentissage, memoire, WIN55,212-2, capsaicine., Introduction The endocannabinoid system, including anandamide (AEA), 2-arachidonoylglycerol (2-AG), and cannabinoid receptors, are known to be associated with a number of physiological functions including pain modulation, psychomotor functions, appetite regulation, [...]

The effects of [sup.9]-tetrahydrocannabinol (THC), the main psychoactive ingredient in cannabis, are a pressing concern for global mental health. Patterns of cannabis use are changing drastically owing to legalization, the availability of synthetic analogues (commonly termed spice), cannavaping and an emphasis on the purported therapeutic effects of cannabis. Many of the reinforcing effects of THC are mediated by the dopamine system. Owing to the complexity of the cannabinoiddopamine interactions that take place, there is conflicting evidence from human and animal studies concerning the effects of THC on the dopamine system. Acute THC administration causes increased dopamine release and neuron activity, whereas long-term use is associated with blunting of the dopamine system. Future research must examine the long-term and developmental dopaminergic effects of THC., Author(s): Michael A. P. Bloomfield [1, 2, 3, 4, 5]; Abhishekh H. Ashok [1, 2, 4]; Nora D. Volkow [6]; Oliver D. Howes (corresponding author) [1, 2, 4] Cannabis is [...]

The cannabinoid receptors CB1 and CB2 are localized in the urinary bladder and play a role in the regulation of its function. We investigated the pathomechanisms through which hyperosmolarity induces detrusor overactivity (DO). We compared urinary bladder activity in response to blockade of CB1 and CB2 receptors using AM281 and AM630, respectively, in normal rats and after hyperosmolar stimulation. Experiments were performed on 44 rats. DO was induced by intravesical instillation of hyperosmolar saline. Surgical procedures and cystometry were performed under urethane anaesthesia. The measurements represent the average of 5 bladder micturition cycles. We analysed basal, threshold, and micturition voiding pressure; intercontraction interval; compliance; functional bladder capacity; motility index; and detrusor overactivity index. The blockage of CB1 and CB2 receptors diminished the severity of hyperosmolar-induced DO. In comparison with naive animals the increased frequency of voiding with no significant effect on intravesical voiding pressure profile was observed as a result of the blockage of CB1 and CB2 receptors. These results demonstrate that hyperosmolar-induced DO is mediated by CB1 and CB2 receptors. Therefore, the cannabinoid pathway could potentially be a target for the treatment of urinary bladder dysfunction. Key words: detrusor overactivity, cannabinoid receptor, CB1, CB2, osmolarity, cystometry, rat. Les recepteurs cannabinoides CB1 et CB2 sont localises dans la vessie et jouent un role dans la regulation de ses fonctions. Les mecanismes pathologiques a travers lesquels l'hyperosmolarite induit l'hyperactivite du detrusor (HD) ont ete examines. Les auteurs ont compare l'activite de la vessie en reponse au blocage des recepteurs CB1 et CB2 a l'aide de AM281 et AM630 respectivement, chez des rats normaux et apres une stimulation hyperosmolaire. Les experiences ont ete realisees avec 44 rats. La HD a ete induite par une instillation intravesicale de saline hyperosmolaire. Les interventions chirurgicales et la cystometrie ont ete realisees sous anesthesie induite par l'urethane. Les mesures representent la moyenne de 5 cycles de miction. Les auteurs ont analyse : la pression de base, seuil, permictionnelle; l'intervalle inter-contraction; l'elasticite; la capacite vesicale fonctionnelle; l'indice de motilite; l'indice d'activite du detrusor. L'instillation intravesicale de saline hyperosmolaire induisait la HD. Le blocage des recepteurs CB1 et CB2 diminuait la severite de la HD induite par l'hyperosmolarite. Comparativement aux animaux naifs, une frequence accrue de miction, sans effet significatif sur le profile des pressions mictionnelles, a ete observee en reponse au blocage des recepteurs CB1 et CB2. Ces resultats demontrent que la HD induite par l'hyperosmolarite est mediee par les recepteurs CB1 et CB2. Ainsi, la voie cannabinoide pourrait devenir une cible potentielle pour traiter la dysfonction urinaire. [Traduit par la Redaction] Mots-cles: hyperactivite du detrusor, recepteur cannabinoide, CB1, CB2, osmolarite, cystometrie, rat., Introduction Past decades have shown an increasing appreciation for the important role of cannabinoid receptors (CB1 and CB2) in urinary bladder function. The cannabinoids affect urine storage and voiding via [...]

The cannabinoid receptors CB1 and CB2 are localized in the urinary bladder and play a role in the regulation of its function. We investigated the pathomechanisms through which hyperosmolarity induces detrusor overactivity (DO). We compared urinary bladder activity in response to blockade of CB1 and CB2 receptors using AM281 and AM630, respectively, in normal rats and after hyperosmolar stimulation. Experiments were performed on 44 rats. DO was induced by intravesical instillation of hyperosmolar saline. Surgical procedures and cystometry were performed under urethane anaesthesia. The measurements represent the average of 5 bladder micturition cycles. We analysed basal, threshold, and micturition voiding pressure; intercontraction interval; compliance; functional bladder capacity; motility index; and detrusor overactivity index. The blockage of CB1 and CB2 receptors diminished the severity of hyperosmolar-induced DO. In comparison with naive animals the increased frequency of voiding with no significant effect on intravesical voiding pressure profile was observed as a result of the blockage of CB1 and CB2 receptors. These results demonstrate that hyperosmolar-induced DO is mediated by CB1 and CB2 receptors. Therefore, the cannabinoid pathway could potentially be a target for the treatment of urinary bladder dysfunction. Key words: detrusor overactivity, cannabinoid receptor, CB1, CB2, osmolarity, cystometry, rat. Les recepteurs cannabinoides CB1 et CB2 sont localises dans la vessie et jouent un role dans la regulation de ses fonctions. Les mecanismes pathologiques a travers lesquels l'hyperosmolarite induit l'hyperactivite du detrusor (HD) ont ete examines. Les auteurs ont compare l'activite de la vessie en reponse au blocage des recepteurs CB1 et CB2 a l'aide de AM281 et AM630 respectivement, chez des rats normaux et apres une stimulation hyperosmolaire. Les experiences ont ete realisees avec 44 rats. La HD a ete induite par une instillation intravesicale de saline hyperosmolaire. Les interventions chirurgicales et la cystometrie ont ete realisees sous anesthesie induite par l'urethane. Les mesures representent la moyenne de 5 cycles de miction. Les auteurs ont analyse : la pression de base, seuil, permictionnelle; l'intervalle inter-contraction; l'elasticite; la capacite vesicale fonctionnelle; l'indice de motilite; l'indice d'activite du detrusor. L'instillation intravesicale de saline hyperosmolaire induisait la HD. Le blocage des recepteurs CB1 et CB2 diminuait la severite de la HD induite par l'hyperosmolarite. Comparativement aux animaux naifs, une frequence accrue de miction, sans effet significatif sur le profile des pressions mictionnelles, a ete observee en reponse au blocage des recepteurs CB1 et CB2. Ces resultats demontrent que la HD induite par l'hyperosmolarite est mediee par les recepteurs CB1 et CB2. Ainsi, la voie cannabinoide pourrait devenir une cible potentielle pour traiter la dysfonction urinaire. [Traduit par la Redaction] Mots-cles: hyperactivite du detrusor, recepteur cannabinoide, CB1, CB2, osmolarite, cystometrie, rat., Introduction Past decades have shown an increasing appreciation for the important role of cannabinoid receptors (CB1 and CB2) in urinary bladder function. The cannabinoids affect urine storage and voiding via [...]

Obesity and its metabolic consequences are a major public health concern worldwide. Obesity is associated with overactivity of the endocannabinoid system, which is involved in the regulation of appetite, lipogenesis, and insulin resistance. Cannabinoid-1 receptor ([CB.sub.1]R) antagonists reduce body weight and improve cardiometabolic abnormalities in experimental and human obesity, but their therapeutic potential is limited by neuropsychiatric side effects. Here we have demonstrated that a [CB.sub.1]R neutral antagonist largely restricted to the periphery does not affect behavioral responses mediated by [CB.sub.1]R in the brains of mice with genetic or diet-induced obesity, but it does cause weight-independent improvements in glucose homeostasis, fatty liver, and plasma lipid profile. These effects were due to blockade of [CB.sub.1]R in peripheral tissues, including the liver, as verified through the use of [CB.sub.1]R -deficient mice with or without transgenic expression of [CB.sub.1]R in the liver. These results suggest that targeting peripheral [CB.sub.1]R has therapeutic potential for alleviating cardiometabolic risk in obese patients., Introduction Endocannabinoids are endogenous lipid mediators that interact with the same G protein-coupled receptors--[CB.sub.1]R and [CB sub.2]R--that recognize plant-derived cannabinoids, and they regulate a broad range of physiological functions. [CB.sub.1]Rs [...]

The article discusses the changes in laws in different states in the US with regards to the use of medical marijuana. Many states as well as medical associations are in favor of abolition of criminal penalties against using marijuana for medical purposes and are advocating for the same.

Endocannabinoids such as anandamide [N-arachidonoylethanolamine (AEA)] and 2-arachidonoyl glycerol (2-AG) are known orexigenic mediators that act via CB1 receptors in hypothalamus and limbic forebrain to induce appetite and stimulate food intake. Circulating endocannabinoid levels inversely correlate with plasma levels of leptin, an anorexigenic mediator that reduces food intake by acting on hypothalamic receptors. Recently, taste has been found to be a peripheral target of leptin. Leptin selectively suppresses sweet taste responses in wild-type mice but not in leptin receptor-deficient db/db mice. Here, we show that endocannabinoids oppose the action of leptin to act as enhancers of sweet taste. We found that administration of AEA or 2AG increases gustatory nerve responses to sweeteners in a concentration-dependent manner without affecting responses to salty, sour, bitter, and umami compounds. The cannabinoids increase behavioral responses to sweet-bitter mixtures and electrophysiological responses of taste receptor cells to sweet compounds. Mice genetically lacking CB1 receptors show no enhancement by endocannnabinoids of sweet taste responses at cellular, nerve, or behavioral levels. In addition, the effects of endocannabinoids on sweet taste responses of taste cells are diminished by AM251, a [CB.sub.1] receptor antagonist, but not by AM630, a [CB.sub.2] receptor antagonist. Immunohistochemistry shows that [CB.sub.1] recaptors are expressed in type II taste cells that also express the T1r3 sweet taste receptor component. Taken together, these observations suggest that the taste organ is a peripheral target of endocannabinoids.' Reciprocal regulation of peripheral sweet taste reception by endocannabinoids and leptin may contribute to their opposing actions on food intake and play an important role in regulating energy homeostasis. energy homeostasis | gustation | reciprocal regulation www.pnas.org/cgi/doi/10.1073/pnas.0912048107

To link to full-text access for this article, visit this link: http://dx.doi.org/10.1016/j.tips.2009.07.006 Byline: Angelo A. Izzo (1)(4), Francesca Borrelli (1)(4), Raffaele Capasso (1)(4), Vincenzo Di Marzo (2)(4), Raphael Mechoulam (3) Abstract: [DELTA].sup.9-tetrahydrocannabinol binds cannabinoid (CB.sub.1 and CB.sub.2) receptors, which are activated by endogenous compounds (endocannabinoids) and are involved in a wide range of physiopathological processes (e.g. modulation of neurotransmitter release, regulation of pain perception, and of cardiovascular, gastrointestinal and liver functions). The well-known psychotropic effects of [DELTA].sup.9-tetrahydrocannabinol, which are mediated by activation of brain CB.sub.1 receptors, have greatly limited its clinical use. However, the plant Cannabis contains many cannabinoids with weak or no psychoactivity that, therapeutically, might be more promising than [DELTA].sup.9-tetrahydrocannabinol. Here, we provide an overview of the recent pharmacological advances, novel mechanisms of action, and potential therapeutic applications of such non-psychotropic plant-derived cannabinoids. Special emphasis is given to cannabidiol, the possible applications of which have recently emerged in inflammation, diabetes, cancer, affective and neurodegenerative diseases, and to [DELTA].sup.9-tetrahydrocannabivarin, a novel CB.sub.1 antagonist which exerts potentially useful actions in the treatment of epilepsy and obesity. Author Affiliation: (1) Department of Experimental Pharmacology, University of Naples Federico II, Naples, Italy (2) Institute of Biomolecular Chemistry, National Research Council, Pozzuoli (NA), Italy (3) Department of Medicinal Chemistry and Natural Products, Hebrew University Medical Faculty, Jerusalem, Israel (4) Endocannabinoid Research Group, Italy

Autophagy can promote cell survival or cell death, but the molecular basis underlying its dual role in cancer remains obscure. Here we demonstrate that [[Delta].sup.9]-tetrahydrocannabinol (THC), the main active component of marijuana, induces human glioma cell death through stimulation of autophagy. Our data indicate that THC induced ceramide accumulation and eukaryotic translation initiation factor 2[alpha] (eIF2[alpha]) phosphorylation and thereby activated an ER stress response that promoted autophagy via tribbles homolog 3-dependent (TRB3-dependent) inhibition of the Akt/mammalian target of rapamycin complex 1 (mTORC1) axis. We also showed that autophagy is upstream of apoptosis in cannabinoid-induced human and mouse cancer cell death and that activation of this pathway was necessary for the antitumor action of cannabinoids in vivo. These findings describe a mechanism by which THC can promote the autophagic death of human and mouse cancer cells and provide evidence that cannabinoid administration may be an effective therapeutic strategy for targeting human cancers., Introduction Macro-autophagy, hereafter referred to as "autophagy," is a highly conserved cellular process in which cytoplasmic materials--including organelles--are sequestered into double-membrane vesicles called autophagosomes and delivered to lysosomes for degradation [...]

The endogenous cannabinoid system plays an important role in the regulation of gastrointestinal function in health and disease. Endocannabinoid levels are regulated by catabolic enzymes. Here, we describe the presence and localization of monoacylglycerol lipase (MGL), the major enzyme responsible for the degradation of 2-arachidonoylglycerol. We used molecular, biochemical, immunohistochemical, and functional assays to characterize the distribution and activity of MGL. MGL mRNA was present in rat ileum throughout the wall of the gut. MGL protein was distributed in the muscle and mucosal layers of the ileum and in the duodenum, proximal colon, and distal colon. We observed MGL expression in nerve cell bodies and nerve fibers of the enteric nervous system. There was extensive colocalization of MGL with PGP 9.5 and calretinin-immunoreactive neurons, but not with nitric oxide synthase. MGL was also present in the epithelium and was highly expressed in the small intestine. Enzyme activity levels were highest in the duodenum and decreased along the gut with lowest levels in the distal colon. We observed both soluble and membrane-associated enzyme activities. The MGL inhibitor URB602 significantly inhibited whole gut transit in mice, an action that was abolished in cannabinoid 1 receptor-deficient mice. In conclusion, MGL is localized in the enteric nervous system where endocannabinoids regulate intestinal motility. MGL is highly expressed in the epithelium, where this enzyme may have digestive or other functions yet to be determined. endocannabinoids; enteric nervous system; URB602; 2-arachidonoyl glycerol

Cholangiocarcinomas are cancers that have poor prognosis and limited treatment options. The noncanonical Wnt pathway is mediated predominantly by Wnt 5a, which activates a [Ca.sup.2+]-dependent pathway involving protein kinase C, or a [Ca.sup.2+]-independent pathway involving the orphan receptor Ror2 and subsequent activation of Jun N[H.sub.2]-terminal kinase (JNK). This pathway is associated with growth-suppressing effects in numerous cell types. We have shown that anandamide decreases cholangiocarcinoma growth in vitro. Therefore, we determined the effects of anandamide on cholangiocarcinoma tumor growth in vivo using a xenograft model and evaluated the effects of anandamide on the noncanonical Wnt signaling pathways. Chronic administration of anandamide decreased tumor growth and was associated with increased Wnt 5a expression in vitro and in vivo. Treatment of cholangiocarcinoma cells with recombinant Wnt 5a decreased cell proliferation in vitro. Neither anandamide nor Wnt 5a affected intracellular calcium release, but both increased the JNK phosphorylation. Stable knockdown of Wnt 5a or Ror2 expression in cholangiocarcinoma cells abolished the effects of anandamide on cell proliferation and JNK activation. Modulation of the endocannabinoid system may be important in cholangiocarcinoma treatment. The antiproliferative actions of the noncanonical Wnt signaling pathway warrants further investigation to dissect the mechanism by which this may occur. biliary tract cancer; receptor tyrosine kinase orphan receptor 2; Jun N[H.sub.2]-terminal kinase

Cirrhosis is associated with marked cardiovascular disturbances. These include hyperdynamic circulation characterized by reduced peripheral vascular resistance and mean arterial pressure and increased cardiac output. Despite the baseline increase in cardiac output, ventricular responsiveness to stimuli is blunted. A number of cellular signaling pathways have been shown to contribute to these abnormalities, including central nervous system cardiovascular dysregulation and humoral factors such as nitric oxide. Endogenous and exogenous cannabinoids have significant cardiovascular effects. Recent evidence suggests that increased activity of the endocannabinoid system at multiple levels contributes to development of both cardiac and vascular changes in cirrhosis. This brief review surveys recent in vivo and in vitro findings in an attempt to highlight the areas of agreement and areas of controversy in the field. The endocannabinoid system affects key cardiovascular regulators, including the autonomic nervous system, cardiac muscle, and vascular smooth muscle. The interplay among these modes of action further complicates interpretation of the in vivo findings. The broad range of cardiovascular actions of endocannabinoids provides ample opportunities for pharmacological manipulation. At the same time, it increases the possibility of undesirable side effects, which need to be carefully evaluated in long-term studies. portal hypertension; vanilloid; anandamide; cirrhotic cardiomyopathy

The endocannabinoid (EC) system regulates food intake and energy metabolism. Cannabinoid receptor type 1 (CB1) antagonists show promise in the treatment of obesity and its metabolic consequences. Although the reduction in adiposity resulting from therapy with CB1 antagonists may not account fully for the concomitant improvements in dyslipidemia, direct effects of overactive EC signaling on plasma lipoprotein metabolism have not been documented. The present study used a chemical approach to evaluate the direct effects of increased EC signaling in mice by inducing acute elevations of endogenously produced cannabinoids through pharmacological inhibition of their enzymatic hydrolysis by isopropyl dodecylfluorophosphonate (IDFP). Acute IDFP treatment increased plasma levels of triglyceride (TG) (2.0- to 3.1-fold) and cholesterol (1.3- to 1.4-fold) in conjunction with an accumulation in plasma of apolipoprotein (apo)E-depleted TG-rich lipoproteins. These changes did not occur in either CB1-null or apoE-null mice, were prevented by pretreatment with CB1 antagonists, and were not associated with reduced hepatic apoE gene expression. Although IDFP treatment increased hepatic mRNA levels of lipogenic genes (Srebp1 and Fas), there was no effect on TG secretion into plasma. Instead, IDFP treatment impaired clearance of an intravenously administered TG emulsion, despite increased post-heparin lipoprotein lipase activity. Therefore, overactive EC signaling elicits an increase in plasma triglyceride levels associated with reduced plasma TG clearance and an accumulation in plasma of apoE-depleted TG-rich lipoproteins. These findings suggest a role of CB1 activation in the pathogenesis of obesity-related hypertriglyceridemia and underscore the potential efficacy of CB1 antagonists in treating metabolic disease. 2-arachidonoylglycerol | hypertriglyceridemia | monoaylglycerol lipase | organophosphorus | cannabinoid receptor

Cannabis sativa is one of the oldest herbal plants in the history of medicine. It was used in various therapeutic applications from pain to epilepsy, but its psychotropic effect has reduced its usage in recent medical practice. However, renewed interest has been fueled by major discoveries revealing that cannabis-derived compounds act through a signaling pathway in the human body. Here we review recent advances showing that endocannabinoid signaling is a key regulator of synaptic communication throughout the central nervous system. Its underlying molecular architecture is highly conserved in synapses from the spinal cord to the neocortex, and as a negative feed-back signal, it provides protection against excess presynaptic activity. The endocannabinoid signaling machinery operates on demand in a synapse-specific manner; therefore, its modulation offers new therapeutic opportunities for the selective control of deleterious neuronal activity in several neurological disorders., Molecular architecture of synaptic endocannabinoid signaling The core concept of neuronal communication involves the synaptic junction as the major site where chemical neurotransmitters convey information from presynaptic neurons to their [...]

The psychoactive cannabinoids from Cannabis sativa L. and the arachidonic acid-derived endocannabinoids are nonselective natural ligands for cannabinoid receptor type 1 ([CB.sub.1]) and [CB.sub.2] receptors. Although the [CB.sub.1] receptor is responsible for the psychomodulatory effects, activation of the [CB.sub.2] receptor is a potential therapeutic strategy for the treatment of inflammation, pain, atherosclerosis, and osteoporosis. Here, we report that the widespread plant volatile (E)-[beta]-caryophyllene [(E)-BCP] selectively binds to the [CB.sub.2] receptor ([K.sub.i] = 155 [+ or -] 4 nM) and that it is a functional [CB.sub.2] agonist. Intriguingly, (E)-BCP is a common constituent of the essential oils of numerous spice and food plants and a major component in Cannabis. Molecular docking simulations have identified a putative binding site of (E)-BCP in the [CB.sub.2] receptor, showing ligand [pi]-[pi] stacking interactions with residues F117 and W258. Upon binding to the [CB.sub.2] receptor, (E)-BCP inhibits adenylate cylcase, leads to intracellular calcium transients and weakly activates the mitogen-activated kinases Erk1/2 and p38 in primary human monocytes. (E)-BCP (500 nM) inhibits lipopolysaccharide (LPS)-induced proinflammatory cytokine expression in peripheral blood and attenuates LPS-stimulated Erk1/2 and JNK1/2 phosphorylation in monocytes. Furthermore, peroral (E)-BCP at 5 mg/kg strongly reduces the carrageenan-induced inflammatory response in wild-type mice but not in mice lacking [CB.sub.2] receptors, providing evidence that this natural product exerts cannabimimetic effects in vivo. These results identify (E)-BCP as a functional nonpsychoactive [CB.sub.2] receptor ligand in foodstuff and as a macrocyclic antiinflammatory cannabinoid in Cannabis. Cannabis | CB2 cannabinoid receptor | foodstuff | inflammation | natural product

Endocannabinoids are endogenous lipid mediators that interact with the same receptors as plant-derived cannabinoids to produce similar biological effects. The well-known appetitive effect of smoking marijuana has prompted inquiries into the possible role of endocannabinoids in the control of food intake and body weight. This brief review surveys recent evidence that endocannabinoids and their receptors are involved at multiple levels in the control of energy homeostasis. Endocannabinoids are orexigenic mediators and are part of the leptinregulated central neural circuitry that controls energy intake. In addition, they act at multiple peripheral sites including adipose tissue, liver, and skeletal muscle to promote lipogenesis and limit fat elimination. Their complex actions could be viewed as anabolic, increasing energy intake and storage and decreasing energy expenditure, as components of an evolutionarily conserved system that has insured survival under conditions of starvation. In the era of plentiful food and limited physical activity, pharmacological inhibition of endocannabinoid activity offers benefits in the treatment of obesity and its hormonal/metabolic consequences. cannabinoid receptors; metabolic syndrome; appetite; lipogenesis; cardiovascular risk factors

The activity-dependent strengthening and weakening of synaptic transmission are hypothesized to be the basis of not only memory and learning but also the refinement of neural circuits during development. Here we report that, in the developing CA1 area of the hippocampus, endocannabinoid (eCB)-mediated heterosynaptic long-term depression (LTD) of glutamatergic excitatory synaptic transmission is associated with PKA-mediated homosynaptic longterm potentiation (LTP). This form of LTD was dominant at postnatal days 2-10 (P2-P10), attenuated during development, and finally disappeared in the mature hippocampus. Heterosynaptic LTD of excitatory postsynaptic currents in the developing hippocampus was expressed presynaptically, spread to neighboring neurons, and was mediated by eCBs. Heterosynaptic LTD of field excitatory postsynaptic potentials was associated with a decrease in fiber volley amplitude with a similar time course. Depression of fiber volleys was blocked by [K.sup.+] channel blockers, suggesting the involvement of the decrease in presynaptic excitability in heterosynaptic LTD. In the P2-P5 hippocampus, eCBs also attenuate LTP and fiber volleys in homosynaptic pathways and help to prevent too much excitability in the neonatal hippocampus where the GABAergic system is poorly developed and even excitatory. In the hippocampus older than P6 (P > 6), however, LTP is protected from eCB-mediated depression by PKA activated at presynaptic sites by high-frequency stimulation, serving to highlight PKA-mediated LTP by weakening inactive synapses even in adjacent cells. Thus, eCBs and PKA make synapses plastic without changing excitability homeostasis in the developing hippocampus. heterosynaptic long-term depression | long-term potentiation | fiber volley | [K.sup.+] channel | slice electrophysiology

Hepatic fibrosis is the response of the liver to chronic injury and is associated with portal hypertension, progression to hepatic cirrhosis, liver failure, and high incidence of hepatocellular carcinoma. On a molecular level, a large number of signaling pathways have been shown to contribute to the activation of fibrogenic cell types and the subsequent accumulation of extracellular matrix in the liver. Recent evidence suggests that the endocannabinoid system is an important part of this complex signaling network. In the injured liver, the endocannabinoid system is upregulated both at the level of endocannabinoids and at the endocannabinoid receptors CB1 and CB2. The hepatic endocannabinoid system mediates both pro- and antifibrogenic effects by activating distinct signaling pathways that differentially affect proliferation and death of fibrogenic cell types. Here we will summarize current findings on the role of the hepatic endocannabinoid system in liver fibrosis and discuss emerging options for its therapeutic exploitation. hepatic stellate cell; cell death; anandamide; 2-arachidonoyl glycerol

Endocannabinoids have been implicated in the mechanisms of implantation, maintenance of pregnancy, and parturition in women. Intrauterine prostaglandin production and actions are also critical in each of these mechanisms. Hence, we have evaluated the effects of cannabinoids on prostaglandin biosynthesis by human gestational membranes. Explants of term amnion and choriodecidua were established and treated with the endogenous endocannabinoids 2-arachidonoyl glycerol and anandamide, as well as the synthetic cannabinoid CP55,940, to determine their ability to modulate PG[E.sub.2] production. The explants were also treated with CP55,940 in the presence of either SRI41716A (a potent and selective antagonist of the cannabinoid receptor CB1) or NS398 [a cyclooxygenase (COX)-2 inhibitor] to determine whether any observed stimulation of PG[E.sub.2] production was mediated through the CB 1-receptor and/or COX-2 activity. All three cannabinoids caused a significant increase in PG[E.sub.2] production in the amnion but not in the choriodecidua. However, separated fetal (chorion) explants responded to cannabinoid treatment in a similar manner to amnion, whereas maternal (decidual) explants did not. The enhanced PG[E.sub.2] production caused by CP55,940 was abrogated by cotreatment with either SR141716A or NS398, illustrating that the cannabinoid action on prostaglandin production in fetal membranes is mediated by CB1 agonism and COX-2. Data from Western blotting show that cannabinoid treatment results in the upregulation of COX-2 expression. This study demonstrates a potential role for endocannabinoids in the modulation of prostaglandin production in late human pregnancy, with potentially important implications for the timing and progression of term and preterm labor and membrane rupture. endocannabinoids; prostaglandin; placenta; amnion; chorion; decidua

To date, the endogenous ligands described for cannabinoid receptors have been derived from membrane lipids. To identify a peptide ligand for [CB.sub.1] cannabinoid receptors, we used the recently described conformation-state sensitive antibodies and screened a panel of endogenous peptides from rodent brain or adipose tissue. This led to the identification of hemopressin (PVNFKFLSH) as a peptide ligand that selectively binds [CB.sub.1] cannabinoid receptors. We find that hemopressin is a [CB.sub.1] receptor-selective antagonist, because it is able to efficiently block signaling by [CB.sub.1] receptors but not by other members of family A G protein-coupled receptors (including the closely related [CB.sub.2] receptors). Hemopressin also behaves as an inverse agonist of [CB.sub.1] receptors, because it is able to block the constitutive activity of these receptors to the same extent as its well characterized antagonist, rimonabant. Finally, we examine the activity of hemopressin in vivo using different models of pain and find that it exhibits antinociceptive effects when administered by either intrathecal, intraplantar, or oral routes, underscoring hemopressin's therapeutic potential. These results represent a demonstration of a peptide ligand for [CB.sub.1] cannabinoid receptors that also exhibits analgesic properties. These findings are likely to have a profound impact on the development of novel therapeutics targeting [CB.sub.1] receptors. G-protein-coupled receptors | rimonabant | inflammatory pain | drugs of abuse

Targeting cannabinoid-2 ([CB.sub.2]) receptors with selective agonists may represent a novel therapeutic avenue in various inflammatory diseases, but the mechanisms by which [CB.sub.2] activation exerts its anti-inflammatory effects and the cellular targets are elusive. Here, we investigated the effects of [CB.sub.2]-receptor activation on TNF-[alpha]-induced signal transduction in human coronary artery endothelial cells in vitro and on endotoxin-induced vascular inflammatory response in vivo. TNF-[alpha] induced NF-[kappa]B and RhoA activation and upregulation of adhesion molecules ICAM-1 and VCAM-1, increased expression of monocyte chemoattractant protein, enhanced transendothelial migration of monocytes, and augmented monocyte-endothelial adhesion. Remarkably, all of the above-mentioned effects of TNF-[alpha] were attenuated by [CB.sub.2] agonists. [CB.sub.2] agonists also decreased the TNF-[alpha]- and/or endotoxin-induced ICAM-1 and VCAM-1 expression in isolated aortas and the adhesion of monocytes to aortic vascular endothelium. [CB.sub.1] and [CB.sub.2] receptors were detectable in human coronary artery endothelial cells by Western blotting, RT-PCR, real-time PCR, and immunofluorescence staining. Because the above-mentioned TNF-[alpha]-induced phenotypic changes are critical in the initiation and progression of atherosclerosis and restenosis, our findings suggest that targeting [CB.sub.2] receptors on endothelial cells may offer a novel approach in the treatment of these pathologies. endothelial activation; inflammation; RhoA; adhesion molecules

Two types of cannabinoid receptor have been cloned and characterized. Whereas C[B.sub.1] receptors are ubiquitously expressed in neurons of the CNS, C[B.sub.2] receptors have been thought to be absent from the CNS. Recent data now question this notion and support the expression of C[B.sub.2] receptors in microglial cells, astrocytes and even some neuron subpopulations. This discrete distribution makes C[B.sub.2] receptors interesting targets for treating neurological disorders because C[B.sub.2]-selective agonists lack psychoactivity. Here, we review evidence supporting the idea that C[B.sub.2] receptors are implicated in the control of fundamental neural cell processes, such as proliferation and survival, and that their pharmacological manipulation might be useful for both delaying the progression of neurodegenerative disorders and inhibiting the growth of glial tumors.