ArticleLiterature Review

Endocannabinoids and vascular function

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Abstract

Marijuana is used by humans for its psychoactive and medicinal effects. The active constituents of marijuana, the cannabinoids, exert effects via a G protein-coupled receptor, CB(1). Two arachidonic acid analogs, N-arachidonylethanolamine and 2-arachidonylglycerol are hypothesized to function as endogenous ligands of the CB(1) receptor. The cannabinoids exert significant vascular effects in humans and laboratory animals. In particular, the cannabinoids produce vasodilation and hypotension. The possible mechanisms for these effects are inhibition of transmitter release from sympathetic nerve terminals, direct effects on vascular smooth muscle cells, and effects on endothelial cell function. The data regarding these effects of the cannabinoids and possible sources of endocannabinoid ligands in the vasculature are the subjects of this review.

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... Endocannabinoids are produced in the wall of different vessels and by their vasodilatory actions they contribute to local vascular control [15][16][17][18][19][20][21][22]. However, the extent of this contribution can be much different in different vascular areas [18][19][20][21][22][23][24]. ...
... Endocannabinoids are produced in the wall of different vessels and by their vasodilatory actions they contribute to local vascular control [15][16][17][18][19][20][21][22]. However, the extent of this contribution can be much different in different vascular areas [18][19][20][21][22][23][24]. Exogenous cannabinoids increased coronary flow in isolated rodent hearts [25], dilated larger coronary arteries [9,10,17,26] and even cardioprotective and antiischemic effects [27][28][29] have been attributed to them. ...
... Endocannabinoid production has been detected in different vascular beds and also in heart [15][16][17][18][19][20][21][22]. Several types of cells of different vascular tissues can be sources of endocannabinoids: endothelial cells, smooth muscle cells, perivascular neurons, platelets, leukocytes, monocytes, macrophages etc. [18,[34][35][36]. ...
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It was tested whether intrinsic CB1R activation modifies myogenic and agonist induced contraction of intramural coronary resistance arteries of the rat. CB1R protein was detected by immuno-histochemistry and by Western blot, its mRNA by qRT-PCR in their wall. Microsurgically prepared cylindrical coronary segments (∼100-150μm) developed myogenic contraction (∼20% of relaxed luminal diameter), from which a substantial relaxation (∼15%) in response to WIN55212 (a specific agonist of the CB1Rs) has been found. CB1R-mediated relaxation was blocked by O2050 and AM251 (neutral antagonist and inverse agonist of the CB1R, respectively) and was partially blocked by the NO synthase blocker LNA. CB1R blockade enhanced myogenic tone and augmented AngII-induced vasoconstriction (from 17,8±1,2 to 29,1±2,9%, p <0,05). Inhibition of diacylglycerol lipase by tetrahydrolipstatin, (inhibitor of endogenous 2-AG production) also augmented coronary vasoconstriction. These observations prove that vascular endocannabinoids are significant negative modulators of the myogenic and agonist-induced tone of intramural coronary arterioles acting through CB1Rs.
... Cannabinoids have complex cardiovascular effects both by modulating the autonomic outflow and also through their direct cardiac and vascular effects (Batkai et al., 2004;Ho and Gardiner, 2009;Lipez-Miranda et al., 2008;Pacher et al., 2005). Targets of cannabinoids in the vascular tissue have been identified as endothelial and vascular smooth muscle cells as well as perivascular neuronal fibers (Hillard, 2000;Lipez-Miranda et al., 2008;Pacher et al., 2005;Randall et al., 2004;Wagner et al., 2001). In vivo studies and studies on isolated vessel segments have shown that cannabinoids (e.g. ...
... In vivo studies and studies on isolated vessel segments have shown that cannabinoids (e.g. anandamide, 2-AG, THC, WIN55212) cause vasodilation in most vascular beds, such as in aorta, coronary, cerebral and mesenteric arteries (Dannert et al., 2007;Hillard, 2000;Hillard et al., 2007;O'Sullivan et al., 2007;Rademacher et al., 2005;Randall et al., 2004;Stanley and O'Sullivan, 2014a;Wagner et al., 2001). Although several receptors may be targets of cannabinoids in vascular tissue, such as CB1, CBe, TRPV1, possibly or indirectly CB2, GPR55 and prostanoid receptors, the vasodilator effects of cannabinoids are attributed mainly to vascular CB1 receptors among others (Batkai et al., 2004;Jarai et al., 2000;Lipez-Miranda et al., 2008;O'Sullivan et al., 2007;Stanley and O'Sullivan, 2014a;Szekeres et al., 2012) and our study is in accordance with these findings. ...
... Since agonist-induced endocannabinoid-release has also been detected from vascular tissue Gyombolai et al., 2012;Mechoulam et al., 1998;Rademacher et al., 2005;Sugiura et al., 1998), it has been proposed that this mechanism might be involved in physiological control of vascular tone. In the vasculature, several sources of endocannabinoids have been described, such as vascular endothelial cells, perivascular neurons, platelets, leukocytes, monocytes, macrophages etc. Hillard, 2000;Lipez-Miranda et al., 2008;Pacher et al., 2005). Agonistinduced release of 2-AG has been detected from vascular endothelial cells (Sugiura et al., 1998), also from endothelium-denuded arteries (Rademacher et al., 2005), from rat aorta (Mechoulam et al., 1998) or from bovine coronaries . ...
... The aim of the present study was to evaluate the possible changes in the expression of CB1 receptors on thoracic aorta from streptozotocin-induced diabetic rats and its functional role by investigating the in vitro effects of the administration of a cannabinoid CB1 receptor agonist on aortic rings. Recently, evidence has accumulated regarding the vasorelaxant effects of cannabinoids in isolated blood vessel preparations [8,9]. Several studies have reported hypotensive effects of the endocannabinoid anandamide [13,14], and an enhancement of these effects has been shown in hypertensive rats [16][17][18][19], as well as increased circulating levels of this endocannabinoid in diabetic patients [20], suggesting that anandamide could have beneficial vascular effects. ...
... The role of the endocannabinoid system has recently emerged as being important in the pathogenesis of type 2 diabetes mellitus, which is a well-known risk factor for cardiovascular disease and heart failure, though the mechanisms involved are not well-understood [8][9][10][11]. ...
... The aim of the present study was to evaluate the possible changes in the expression of CB 1 receptors on thoracic aorta from streptozotocin-induced diabetic rats and its functional role by investigating the in vitro effects of the administration of a cannabinoid CB 1 receptor agonist on aortic rings. Recently, evidence has accumulated regarding the vasorelaxant effects of cannabinoids in isolated blood vessel preparations [8,9]. Several studies have reported hypotensive effects of the endocannabinoid anandamide [13,14], and an enhancement of these effects has been shown in hypertensive rats [16][17][18][19], as well as increased circulating levels of this endocannabinoid in diabetic patients [20], suggesting that anandamide could have beneficial vascular effects. ...
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Previous studies have suggested a role of the endocannabinoid system in metabolic diseases, such as diabetes. We investigated the effect of diabetes on cannabinoid receptor type 1 (CB1) expression and cannabinoid-induced vasorelaxation in rat aorta rings. Aortas from healthy rats and from rats with experimentally induced diabetes were used to compare the vasorelaxant effect of the cannabinoid agonist arachidonylcyclopropylamide (ACPA) and CB1 expression and localization. After 4–8 weeks of diabetes induction, CB1 receptor expression and CB1 phosphorylation were higher in aortic rings, in association with greater vasorelaxation induced by the CB1 agonist ACPA compared to healthy rats. The vasorelaxant effect observed in healthy rats is similar throughout the study. Further studies are needed to elucidate the implications of CB1 receptor overexpression in diabetes and its influence on the progression of the cardiovascular complications of this metabolic disease.
... 21 These effects are thought to be mediated by CB1 receptors located on neurons and smooth muscle 22 and via stimulation of non-CB1 or non-CB2 receptors located on endothelial cells 23 which can also cause vasodilation. 24 This suggestion is consistent with our finding that the marijuana users in the present study had low resting diastolic blood pressure throughout the month of abstinence. The marijuana-associated cerebrovascular changes might be due to changes in the density of CB1 receptors in the brain and blood vessels as a result of the use of high doses of the drug. ...
... Chronic injections of THC have been shown to increase in the number of these receptors in the brain. 24 Therefore, it is possible that chronic intake of marijuana by drug users might affect cerebrovascular resistance through changes mediated in blood vessels or in the brain parenchyma. ...
Article
Objective: To determine possible effects of prolonged marijuana use on the cerebrovascular system during a month of monitored abstinence and to assess how the intensity of current use might have influenced cerebrovascular perfusion in these marijuana users. Method: The authors recorded blood flow velocity in the anterior and middle cerebral arteries using transcranial Doppler sonography in three groups of marijuana users who differed in the intensity of recent use (light: n 11; moderate: n 23; and heavy: n 20) and in control subjects (n 18) to assess the nature and duration of any potential abnormalities. Blood flow velocity was recorded within 3 days of admission and 28 to 30 days of monitored abstinence on an inpatient research unit in order to evaluate subacute effects of the drug and any abstinence-generated changes. Results: Pulsatility index, a measure of cerebrovascular resistance, and systolic velocity were significantly increased in the marijuana users vs control subjects. These increases persisted in the heavy marijuana users after a month of monitored abstinence. Conclusions: Chronic marijuana use is associated with increased cerebrovascular resistance through changes mediated, in part, in blood vessels or in the brain parenchyma. These findings might provide a partial explanation for the cognitive deficits observed in a similar group of marijuana users.
... Similar to cannabinoids and following a brief pressor phase, SCB's can cause longstanding hypotension and bradycardia as a result of a decrease in the sympathetic tone [5] . Nonneural sites of the cannabinoids action on the vascular smooth muscle and endothelial cells can also add to the degree of systemic hypotension [6] . Animal studies in canines and rodents using different vascular beds suggested a direct effect of cannabinoids on smooth muscle cells mediated through the modulation of calcium and potassium cellular transport resulting in hyperpolarization and relaxation [7,8] . ...
... Cannabinoids also have endothelialdependent effects on the vascular beds. This can be initiated by binding to CB1 receptors on the surface of the endothelial cell and to a different type of receptor that might not be specific to the class of cannabinoids [6] . Taken all together, it is reasonable to state that SCB is a more potent drug than the natural cannabinoids can potentially result in major vascular compromise followed by stasis secondary to vascular paralysis. ...
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Synthetic cannabinoids have become a common drug of abuse in recent years and their toxicities have come to light as well. They are known to be notorious for the kidneys, with acute tubular necrosis, acute interstitial nephritis, and rhabdomyolysis-induced renal injury being the frequent nephrotoxic outcomes in users. We report a case of bilateral renal cortical necrosis, leading to irreversible renal damage and lifelong dialysis dependency. Key Words: Synthetic cannabinoids, Renal cortical necrosis, Dialysis
... AEA exerts its vasorelaxant effect on endothelial cells in various ways, such as by upregulating the expression and activity of the inducible NO synthase (NO-mediated pathway) [23]. In the cerebral circulation, CB1 also has vasodilatory effects directly on vascular smooth muscle by inhibiting calcium entry through L-type calcium channels [24]. ...
Article
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Background The endocannabinoid system plays a key role in female reproduction, including implantation, decidualization and placentation. In the present study, we aimed to analyze cannabinoid receptor 1 (CB1), CB2 and fatty acid amid hydrolase (FAAH) expressions and localization in normal and preeclamptic placenta, in order to determine whether placental endocannabinoid expression pattern differs between normal pregnancy and preeclampsia.Methods Eighteen preeclamptic patients and 18 normotensive, healthy pregnant women with uncomplicated pregnancies were involved in our case¿control study. We determined CB1, CB2 and FAAH expressions by Western blotting and immunohistochemistry in placental samples collected directly after Cesarean section.ResultsCB1 expression semi-quantified by Western blotting was significantly higher in preeclamptic placenta, and these findings were confirmed by immunohistochemistry. CB1 immunoreactivity was markedly stronger in syncytiotrophoblasts, the mesenchymal core, decidua, villous capillary endothelial and smooth muscle cells, as well as in the amnion in preeclamptic samples compared to normal pregnancies. However, we did not find significant differences between preeclamptic and normal placenta in terms of CB2 and FAAH expressions and immunoreactivity.Conclusions We observed markedly higher expression of CB1 protein in preeclamptic placental tissue. Increased CB1 expression might cause abnormal decidualization and impair trophoblast invasion, thus being involved in the pathogenesis of preeclampsia. Nevertheless, we did not find significant differences between preeclamptic and normal placental tissue regarding CB2 and FAAH expressions. While the detailed pathogenesis of preeclampsia is still unclear, the endocannabinoid system could play a role in the development of the disease.
... Palmitoylethanolamide (PEA) and oleoylethanolamide (OEA) are noncannabinoid fatty-acid ethanolamides that share biosynthetic and metabolic pathways with AEA, but do not activate cannabinoid receptors. Similarly, 2-oleoylglycerol (2-OG), like 2-AG, is a 2-monoacylglycerol and has overlapping mechanisms of synthesis and degradation with 2-AG such that their concentrations often increase and decrease together (Hillard, 2000;Katona & Freund, 2012). In the brain, eCB/CB1 receptor signaling subserves activitydependent, retrograde synaptic signaling. ...
... As CB-1 receptors in their functioning are closely related to the functioning of potassium and calcium ion channels, as this haemodynamic responses on CB1 activation can be explained in such ways: the stimulation of the CB1 receptors localized in the walls of blood vessels causes inactivation of calcium ion channels that leads to vasodilation and reduced peripheral vascular resistance, followed by the fall of blood pressure [8,17]; the stimulation of the CB1 receptors localized in heart results in inactivation of the calcium ion channels that further reduces the transmembrane calcium flow and thus reduces inotropic function of the heart. The negative inotropic effect was also observed for atriums [3,4]; the stimulation of the CB1 receptors localized in heart results in potassium ion channels activation and leads to bradycardia. ...
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Introduction. Heart failure is a clinical syndrome associated with the high rates of short-time and long-time mortality. The pathological role of several neurohumoral systems is well-established in heart failure progression. According to the data available from the basic experiments the role of the endogenous cannabinoid system in heart failure progression is considered. Aim. To make a review of literature and topical scientific sources regarding the possible pathological role of endogenous cannabioid system in heart failure syndrome. Materials and methods. Content analysis, method of system and comparative analysis, bibliosemantic method of research of actual scientific researches on the possible pathological role of endogenous cannabioid system in heart failure syndrome were used. Results. So we have found that several pathological processes in heart failure syndrome are the consequences of endogenous cannabinoid system influence on the hemodynamic. For the majority of patients with the end-stage heart failure a strong and progressive loss of appetite and weight are observed. There are no doubt that this fact can be explained by impaired liver function as the phenomena of “congestion liver,” but this is probably also due to the hyperactivation of endogenous cannabinoid system. As its known, the activation of cannabinoid system due to the activation of CB1 receptors causes an increase in appetite, changes in metabolism of adipose tissue and further leads to obesity. The drug rimonabant was studied as a central cannabinoid receptor blocker as blocking the CB1 receptors that results in the loss of appetite and weight. Heart failure is a condition associated with the hyperstimulation of cannabinoid receptors and/or the depletion of effects of the mediators on them, which leads to loss of appetite and weight. Heart failure is associated with the development of abnormal liver function, elevated liver enzymes and progressive fibrosis process in liver. Also the hyperactivation with further depletion of CB1 is strongly related with the progressive cirrhotic process in the liver as it was observed in several experiments on mice. Depression. For most patients with the high functional class of heart failure the development of depression is usually observed. According to the own observations, among the patients with heart failure NYHA I the depression rate is not more than 5,0 %, in NYHA II – 12,0 % in NYHA III – 40,0 %, in NYHA IV – up to 70,0 %. Theoretically, this could be due to hyperactivation and further depletion of CB1 stimulation in the central nervous system, as its known that stimulation of the CB1 causes euphoria, inhibition/depletion leads to depression. Pain. The acute decompensation of chronic heart failure does not often accompany the patients’ complaints on pain of muscular origin. CB1 receptor activation is known to lead to stable analgesia, inhibition/depletion – to the pain. Conclusions. The hyperstimulation with further depletion of CB1 receptors and mediators results in hypotension, bradycardia, depression, muscle pain and liver cirrhosis – that usually accompanies the decompensated and end-stage heart failure. Further discovering of CB1 exogenous agents acting on central nervous system and/or peripheral CB1 receptors can result in creating the new group of drugs in heart failure treatment.
... 2-AG (and 2-OG) concentrations increased by nearly twofold and were unaffected by opioid antagonist pretreatment, suggesting that 2-AG in particular is the eCB involved in this model of EIH. 2-OG and 2-AG have overlapping mechanisms of synthesis and degradation, such that their concentrations often increase and decrease together [22], and results from this study confirm this relationship. The same is true for the N-acylethanolamines (NAEs) with regards to overlapping mechanisms of synthesis and degradation, and results from this study indicated AEA and OEA responded in a similar manner but PEA did not. ...
Article
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Objective: The purpose of this study was to examine the interaction between the endogenous opioid and endocannabinoid (eCB) systems in a pain modulatory process known as exercise-induced hypoalgesia (EIH). Design: Randomized controlled trial. Setting: Clinical research unit in a hospital. Subjects: Fifty-eight healthy men and women (mean age = 21 ± 3 years) participated in this study. Methods: Participants were administered (randomized, double-blind, counterbalanced procedure) an opioid antagonist (i.e., naltrexone) and a placebo prior to performing pain testing and isometric exercise. Results: Results indicated that 2-arachidonoylglycerol (2-AG) and 2-oleoylglycerol (2-OG) increased significantly (P < 0.05) following exercise in both placebo and naltrexone conditions. In comparison, N-arachidonylethanolamine (AEA) and oleoylethanolamine (OEA) increased significantly (P < 0.05) following exercise in the placebo condition but not the naltrexone condition. There were no significant (P > 0.05) differences in palmitolethanolamine (PEA) between the placebo and naltrexone conditions. Conclusions: As reductions in pain (i.e., EIH) were observed following both conditions, these results suggest that the opioid system may not be the primary system involved in exercise-induced hypoalgesia and that 2-AG and 2-OG could contribute to nonopioid exercise-induced hypoalgesia. Moreover, as exercise-induced increases in AEA and OEA were blocked by naltrexone pretreatment, this suggests that the opioid system may be involved in the increase of AEA and OEA following exercise.
... TBI has been well documented in producing cerebral blood flow pathology (Kelly et al., 1997) as well as interfering with BBB integrity (Baskaya et al., 1997). Given that cannabinoids are known to exert vascular effects, producing vasodilation as well as hypotension (reviewed in Hillard, 2000b), their manipulation may hold promise as protectants against cerebrovascular damage. Below, we review studies examining the effects of cannabinoids on TBI-induced disruption of BBB integrity. ...
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The endogenous cannabinoid (endocannabinoid) system regulates a diverse array of physiological processes and unsurprisingly possesses considerable potential targets for the potential treatment of numerous disease states, including two receptors (i.e., CB 1 and CB 2 receptors) and enzymes regulating their endogenous ligands N-arachidonoylethanolamine (anandamide) and 2-arachidonyl glycerol (2-AG). Increases in brain levels of endocannabinoids to pathogenic events suggest this system plays a role in compensatory repair mechanisms. Traumatic brain injury (TBI) pathology remains mostly refractory to currently available drugs, perhaps due to its heterogeneous nature in etiology, clinical presentation, and severity. Here, we review pre-clinical studies assessing the therapeutic potential of cannabinoids and manipulations of the endocannabinoid system to ameliorate TBI pathology. Specifically, manipulations of endocannabinoid degradative enzymes (e.g., fatty acid amide hydrolase, monoacylglycerol lipase, and α/β-hydrolase domain-6), CB 1 and CB 2 receptors, and their endogenous ligands have shown promise in modulating cellular and molecular hallmarks of TBI pathology such as; cell death, excitotoxicity, neuroinflammation, cerebrovascular breakdown, and cell structure and remodeling. TBI-induced behavioral deficits, such as learning and memory, neurological motor impairments, post-traumatic convulsions or seizures, and anxiety also respond to manipulations of the endocannabinoid system. As such, the endocannabinoid system possesses potential drugable receptor and enzyme targets for the treatment of diverse TBI pathology. Yet, full characterization of TBI-induced changes in endocannabinoid ligands, enzymes, and receptor populations will be important to understand that role this system plays in TBI pathology. Promising classes of compounds, such as the plant-derived phytocannabinoids, synthetic cannabinoids, and endocannabinoids, as well as their non-cannabinoid receptor targets, such as TRPV1 receptors, represent important areas of basic research and potential therapeutic interest to treat TBI.
... At doses of 0.03-20 mg kg À1 (i.v.), 1 was active in all of these tests, and the effects were blocked by the CB 1 receptor antagonist, rimonabant (10 mg kg À1 ) [31][32][33]. However, it should be noted that rimonabant is not a specific ligand for the CB 1 receptor when employed at concentrations of >1 μM [34,35] and, therefore, at the concentrations reached in vivo. ...
Chapter
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Cannabis sativa has been used for recreational, therapeutic and other uses for thousands of years. The plant contains more than 120 C21 terpenophenolic constituents named phytocannabinoids. The Δ9-tetrahydrocannabinol type class of phytocannabinoids comprises the largest proportion of the phytocannabinoid content. Δ9-tetrahydrocannabinol was first discovered in 1971. This led to the discovery of the endocannabinoid system in mammals, including the cannabinoid receptors CB1 and CB2. Δ9-Tetrahydrocannabinol exerts its well-known psychotropic effects through the CB1 receptor but this effect of Δ9-tetrahydrocannabinol has limited the use of cannabis medicinally, despite the therapeutic benefits of this phytocannabinoid. This has driven research into other targets outside the endocannabinoid system and has also driven research into the other non-psychotropic phytocannabinoids present in cannabis. This chapter presents an overview of the molecular pharmacology of the seven most thoroughly investigated phytocannabinoids, namely Δ9-tetrahydrocannabinol, Δ9-tetrahydrocannabivarin, cannabinol, cannabidiol, cannabidivarin, cannabigerol, and cannabichromene. The targets of these phytocannabinoids are defined both within the endocannabinoid system and beyond. The pharmacological effect of each individual phytocannabinoid is important in the overall therapeutic and recreational effect of cannabis and slight structural differences can elicit diverse and competing physiological effects. The proportion of each phytocannabinoid can be influenced by various factors such as growing conditions and extraction methods. It is therefore important to investigate the pharmacology of these seven phytocannabinoids further, and characterise the large number of other phytocannabinoids in order to better understand their contributions to the therapeutic and recreational effects claimed for the whole cannabis plant and its extracts.
... 2-AG (and 2-OG) concentrations increased by nearly twofold and were unaffected by opioid antagonist pretreatment, suggesting that 2-AG in particular is the eCB involved in this model of EIH. 2-OG and 2-AG have overlapping mechanisms of synthesis and degradation, such that their concentrations often increase and decrease together [22], and results from this study confirm this relationship. The same is true for the N-acylethanolamines (NAEs) with regards to overlapping mechanisms of synthesis and degradation, and results from this study indicated AEA and OEA responded in a similar manner but PEA did not. ...
... Other reported arrhythmias include sinus bradycardia, second-degree atrioventricular block and atrial fibrillation (Akins and Awdeh, 1981;Singh, 2000). The cardiovascular effects of eCBs have been extensively examined and reviewed (Hillard, 2000;Kunos et al., 2000). Here, the discussion is narrowed down to the results of rodent studies that have explored the cardiovascular effects of AEA signaling enhancement. ...
Article
Numerous studies have documented a link between psychological disorders and cardiac disease. Yet, no systematic attempts have been made to develop pharmacological approaches for mood and anxiety disorders that could also be beneficial for cardiac health. The endocannabinoid system has been implicated in the regulation of stress, emotional behavior and cardiovascular function. General preclinical findings indicate that the endocannabinoid anandamide modulates physiological and behavioral stress responses and may also protect the heart from arrhythmias. Moreover, recent experimental studies suggest that pharmacological enhancement of anandamide signaling via inhibition of its degrading enzyme fatty acid amide hydrolase (FAAH) exerts anxiolytic- and antidepressive-like effects and improves cardiac autonomic function and the electrical stability of the myocardium in rodent models that reproduce aspects of human psychological/cardiac comorbidity. Here we summarize and discuss such experimental findings, which might guide future preclinical studies towards a systematic evaluation of the therapeutic potential of pharmacological approaches that target FAAH activity for the treatment of the comorbidity between psychological disorders and cardiac disease.
... 27 The same is true for 2-AG and 2-OG. 26 The present study confirms these relationships. ...
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The purpose of this study was to examine opioid and endocannabinoid mechanisms of exercise-induced hypoalgesia (EIH). Fifty-eight men and women (mean age = 21 yrs) completed three sessions. During the first session, participants were familiarized with the temporal summation of heat pain and pressure pain protocols. In the exercise sessions, following double-blind administration of either an opioid antagonist (50 mg naltrexone) or placebo, participants rated the intensity of heat pulses and indicated their pressure pain thresholds (PPT) and ratings (PPR) before and after 3 minutes of submaximal isometric exercise. Blood was drawn before and after exercise. Results indicated circulating concentrations of two endocannabinoids, N-arachidonylethanolamine (AEA) and 2-arachidonoylglycerol (2-AG) as well as related lipids oleoylethanolamide (OEA), palmitoylethanolamide (PEA), N-docsahexaenoylethanolamine (DHEA), and 2-oleoylglycerol (2-OG) increased significantly (p < 0.05) following exercise. PPT increased significantly (p < 0.05) while PPR decreased significantly (p < 0.05) following exercise. Also, temporal summation ratings were significantly lower (p < 0.05) following exercise. These changes in pain responses did not differ between placebo or naltrexone conditions (p > 0.05). A significant association was found between EIH and DHEA. These results suggest involvement of a non-opioid mechanism in EIH following isometric exercise. Perspective Currently, the mechanisms responsible for exercise-induced hypoalgesia (EIH) are unknown. This study provides support for a potential endocannabinoid mechanism of EIH following isometric exercise.
... the cardiovascular system (Hillard, 2000), reproductive endocrine processes (Wenger, Toth, et al., 1999), and the control of energetic metabolism (Guzmán and Sánchez, 1999). In the brain, endocannabinoids participate in processes such as the control of movement (Consroe, 1998;Sañudo-Peña et al., 1999;Romero et al., 2002;Fernández-Ruiz et al., 2002), learning and memory (Hampson and Deadwyler, 1999;Castellano et al., 2003), brain reward (Gardner and Vorel, 1998;Basavarajappa and Hungund, 2002;Parolaro and Rubino, 2002), nociception (Walker et al., , 2002Pertwee, 2001), control of appetite (Berry and Mechoulam, 2002), and emesis (Mechoulam and Hanus, 2001;Di Carlo and Izzo, 2003). ...
... Some of the same effects induced by marijuana are also caused by endogenous analogs, the so-called endocannabinoids (eCBs) that differ chemically from plant-derived or synthetic cannabinoid drugs. Endocannabinoids and their targets (i.e. the eCB system) exert these effects on the cardiovascular system by acting on neurotransmitter release at the central nervous system (CNS) and sympathetic nerve terminals or locally by modulating vascular smooth muscle cells (VSMCs), inflammatory cells and endothelial function [6]. There is growing evidence demonstrating that the eCB system is implicated both in cardiovascular physiology (blood pressure, cardiac contractility and heart rate) [7,8] and the pathogenesis of hypertension, heart disease and atherosclerosis [9][10][11]. ...
Article
Rationale: Cardiovascular disease is now recognized as the number one cause of death in the world, and the size of the population at risk continues to increase rapidly. The dysregulation of the endocannabinoid (eCB) system plays a central role in a wide variety of conditions including cardiovascular disorders. Cannabinoid receptors, their endogenous ligands, as well as enzymes conferring their synthesis and degradation, exhibit overlapping distributions in the cardiovascular system. Furthermore, the pharmacological manipulation of the eCB system has effects on blood pressure, cardiac contractility and endothelial vasomotor control. Growing evidence from animal studies supports the significance of the eCB system in cardiovascular disorders. Objective: To summarize the literature surrounding the eCB system in cardiovascular function and disease and the new compounds that may potentially extend the range of available interventions. Results: Drugs targeting CB1R, CB2R, TRPV1 and PPARs are proven effective in animal models mimicking cardiovascular disorders such as hypertension, atherosclerosis and myocardial infarction. Despite the setback of two clinical trials that exhibited unexpected harmful side-effects, preclinical studies are accelerating the development of more selective drugs with promising results devoid of adverse effects. Conclusion: Over the last years, increasing evidence from basic and clinical research supports the role of the eCB system in cardiovascular function. Whereas new discoveries are paving the way for the identification of novel drugs and therapeutic targets, the close cooperation of researchers, clinicians and pharmaceutical companies is needed to achieve successful outcomes.
... En efecto, la anandamida y el 2-araquidonilglicerol sólo se detectan en monocitos y plaquetas de animales infartados experimentalmente. Los animales tratados con anandamida reducen su tasa de sobrevivencia a la mitad de la de los controles, en tanto que el bloqueo del receptor CB1 restaura la presión arterial media, aunque incrementa la mortalidad (33,77,78). ...
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In a wide sense, a palliative agent is a remedy that attenuates some symptoms associated with a disease, whereas a therapeutic agent is the one capable of curing a disease. Marihuana (Cannabis sativa) is a plant from Central Asia and its main active components (cannabinoids) are three: tetrahydrocannabinol, cannabinol and cannabidiol. They possess psychotropic and vegetative effects and, empirically, are reputed to exert some supposedly therapeutic actions involving the control of pain, vomiting, intraocular pressure and many other ailments. In agreement with official data from the "Consejo Nacional contra las Adicciones" (CONADIC, Mexico), during 1998-2000, the most extensively abused substances were marihuana, cocaine and industrial solvents. The consumption of marihuana in Mexico has increased with time. The average prevalence of the use of cannabis among the urban population from 12 to 65 years of age is 5.3%. The cities with the highest consumption of marihuana are Tijuana (14.7%), Ciudad Juárez (9.2%), Guadalajara (7.5%), Mexico City (7.3%), Monterrey (4.1%) and Matamoros (3.6%), a fact that indicates that the north-central region of Mexico is the most affected. Marihuana is the main drug consumed by almost all age groups without any distinction of gender. The consumption is predominantly higher in males (13.9%) than in females (6.9%), and among children from 12 to 17 years old who do not live with their families. The percentage of adolescents consuming marihuana is larger among youths who are not students (4.2%) than in the student population (1.3%). Thus, marihuana consumption is a real problem of public health in Mexico. The existence of at least two receptors to cannabinoids is well known, as well as a group of substances synthesized by the organism itself, denominated endocannabinoids, whose pharmacological properties resemble those of the plant. These observations have caused some parliamentary discussions that have led some countries to approve the use of the synthetic cannabinoid-related substances for therapeutic purposes. In the present review, recent literature was analyzed in order to offer an objective scientific perspective about the use of marihuana. Five relevant observations are pointed out: 1) Studies with positive findings, lack adequate controls. 2) The standards of comparison used, are not the most suitable, for example, the supposed analgesic property of cannabinoids is commonly compared with codeine, and the possible antiemetic capability of cannabinoids is not compared with well-known commercial and safe drugs with verified potency, such as the 5HT 3 receptor subtype agonist, odansetron. 3) Some authors claim that the plant may acts as a whole, and therefore some of the synthetic cannabinoids approved in other countries for therapeutic uses might not produce notable effects. 4) Only a few patients experience some improvement in their symptoms; however most of them experience the psychotropic actions of cannabinoids. And, 5) there are ethical aspects to reconsider in the case of patients who never before had consumed cannabinoids. The following aspects of the clinical use of cannabinoids are discussed in this review. For example, diverse reports suggest that marihuana increases food intake through CB1 receptor-stimulation producing hyperphage by itself, as well as anorexia related to immunodeficiency syndrome and cancer treatment. However, these patients also experience the psychotropic side-effects of marihuana and which lead them to leave the treatment. Regarding pain, cannabinoids produce spinal analgesia in experimental animals, which might be mediated by suppression of neuronal nocyceptive activity and the activation of opioid receptors. Nevertheless, most researchers who are exploring the efficacy of cannabinoids in pain treatment employ codeine as a reference, although codeine is in disuse due to its vegetative effects and poor potency, and do not compare it with other powerful analgesics such as opioids or prostaglandin inhibitors. In the immunologic system, cannabinoids act on CB2 receptors, decreasing the function of immune T and B cells, killer cells and macrophages. Therefore, infection processes might be increased in debilitated patients. By contrast, the immunosuppressant action of cannabinoids could be useful in hyperactivity of the immunologic system, as in the case of multiple sclerosis. On the other hand, recent findings suggest that a lipid imbalance (mainly with arachidonic acid) is a primary factor in the etiology of cystic fibrosis. Since the endocannabinoids are fatty acid derivatives, it has been hypothesized that the patients who suffer cystic fibrosis can receive benefits by the administration of cannabinoids (i.e. restoring the balance between fatty acids, reducing the symptoms and increasing life expectancies). Regardind reproduction research, prenatal cannabinoid exposure has been associated with a high perinatal morbidity but the possible long-term consequences are still poorly understood. Therefore, animal models of perinatal cannabinoid exposure have provided a useful tool for examining the developmental effects of the offspring. Results show alteration in the ontogeny of spontaneous locomotor activity and exploratory behavior. Adult animals exposed during pregnancy and lactation exhibited persistent alterations of the behavioral response to novelty, social interactions and sexual behavior. However, available data regarding the long-term behavioral and cognitive effects in humans are scarce to be compared with animal results. In other studies, some endocannabinoids generated in monocytes and platelets show that they are potent vasodilators and related to hypotension following hemorrhagic shock. Thus, animals treated with anandamide reduce their survival rate. In contrast, administration of the CB1 antagonist (SR141716A) increases the arterial pressure, the respiratory frequency and the survival rate in a dose-response manner. Thus, inhibition of the endogenous cannabinoids reverts the hemorrhagic shock with notorious efficacy, similar to endogenous opioids. In this sense, some other reports suggest that cannabinoids are useful to treat glaucoma, because cannabis reduces intraocular pressure in 60% of the users, although there are other drugs lacking psychotropic effects with proved and accepted efficacy in the treatment of glaucoma. Marihuana may also have certain anticonvulsivant properties; however delta-9THC alters sleep patterns in humans and could not be recommendable. In spite of some positive reports on the treatment of partial or tonic-clonic seizures, there is a lack of controlled studies.
... 36 CB 1 Rs are highly expressed in endothelial cells 8 as well as cerebrovascular smooth muscle cells 9 and several mechanisms have been proposed to explain CB 1 R-induced CBF decrease. 37,38 Interestingly, CB 1 R agonists stimulate production of nitric-oxide (NO), a potent vasoactive molecule that induces CBF decrease. NO appears to be produced in response to CB 1 receptor stimulation in a G i/o -selective manner without an obvious Ca 2þ transient. ...
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We have recently reported cannabinoid-induced rapid changes in the structure of individual neurons. In order to investigate the presence of similar effects at the regional level, measures of brain tissue biomechanics are required. However, cannabinoids are known to alter cerebral blood flow (CBF), putatively resulting in presently unexplored changes in cerebral tissue biomechanics. Here we used magnetic resonance elastography (MRE) and flow-sensitive alternating inversion recovery (FAIR) imaging to measure in vivo alterations of mechanical properties and CBF, respectively, in the rat hippocampus, a brain region with a high density of type-1 cannabinoid receptors (CB1R). Systemic injection of the cannabinoid agonist CP55,940 (0.7 mg/kg) induced a significant stiffness decrease of 10.5�1.2% at 15 minutes. FAIR imaging indicated a comparable decrease (11.3�1.9%) in CBF. Both effects were specific to CB1R activation, as shown by pretreatment with the CB1R-specific antagonist AM251. Strikingly, similar rapid parallel changes of brain elasticity and CBF were also observed after systemic treatment with the hypotensive drug nicardipine. Our results reveal important drug-induced parallel changes in CBF and brain mechanical characteristics, and show that blood flowdependent tissue softening has to be considered as an important putative confounding factor when cerebral viscoelastic changes are investigated. http://jcb.sagepub.com/content/early/2015/09/23/0271678X15606923.abstract
... 5 Cannabinoids can rapidly alter neurotransmitter release from nerve terminals, potently activating vascular smooth muscle cells while disrupting endothelial cell function, potentially resulting in both ischemia and hemorrhage. 6 Transient vasospasm may also be a mechanism for the recently reported spice-associated acute renal failure, 7 or arrhythmias and myocardial infarctions seen in healthy adolescents. 2 Alternatively, spice may cause ICH via direct sympathomimetic effects, a mechanism supported clinically by reports of concurrent tachyarrhythmias, palpitations, xerostomia, diaphoresis, and mydriasis. ...
Article
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The association between the street drug spice (K-2 or herbal incense), a synthetic marijuana, and intracranial hemorrhage (ICH) has not yet been described, but it has with acute ischemic stroke (AIS),¹ seizure, and myocardial infarction.² Two young patients (31 and 25 years old) independently presented to our hospital with subarachnoid hemorrhage (SAH) after spice inhalation. The first also had 2 large intraparenchymal hemorrhages (IPH); the other also had AIS. Both were previously healthy without hypertension, coagulopathy, bleeding diathesis, thrombocytopenia, intracranial aneurysm, arteriovenous malformation, connective tissue disease, or anticoagulant/antiplatelet medication use.
... Additionally, anandamide might reduce the formation of NO by inducible nitric oxide synthase (iNOS) in macrophages located in the meninges (33) via CB 1 or CB 2 receptors activation (36). However, since the CB 1 receptors are present in the smooth muscle of cerebral arteries and other vascular beds (37), it is possible that they are also represented in the smooth muscle of dural arteries. Therefore, it is intriguing to speculate that peripheral anandamide via these or other receptors may inhibit NO release in the smooth muscle of dural arteries, indirectly reducing trigeminal hyperalgesia. ...
Article
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Systemic nitroglycerin (NTG) activates brain nuclei involved in nociceptive transmission as well as in neuroendocrine and autonomic functions in rats. These changes are considered relevant for migraine because NTG consistently provokes spontaneous-like migraine attacks in migraineurs. Several studies have suggested a relationship between the endocannabinoid levels and pain mediation in migraine. URB937, a peripheral inhibitor of fatty acid amide hydrolase (FAAH)-the enzyme that degrades anandamide, produces analgesia in animal models of pain, but there is no information on its effects in migraine. We evaluated whether URB937 alters nociceptive responses in the animal model of migraine based on NTG administration in male rats, using the tail flick test and the plantar and orofacial formalin tests, under baseline conditions and after NTG administration. Furthermore, we investigated whether URB937 affects NTG-induced c-Fos expression in the brain. During the tail flick test, URB937 showed an antinociceptive effect in baseline conditions and it blocked NTG-induced hyperalgesia. URB937 also proved effective in counteracting NTG-induced hyperalgesia during both the plantar and orofacial formalin tests. Mapping of brain nuclei activated by NTG indicates that URB937 significantly reduces c-Fos expression in the nucleus trigeminalis caudalis and the locus coeruleus. The data suggest that URB937 is capable of changing, probably via indirect mechanisms, the functional status of central structures that are important for pain transmission in an animal model of migraine. © International Headache Society 2015 Reprints and permissions: sagepub.co.uk/journalsPermissions.nav.
... The involvement of the ECS in the pathophysiology of stroke is even more evident in animal models (Schäbitz et al., 2002;Muthian et al., 2004;Zarruk et al., 2012;. In the transient middle cerebral artery occlusion (tMCAO) model using CB 1 R −/− mice, a greater lesion volume was observed than in wild-type animals due to a decrease in CBF after reperfusion, probably due to a direct effect of CB 1 R activation on cerebrovascular smooth muscle cells (Hillard, 2000;Parmentier-Batteur et al., 2002). However, the administration of pharmacological treatments aimed at modulating CB 1 R function show controversial results. ...
Article
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Stroke is the second leading cause of death worldwide following coronary heart disease. Despite significant efforts to find effective treatments to reduce neurological damage, many patients suffer from sequelae that impair their quality of life. For this reason, the search for new therapeutic options for the treatment of these patients is a priority. Glial cells, including microglia, astrocytes and oligodendrocytes, participate in crucial processes that allow the correct functioning of the neural tissue, being actively involved in the pathophysiological mechanisms of ischemic stroke. Although the exact mechanisms by which glial cells contribute in the pathophysiological context of stroke are not yet completely understood, they have emerged as potentially therapeutic targets to improve brain recovery. The endocannabinoid system has interesting immunomodulatory and protective effects in glial cells, and the pharmacological modulation of this signaling pathway has revealed potential neuroprotective effects in different neurological diseases. Therefore, here we recapitulate current findings on the potential promising contribution of the endocannabinoid system pharmacological manipulation in glial cells for the treatment of ischemic stroke.
... Cannabinoids provide protective role in atherosclerosis progression and in cerebral and myocardial ischemia. [9][10][11] Anandamide limits infarct size induced by ischemiareperfusion injury and the pharmacological profile of this response fails to match with any of the previously known mechanisms of cannabinoid action. [12] Thromboxane-A2 is the therapeutic target of blood clotting disorder [13] and its ligand Aspirin is helpful in giving relief from skeletal pain, viz. ...
Article
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Knowledge of cardiovascular diseases and improved diagnostic capacity is rapidly expanding with the advancement of medical sciences. However, heart diseases are a challenge to human life. Few important therapeutic targets for cardiovascular diseases were collected from mining of various bibliographic sources. Different proteins and bioactive small molecules are taken into consideration for target search. From ancient times, medicinal plants are shown to have remedial effect on cardiovascular system of human body, yet their modes of action are not completely understood till now. Selected plant derivatives, which have been examined under in vitro conditions to be effective against various heart diseases, were subjected to molecular docking with proposed targets using a bioinformatics tool, Hex 8.0. We have explored eight targets for five types of cardiovascular diseases and ten different ligands from herbal plants with a brief description about the cardiovascular diseases, their symptoms, target, ligand, source of the ligand and their mechanism of action. All the reported synthetic and phytocompounds were found to have good binding energies with all potential disease targets. Among all, Forskolin is found to be the best inhibitor of Angiotensin II type I receptor with the E-score of -369.96 for Atherosclerosis.
... Palmitoylethanolamide (PEA) and oleoylethanolamide (OEA) are noncannabinoid fatty-acid ethanolamides that share biosynthetic and metabolic pathways with AEA, but do not activate cannabinoid receptors. Similarly, 2-oleoylglycerol (2-OG), like 2-AG, is a 2-monoacylglycerol and has overlapping mechanisms of synthesis and degradation with 2-AG such that their concentrations often increase and decrease together (Hillard, 2000;Katona & Freund, 2012). In the brain, eCB/CB1 receptor signaling subserves activitydependent, retrograde synaptic signaling. ...
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Previous reports have shown improvements in mood and increases in endocannabinoids in healthy adults following a session of aerobic exercise, but it is unclear whether adults with posttraumatic stress disorder (PTSD) experience similar responses. The purpose of this study was to examine psychobiological responses (plasma endocannabinoids [eCBs], mood, and pain) to aerobic exercise in a sample of adults with a diagnosis of PTSD (n = 12) and healthy controls (n = 12). Participants engaged in an aerobic exercise session in which they ran on a treadmill for 30 min at a moderate intensity (70 to 75% maximum heart rate [MHR]). Results indicated improvements in mood states and reductions in pain for both groups following exercise, ds = 0.19 to 1.53. Circulating concentrations of N-arachidonylethanolamine (AEA), 2-arachidonoylglycerol (2-AG), and oleoylethanolamide (OEA) significantly increased (ps = .000 to .050) following the aerobic exercise session for both groups. There were no significant time, group, or interaction effects (ps = .062 to .846) for palmitoylethanolamide (PEA) and 2-oleoylglycerol (2-OG). Although eCBs increased significantly for both groups, within-group effect size calculations indicated the healthy controls experienced a greater magnitude of change for AEA when compared with adults with PTSD, d = 1.21 and d = 0.45, respectively; as well as for 2-AG, d = 0.43 and d = 0.21, respectively. The findings from this study indicated that adults with and without PTSD reported significant mood improvements following 30 min of moderate-intensity aerobic exercise. In addition, the endocannabinoid system was activated in adults with and without PTSD, although effect sizes suggest that adults with PTSD may have a blunted endocannabinoid response to exercise.
... PEA and OEA are noncannabinoid fatty-acid ethanolamides that share some biosynthetic and metabolic pathways with AEA and belong to the family of N-acyl ethanolamides, but are agonists at peroxisome proliferator-activated receptors as opposed to CB1 and CB2 receptors. Similarly, 2-OG is a monoacylglycerol and is a structural analog of 2-AG as both have overlapping mechanisms of synthesis and degradation (Di Marzo et al., 2005;Hillard, 2000). ...
Article
The endocannabinoid (eCB) system is a modulatory system that is both altered by stress and mediates the effects of acute stress, including contributing to restoration of homeostasis. Earlier studies suggest that circulating eCBs are dysregulated in adults with post-traumatic stress disorder (PTSD); however, it is not known whether circulating eCBs remain responsive to stress. The purpose of this study was to examine eCB and psychological responses to physical (exercise) and psychosocial (Trier Social Stress Test) stressors, using a randomized, counterbalanced procedure in adults with PTSD and healthy controls (N = 20, mean age = 24, SD = 7 yrs). Results from mixed-design, repeated measures ANOVAs revealed significant increases (p <.05) in N-arachidonoylethanolamine (AEA) and oleoylethanolamide (OEA) following exercise and psychosocial stress in both groups. However, only the control group exhibited a significant increase (p <.05) in 2-arachidonoylglycerol (2-AG) following exercise and psychosocial stress exposure. These data extend our current understanding of circulating eCB responsiveness in PTSD, and provide preliminary evidence to suggest that the eCB system is hypoactive in PTSD following exposure to physical and psychosocial stressors.
... "runner's high") (Fuss et al., 2015) or the absence of pain during high-stress situations. Peripherally, endocannabinoids have been shown to act both as bronchodilators (Calignano et al., 2000) as well as vasodilators (Hillard, 2000;Wagner et al., 2001), thus promoting increased lung tissue perfusion as well as facilitating blood flow in the periphery. Together with our observation of increased intercostal muscle activity associated with greater heat production, the WHM may lead to improved heat exchange between lung tissue and blood, promoting increased perfusion of extremities during cold, thus ameliorating the dangers of tissue damage (such as frostbite) at the expense of irradiating a higher percentage of body heat. ...
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The defense of body temperature against environmental thermal challenges is a core objective of homeostatic regulation governed by the autonomic nervous system. Autonomous mechanisms of thermoregulation are only weakly affected by top-down modulation, allowing only transient tolerance for extreme cold. There is however, anecdotal evidence of a unique set of individuals known for extreme cold tolerance. Here we present a case study of a 57-year old Dutch national, Wim Hof, the so-called "Iceman", with the ability to withstand frequent prolonged periods of extreme cold exposure based on the practice of a self-developed technique involving a combination of forced breathing, cold exposure and meditation (collectively referred to as the Wim Hof Method, henceforth "WHM"). The relative contributions of the brain and the periphery that endow the Iceman with these capabilities is unknown. To investigate this, we conducted multi-modal imaging assessments of the brain and the periphery using a combination of fMRI and PET/CT imaging. Thermoregulatory defense was evoked by subjecting the Iceman (and a cohort of typical controls) to a fMRI paradigm designed to generate periods of mild hypothermia interspersed by periods of return to basal core body temperature. fMRI was acquired in two separate sessions: in a typical (passive) state and following the practice of WHM. In addition, the Iceman also underwent a whole body PET/CT imaging session using the tracers C11-hydroxyephedrine (HED) and 18F-fluorodeoxyglucose (FDG) during both thermoneutral and prolonged mild cold conditions. This acquisition allowed us to determine changes in sympathetic innervation (HED) and glucose consumption (FDG) in muscle and fat tissues in the absence of the WHM. fMRI analyses indicated that the WHM activates primary control centers for descending pain/cold stimuli modulation in the periaqueductal gray (PAG), possibly initiating a stress-induced analgesic response. In addition, the WHM also engages higher-order cortical areas (left anterior and right middle insula) that are uniquely associated with self-reflection, and which facilitate both internal focus and sustained attention in the presence of averse (e.g. cold) external stimuli. However, the activation of brown adipose tissue (BAT) was unremarkable. Finally, forceful respiration results in increased sympathetic innervation and glucose consumption in intercostal muscle, generating heat that dissipates to lung tissue and warms circulating blood in the pulmonary capillaries. Our results provide compelling evidence for the primacy of the brain (CNS) rather than the body (peripheral mechanisms) in mediating the Iceman's responses to cold exposure. They also suggest the compelling possibility that the WHM might allow practitioners to develop higher level of control over key components of the autonomous system, with implications for lifestyle interventions that might ameliorate multiple clinical syndromes.
... stimulating release o f secondary transmitter substances from endothelial cells or by direct action on the smooth muscle (for review see Hillard, 2000). The CB 1 receptor agonist arachidonylethanolamide (also known as anandamide) has been shown to induce endothelium-independent relaxation responses in rat coronary arteries with maximal relaxation observed with IpM anandamide, whilst the CB2 agonist palmitoylethanolamide was without effect (White et al, 2001). ...
Thesis
This thesis describes experiments to characterise non-adrenergic, non-cholinergic (NANC) relaxation responses in the rabbit vaginal wall. Specifically the roles of nitric oxide (NO), neuropeptides, purines and pyrimidines as mediators of these responses were investigated. The results of this investigation suggest that after inhibition of adrenergic and cholinergic responses, electrical field stimulation (EFS) of pre-contracted vaginal wall strips results in NANC relaxations. These relaxations are partially mediated by NO acting via soluble guanylate cyclase to increase levels of the second messenger cyclic guanosine-3', 5'-monophosphate (cGMP). However the major proportion of these responses is not mediated by NO and is not accompanied by increased cGMP or cyclic adenosine-3', 5'-monophosphate (cAMP). Vasoactive intestinal peptide (VlP)-related neuropeptides are able to concentration-dependently induce relaxation responses in the vaginal wall. However, my results suggest that these neuropeptides are not involved in NANC relaxations, since they are associated with increased cAMP and are inhibited by a-chymotrypsin, whilst NANC relaxations are unaffected. Other neuropeptides investigated did not induce relaxations, and so are unlikely to be involved in mediating NANC responses in the vaginal wall. Purines and pyrimidines were also found to induce relaxation responses in the vaginal wall. Furthermore adenosine- and ATP-induced responses are associated with increased cAMP levels. However the fact that inhibitors of these responses have no effect on NANC relaxations and the fact that NANC relaxations are not associated with increased cAMP levels suggest that purines and pyrimidines are also not mediators of NANC responses in this tissue. NANC relaxations of vaginal wall strips from ovariectomized rabbits were also investigated, but were not found to differ greatly from those from control animals. In conclusion, NANC relaxation responses in the rabbit vaginal wall from both normal and ovariectomized animals are in part mediated by NO, whilst the mediator of the major component of these responses remains unidentified.
... Both endogenous cannabinoids and phytocannabinoids as well as synthetic agents that act on the endocannabinoid system have the potential to impact the function of a wide range of organ systems and clinical conditions, including: anxiety and stress disorders, immune function, chronic pain and musculoskeletal conditions, mood regulation or depression, insomnia or sleep quality, and appetite signaling/food intake disorders. In this regard, research involving CBD has demonstrated various benefits such as mood regulating, neuroprotective, anti-inflammatory, anxiolytic, immunomodulatory, antiseizure and vascular effects (Schultes 1969;Campos et al. 2016;Hillard 2000). ...
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We determined the effects of a commercially available, GRAS (Generally Recognized As Safe) by independent conclusion, CBD-containing hemp oil extract on stress resilience, perceived recovery, mood, affect, body composition, and clinical safety markers in healthy human subjects. Methods: Using a randomized, placebo-controlled, double-blind design, 65 overweight, but otherwise healthy men and women (35.2 ± 11.4 years, 28.5 ± 3.3 kg/m²) ingested either Hemp Oil Extract [Hemp, 60 mg/d PlusCBDTM Extra Strength Hemp Extract Oil (15 mg hemp-derived CBD)] or a placebo (PLA) every day for six weeks while continuing to follow their normal diet and physical activity patterns. Outcome variables included changes in stress resilience, a 14-item panel of various psychometric parameters, heart-rate variability, plasma chromogranin A, body composition, and general markers of health. Data were analyzed using mixed factorial ANOVA, t-tests with 95% confidence intervals, and effect sizes (ES). Results: HDL cholesterol significantly improved in the Hemp group (p = 0.004; ES = 0.75). No other statistically significant group x time interaction effects were observed. Statistical tendencies for between-group differences were found for ‘I Get Pleasure From Life’ (p = 0.06, ES = 0.48) and ‘Ability to Cope with Stress’ (p = 0.07, ES = 0.46). Sleep quality (Hemp, p = 0.005, ES = 0.54) and sleep quantity (Hemp, p = 0.01, ES = 0.58) exhibited significant within-group changes. All values for hepato-renal function, cardiovascular health, fasting blood lipids, and whole blood cell counts remained within normal clinical limits with no between-group differences over time being identified. Conclusions: Hemp supplementation improved HDL cholesterol, tended to support psychometric measures of perceived sleep, stress response, and perceived life pleasure and was well tolerated with no clinically relevant safety concerns. Registered at clinicaltrials.gov: NCT04294706.
... The reported cases of hemorrhagic strokes following acute use of synthetic cannabinoids can be explained by the transient vasospasm observed immediately after use [110]. The capacity of synthetic cannabinoids to alter neurotransmitter release from nerve terminals can lead to activation of smooth muscle cells which are associated with disruption of endothelial cell function and can, therefore, lead to ischemia or hemorrhage [111]. Figure 4 summarizes the main pathophysiological mechanisms of strokes associated with synthetic cannabinoid abuse. ...
Article
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Drugs of abuse are associated with stroke, especially in young individuals. The major classes of drugs linked to stroke are cocaine, amphetamines, heroin, morphine, cannabis, and new synthetic cannabinoids, along with androgenic anabolic steroids (AASs). Both ischemic and hemorrhagic stroke have been reported due to drug abuse. Several common mechanisms have been identified, such as arrhythmias and cardioembolism, hypoxia, vascular toxicity, vascular spasm and effects on the thrombotic mechanism, as causes for ischemic stroke. For hemorrhagic stroke, acute hypertension, aneurysm formation/rupture and angiitis-like changes have been implicated. In AAS abuse, the effect of blood pressure is rather substance specific, whereas increased erythropoiesis usually leads to thromboembolism. Transient vasospasm, caused by synthetic cannabinoids, could lead to ischemic stroke. Opiates often cause infective endocarditis, resulting in ischemic stroke and hypereosinophilia accompanied by pyogenic arthritis, provoking J. Clin. Med. 2019, 8, 1295 2 of 43 hemorrhagic stroke. Genetic variants are linked to increased risk for stroke in cocaine abuse. The fact that case reports on cannabis-induced stroke usually refer to the young population is very alarming.
... There are three types of cannabinoids: botanical (marijuana and hashish), endogenous [anandamide,, and palmitoylethanolamide (PEA)], and synthetic cannabinoids (nabilone and dronabinol). The endocannabinoid system modulates selective pathways in the brain (De Vries et al., 2001;Fattore et al., 1999;Fernández-Ruiz et al., 2002;Guindon & Beaulieu, 2010), immune and cardiovascular system (Hillard, 2000;Parolaro, 1999) and also, has been hypothesized to be implicated in energy metabolism as a "fat sensor" through a potential GPR119 activation (Hansen et al., 2012). ...
Article
Introduction: Obesity is a pandemic problem associated to development of chronic degenerative diseases. N-arachidonylglycine (NAGly) is speculated to participate in pain regulation, immunity and insulin secretion; some N-acyl amino acids induce hyperphagia; in light of this, NAGly metabolic functions related to energy homeostasis has not been clarified yet. We aim to elucidate the effect of NAGly administration on weight gain, food intake, diet preferences and inflammatory profile changes in a murine model. Methods: 8-week-old BALB/c mice (n=78) were allocated into 4 groups for either sex: control, vector, NAGly-LD (1nM) and NAGly-HD (10nM). NAGly was subcutaneous administered 5 consecutive days for 3 weeks. Mice were exposed to standard diet (SD), high-fat diet (HFD) and high-sugar diet (HSD) simultaneously; weight gain, food intake and diet preferences were evaluated for 21-days. Finally, cytokines were analyzed by enzyme-linked immunosorbent assay (ELISA). Results: final weight gain was found higher in those following NAGly [LD: 21.6±1.1 g and HD: 21.4±2.1 g, (p=0.001)]. NAGly groups consumed more food in the first days; NAGly groups consumed more HFD [5.06±1.60; (p=0.001)] and HSD [1.10±0.69; (p=0.001)]. Conclusion: Our data propose that subcutaneous NAGly promotes acute hyperphagia events. We propose that NAGly might play a role related to the hunger-satiety circuit.
... Stimulation of CB receptors results in a number of signaling events, including inhibition of adenylate cyclase, activation of mitogen-activated protein kinase (MAPK) signaling and modulation of ion channels' activity (Matsuda et al., 1990;Felder et al., 1995;Slipetz et al., 1995;Gebremedhin et al., 1999;Hillard, 2000a;Demuth and Molleman, 2006;Turu and Hunyady, 2010;Franklin and Carrasco, 2013;Sánchez-Pastor et al., 2014;Szabó et al., 2014;Bondarenko et al., 2018). For instance, CBs target (either directly or via secondary signaling events) calcium, potassium, and TRP channel families (Hillard, 2000b;Caterina, 2014). Besides canonical CB receptors, G protein-coupled receptors GPR55 and GPR119 are advanced as eCB sensors (Godlewski et al., 2009). ...
Chapter
The endocannabinoid (eCB) system comprises endogenously produced cannabinoids (CBs), enzymes of their production and degradation, and CB-sensing receptors and transporters. The eCB system plays a critical role in virtually all stages of animal development. Studies on eCB system components and their physiological role have gained increasing attention with the rising legalization and medical use of marijuana products. The latter represent exogenous interventions that target the eCB system. This chapter summarizes knowledge in the field of CB contribution to gametogenesis, fertilization, embryo implantation, fetal development, birth, and adolescence-equivalent periods of ontogenesis. The material is complemented by the overview of data from our laboratory documenting the functional presence of the eCB system within cerebral arteries of baboons at different stages of development.
... Diff erences between the hemodynamic profi le of various cannabinoids may refl ect quantitative diff erences in cannabinoid CB (1) receptor expression in diff erent tissues and/or the involvement of as-yet-unidentifi ed receptors (Wagner et al., 2001). The possible mechanisms for these eff ects are inhibition of transmitter release from sympathetic nerve terminals, direct eff ects on vascular smooth muscle cells, and eff ects on endothelial cell function (Hillard, 2000). Iancu R et al Endocannabinoid and Ocular Vascular Integrity Nepal J Ophthalmol 2018;Vol 10 (20): 173-180 One of the fi rst studies regarding the eff ects of Anandamide on cerebral circulation has shown that the vasodilator response can be completely blocked by indomethacin, a non-selective cyclooxygenase inhibitor (Ellis et al, 1995). ...
Article
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The focus of this review is the role of endocannabinoid system in ocular and systemic circulation. By critically examining preclinical and clinical research, we explore the cannabinoid receptors localization and vascular implications as well as their interaction with other anti-inflammatory drugs. The objective is to transfer knowledge on the use of cannabinoids, specifically their effect on ocular circulation and intraocular pressure, and provide a better understanding of the endocannabinoid system complexity in modulating local and systemic circulations in order to identify potential uses and limitations of cannabinoid-based therapeutics.
... [7,16] CBD is also known to exert vascular effects, producing vasodilation as well as hypotension that may hold promise as protectant against cerebrovascular damage associated with stroke. [53,105] CBD has several features that may be exploited for the treatment of AD, including the prevention of glutamate-induced excitotoxicity, reduction of proinflammatory mediators, and the ability to scavenge reactive oxygen species (ROS) and reduce lipid peroxidation. [16,32,48,59] ...
Article
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Background Numerous physical, psychological, and emotional benefits have been attributed to marijuana since its first reported use in 2,600 BC in a Chinese pharmacopoeia. The phytocannabinoids, cannabidiol (CBD), and delta-9-tetrahydrocannabinol (Δ9-THC) are the most studied extracts from cannabis sativa subspecies hemp and marijuana. CBD and Δ9-THC interact uniquely with the endocannabinoid system (ECS). Through direct and indirect actions, intrinsic endocannabinoids and plant-based phytocannabinoids modulate and influence a variety of physiological systems influenced by the ECS. Methods In 1980, Cunha et al. reported anticonvulsant benefits in 7/8 subjects with medically uncontrolled epilepsy using marijuana extracts in a phase I clinical trial. Since then neurological applications have been the major focus of renewed research using medical marijuana and phytocannabinoid extracts. Results Recent neurological uses include adjunctive treatment for malignant brain tumors, Parkinson's disease, Alzheimer's disease, multiple sclerosis, neuropathic pain, and the childhood seizure disorders Lennox-Gastaut and Dravet syndromes. In addition, psychiatric and mood disorders, such as schizophrenia, anxiety, depression, addiction, postconcussion syndrome, and posttraumatic stress disorders are being studied using phytocannabinoids. Conclusions In this review we will provide animal and human research data on the current clinical neurological uses for CBD individually and in combination with Δ9-THC. We will emphasize the neuroprotective, antiinflammatory, and immunomodulatory benefits of phytocannabinoids and their applications in various clinical syndromes.
... The cardiovascular effects of anandamide are largely (though not completely) consistent with the effects of D 9 -THC (7). Its administration causes a decrease in vascular tone, an associated decrease in blood pressure, and an increase in vascular flow (Hillard 2000). Most studies of non-medical (recreational) use of cannabis examine the effects of smoking it, as this is the most common method of application in these conditions. ...
Article
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Cannabis spp. are some of the most controversial medicinal plants in the world. They contain great amounts of biologically active secondary metabolites, including the typical phenolic compounds called cannabinoids. Because of their low toxicity and complex biological activities, cannabinoids can be useful in the therapy of various diseases, but adverse psychological effects (of Δ9-THC in particular) raise concerns. This review summarizes the current knowledge of selected active C. indica compounds and their therapeutic potential. We summarize the main compounds contained in cannabis, the mechanisms of their effects, and their potential therapeutic applications. Further, we mention some of the clinical tests used to evaluate the efficacy of cannabinoids in therapy.
... Recently, it was shown that SCs cause hypoten- sion and bradycardia in a rat model, and it is thought to occur via the inhibition of sympathetic activity. Hence, increased para- sympathetic activity may trigger a penile erection (Hillard, 2000;Succu et al., 2006). ...
Article
Objective: To summarize the potential therapeutic benefits of medical marijuana for patients with traumatic brain injury (TBI). Methods: A systematic search was conducted using PubMed and Cochran's library for information regard the safety and efficacy of medical marijuana as a therapeutic agent. We investigated, in depth, articles specifically evaluating medical marijuana's use in TBI, as well as articles that summarized the effects of marijuana in general. Articles from the year 2000-2020 were included. Results: A total of 37 articles met our inclusion criteria. An additional 3 articles were obtained from reference lists. Conclusion: Studies have shown that medical marijuana can potentially aid the recovery from TBI by modulating the endocannabinoid system, reducing inflammation and secondary injury. Adverse cognitive and physiological effects have been observed in the acute setting as well as chronically, though more research is necessitated. There is also the concern of significant drug-drug interactions that have not been thoroughly studied. Thus, while there is evidence that medical marijuana can be beneficial in the treatment of TBI, more research is necessitated to fully explore the long-term efficacy and adverse effects.
Article
Excessive glutamate-mediated synaptic transmission and secondary excitotoxicity have been proposed as key determinants of neurodegeneration in many neurological diseases. Soluble mediators of inflammation have recently gained attention owing to their ability to enhance glutamate transmission and affect synaptic sensitivity to neurotransmitters. In the complex crosstalk between soluble immunoactive molecules and synapses, the endocannabinoid system (ECS) plays a central role, exerting an indirect neuroprotective action by inhibiting cytokine-dependent synaptic alterations, and a direct neuroprotective effect by limiting glutamate transmission and excitotoxic damage. On the other hand, the endocannabinoid (eCB)-mediated control of synaptic transmission is altered by proinflammatory cytokines with consequent effects in central nervous system (CNS) disorders. In this review, we summarize the interactions, at the pre- and postsynaptic level, between major inflammatory cytokines and the ECS. In addition, the behavioral and clinical consequences of the modulation of synaptic transmission during neuroinflammation are discussed.
Article
Objective Pathological angiogenesis is a hallmark of various diseases characterized by local hypoxia and inflammation. These disorders can be treated with inhibitors of angiogenesis, but current compounds display a variety of side effects and lose efficacy over time. This makes the identification of novel signaling pathways and pharmacological targets involved in angiogenesis a top priority. Approach and Results Here, we show that inactivation of FAAH (fatty acid amide hydrolase), the enzyme responsible for degradation of the endocannabinoid anandamide, strongly impairs angiogenesis in vitro and in vivo. Both, the pharmacological FAAH inhibitor URB597 and anandamide induce downregulation of gene sets for cell cycle progression and DNA replication in endothelial cells. This is underscored by cell biological experiments, in which both compounds inhibit proliferation and migration and evoke cell cycle exit of endothelial cells. This prominent antiangiogenic effect is also of pathophysiological relevance in vivo, as laser-induced choroidal neovascularization in the eye of FAAH −/− mice is strongly reduced. Conclusions Thus, elevation of endogenous anandamide levels by FAAH inhibition represents a novel antiangiogenic mechanism.
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Millions of Americans use cannabis for medical purposes including but not limited to pain, nausea, mood changes and appetite stimulation. The use of cannabinoid in the palliative care setting is a relatively new trend. Given the fact that a patient receiving palliative care is not necessarily approaching death, the increasing need for palliative care as the American population ages, this literature review was compiled in order to examine the potential efficacy of cannabis in treating the mental health comorbidities of palliative care patients. We attempted to create the most comprehensive report on cannabinoid use in palliative psychiatry. It summarizes the most recently published science on cannabinoid use in palliative care patients and its impact on mood and anxiety symptoms. The mechanism of action of cannabinoids on their associated receptors was elucidated, as were the pharmacological roles that specific molecules in cannabinoids, like cannabidiolic acid and terpenes, play in cannabinoids’ overall efficacy. The legal impediments to widespread cannabis use were also explored. While the potential efficacy of cannabinoids has proven to be mixed, more research is necessary to ensure that a potentially vital resource in treating palliative care patients does not go underutilized.
Article
Anandamide (N-arachidonoylethanolamine, AEA), an endogenous cannabinoid receptor agonist, causes potent vasodilation in the cerebral circulation through an endothelial-dependent or -independent mechanism. We have investigated the processing of [ ]AEA in cultured mouse cerebral microvascular endothelial cells (MEC) in order to better understand its mechanism of action in the cerebral vasculature. These cells took up anandamide very quickly, reaching a maximum value in 5 min and remaining at that level for at least 8 h. Analysis of the cell lipids demonstrated that, in addition to free anandamide, radioactivity was incorporated into phosphatidylcholine (PC), phosphatidylinositol (PI), and phosphatidylethanolamine (PE) in a time-dependent manner. Analysis of the hydrolyzed cell lipids indicated that anandamide was converted to arachidonic acid, a process that was inhibited by the selective fatty acid amide hydrolase inhibitor oleyl trifluoromethyl ketone (OTMK). Phospholipase A2 (PLA2) hydrolysis of the PC, PI, and PE fractions indicated that the arachidonic acid formed from anandamide was esterified predominately into sn-2 position of the endothelial phospholipids. Furthermore, anandamide and arachidonic acid were released when the cells were incubated with A23187. These results suggest that the biological activity of anandamide might be regulated by its rapid uptake and calcium-dependent release in endothelial cells, and conversion of anandamide to arachidonic acid might serve as an inactivation process in the cerebral microcirculation.
Article
The endocannabinoid system has a key role in female reproduction, including implantation, decidualization and placentation. A growing number of studies indicate that placental and peripheral blood anandamide levels correlate closely with both spontaneous miscarriage and ectopic pregnancy. Anandamide has also been implicated in blood pressure regulation. In this study, we aimed to determine circulating anandamide levels in preeclampsia for the first time in the literature. Forty-three preeclamptic patients and 71 healthy pregnant women were involved in this case-control study. Serum anandamide concentrations were determined by high-performance liquid chromatography-mass spectrometry technique. Serum total soluble fms-like tyrosine kinase-1 (sFlt-1) and biologically active placental growth factor (PlGF) levels were measured by electrochemiluminescence immunoassay. For statistical analyses, nonparametric methods were applied. Serum levels of anandamide were significantly lower in preeclamptic patients than in healthy pregnant women (0.75 (0.44-1.03) ng ml(-1) vs. 1.30 (0.76-2.0) ng ml(-1), P<0.001). Preeclamptic patients had significantly higher sFlt-1 levels (12 121 (7963-18 316) pg ml(-1) vs. 2299 (1393-3179) pg ml(-1), P<0.001) and significantly lower PlGF concentrations (71.2 (39.2-86.4) pg ml(-1) vs. 256.8 (181.1-421.0) pg ml(-1), P<0.001) as compared with healthy pregnant women. Serum anandamide concentrations did not correlate with serum levels of sFlt-1 and PlGF in our healthy pregnant and preeclamptic groups. In conclusion, we demonstrated for the first time in the literature that serum anandamide concentrations are decreased in women with preeclampsia. However, the cause and consequence of this observation remain to be determined.Hypertension Research advance online publication, 26 February 2015; doi:10.1038/hr.2015.20.
Thesis
Weefseldoorbloeding wordt geregeld door een complexe reeks mechanismen die, hoofdzakelijk door het regelen van de diameter van de bloedvaten, zorgen voor het behoud van de weefselhomeostase. Vasodilatatie speelt een belangrijke rol in de regeling van de doorbloeding van een bepaald vaatbed. Het voornaamste doel van het onderzoek verricht in het kader van deze thesis, was meer te weten te komen over het belang en de werkingsmechanismen van verschillende vasodilaterende stoffen (EDHF, cannabinoïden, ...) in geïsoleerde maag- en mesenterische arteriën van de rat om zo tot een beter inzicht te komen over hun rol in de gastro-intestinale doorbloeding. In dit onderzoek werd gebruik gemaakt van verschillende in vitro technieken op geïsoleerde bloedvaten: membraanpotentiaal metingen met behulp van conventionele micro-elektroden, isometrische tensiemetingen met een draadmyograaf en calcium bepalingen door middel van confocale microscopie.
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This study aims to present the management of priapism in adult men in Port Harcourt, Nigeria. All patients who presented with priapism in 2 hospitals in Port Harcourt from July 2007 to April 2014 were prospectively studied.Treatment was assigned based on clinical presentation. Data analyzed included:age on clinical presentation,riskfactor, mode,and outcome of management.There were 18 patients aged 17 to 60 years(median age:30years).Threepatients(16.7%)presentedwithstutteringpriapism.Mostofthe patientspresentedafter24hoursofonset.Sixteenpatients(89.9%)hadhematological disorders.Fivepatients(27.8%)tooksuspectedaphrodisiacmedications.Sevenpatients (38.9%)weremanagedconservatively.Therestachieveddetumescencefollowing glandulo-cavernousshunting.Erectilefunctionaftertreatmentwassatisfactoryin5 patients(27.8%).ThecommonestcauseofpriapisminPortHarcourtwashematological disorder.Mostofthepatientspresentedlate.Prevalenceoferectiledysfunctionafter treatmentwashigh
Chapter
A number of recreationally used drugs, licit and illicit, have been linked to ischemic and hemorrhagic stroke. In some cases, for example, ethanol and tobacco, epidemiologic data convincingly identify the agents as risk factors without implying direct temporal causality. In the case of psychostimulant drugs-including methamphetamine, 3,4-methylenedioxymetamphetamine ("ecstasy"), cathinone derivatives ("bath salts"), and cocaine, as well as cannabis products-linkage is based on case reports and limited epidemiologic data, but temporal association of use, plus biological plausibility, suggest direct causality. Recreational drug use should be considered in any patient with a stroke, regardless of age.
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Reductions in state anxiety have been reported following an acute bout of aerobic exercise. However, less is known regarding anxiety and fear ratings to specific threatening stimuli following an acute bout of aerobic exercise in women with PTSD. Moreover, the mechanisms responsible for the anxiolytic effects of exercise are not fully understood, although recent studies suggest a role for the endocannabinoid (eCB) system. Thus, this study utilized a randomized, counterbalanced approach to examine anxiety and fear ratings to predictable or unpredictable electric shock administration and circulating concentrations of eCBs and mood states immediately following moderate-intensity aerobic exercise (30 min on treadmill at 70–75% maximum heart rate) and a quiet rest control condition in women with and without a history of trauma, and in women with PTSD (N = 42). Results revealed that anxiety and fear ratings to unpredictable and predictable threats were significantly (p < .05) lower following exercise compared to quiet rest, with correlational analyses indicating those with greater increases in circulating eCBs had greater reductions in anxiety and fear ratings to unpredictable and predictable threats following exercise. Also, there were significant (p < .05) reductions in fatigue, confusion, total mood disturbance, and increases in positive affect following exercise for the entire sample. Non-trauma controls and PTSD groups reported significant (p < .05) increases in vigor, with additional mood improvements following exercise for the PTSD group (i.e., decreases in state anxiety, negative affect, tension, anger, and depression). Results from this study suggest that aerobic exercise exerts psychological benefits in women with PTSD, potentially due to exercise-induced increases in circulating concentrations of eCBs.
Chapter
Multiple Sclerosis and Cannabis – Benefits, Risks, and Special Considerations People with multiple sclerosis (MS) are interested in and use cannabis, and MS health professionals may be involved in the decision-making process about cannabis and provide care to those with MS who use cannabis. There is evidence that cannabis has therapeutic symptomatic effects in MS. Likewise, there is evidence that cannabis has side effects, drug interactions, and other potentially significant negative effects. People with MS and health professionals may not be knowledgeable about these potential beneficial and adverse effects and, as a result, in the MS community, informed decision-making may not be occurring. The aim of this chapter is to provide practical, MS-relevant information about the benefits and risks of cannabis so that, as with any medication, health professionals may effectively provide objective cannabis information, facilitate informed decision-making, and optimize safety and effectiveness in those patients who choose to use cannabis. The Evidence for Cannabis Use in Movement Disorders This chapter reviews the evidence for the efficacy and tolerability of cannabis in movement disorders. We present all the available preclinical and clinical studies of cannabis in Parkinson disease, Huntington’s disease, dystonia, Tourette syndrome, and other movement disorders. To date, there is not sufficient evidence to suggest that cannabis and its many derivative forms are effective and safe in any movement disorder. There is limited evidence for benefit of delta-9- tetrahydrocannabinol (Δ9-THC) and its synthetic analogs in Tourette syndrome and insufficient evidence to support its use in Parkinson disease, Huntington’s disease, and dystonia. There are no controlled clinical trials for the use of cannabis in essential tremor, restlessness legs syndrome, or rapid eye movement sleep behavior disorder. Overall, cannabidiol (CBD) was generally better tolerated than THC. Dizziness was one of the most common side effects of cannabinoids. Dizziness, falls, cognition, and liver function are common concerns posed by the elderly. Elderly persons and those with more advanced PD and HD should use cannabis cautiously. Cannabinoids in Neurosurgery This chapter will review the published literature for the treatment of neurosurgical conditions, including chronic low back and radicular pain, malignant gliomas, traumatic spinal cord and brain injury, and cerebrovascular hemorrhage. Summarizing the results, we have concluded that there is limited evidence to support or deny any benefits of the cannabinoid effectiveness for neurosurgery patients. Further epidemiological and clinical studies with rigorous study designs overcoming methodological limitations are needed to clarify contradictory findings. Therefore, the lack of conclusive scientific validation on short- and long-term safety, efficacy, and health risks should be the reason to limit the use of cannabinoids at the present time.
Chapter
Cannabinoids are known to modulate cardiovascular functions including heart rate, vascular tone, and blood pressure in humans and animal models. Essential components of the endocannabinoid system, namely, the production, degradation, and signaling pathways of endocannabinoids have been described not only in the central and peripheral nervous system but also in myocardium, vasculature, platelets, and immune cells. The mechanisms of cardiovascular responses to endocannabinoids are often complex and may involve cannabinoid CB1 and CB2 receptors or non-CB1/2 receptor targets. Preclinical and some clinical studies have suggested that targeting the endocannabinoid system can improve cardiovascular functions in a number of pathophysiological conditions, including hypertension, metabolic syndrome, sepsis, and atherosclerosis. In this chapter, we summarize the local and systemic cardiovascular effects of cannabinoids and highlight our current knowledge regarding the therapeutic potential of endocannabinoid signaling and modulation.
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Abstract BACKGROUND Inflammation is crucial to tumor progression. A traumatic event at a specific site in the brain activates the signaling molecules, which triggers inflammation as the initial response within the tumor and its surroundings. The educated immune cells and secreted proteins then initiate the inflammatory cascade leading to persistent chronic inflammation. Therefore, estimation of the circulating inflammatory indicators kynurenine (KYN), interleukin-6 (IL-6), tissue-inhibitor of matrix-metalloproteinase-1 and human telomerase reverse transcriptase (hTERT) along with neutrophil-lymphocyte ratio (NLR) has prognostic value. AIM To assess the utility of chosen inflammatory marker panel in estimating systemic inflammation. METHODS The chosen markers were quantitatively evaluated in 90 naive, molecularly subtyped plasma samples of glioma. A correlation between the markers and confounders was assessed to establish their prognostication power. Follow-up on the levels of the indicators was done 3-mo post-surgery. To establish the validity of circulating KYN, it was also screened qualitatively by dot-immune-assay and by immunofluorescence-immunohistochemistry in tumor tissues. RESULTS Median values of circulating KYN, IL-6, hTERT, tissue-inhibitor of matrixmetalloproteinase- 1 and NLR in isocitrate-dehydrogenase-mutant/wildtype and within the astrocytic sub-groups were estimated, which differed from controls, reaching statistical significance (P < 0.0001). All markers negatively correlated Abstract BACKGROUND Inflammation is crucial to tumor progression. A traumatic event at a specific site in the brain activates the signaling molecules, which triggers inflammation as the initial response within the tumor and its surroundings. The educated immune cells and secreted proteins then initiate the inflammatory cascade leading to persistent chronic inflammation. Therefore, estimation of the circulating inflammatory indicators kynurenine (KYN), interleukin-6 (IL-6), tissue-inhibitor of matrix-metalloproteinase-1 and human telomerase reverse transcriptase (hTERT) along with neutrophil-lymphocyte ratio (NLR) has prognostic value. AIM To assess the utility of chosen inflammatory marker panel in estimating systemic inflammation. METHODS The chosen markers were quantitatively evaluated in 90 naive, molecularly subtyped plasma samples of glioma. A correlation between the markers and confounders was assessed to establish their prognostication power. Follow-up on the levels of the indicators was done 3-mo post-surgery. To establish the validity of circulating KYN, it was also screened qualitatively by dot-immune-assay and by immunofluorescence-immunohistochemistry in tumor tissues. RESULTS Median values of circulating KYN, IL-6, hTERT, tissue-inhibitor of matrixmetalloproteinase- 1 and NLR in isocitrate-dehydrogenase-mutant/wildtype and within the astrocytic sub-groups were estimated, which differed from controls, reaching statistical significance (P < 0.0001). All markers negatively correlated with mortality (P < 0.0001). Applying combination-statistics, the panel of KYN, IL- 6, hTERT and NLR achieved higher sensitivity and specificity (> 90%) than standalone markers, to define survival. The inflammatory panel could discriminate between WHO grades, and isocitrate-dehydrogenase-mutant/wildtype and define differential survival between astrocytic isocitrate-dehydrogenase-mutant/ wildtype. Therefore, its assessment for precise disease prognosis is indicated. Association of KYN with NLR, IL-6 and hTERT was significant. Cox-regression described KYN, IL-6, NLR, and hTERT as good prognostic markers, independent of confounders. Multivariate linear-regression analysis confirmed the association of KYN and hTERT with inflammation marker IL-6.There was a concomitant significant decrease in their levels in a 3-mo follow-up. CONCLUSION The first evidence-based study of circulating-KYN in molecularly defined gliomas, wherein the tissue expression was found to be concomitant with plasma levels. A non-invasive model for assessing indicators of chronic systemic inflammation is proposed. Key Words: Circulating; Glioma; Inflammatory marker; Kynurenine; Non-invasive; Prognostic
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One of the most important causes of brain injury in the neonatal period is a perinatal hypoxic-ischemic event. This devastating condition can lead to long-term neurological deficits or even death. After hypoxic-ischemic brain injury, a variety of specific cellular mechanisms are set in motion, triggering cell damage and finally producing cell death. Effective therapeutic treatments against this phenomenon are still unavailable because of complex molecular mechanisms underlying hypoxic-ischemic brain injury. After a thorough understanding of the mechanism underlying neural plasticity following hypoxic-ischemic brain injury, various neuroprotective therapies have been developed for alleviating brain injury and improving long-term outcomes. Among them, the endocannabinoid system emerges as a natural system of neuroprotection. The endocannabinoid system modulates a wide range of physiological processes in mammals and has demonstrated neuroprotective effects in different paradigms of acute brain injury, acting as a natural neuroprotectant. The aim of this review is to study the use of different therapies to induce long-term therapeutic effects after hypoxic-ischemic brain injury, and analyze the important role of the endocannabinoid system as a new neuroprotective strategy against perinatal hypoxic-ischemic brain injury.
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Arachidonylethanolamide, an arachidonic acid derivative in porcine brain, was identified in a screen for endogenous ligands for the cannabinoid receptor. The structure of this compound, which has been named "anandamide," was determined by mass spectrometry and nuclear magnetic resonance spectroscopy and was confirmed by synthesis. Anandamide inhibited the specific binding of a radiolabeled cannabinoid probe to synaptosomal membranes in a manner typical of competitive ligands and produced a concentration-dependent inhibition of the electrically evoked twitch response to the mouse vas deferens, a characteristic effect of psychotropic cannabinoids. These properties suggest that anandamide may function as a natural ligand for the cannabinoid receptor.
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The endogenous cannabinoid receptor agonist anandamide is present in central and peripheral tissues. As the kidney contains both the amidase that degrades anandamide and transcripts for anandamide receptors, we characterized the molecular components of the anandamide signaling system and the vascular effects of exogenous anandamide in the kidney. We show that anandamide is present in kidney homogenates, cultured renal endothelial cells (EC), and mesangial cells; these cells also contain anandamide amidase. Reverse-transcriptase PCR shows that EC contain transcripts for cannabinoid type 1 (CB1) receptors, while mesangial cells have mRNA for both CB1 and CB2 receptors. EC exhibit specific, high-affinity binding of anandamide (Kd = 27.4 nM). Anandamide (1 microM) vasodilates juxtamedullary afferent arterioles perfused in vitro; the vasodilation can be blocked by nitric oxide (NO) synthase inhibition with L-NAME (0.1 mM) or CB1 receptor antagonism with SR 141716A (1 microM), but not by indomethacin (10 microM). Anandamide (10 nM) stimulates CB1-receptor-mediated NO release from perfused renal arterial segments; a similar effect was seen in EC. Finally, anandamide (1 microM) produces a NO-mediated inhibition of KCl-stimulated [3H]norepinephrine release from sympathetic nerves on isolated renal arterial segments. Hence, an anandamide signaling system is present in the kidney, where it exerts significant vasorelaxant and neuromodulatory effects.
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An endogenous cannabimimetic molecule, 2-arachidonoylglycerol, induces a rapid, transient increase in intracellular free Ca2+ concentrations in NG108–15 cells through a cannabinoid CB1 receptor-dependent mechanism. We examined the activities of 24 relevant compounds (2-arachidonoylglycerol, its structural analogues, and several synthetic cannabinoids). We found that 2-arachidonoylglycerol is the most potent compound examined so far: its activity was detectable from as low as 0.3 nm, and the maximal response induced by 2-arachidonoylglycerol exceeded the responses induced by others. Activities of HU-210 and CP55940, potent cannabinoid receptor agonists, were also detectable from as low as 0.3 nm, whereas the maximal responses induced by these compounds were low compared with 2-arachidonoylglycerol. Anandamide was also found to act as a partial agonist in this assay system. We confirmed that free arachidonic acid failed to elicit a response. Furthermore, we found that a metabolically stable ether-linked analogue of 2-arachidonoylglycerol possesses appreciable agonistic activity, although its activity was apparently lower than that of 2-arachidonoylglycerol. We also confirmed that pretreating cells with various cannabinoid receptor agonists nullified the response induced by 2-arachidonoylglycerol, whereas pretreating cells with other neurotransmitters or neuromodulators did not affect the response. These results strongly suggested that the cannabinoid CB1 receptor is originally a 2-arachidonoylglycerol receptor, and 2-arachidonoylglycerol is the intrinsic physiological ligand for the cannabinoid CB1 receptor.
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Cannabinoids, including the endogenous ligand arachidonyl ethanolamide (anandamide), elicit not only neurobehavioral but also cardiovascular effects. Two cannabinoid receptors, CB1 and CB2, have been cloned, and studies with the selective CB1 receptor antagonist SR141716A have implicated peripherally located CB1 receptors in the hypotensive action of cannabinoids. In rat mesenteric arteries, anandamide-induced vasodilation is inhibited by SR141716A, but other potent CB1 receptor agonists, such as HU-210, do not cause vasodilation, which implicates an as-yet-unidentified receptor in this effect. Here we show that "abnormal cannabidiol" (Abn-cbd) is a neurobehaviorally inactive cannabinoid that does not bind to CB1 receptors, yet causes SR141716A-sensitive hypotension and mesenteric vasodilation in wild-type mice and in mice lacking CB1 receptors or both CB1 and CB2 receptors. Hypotension by Abn-cbd is also inhibited by cannabidiol (20 microgram/g), which does not influence anandamide- or HU-210-induced hypotension. In the rat mesenteric arterial bed, Abn-cbd-induced vasodilation is unaffected by blockade of endothelial NO synthase, cyclooxygenase, or capsaicin receptors, but it is abolished by endothelial denudation. Mesenteric vasodilation by Abn-cbd, but not by acetylcholine, sodium nitroprusside, or capsaicine, is blocked by SR141716A (1 microM) or by cannabidiol (10 microM). Abn-cbd-induced vasodilation is also blocked in the presence of charybdotoxin (100 nM) plus apamin (100 nM), a combination of K(+)-channel toxins reported to block the release of an endothelium-derived hyperpolarizing factor (EDHF). These findings suggest that Abn-cbd and cannabidiol are a selective agonist and antagonist, respectively, of an as-yet-unidentified endothelial receptor for anandamide, activation of which elicits NO-independent mesenteric vasodilation, possibly by means of the release of EDHF.
Article
ANANDAMIDE (N-arachidonoyl-ethanolamine) was recently identified as a brain arachidonate derivative that binds to and activates cannabinoid receptors1–4, yet the mechanisms underlying formation, release and inactivation of this putative messenger molecule are still unclear. Here we report that anandamide is produced in and released from cultured brain neurons in a calcium ion-dependent manner when the neurons are stimulated with membrane-depolarizing agents. Anandamide formation occurs through phos-phodiesterase-mediated cleavage of a novel phospholipid precursor, N-arachidonoyl-phosphatidylethanolamine. A similar mechanism also governs the formation of a family of anandamide congeners, whose possible roles in neuronal signalling remain unknown. Our results and those of others5,6indicate therefore that multiple biochemical pathways may participate in anandamide formation in brain tissue. The life span of extracellular anandamide is limited by a rapid and selective process of cellular uptake, which is accompanied by hydrolytic degradation to ethanolamine and arachidonate. Our results thus strongly support the proposed role of anandamide as an endogenous neuronal messenger.
Article
Four chiral congeners of arachidonylethanolamide (anandamide) have been synthesized and evaluated for (a) their ability to bind to the cannabinoid receptor in rat forebrain membranes and (b) their pharmacological potency as measured by the compounds' ability to inhibit electrically-evoked contractions of the mouse vas deferens. The lead analog was also tested for its potency in vivo. Of the analogs tested, (R)-(+)-arachidonyl-1'-hydroxy-2'-propylamide [(R)-methanandamide] exhibited the highest affinity for the cannabinoid receptor with a Ki of 20 +/- 1.6 nM, 4-fold lower than that of anandamide (Ki = 78 +/- 2 nM). Moreover, determination of the cannabinoid binding affinity in the presence and absence of the protease inhibitor phenylmethanesulfonyl fluoride (PMSF) revealed that (R)-methanandamide possesses a remarkable stability to aminopeptidase hydrolysis. Pharmacological studies on mouse isolated vasa deferentia demonstrated that all four analogs produce concentration-related inhibition of the twitch response and the order of potency is the same as the rank order of the affinities of these agonists for cannabinoid binding sites. Furthermore, experiments with mice have demonstrated that (R)-methanandamide also possesses cannabimimetric properties in vivo, as established by the four tests of hypothermia, hypokinesia, ring immobility, and antinociception.
Article
The stimulus-induced biosynthesis of the endocannabinoid 2-arachidonoylglycerol (2-AG) in intact mouse J774 macrophages and the inactivation of 2-AG by the same cells or by rat circulating macrophages was studied. By using gas chromatography-mass spectrometry, we found that ionomycin (5 µm) and lipopolysaccharide (LPS, 200 µg·mL−1) cause a 24-fold and 2.5-fold stimulation of 2-AG levels in J774 cells, respectively, thus providing unprecedented evidence that this cannabimimetic metabolite can be synthesized by macrophages. In J774 cells, LPS also induced a 7.8-fold increase of the levels of the other endocannabinoid, anandamide, and, in rat circulating macrophages, an almost twofold increase of 2-AG levels. Extracellular [3H]2-AG was cleared from the medium of intact J774 macrophages (t1/2 = 19–28 min) and esterified to phospholipids, diacylglycerols and triglycerides or hydrolyzed to [3H]arachidonic acid and glycerol. These catabolic processes were attenuated differentially by various enzyme inhibitors. Rat circulating macrophages were shown to contain enzymatic activities for the hydrolysis of 2-AG, including: (a) fatty acid amide hydrolase (FAAH), the enzyme responsible for anandamide breakdown and previously shown to catalyse also 2-AG hydrolysis, and (b) a 2-AG hydrolase activity different from FAAH and down-regulated by LPS. High levels of FAAH mRNA were found in circulating macrophages but not platelets, which, however, contain a 2-AG hydrolase. Both platelets and macrophages were shown to express the mRNA for the CB1 cannabinoid receptor. A macrophage 2-AG hydrolase with apparent Km = 110 µm and Vmax = 7.9 nmol·min−1·(mg protein)−1 was partially characterized in J774 cells and found to exhibit an optimal pH of 6–7 and little or no sensitivity to typical FAAH inhibitors. These findings demonstrate for the first time that macrophages participate in the homeostasis of the hypotensive and immunomodulatory endocannabinoid 2-AG through metabolic mechanisms that are subject to regulation.
Article
Both morphine and anandamide significantly stimulated cultured endothelial intracellular calcium level increases in a concentration-dependent manner in cells pre-loaded with fura 2/AM. Morphine is more potent than anandamide (approximately 275 vs. 135 nM [Ca]i), and the [Ca]i for both ligands was blocked by prior exposure of the cells to their respective receptor antagonist, i.e., naloxone and SR 171416A. Various opioid peptides did not exhibit this ability, indicating a morphine-μ3-mediated process. In comparing the sequence of events concerning morphine's and anandamide's action in stimulating both [Ca]i and nitric oxide (NO) production in endothelial cells, we found that the first event precedes the second by 40±8 sec. The opiate and cannabinoid stimulation of [Ca]i was attenuated in cells leeched of calcium, strongly suggesting that intracellular calcium levels regulate NOS activity.
Article
Human vascular endothelial cells were found to generate and release 2-arachidonoylglycerol, an endogenous cannabinoid receptor ligand, upon stimulation with thrombin or A23187. We confirmed that vascular smooth muscle cells as well as endothelial cells possess cannabinoid CB1 receptor mRNA. 2-Arachidonoylglycerol, generated in vascular tissues, may play an important role in modulating vascular tone through acting on the cannabinoid CB1 receptor expressed on vascular smooth muscle cells, endothelial cells as well as peripheral nerve terminals.
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In anaesthetised rats, the endogenous cannabinoid anandamide has potent cardiovascular effects that include a brief pressor effect and a more prolonged depressor response. The depressor response is attenuated after transection of the cervical spinal cord or blockade of alpha-adrenergic receptors by phentolamine, and is dose-dependently inhibited by a selective antagonist of the CB1 cannabinoid receptor. The pressor component is not affected by any of these interventions. This suggests that the depressor response is due to inhibition of sympathetic tone mediated by CB1 receptors, whereas the pressor component is due to a peripheral action that does not involve the same receptors or the sympathetic nervous system.
Article
SR141716A is the first selective and orally active antagonist of the brain cannabinoid receptor. This compound displays nanomolar affinity for the central cannabinoid receptor but is not active on the peripheral cannabinoid receptor. In vitro, SR141716A antagonises the inhibitory effects of cannabinoid receptor agonists on both mouse vas deferens contractions and adenylyl cyclase activity in rat brain membranes. After intraperitoneal or oral administration SR141716A antagonises classical pharmacological and behavioural effects of cannabinoid receptor agonists. This compound should prove to be a powerful tool for investigating the in vivo functions of the anandamide/cannabinoid system.
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In experienced marijuana smokers, marijuana smoking was accompanied by a significant bilateral increase in cerebral blood flow (CBF) especially in the frontal regions and cerebral blood velocity. The post-marijuana CBF increase could not be explained on the basis on changes in general circulation or respiration. Similarly, the CBF increase was unrelated to plasma levels of tetrahydrocannabinol and extracranial circulation. Behavioral changes showed significant correlations with CBF. CBF and brain function are closely coupled and therefore it seemed highly likely that CBF changes after marijuana were closely related to its effect on mood and behavior.
Article
Since the identification of nitric oxide (NO) as an important mediator of endothelium-dependent relaxation, it has become clear that there is an additional endothelial relaxant factor, termed the endothelium-derived hyperpolarizing factor (EDHF). The identity of EDHF has remained elusive, but it is thought to be an arachidonic acid metabolite. We now report that EDHF-mediated relaxations in the rat mesenteric arterial bed are blocked by a highly selective cannabinoid receptor antagonist, SR141716A, consistent with EDHF being a cannabinoid-like substance. Furthermore, in conscious rats,. the NO-independent depressor and regional vasodilator effects of bradykinin were inhibited by SR141716A. The relaxations in the isolated mesentery were accompanied by the accumulation of an arachidonic acid metabolite, which co-eluted on TLC separation with arachidonoylethanolamide (anandamide), an endogenous cannabinoid derived from arachidonate. We further report that anandamide is a potent vasorelaxant in the mesentery, acting via a hyperpolarizing mechanism. These findings suggest that an endogenous cannabinoid is an endothelium-derived vasorelaxant, which may be EDHF.
Article
The endogenous cannabinoid, anandamide, has been suggested as an endothelium-derived hyperpolarizing factor (EDHF). We found that anandamide-evoked relaxation in isolated segments of rat mesenteric artery was associated with smooth muscle hyperpolarization. However, although anandamide-evoked relaxation was inhibited by either charybdotoxin (ChTX) or iberiotoxin, inhibition of the relaxation to EDHF required a combination of ChTX and apamin. The relaxations induced by either anandamide or EDHF were not inhibited by the cannabinoid receptor (CB1) antagonist SRI41716A, or mimicked by selective CB1 agonists. Thus, anandamide appears to cause smooth muscle relaxation via a CB1 receptor-independent mechanism and cannabinoid receptor activation apparently does not contribute to EDHF-mediated relaxation in this resistance artery. British Journal of Pharmacology (1997) 121, 1509–1511; doi:10.1038/sj.bjp.0701361
Article
1. The effects of anandamide on K+ currents and membrane potential have been examined in freshly-isolated smooth muscle cells from rat hepatic artery and the results compared with the effects of this arachidonic acid derivative on tension and membrane potential changes in segments of whole artery. 2. In the presence of 0.3 mM L-NOARG and 10 microM indomethacin, anandamide (0.1-100 microM) and endothelium-derived hyperpolarizing factor (EDHF; liberated by acetylcholine, 0.01-10 microM) each relaxed endothelium-intact segments of hepatic artery precontracted with phenylephrine. These effects of anandamide, but not those of EDHF, were antagonized by the cannabinoid receptor antagonist, SR141716A (3 microM). 3. The relaxant effects of anandamide were unaffected by a toxin combination (apamin plus charybdotoxin, each 0.3 microM) which abolishes EDHF relaxations and were essentially unchanged in endothelium-denuded arteries. The relaxant effects of anandamide in endothelium-intact arteries were significantly reduced in a physiological salt solution containing 30 mM KCl and abolished when the K+ concentration was raised to 60 mM. 4. Anandamide (10 microM), acetylcholine (1 microM, via release of EDHF) and levcromakalim (10 microM) each markedly hyperpolarized the membrane potential of the smooth muscle cells of endothelium-intact arteries. However, when the endothelium was removed, the hyperpolarizing effects of both anandamide (10 microM) and acetylcholine were essentially abolished whereas those of levcromakalim (10 microM) were unaffected. 5. Under voltage-clamp conditions, anandamide (10 microM) abolished spontaneous transient outward currents (STOCs) in freshly-isolated single hepatic artery cells held at 0 mV but had no effect on the holding current at this potential. In current-clamp mode, the spontaneous hyperpolarizing potentials which corresponded to the STOCs were abolished with no significant change in basal membrane potential. 6. Anandamide (10 microM) abolished the iberiotoxin-sensitive K+ current (IBK(Ca)) produced by caffeine and the corresponding hyperpolarizations generated by this xanthine derivative in current-clamp mode. In contrast, anandamide had no effect on IBK(Ca) generated on exposure to NS1619 (30 microM). 7. It was concluded that anandamide is not EDHF in the rat hepatic artery. Anandamide-induced hyperpolarization is exerted indirectly and requires the presence of the endothelium. Anandamide also acts on the smooth muscle cells to inhibit processes which require functional intracellular calcium stores. This direct action seems more important than membrane hyperpolarization in relaxing phenylephrine-contracted vessels.
Article
1. Relaxation of the methoxamine-precontracted rat small mesenteric artery by endothelium-derived hyperpolarizing factor (EDHF) was compared with relaxation to the cannabinoid, anandamide (arachidonylethanolamide). EDHF was produced in a concentration- and endothelium-dependent fashion in the presence of NG-nitro-L-arginine methyl ester (L-NAME, 100 microM) by either carbachol (pEC50 [negative logarithm of the EC50] = 6.19 +/- 0.01, Rmax [maximum response] = 93.2 +/- 0.4%; n = 14) or calcium ionophore A23187 (pEC50 = 6.46 +/- 0.02, Rmax = 83.6 +/- 3.6%; n = 8). Anandamide responses were independent of the presence of endothelium or L-NAME (control with endothelium: pEC50 = 6.31 +/- 0.06, Rmax = 94.7 +/- 4.6%; n = 10; with L-NAME: pEC50 = 6.33 +/- 0.04, Rmax = 93.4 +/- 6.0%; n = 4). 2. The selective cannabinoid receptor antagonist, SR 141716A (1 microM) caused rightward shifts of the concentration-response curves to both carbachol (2.5 fold) and A23187 (3.3 fold). It also antagonized anandamide relaxations in the presence or absence of endothelium giving a 2 fold shift in each case. SR 141716A (10 microM) greatly reduced the Rmax values for EDHF-mediated relaxations to carbachol (control, 93.2 +/- 0.4%; SR 141716A, 10.7 +/- 2.5%; n = 5; P < 0.001) and A23187 (control, 84.8 +/- 2.1%; SR 141716A, 3.5 +/- 2.3%; n = 6; P < 0.001) but caused a 10 fold parallel shift in the concentration-relaxation curve for anandamide without affecting Rmax. 3. Precontraction with 60 mM KCl significantly reduced (P < 0.01; n = 4 for all) relaxations to 1 microM carbachol (control 68.8 +/- 5.6% versus 17.8 +/- 7.1%), A23187 (control 71.4 +/- 6.1% versus 3.9 +/- 0.45%) and anandamide (control 71.1 +/- 7.0% versus 5.2 +/- 3.6%). Similar effects were seen in the presence of 25 mM K+. Incubation of vessels with pertussis toxin (PTX; 400 ng ml-1, 2 h) also reduced (P < 0.01; n = 4 for all) relaxations to 1 microM carbachol (control 63.5 +/- 7.5% versus 9.0 +/- 3.2%), A23187 (control 77.0 +/- 5.8% versus 16.2 +/- 7.1%) and anandamide (control 89.8 +/- 2.2% versus 17.6 +/- 8.7%). 4. Incubation of vessels with the protease inhibitor phenylmethylsulphonyl fluoride (PMSF; 200 microM) significantly potentiated (P < 0.01), to a similar extent (approximately 2 fold), relaxation to A23187 (pEC50: control, 6.45 +/- 0.04; PMSF, 6.74 +/- 0.10; n = 4) and anandamide (pEC50: control, 6.31 +/- 0.02; PMSF, 6.61 +/- 0.08; n = 8). PMSF also potentiated carbachol responses both in the presence (pEC50: control, 6.25 +/- 0.01; PMSF, 7.00 +/- 0.01; n = 4; P < 0.01) and absence (pEC50: control, 6.41 +/- 0.04; PMSF, 6.88 +/- 0.04; n = 4; P < 0.001) of L-NAME. Responses to the nitric oxide donor S-nitroso-N-acetylpenicillamine (SNAP) were also potentiated by PMSF (pEC50: control, 7.51 +/- 0.06; PMSF, 8.00 +/- 0.05, n = 4, P < 0.001). 5. EDHF-mediated relaxation to carbachol was significantly attenuated by the K+ channel blocker tetraethylammonium (TEA; 1 mM) (pEC50: control, 6.19 +/- 0.01; TEA, 5.61 +/- 0.01; n = 6; P < 0.01). In contrast, TEA (1 mM) had no effect on EDHF-mediated relaxation to A23187 (pEC50: control, 6.47 +/- 0.04; TEA, 6.41 +/- 0.02, n = 4) or on anandamide (pEC50: control, 6.28 +/- 0.06; TEA, 6.09 +/- 0.02; n = 5). TEA (10 mM) significantly (P < 0.01) reduced the Rmax for anandamide (control, 94.3 +/- 4.0%; 10 mM TEA, 60.7 +/- 4.4%; n = 5) but had no effect on the Rmax to carbachol or A23187. 6. BaCl2 (100 microM), considered to be selective for blockade of inward rectifier K+ channels, had no significant effect on relaxations to carbachol or A23187, but caused a small shift in the anandamide concentration-response curve (pEC50: control, 6.39 +/- 0.01; Ba2+, 6.20 +/- 0.01; n = 4; P < 0.01). BaCl2 (1 mM; which causes non-selective block of K+ channels) significantly (P < 0.01) attenuated relaxations to all three agents (pEC50 values: carbachol, 5.65 +/- 0.02; A23187, 5.84 +/- 0.04; anandamide, 5.95 +/- 0.02; n = 4 for each). 7. Apamin (1mu M), a selective blocker of small conductance, Ca2+-activated, K+ channels (SKCa), 4-aminopyridine (1mM), a blocker of delayed rectifier, voltage-dependent, K+ channels (Kv), and ciclazindol (10mu M), an inhibitor of Kv and adenosine 5'-triphosphate (ATP)-sensitive K+ channels (KATP), significantly reduced EDHF-mediated relaxations to carbachol, but had no significant effects on A23187 or anandamide responses. 8. Glibenclamide (10mu M), a KATP inhibitor and charybdotoxin (100 or 300nM), a blocker of several K+ channel subtypes, had no significant effect on relaxations to any of the agents. Iberiotoxin (50nM), an inhibitor of large conductance, Ca2+-activated, K+ channels (BKCa), had no significant effect on the relaxation responses, either alone or in combination with apamin (1muM). Also, a combination of apamin (1muM) with either glibenclamide (10muM) or 4-aminopyridine (1mM) did not inhibit relaxation to carbachol significantly more than apamin alone. Neither combination had any significant effect on relaxation to A23187 or anandamide. 9. A combination of apamin (1muM) with charybdotoxin (100nM) abolished EDHF-mediated relaxation to carbachol, but had no significant effect on that to A23187. Apamin (1muM) and charybdotoxin (300nM) together consistently inhibited the response to A23187, while apamin (1muM) and ciclazindol (10muM) together inhibited relaxations to both carbachol and A23187. None of these toxin combinations had any significant effect on relaxation to anandamide. 10. It was concluded that the differential sensitivity to K+ channel blockers of EDHF-mediated responses to carbachol and A23187 might be due to actions on endothelial generation of EDHF, as well as its actions on the vascular smooth muscle, and suggests care must be taken in choosing the means of generating EDHF when making comparative studies. Also, the relaxations to EDHF and anandamide may involve activation of cannabinoid receptors, coupled via PTX-sensitive G-proteins to activation of K+ conductances. The results support the hypothesis that EDHF is an endocannabinoid but relaxations to EDHF and anandamide show differential sensitivity to K+ channel blockers, therefore it is likely that anandamide is not identical to EDHF in the small rat mesenteric artery.
Article
The hypothesis that the capability of agents to mobilize arachidonic acid (AA) could predict increased anandamide (ANA) synthesis in a macrophage cell line has been examined. Lipopolysaccharide (LPS), platelet-activating factor (PAF) and cannabinoids such as Delta9-tetrahydrocannabinol (THC) and anandamide were all found to be agonists for the release of AA and led to increased ANA synthesis in RAW264.7 mouse macrophage cells. Nitric oxide, in contrast, stimulated AA release without raising ANA levels. ANA stimulation of its own synthesis indicates the existence of a positive feedback mechanism. The possible involvement of the CB2 receptor in THC-mediated AA release and ANA synthesis is addressed using the antagonist SR144528. ANA synthesis is also increased by the combination of calcium ionophore and indomethacin, suggesting that ANA is metabolized by a cyclooxygenase in this system. The data imply that ANA could play a role in the response of the immune system to cannabinoids and bacterial endotoxins and that AA mobilization is a predictor for increased ANA synthesis.
Article
The aim of the present study was to analyse the cardiovascular actions of the synthetic CB1/CB2 cannabinoid receptor agonist WIN55212-2, and specifically to determine its sites of action on sympathetic cardiovascular regulation. Pithed rabbits in which the sympathetic outflow was continuously stimulated electrically or which received a pressor infusion of noradrenaline were used to study peripheral prejunctional and direct vascular effects, respectively. For studying effects on brain stem cardiovascular regulatory centres, drugs were administered into the cisterna cerebellomedullaris in conscious rabbits. Overall cardiovascular effects of the cannabinoid were studied in conscious rabbits with intravenous drug administration. In pithed rabbits in which the sympathetic outflow was continuously electrically stimulated, intravenous injection of WIN55212-2 (5, 50 and 500 μg kg−1) markedly reduced blood pressure, the spillover of noradrenaline into plasma and the plasma noradrenaline concentration, and these effects were antagonized by the CB1 cannabinoid receptor-selective antagonist SR141716A. The hypotensive and the sympathoinhibitory effect of WIN55212-2 was shared by CP55940, another mixed CB1/CB2 cannabinoid receptor agonist, but not by WIN55212-3, the enantiomer of WIN55212-2, which lacks affinity for cannabinoid binding sites. WIN55212-2 had no effect on vascular tone established by infusion of noradrenaline in pithed rabbits. Intracisternal application of WIN55212-2 (0.1, 1 and 10 μg kg−1) in conscious rabbits increased blood pressure and the plasma noradrenaline concentration and elicited bradycardia; this latter effect was antagonized by atropine. In conscious animals, intravenous injection of WIN55212-2 (5 and 50 μg kg−1) caused bradycardia, slight hypotension, no change in the plasma noradrenaline concentration, and an increase in renal sympathetic nerve firing. The highest dose of WIN55212-2 (500 μg kg−1) elicited hypotension and tachycardia, and sympathetic nerve activity and the plasma noradrenaline concentration declined. The results obtained in pithed rabbits indicate that activation of CB1 cannabinoid receptors leads to marked peripheral prejunctional inhibition of noradrenaline release from postganglionic sympathetic axons. Intracisternal application of WIN55212-2 uncovered two effects on brain stem cardiovascular centres: sympathoexcitation and activation of cardiac vagal fibres. The highest dose of systemically administered WIN55212-2 produced central sympathoinhibition; the primary site of this action is not known. British Journal of Pharmacology (1999) 126, 457–466; doi:10.1038/sj.bjp.0702337
Article
Delta9-Tetrahydrocannabinol (Delta9-THC), the major psychoactive ingredient in preparations of Cannabis sativa (marijuana, hashish), elicits central nervous system (CNS) responses, including cognitive alterations and euphoria. These responses account for the abuse potential of cannabis, while other effects such as analgesia suggest potential medicinal applications. To study the role of the major known target of cannabinoids in the CNS, the CB1 cannabinoid receptor, we have produced a mouse strain with a disrupted CB1 gene. CB1 knockout mice appeared healthy and fertile, but they had a significantly increased mortality rate. They also displayed reduced locomotor activity, increased ring catalepsy, and hypoalgesia in hotplate and formalin tests. Delta9-THC-induced ring-catalepsy, hypomobility, and hypothermia were completely absent in CB1 mutant mice. In contrast, we still found Delta9-THC-induced analgesia in the tail-flick test and other behavioral (licking of the abdomen) and physiological (diarrhea) responses after Delta9-THC administration. Thus, most, but not all, CNS effects of Delta9-THC are mediated by the CB1 receptor.
Article
Experiments were designed to determine whether anandamide affects cytosolic Ca2+ concentrations in endothelial cells and, if so, whether CB1 cannabinoid receptors are involved. To this effect, human umbilical vein-derived EA.hy926 endothelial cells were loaded with fura-2 to monitor changes in cytosolic Ca2+ using conventional fluorescence spectrometry methods. Anandamide induced an increase in Ca2+ in endothelial cells which, in contrast to histamine, developed slowly and was transient. Anandamide caused a concentration-dependent release of Ca2+ from intracellular stores without triggering capacitative Ca2+ entry, contrary to histamine or the endoplasmic reticulum Ca2+-ATPase inhibitor thapsigargin. Anandamide pretreatment slightly reduced the mobilization of Ca2+ from intracellular stores that was evoked by histamine. The mobilization of Ca2+ from intracellular stores evoked by anandamide was impaired by 10 mM caffeine. Anandamide and histamine each significantly increased NO synthase activity in EA.hy926 cells, as determined by the enhanced conversion of L-[3H]-arginine to L-[3H]-citruline. The CB1 cannabinoid receptor antagonist SR141716A (1 μM) only produced a marginal reduction of the mobilization of Ca2+ produced by 5 μM anandamide. However, at 5 μM SR141716A elicited the release of Ca2+ from intracellular stores. This concentration strongly impaired the mobilization of cytosolic Ca2+ evoked by either anandamide, histamine or thapsigargin. Pretreatment of the cells with either 200 μM phenylmethylsulphonyl fluoride (to inhibit the conversion of anandamide into arachidonic acid) or 400 ng ml−1 pertussis toxin (to uncouple CB1 cannabinoid receptors from Gi/o proteins) had no significant effect on the mobilization of cytosolic Ca2+ evoked by either anandamide, or histamine. Taken together the results demonstrate that anandamide mobilizes Ca2+ from a caffeine-sensitive intracellular Ca2+ store that functionally overlaps in part with the internal stores mobilized by histamine. However, a classical CB1 cannabinoid receptor-mediated and pertussis toxin-sensitive mechanism does not mediate this novel effect of anandamide in endothelial cells. The mobilization of cytosolic Ca2+ in endothelial cells may account for the endothelium-dependent and NO-mediated vasodilator actions of anandamide. Due to its non-specific inhibition of Ca2+ signalling in endothelial cells, SR141716A may not be used to assess the physiological involvement of endogenous cannabinoids to endothelium-dependent control of vascular smooth muscle tone. British Journal of Pharmacology (1999) 126, 1593–1600; doi:10.1038/sj.bjp.0702483
Article
The aim of the current study was to characterize which cannabinoid receptors, if any, are present on rat carotid artery smooth muscle. Additionally, the effects of cannabinoids on carotid artery tone, on cyclic AMP accumulation and on forskolin-induced relaxation were examined in the same tissue. Stimulation of carotid arteries with forskolin (10 μM) significantly increased cyclic AMP accumulation, an effect that was inhibited in a concentration-dependent manner by the cannabinoid receptor agonist, methanandamide. Similar inhibition was seen with the CB1 agonist HU-210 but this inhibition was not mimicked by the CB2 agonist, WIN 55,2212-2. The inhibitory effect of methanandamide on cyclic AMP accumulation was prevented by incubation of the arteries with pertussis toxin and was significantly reduced by LY320135, a selective CB1 antagonist, but not by SR 144528, a CB2-selective antagonist. Methanandamide failed to relax carotid arteries pre-contracted with phenylephrine, but inhibited forskolin-induced relaxation of these arteries. This functional inhibition of relaxation by methanandamide was inhibited by CB1-selective (LY320135 and SR 141716A), but not a CB2-selective antagonist (SR 144528). These data demonstrate the presence of functional G protein-linked cannabinoid receptors of the CB1 subtype in the rat carotid artery, but show that these receptors inhibit cyclic AMP accumulation rather than cause relaxation. British Journal of Pharmacology (1999) 128, 597–604; doi:10.1038/sj.bjp.0702842
Article
1. We have shown that the endocannabinoid anandamide and its stable analogue methanandamide relax rings of rabbit superior mesenteric artery through endothelium-dependent and -independent mechanisms that are unaffected by blockade of NO synthase and cyclooxygenase. 2. The endothelium-dependent component of the responses was attenuated by the gap junction inhibitor 18alpha-glycyrrhetinic acid (18alpha-GA; 50 microM), and a synthetic connexin-mimetic peptide homologous to the extracellular Gap 27 sequence of connexin 43 (43Gap 27, SRPTEKTIFII; 300 microM). By contrast, the corresponding connexin 40 peptide (40Gap 27, SRPTEKNVFIV) was inactive. 3. The cannabinoid CB1 receptor antagonist SR141716A (10 microM) also attenuated endothelium-dependent relaxations but this inhibition was not observed with the CB1 receptor antagonist LY320135 (10 microM). Furthermore, SR141716A mimicked the effects of 43Gap 27 peptide in blocking Lucifer Yellow dye transfer between coupled COS-7 cells (a monkey fibroblast cell line), whereas LY320135 was without effect, thus suggesting that the action of SR141716A was directly attributable to effects on gap junctions. 4. The endothelium-dependent component of cannabinoid-induced relaxation was also attenuated by AM404 (10 microM), an inhibitor of the high-affinity anandamide transporter, which was without effect on dye transfer. 5. Taken together, the findings suggest that cannabinoids derived from arachidonic acid gain access to the endothelial cytosol via a transporter mechanism and subsequently stimulate relaxation by promoting diffusion of an to adjacent smooth muscle cells via gap junctions. 6. Relaxations of endothelium-denuded preparations to anandamide and methanandamide were unaffected by 43Gap 27 peptide, 18alpha-GA, SR141716A, AM404 and indomethacin and their genesis remains to be established.