endogenous cannabinoid system: Topics by Science.gov

Sample records for endogenous cannabinoid system

Phytocannabinoids and endocannabinoids.

PubMed

Fisar, Zdenek

2009-01-01

Progress in understanding the molecular mechanisms of cannabis action was made after discovery of cannabinoid receptors in the brain and the finding of endogenous metabolites with affinity to them. Activation of cannabinoid receptors on synaptic terminals results in regulation of ion channels, neurotransmitter release and synaptic plasticity. Neuromodulation of synapses by the cannabinoids is proving to have a wide range of functional effects, making them potential targets as medical preparations in a variety of illnesses, including some mental disorders and neurodegenerative illnesses. Cannabis contains a large amount of substances with affinity for the cannabinoid receptors. The endocannabinoids are a family of lipid neurotransmitters that engage the same membrane receptors targeted by tetrahydrocannabinol and that mediate retrograde signal from postsynaptic neurons to presynaptic ones. Discovery of endogenous cannabinoids and studies of the physiological functions of the cannabinoid system in the brain and body are producing a number of important findings about the role of membrane lipids and fatty acids in nerve signal transduction. Plant, endogenous and synthetic cannabinoids are using in these studies. The role of lipid membranes in the cannabinoid system follows from the fact that the source and supply of endogenous cannabinoids are derived from arachidonic acid, an important membrane constituent. The study of structure-activity relationships of molecules which influence the cannabinoid system in the brain and body is crucial in search of medical preparations with the therapeutic effects of the phytocannabinoids without the negative effects on cognitive function attributed to cannabis.
21 CFR 862.3870 - Cannabinoid test system.

Code of Federal Regulations, 2010 CFR

2010-04-01

... measure any of the cannabinoids, hallucinogenic compounds endogenous to marihuana, in serum, plasma... cannabinoid use or abuse and in monitoring levels of cannabinoids during clinical investigational use. (b...
Cannabinoids and atherosclerosis.

PubMed

Fisar, Zdenek

2009-01-01

The endocannabinoids are a family of lipid neurotransmitters that engage the same membrane receptors targeted by tetrahydrocannabinol and that mediate retrograde signal from postsynaptic neurons to presynaptic ones. Discovery of endogenous cannabinoids and studies of the physiological functions of the cannabinoid system in the brain and body are producing a number of important findings about the role of membrane lipids and fatty acids. The role of lipid membranes in the cannabinoid system follows from the fact that the source and supply of endogenous cannabinoids are derived from arachidonic acid. The study of molecules which influence the cannabinoid system in the brain and body is crucial in search of medical preparations with the therapeutic effects of the phytocannabinoids without the negative effects on cognitive function attributed to cannabis. Basic information about function and role of the endocannabinoid system is summarized in the paper; possible therapeutic action of cannabinoids, effects on atherosclerosis specially, is described at the close.
[The role of endocannabinoid system in physiological and pathological processes in the eye].

PubMed

Nadolska, Krystyna; Goś, Roman

2008-01-01

Plant of Cannabis sativa/ marihuana except for its psychotropic effects possesses a range of pharmacological properties, that has been utilized for medical purposes over a period of millenia. Investigations concerning biochemical mechanism of action of the main and most active pharmacological compound of Cannabis sativa, cannabinoid 9-THC, contributed to the discovery of cannabinoid receptors both in the central nervous system (CNS) and peripheral tissues, that mediated actions of this substance. The discovery made possible identification of a new, endogenous signaling system reffered to as the endocannabinoid system. Besides cannabinoid receptors CB1 and CB2, the system includes it's endogenic ligands (endocannabinoids) and compounds that participate in their biosynthesis and inactivation. Structure and functioning of the endocannabinoid system is conservative in all vertebrates. It's activation with plant, synthetic and endogenous cannabinoids has an influence on multiple physiological and pathological processes within the eye.
Functional interactions between endogenous cannabinoid and opioid systems: focus on alcohol, genetics and drug-addicted behaviors.

PubMed

López-Moreno, J A; López-Jiménez, A; Gorriti, M A; de Fonseca, F Rodríguez

2010-04-01

Although the first studies regarding the endogenous opioid system and addiction were published during the 1940s, addiction and cannabinoids were not addressed until the 1970s. Currently, the number of opioid addiction studies indexed in PubMed-Medline is 16 times greater than the number of cannabinoid addiction reports. More recently, functional interactions have been demonstrated between the endogenous cannabinoid and opioid systems. For example, the cannabinoid brain receptor type 1 (CB1) and mu opioid receptor type 1 (MOR1) co-localize in the same presynaptic nerve terminals and signal through a common receptor-mediated G-protein pathway. Here, we review a great variety of behavioral models of drug addiction and alcohol-related behaviors. We also include data providing clear evidence that activation of the cannabinoid and opioid endogenous systems via WIN 55,512-2 (0.4-10 mg/kg) and morphine (1.0-10 mg/kg), respectively, produces similar levels of relapse to alcohol in operant alcohol self-administration tasks. Finally, we discuss genetic studies that reveal significant associations between polymorphisms in MOR1 and CB1 receptors and drug addiction. For example, the SNP A118G, which changes the amino acid aspartate to asparagine in the MOR1 gene, is highly associated with altered opioid system function. The presence of a microsatellite polymorphism of an (AAT)n triplet near the CB1 gene is associated with drug addiction phenotypes. But, studies exploring haplotypes with regard to both systems, however, are lacking.
The Endocannabinoid System Modulating Levels of Consciousness, Emotions and Likely Dream Contents.

PubMed

Murillo-Rodriguez, Eric; Pastrana-Trejo, Jose Carlos; Salas-Crisóstomo, Mireille; de-la-Cruz, Miriel

2017-01-01

Cannabinoids are derivatives that are either compounds occurring naturally in the plant, Cannabis sativa or synthetic analogs of these molecules. The first and most widely investigated of the cannabinoids is Δ9-tetrahydrocannabinol (Δ9-THC), which is the main psychotropic constituent of cannabis and undergoes significant binding to cannabinoid receptors. These cannabinoid receptors are seven-transmembrane receptors that received their name from the fact that they respond to cannabinoid compounds, including Δ9-THC. The cannabinoid receptors have been described in rat, human and mouse brains and they have been named the CB1 and CB2 cannabinoid receptors. Later, an endogenous molecule that exerts pharmacological effects similar to those described by Δ9-THC and binds to the cannabinoid receptors was discovered. This molecule, named anandamide, was the first of five endogenous cannabinoid receptor agonists described to date in the mammalian brain and other tissues. Of these endogenous cannabinoids or endocannabinoids, the most thoroughly investigated to date have been anandamide and 2-arachidonoylglycerol (2-AG). Over the years, a significant number of articles have been published in the field of endogenous cannabinoids, suggesting a modulatory profile in multiple neurobiological roles of endocannabinoids. The general consensus accepts that the endogenous cannabinoid system includes natural ligands (such as anandamide and 2- AG), receptors (CB1 and CB2), and the main enzymes responsible for the hydrolysis of anandamide and 2-AG (fatty acid amide hydrolase [FAAH] and monoacylglycerol lipase [MAGL], respectively) as well as the anandamide membrane transporter (AMT). To date, diverse pieces of evidence have shown that the endocannabinoid system controls multiple functions such as feeding, pain, learning and memory and has been linked with various disturbances, such as Parkinson´s disease. Among the modulatory properties of the endocannabinoid system, current data indicate that the sleep-wake cycle is under the influence of endocannabinoids since the blocking of the CB1 cannabinoid receptor or the pharmacological inhibition of FAAH activity promotes wakefulness, whereas the obstruction of AMT function enhances sleep. However, no solid evidence is available regarding the role of the endocannabinoid system in an unquestionable emotional component of the sleep: Dream activity. Since dreaming is a mental activity that occurs during sleep (characterized by emotions, sensory perceptions, and bizarre components) and the endocannabinoid system modulates neurobiological processes involving consciousness, such as learning and memory, attention, pain perception, emotions and sleep, it is acceptable to hypothesize that the endocannabinoid system might be modulating dream activity. In this regard, an accumulative body of evidence in human and animal models has been reported regarding the role of the endocannabinoid system in the control of emotional states and dreams. Moreover, preliminary studies in humans have indicated that treatment with cannabinoids may decrease post-traumatic stress disorder symptoms, including nightmares. Thus, based on a review of the literature available in PubMed, this article hypothesizes a conceptual framework within which the endocannabinoid system might influence the generation of dream experiences. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.
On-demand activation of the endocannabinoid system in the control of neuronal excitability and epileptiform seizures.

PubMed

Lutz, Beat

2004-11-01

Neurons intensively exchange information among each other using both inhibitory and excitatory neurotransmitters. However, if the balance of excitation and inhibition is perturbed, the intensity of excitatory transmission may exceed a certain threshold and epileptic seizures can occur. As the occurrence of epilepsy in the human population is about 1%, the search for therapeutic targets to alleviate seizures is warranted. Extracts of Cannabis sativa have a long history in the treatment of various neurological diseases, including epilepsy. However, cannabinoids have been reported to exert both pro- and anti-convulsive activities. The recent progress in understanding the endogenous cannabinoid system has allowed new insights into these opposing effects of cannabinoids. When excessive neuronal activity occurs, endocannabinoids are generated on demand and activate cannabinoid type 1 (CB1) receptors. Using mice lacking CB1 receptors in principal forebrain neurons in a model of epileptiform seizures, it was shown that CB1 receptors expressed on excitatory glutamatergic neurons mediate the anti-convulsive activity of endocannabinoids. Systemic activation of CB1 receptors by exogenous cannabinoids, however, are anti- or pro-convulsive, depending on the seizure model used. The pro-convulsive activity of exogenous cannabinoids might be explained by the notion that CB1 receptors expressed on inhibitory GABAergic neurons are also activated, leading to a decreased release of GABA, and to a concomitant increase in seizure susceptibility. The concept that the endogenous cannabinoid system is activated on demand suggests that a promising strategy to alleviate seizure frequency is the enhancement of endocannabinoid levels by inhibiting the cellular uptake and the degradation of these endogenous compounds.
Opioid, cannabinoid, and transient receptor potential (TRP) systems: effects on body temperature

PubMed Central

Rawls, Scott M.; Benamar, Khalid

2014-01-01

Cannabinoid and opioid drugs produce marked changes in body temperature. Recent findings have extended our knowledge about the thermoregulatory effects of cannabinoids and opioids, particularly as related to delta opioid receptors, endogenous systems, and transient receptor potential (TRP) channels. Although delta opioid receptors were originally thought to play only a minor role in thermoregulation compared to mu and kappa opioid receptors, their activation has been shown to produce hypothermia in multiple species. Endogenous opioids and cannabinoids also regulate body temperature. Mu and kappa opioid receptors are thought to be in tonic balance, with mu and kappa receptor activation producing hyperthermia and hypothermia, respectively. Endocannabinoids participate in the febrile response, but more studies are needed to determine if a cannabinoid CB1 receptor tone exerts control over basal body temperature. A particularly intense research focus is TRP channels, where TRPV1 channel activation produces hypothermia whereas TRPA1 and TRPM8 channel activation causes hyperthermia. The marked hyperthermia produced by TRPV1 channel antagonists suggests these warm channels tonically control body temperature. A better understanding of the roles of cannabinoid, opioid, and TRP systems in thermoregulation may have broad clinical implications and provide insights into interactions among neurotransmitter systems involved in thermoregulation. PMID:21622235
Cannabinoids as Anticancer Drugs.

PubMed

Ramer, Robert; Hinz, Burkhard

2017-01-01

The endocannabinoid system encompassing cannabinoid receptors, endogenous receptor ligands (endocannabinoids), as well as enzymes conferring the synthesis and degradation of endocannabinoids has emerged as a considerable target for pharmacotherapeutical approaches of numerous diseases. Besides palliative effects of cannabinoids used in cancer treatment, phytocannabinoids, synthetic agonists, as well as substances that increase endogenous endocannabinoid levels have gained interest as potential agents for systemic cancer treatment. Accordingly, cannabinoid compounds have been reported to inhibit tumor growth and spreading in numerous rodent models. The underlying mechanisms include induction of apoptosis, autophagy, and cell cycle arrest in tumor cells as well as inhibition of tumor cell invasion and angiogenic features of endothelial cells. In addition, cannabinoids have been shown to suppress epithelial-to-mesenchymal transition, to enhance tumor immune surveillance, and to support chemotherapeutics' effects on drug-resistant cancer cells. However, unwanted side effects include psychoactivity and possibly pathogenic effects on liver health. Other cannabinoids such as the nonpsychoactive cannabidiol exert a comparatively good safety profile while exhibiting considerable anticancer properties. So far experience with anticarcinogenic effects of cannabinoids is confined to in vitro studies and animal models. Although a bench-to-bedside conversion remains to be established, the current knowledge suggests cannabinoid compounds to serve as a group of drugs that may offer significant advantages for patients suffering from cancer diseases. The present review summarizes the role of the endocannabinoid system and cannabinoid compounds in tumor progression. © 2017 Elsevier Inc. All rights reserved.
Endogenous cannabinoid receptor agonists inhibit neurogenic inflammations in guinea pig airways.

PubMed

Yoshihara, Shigemi; Morimoto, Hiroshi; Ohori, Makoto; Yamada, Yumi; Abe, Toshio; Arisaka, Osamu

2005-09-01

Although neurogenic inflammation via the activation of C fibers in the airway must have an important role in the pathogenesis of asthma, their regulatory mechanism remains uncertain. The pharmacological profiles of endogenous cannabinoid receptor agonists on the activation of C fibers in airway tissues were investigated and the mechanisms how cannabinoids regulate airway inflammatory reactions were clarified. The effects of endogenous cannabinoid receptor agonists on electrical field stimulation-induced bronchial smooth muscle contraction, capsaicin-induced bronchoconstriction and capsaicin-induced substance P release in guinea pig airway tissues were investigated. The influences of cannabinoid receptor antagonists and K+ channel blockers to the effects of cannabinoid receptor agonists on these respiratory reactions were examined. Both endogenous cannabinoid receptor agonists, anandamide and palmitoylethanolamide, inhibited electrical field stimulation-induced guinea pig bronchial smooth muscle contraction, but not neurokinin A-induced contraction. A cannabinoid CB2 antagonist, SR 144528, reduced the inhibitory effect of endogenous agonists, but not a cannabinoid CB1 antagonist, SR 141716A. Inhibitory effects of agonists were also reduced by the pretreatment of large conductance Ca2+ -activated K+ channel (maxi-K+ channel) blockers, iberiotoxin and charybdotoxin, but not by other K+ channel blockers, dendrotoxin or glibenclamide. Anandamide and palmitoylethanolamide blocked the capsaicin-induced release of substance P-like immunoreactivity from guinea pig airway tissues. Additionally, intravenous injection of palmitoylethanolamide dose-dependently inhibited capsaicin-induced guinea pig bronchoconstriction, but not neurokinin A-induced reaction. However, anandamide did not reduce capsaicin-induced guinea pig bronchoconstriction. These findings suggest that endogenous cannabinoid receptor agonists inhibit the activation of C fibers via cannabinoid CB2 receptors and maxi-K+ channels in guinea pig airways. Copyright (c) 2005 S. Karger AG, Basel.
Immunomodulatory lipids in plants: plant fatty acid amides and the human endocannabinoid system.

PubMed

Gertsch, Jürg

2008-05-01

Since the discovery that endogenous lipid mediators show similar cannabimimetic effects as phytocannabinoids from CANNABIS SATIVA, our knowledge about the endocannabinoid system has rapidly expanded. Today, endocannabinoid action is known to be involved in various diseases, including inflammation and pain. As a consequence, the G-protein coupled cannabinoid receptors, endocannabinoid transport, as well as endocannabinoid metabolizing enzymes represent targets to block or enhance cannabinoid receptor-mediated signalling for therapeutic intervention. Based on the finding that certain endocannabinoid-like fatty acid N-alkylamides from purple coneflower ( ECHINACEA spp.) potently activate CB2 cannabinoid receptors we have focused our interest on plant fatty acid amides (FAAs) and their overall cannabinomodulatory effects. Certain FAAs are also able to partially inhibit the action of fatty acid amide hydrolase (FAAH), which controls the breakdown of endocannabinoids. Intriguingly, plants lack CB receptors and do not synthesize endocannabinoids, but express FAAH homologues capable of metabolizing plant endogenous N-acylethanolamines (NAEs). While the site of action of these NAEs in plants is unknown, endogenous NAEs and arachidonic acid glycerols in animals interact with distinct physiological lipid receptors, including cannabinoid receptors. There is increasing evidence that also plant FAAs other than NAEs can pharmacologically modulate the action of these endogenous lipid signals. The interference of plant FAAs with the animal endocannabinoid system could thus be a fortunate evolutionary cross point with yet unexplored therapeutic potential.
Role of the cannabinoid system in pain control and therapeutic implications for the management of acute and chronic pain episodes.

PubMed

Manzanares, J; Julian, Md; Carrascosa, A

2006-07-01

Cannabis extracts and synthetic cannabinoids are still widely considered illegal substances. Preclinical and clinical studies have suggested that they may result useful to treat diverse diseases, including those related with acute or chronic pain. The discovery of cannabinoid receptors, their endogenous ligands, and the machinery for the synthesis, transport, and degradation of these retrograde messengers, has equipped us with neurochemical tools for novel drug design. Agonist-activated cannabinoid receptors, modulate nociceptive thresholds, inhibit release of pro-inflammatory molecules, and display synergistic effects with other systems that influence analgesia, especially the endogenous opioid system. Cannabinoid receptor agonists have shown therapeutic value against inflammatory and neuropathic pains, conditions that are often refractory to therapy. Although the psychoactive effects of these substances have limited clinical progress to study cannabinoid actions in pain mechanisms, preclinical research is progressing rapidly. For example, CB(1)mediated suppression of mast cell activation responses, CB(2)-mediated indirect stimulation of opioid receptors located in primary afferent pathways, and the discovery of inhibitors for either the transporters or the enzymes degrading endocannabinoids, are recent findings that suggest new therapeutic approaches to avoid central nervous system side effects. In this review, we will examine promising indications of cannabinoid receptor agonists to alleviate acute and chronic pain episodes. Recently, Cannabis sativa extracts, containing known doses of tetrahydrocannabinol and cannabidiol, have granted approval in Canada for the relief of neuropathic pain in multiple sclerosis. Further double-blind placebo-controlled clinical trials are needed to evaluate the potential therapeutic effectiveness of various cannabinoid agonists-based medications for controlling different types of pain.
Cannabinoid signaling in health and disease.

PubMed

Lu, Yan; Anderson, Hope D

2017-04-01

Cannabis sativa has long been used for medicinal purposes. To improve safety and efficacy, compounds from C. sativa were purified or synthesized and named under an umbrella group as cannabinoids. Currently, several cannabinoids may be prescribed in Canada for a variety of indications such as nausea and pain. More recently, an increasing number of reports suggest other salutary effects associated with endogenous cannabinoid signaling including cardioprotection. The therapeutic potential of cannabinoids is therefore extended; however, evidence is limited and mechanisms remain unclear. In addition, the use of cannabinoids clinically has been hindered due to pronounced psychoactive side effects. This review provides an overview on the endocannabinoid system, including known physiological roles, and conditions in which cannabinoid receptor signaling has been implicated.
The Endocannabinoid System, Aggression, and the Violence of Synthetic Cannabinoid Use, Borderline Personality Disorder, Antisocial Personality Disorder, and Other Psychiatric Disorders.

PubMed

Kolla, Nathan J; Mishra, Achal

2018-01-01

Endogenous and exogenous cannabinoids bind to central cannabinoid receptors to control a multitude of behavioral functions, including aggression. The first main objective of this review is to dissect components of the endocannabinoid system, including cannabinoid 1 and cannabinoid 2 receptors; the endogenous cannabinoids anandamide and 2-arachidonoylglycerol; and the indirect cannabinoid modulators fatty acid amide hydrolase and monoacylglycerol lipase; that have shown abnormalities in basic research studies investigating mechanisms of aggression. While most human research has concluded that the active ingredient of marijuana, Δ9-tetrahydrocannabinol, tends to dampen rather than provoke aggression in acute doses, recent evidence supports a relationship between the ingestion of synthetic cannabinoids and emergence of violent or aggressive behavior. Thus, another objective is to evaluate the emerging clinical data. This paper also discusses the relationship between prenatal and perinatal exposure to cannabis as well as use of cannabis in adolescence on aggressive outcomes. A final objective of the paper is to discuss endocannabinoid abnormalities in psychotic and affective disorders, as well as clinically aggressive populations, such as borderline personality disorder and antisocial personality disorder. With regard to the former condition, decreased anandamide metabolites have been reported in the cerebrospinal fluid, while some preliminary evidence suggests that fatty acid amide hydrolase genetic polymorphisms are linked to antisocial personality disorder and impulsive-antisocial psychopathic traits. To summarize, this paper will draw upon basic and clinical research to explain how the endocannabinoid system may contribute to the genesis of aggressive behavior.
The Role of Endocannabinoid Signaling in Cortical Inhibitory Neuron Dysfunction in Schizophrenia

PubMed Central

Volk, David W.; Lewis, David A.

2015-01-01

Cannabis use has been reported to increase the risk of developing schizophrenia and to worsen symptoms of the illness. Both of these outcomes might be attributable to the disruption by cannabis of the endogenous cannabinoid system's spatiotemporal regulation of the inhibitory circuitry in the prefrontal cortex that is essential for core cognitive processes, such as working memory, which are impaired in schizophrenia. In the healthy brain, the endocannabinoid 2-arachidonylglycerol (2-AG) is 1) synthesized by diacylglycerol lipase in pyramidal neurons; 2) travels retrogradely to nearby inhibitory axon terminals that express the primary cannabinoid receptor CB1R; 3) binds to CB1R which inhibits GABA release from the cholecystokinin-containing population of interneurons; and 4) is metabolized by either monoglyceride lipase, which is located in the inhibitory axon terminal, or by α-β-hydrolase domain 6, which is co-localized presynaptically with diacylglycerol lipase. Investigations of the endogenous cannabinoid system in the prefrontal cortex of subjects with schizophrenia have found evidence of higher metabolism of 2-AG, as well as both greater CB1R receptor binding and lower levels of CB1R mRNA and protein. Current views on the potential pathogenesis of these alterations, including disturbances in the development of the endogenous cannabinoid system, are discussed. In addition, how interactions between these alterations in the endocannabinoid system and those in other inhibitory neurons in the prefrontal cortex in subjects with schizophrenia might increase the liability to adverse outcomes with cannabis use is considered. PMID:26210060
Endogenous cannabinoids mediate retrograde signals from depolarized postsynaptic neurons to presynaptic terminals.

PubMed

Ohno-Shosaku, T; Maejima, T; Kano, M

2001-03-01

Endogenous cannabinoids are considered to function as diffusible and short-lived modulators that may transmit signals retrogradely from postsynaptic to presynaptic neurons. To evaluate this possibility, we have made a paired whole-cell recording from cultured hippocampal neurons with inhibitory synaptic connections. In about 60% of pairs, a cannabinoid agonist greatly reduced the release of the inhibitory neurotransmitter GABA from presynaptic terminals. In most of such pairs but not in those insensitive to the agonist, depolarization of postsynaptic neurons and the resultant elevation of intracellular Ca2+ concentration caused transient suppression of inhibitory synaptic currents, which is mainly due to reduction of GABA release. This depolarization-induced suppression was completely blocked by selective cannabinoid antagonists. Our results reveal that endogenous cannabinoids mediate retrograde signals from depolarized postsynaptic neurons to presynaptic terminals to cause the reduction of transmitter release.
Genetic variability in the human cannabinoid receptor 1 is associated with resting state EEG theta power in humans.

PubMed

Heitland, I; Kenemans, J L; Böcker, K B E; Baas, J M P

2014-11-01

It has long been postulated that exogenous cannabinoids have a profound effect on human cognitive functioning. These cannabinoid effects are thought to depend, at least in parts, on alterations of phase-locking of local field potential neuronal firing. The latter can be measured as activity in the theta frequency band (4-7Hz) by electroencephalogram. Theta oscillations are supposed to serve as a mechanism in neural representations of behaviorally relevant information. However, it remains unknown whether variability in endogenous cannabinoid activity is involved in theta rhythms and therefore, may serve as an individual differences index of human cognitive functioning. To clarify this issue, we recorded resting state EEG activity in 164 healthy human subjects and extracted EEG power across frequency bands (δ, θ, α, and β). To assess variability in the endocannabinoid system, two genetic polymorphisms (rs1049353, rs2180619) within the cannabinoid receptor 1 (CB1) were determined in all participants. As expected, we observed significant effects of rs1049353 on EEG power in the theta band at frontal, central and parietal electrode regions. Crucially, these effects were specific for the theta band, with no effects on activity in the other frequency bands. Rs2180619 showed no significant associations with theta power after Bonferroni correction. Taken together, we provide novel evidence in humans showing that genetic variability in the cannabinoid receptor 1 is associated with resting state EEG power in the theta frequency band. This extends prior findings of exogenous cannabinoid effects on theta power to the endogenous cannabinoid system. Copyright © 2014 Elsevier B.V. All rights reserved.
Cannabis: old medicine with new promise for neurological disorders.

PubMed

Carter, Gregory T; Weydt, Patrick

2002-03-01

Marijuana is a complex substance containing over 60 different forms of cannabinoids, the active ingredients. Cannabinoids are now known to have the capacity for neuromodulation, via direct, receptor-based mechanisms at numerous levels within the nervous system. These have therapeutic properties that may be applicable to the treatment of neurological disorders; including anti-oxidative, neuroprotective, analgesic and anti-inflammatory actions; immunomodulation, modulation of glial cells and tumor growth regulation. This article reviews the emerging research on the physiological mechanisms of endogenous and exogenous cannabinoids in the context of neurological disease.
Medical marijuana: emerging applications for the management of neurologic disorders.

PubMed

Carter, Gregory T; Ugalde, Vivian

2004-11-01

Marijuana contains over 60 different types of cannabinoids, which are its medicinally active ingredients. Cannabinoids have the capacity for neuromodulation--through direct, receptor-based mechanisms--at many levels within the nervous system, providing therapeutic properties that may be applicable to the treatment of neurologic disorders. These include antioxidation, neuroprotection, analgesia, anti-inflammation, immunomodulation, modulation of glial cells, and tumor growth regulation. This article reviews the current and emerging research on the physiologic mechanisms of endogenous and exogenous cannabinoids and their applications in the management of neurologic disease.
Therapeutic potential of cannabinoids in schizophrenia.

PubMed

Kucerova, Jana; Tabiova, Katarina; Drago, Filippo; Micale, Vincenzo

2014-04-01

Increasing evidence suggests a close relationship between the endocannabinoid system and schizophrenia. The endocannabinoid system comprises of two G protein-coupled receptors (the cannabinoid receptors 1 and 2 [CB1 and CB2] for marijuana's psychoactive principle Δ(9)-tetrahydrocannabinol), their endogenous small lipid ligands (namely anandamide [AEA] and 2-arachidonoylglycerol [2-AG], also known as endocannabinoids), and proteins for endocannabinoid biosynthesis and degradation. It has been suggested to be a pro-homeostatic and pleiotropic signalling system activated in a time- and tissue-specific manner during pathophysiological conditions. In the brain, activation of this system impacts the release of numerous neurotransmitters in various systems and cytokines from glial cells. Hence, the endocannabinoid system is strongly involved in neuropsychiatric disorders, such as schizophrenia. Therefore, adolescence use of Cannabis may alter the endocannabinoid signalling and pose a potential environmental risk to develop psychosis. Consistently, preclinical and clinical studies have found a dysregulation in the endocannabinoid system such as changed expression of CB1 and CB2 receptors or altered levels of AEA and 2-AG . Thus, due to the partial efficacy of actual antipsychotics, compounds which modulate this system may provide a novel therapeutic target for the treatment of schizophrenia. The present article reviews current available knowledge on herbal, synthetic and endogenous cannabinoids with respect to the modulation of schizophrenic symptomatology. Furthermore, this review will be highlighting the therapeutic potential of cannabinoid-related compounds and presenting some promising patents targeting potential treatment options for schizophrenia.

Cannabinoid Regulation of Acute and Anticipatory Nausea

PubMed Central

Rock, Erin M.; Sticht, Martin A.; Limebeer, Cheryl L.; Parker, Linda A.

2016-01-01

Abstract Chemotherapy-induced nausea is one of the most distressing symptoms reported by patients undergoing treatment, and even with the introduction of newer antiemetics such as ondansetron and aprepitant, nausea remains problematic in the clinic. Indeed, when acute nausea is not properly managed, the cues of the clinic can become associated with this distressing symptom resulting in anticipatory nausea for which no effective treatments are available. Clinical trials exploring the potential of exogenous or endogenous cannabinoids to reduce chemotherapy-induced nausea are sparse; therefore, we must rely on the data from pre-clinical rat models of nausea. In this review, we explore the human and pre-clinical animal literature examining the potential for exogenous and endogenous cannabinoid treatments to regulate chemotherapy-induced nausea. The pre-clinical evidence points to a compelling need to evaluate the antinausea potential of cannabidiol, cannabidiolic acid, and treatments that boost the functioning of the endocannabinoid system in human clinical trials. PMID:28861486
The role of cannabinoids in adult neurogenesis

PubMed Central

Prenderville, Jack A; Kelly, Áine M; Downer, Eric J

2015-01-01

The processes underpinning post-developmental neurogenesis in the mammalian brain continue to be defined. Such processes involve the proliferation of neural stem cells and neural progenitor cells (NPCs), neuronal migration, differentiation and integration into a network of functional synapses within the brain. Both intrinsic (cell signalling cascades) and extrinsic (neurotrophins, neurotransmitters, cytokines, hormones) signalling molecules are intimately associated with adult neurogenesis and largely dictate the proliferative activity and differentiation capacity of neural cells. Cannabinoids are a unique class of chemical compounds incorporating plant-derived cannabinoids (the active components of Cannabis sativa), the endogenous cannabinoids and synthetic cannabinoid ligands, and these compounds are becoming increasingly recognized for their roles in neural developmental processes. Indeed, cannabinoids have clear modulatory roles in adult neurogenesis, probably through activation of both CB1 and CB2 receptors. In recent years, a large body of literature has deciphered the signalling networks involved in cannabinoid-mediated regulation of neurogenesis. This timely review summarizes the evidence that the cannabinoid system is intricately associated with neuronal differentiation and maturation of NPCs and highlights intrinsic/extrinsic signalling mechanisms that are cannabinoid targets. Overall, these findings identify the central role of the cannabinoid system in adult neurogenesis in the hippocampus and the lateral ventricles and hence provide insight into the processes underlying post-developmental neurogenesis in the mammalian brain. PMID:25951750
The gastrointestinal tract – a central organ of cannabinoid signaling in health and disease

PubMed Central

Hasenoehrl, Carina; Taschler, Ulrike; Storr, Martin; Schicho, Rudolf

2016-01-01

Background and Purpose In ancient medicine, extracts of the marijuana plant Cannabis sativa were used against diseases of the gastrointestinal (GI) tract. Today, our knowledge of the ingredients of the Cannabis plant has remarkably advanced enabling us to use a variety of herbal and synthetic cannabinoid compounds to study the endocannabinoid system (ECS), a physiologic entity that controls tissue homeostasis with the help of endogenously produced cannabinoids and their receptors. After many anecdotal reports suggested beneficial effects of Cannabis in GI disorders, it was not surprising to discover that the GI tract accommodates and expresses all the components of the ECS. Cannabinoid receptors and their endogenous ligands, the endocannabinoids, participate in the regulation of GI motility, secretion, and the maintenance of the epithelial barrier integrity. In addition, other receptors, such as the transient receptor potential cation channel subfamily V member 1 (TRPV1), the peroxisome proliferator-activated receptor alpha (PPARα) and the G-protein coupled receptor 55 (GPR55), are important participants in the actions of cannabinoids in the gut and critically determine the course of bowel inflammation and colon cancer. The following review summarizes important and recent findings on the role of cannabinoid receptors and their ligands in the GI tract with emphasis on GI disorders, such as irritable bowel syndrome, inflammatory bowel disease and colon cancer. PMID:27561826
Cannabinoid agonists and antagonists modulate lithium-induced conditioned gaping in rats.

PubMed

Parker, Linda A; Mechoulam, Raphael

2003-01-01

Considerable evidence indicates that conditioned gaping in rats reflects nausea in this species that does not vomit. A series of experiments evaluated the potential of psychoactive cannabinoid agonists, delta-9-THC and HU-210, and non-psychoactive cannabinoids, Cannabidiol (CBD) and its dimethylheptyl homolog (CBD-dmh), to interfere with the establishment and the expression of conditioned gaping in rats. All agents attenuated both the establishment and the expression of conditioned gaping. Furthermore, the CB1 antagonist, SR-141716, reversed the suppressive effect of HU-210 on conditioned gaping. Finally, SR-141716 potentiated lithium-induced conditioned gaping, suggesting that the endogenous cannabinoid system plays a role in the control of nausea.
Cannabinoid/opioid crosstalk in the central nervous system.

PubMed

Corchero, Javier; Manzanares, Jorge; Fuentes, José A

2004-01-01

Promising therapeutic uses and a great variety of pharmacological effects are the leading forces that focus actual cannabinoid research. Cannabinoid and opioid systems share neuroanatomical, neurochemical, and paharmacological features. This fact supports the notion that actions induced by each one of these types of drugs involved an interaction between the endogenous opioid and endocannabinoid neuronal systems. Over the last decade our group and others have investigated cannabinoid/opioid crosstalk in the central nervous system by studying the mechanisms underlying pharmacological and biochemical interactions between the two systems in experimental paradigms of antinociception, drug reinforcement, and anxiety. The goal of this review is to revise the latest work done on this subject, with special emphasis on the research done with genetically modified animals. Whereas clinical progress is going ahead slowly, basic research in this area is progressing rapidly. Clinical applications derived from the cannabinoid/opioid crosstalk and based tightly on medical evidence are yet to come, but it is hoped that knowledge of this central messenger interaction will help to develop new alternatives for the treatment of some pathological states.
Increasing Endocannabinoid Levels in the Ventral Pallidum Restore Aberrant Dopamine Neuron Activity in the Subchronic PCP Rodent Model of Schizophrenia

PubMed Central

Chen, Li; Lodge, Daniel J

2015-01-01

Background: Schizophrenia is a debilitating disorder that affects 1% of the US population. While the exogenous administration of cannabinoids such as tetrahydrocannabinol is reported to exacerbate psychosis in schizophrenia patients, augmenting the levels of endogenous cannabinoids has gained attention as a possible alternative therapy to schizophrenia due to clinical and preclinical observations. Thus, patients with schizophrenia demonstrate an inverse relationship between psychotic symptoms and levels of the endocannabinoid anandamide. In addition, increasing endocannabinoid levels (by blockade of enzymatic degradation) has been reported to attenuate social withdrawal in a preclinical model of schizophrenia. Here we examine the effects of increasing endogenous cannabinoids on dopamine neuron activity in the sub-chronic phencyclidine (PCP) model. Aberrant dopamine system function is thought to underlie the positive symptoms of schizophrenia. Methods: Using in vivo extracellular recordings in chloral hydrate–anesthetized rats, we now demonstrate an increase in dopamine neuron population activity in PCP-treated rats. Results: Interestingly, endocannabinoid upregulation, induced by URB-597, was able to normalize this aberrant dopamine neuron activity. Furthermore, we provide evidence that the ventral pallidum is the site where URB-597 acts to restore ventral tegmental area activity. Conclusions: Taken together, we provide preclinical evidence that augmenting endogenous cannabinoids may be an effective therapy for schizophrenia, acting in part to restore ventral pallidal activity. PMID:25539511
Reducing cannabinoid abuse and preventing relapse by enhancing endogenous brain levels of kynurenic acid

PubMed Central

Justinova, Zuzana; Mascia, Paola; Wu, Hui-Qiu; Secci, Maria E.; Redhi, Godfrey H.; Panlilio, Leigh V.; Scherma, Maria; Barnes, Chanel; Parashos, Alexandra; Zara, Tamara; Fratta, Walter; Solinas, Marcello; Pistis, Marco; Bergman, Jack; Kangas, Brian D.; Ferré, Sergi; Tanda, Gianluigi; Schwarcz, Robert; Goldberg, Steven R.

2013-01-01

In the reward circuitry of the brain, alpha-7-nicotinic acetylcholine receptors (α7nAChRs) modulate effects of delta-9-tetrahydrocannabinol (THC), marijuana’s main psychoactive ingredient. Kynurenic acid (KYNA) is an endogenous negative allosteric modulator of α7nAChRs. Here we report that the kynurenine 3-monooxygenase (KMO) inhibitor Ro 61-8048 increases brain KYNA levels and attenuates cannabinoid-induced increases in extracellular dopamine in reward-related brain areas. In the self-administration model of drug abuse, Ro 61-8048 reduced the rewarding effects of THC and the synthetic cannabinoid WIN 55,212-2 in squirrel monkeys and rats, respectively, and it also prevented relapse to drug-seeking induced by re-exposure to cannabinoids or cannabinoid-associated cues. The effects of enhancing endogenous KYNA levels with Ro 61-8048 were prevented by positive allosteric modulators of α7nAChRs. Despite a clear need, there are currently no medications approved for treatment of marijuana dependence. Modulation of KYNA provides a novel pharmacological strategy for achieving abstinence from marijuana and preventing relapse. PMID:24121737
Reducing cannabinoid abuse and preventing relapse by enhancing endogenous brain levels of kynurenic acid.

PubMed

Justinova, Zuzana; Mascia, Paola; Wu, Hui-Qiu; Secci, Maria E; Redhi, Godfrey H; Panlilio, Leigh V; Scherma, Maria; Barnes, Chanel; Parashos, Alexandra; Zara, Tamara; Fratta, Walter; Solinas, Marcello; Pistis, Marco; Bergman, Jack; Kangas, Brian D; Ferré, Sergi; Tanda, Gianluigi; Schwarcz, Robert; Goldberg, Steven R

2013-11-01

In the reward circuitry of the brain, α-7-nicotinic acetylcholine receptors (α7nAChRs) modulate effects of Δ(9)-tetrahydrocannabinol (THC), marijuana's main psychoactive ingredient. Kynurenic acid (KYNA) is an endogenous negative allosteric modulator of α7nAChRs. Here we report that the kynurenine 3-monooxygenase (KMO) inhibitor Ro 61-8048 increases brain KYNA levels and attenuates cannabinoid-induced increases in extracellular dopamine in reward-related brain areas. In the self-administration model of drug abuse, Ro 61-8048 reduced the rewarding effects of THC and the synthetic cannabinoid WIN 55,212-2 in squirrel monkeys and rats, respectively, and it also prevented relapse to drug-seeking induced by reexposure to cannabinoids or cannabinoid-associated cues. The effects of enhancing endogenous KYNA levels with Ro 61-8048 were prevented by positive allosteric modulators of α7nAChRs. Despite a clear need, there are no medications approved for treatment of marijuana dependence. Modulation of KYNA offers a pharmacological strategy for achieving abstinence from marijuana and preventing relapse.
Enhancing acupuncture by low dose naltrexone.

PubMed

Hesselink, Jan M Keppel; Kopsky, David J

2011-06-01

To find appropriate and effective treatment options for chronic pain syndromes is a challenging task. Multimodal treatment approach has been gaining acceptance for chronic pain. However, combining treatments, such as acupuncture, with rational pharmacology is still in its infancy. Acupuncture influences the opioid and cannabinoid system through releasing endogenous receptor ligands. Low dose naltrexone also acts on both these systems, and upregulates the opioid and cannabinoid receptors. The authors hypothesise that low dose naltrexone could enhance the pain-relieving effect of acupuncture.
Bimodal control of stimulated food intake by the endocannabinoid system.

PubMed

Bellocchio, Luigi; Lafenêtre, Pauline; Cannich, Astrid; Cota, Daniela; Puente, Nagore; Grandes, Pedro; Chaouloff, Francis; Piazza, Pier Vincenzo; Marsicano, Giovanni

2010-03-01

Activation of cannabinoid type-1 receptors (CB(1)) is universally recognized as a powerful endogenous orexigenic signal, but the detailed underlying neuronal mechanisms are not fully understood. Using combined genetic and pharmacological approaches in mice, we found that ventral striatal CB(1) receptors exerted a hypophagic action through inhibition of GABAergic transmission. Conversely, brain CB(1) receptors modulating excitatory transmission mediated the well-known orexigenic effects of cannabinoids.
Endocannabinoid system and drug addiction: new insights from mutant mice approaches.

PubMed

Maldonado, Rafael; Robledo, Patricia; Berrendero, Fernando

2013-08-01

The involvement of the endocannabinoid system in drug addiction was initially studied by the use of compounds with different affinities for each cannabinoid receptor or for the proteins involved in endocannabinoids inactivation. The generation of genetically modified mice with selective mutations in these endocannabinoid system components has now provided important advances in establishing their specific contribution to drug addiction. These genetic tools have identified the particular interest of CB1 cannabinoid receptor and endogenous anandamide as potential targets for drug addiction treatment. Novel genetic tools will allow determining if the modulation of CB2 cannabinoid receptor activity and 2-arachidonoylglycerol tone can also have an important therapeutic relevance for drug addiction. Copyright © 2013 Elsevier Ltd. All rights reserved.
[The endogenous opioid system and drug addiction].

PubMed

Maldonado, R

2010-01-01

Drug addiction is a chronic brain disorder leading to complex adaptive changes within the brain reward circuits. Several neurotransmitters, including the endogenous opioid system are involved in these changes. The opioid system plays a pivotal role in different aspects of addiction. Thus, opioid receptors and endogenous opioid peptides are largely distributed in the mesolimbic system and modulate dopaminergic activity within the reward circuits. Opioid receptors and peptides are selectively involved in several components of the addictive processes induced by opioids, cannabinoids, psychostimulants, alcohol and nicotine. This review is focused on the contribution of each component of the endogenous opioid system in the addictive properties of the different drugs of abuse. Copyright 2010 Elsevier Masson SAS. All rights reserved.
Characterization of the hypothermic effect of the synthetic cannabinoid HU-210 in the rat. Relation to the adrenergic system and endogenous pyrogens.

PubMed

Ovadia, H; Wohlman, A; Mechoulam, R; Weidenfeld, J

1995-02-01

In the present study we have characterized the hypothermic effect of the psychoactive cannabinoid HU-210, by investigating its interaction with the endogenous pyrogens, IL-1 and PGE2. We also studied the involvement of the adrenergic system in mediation of this hypothermic effect. Injection of HU-210 directly into the preoptic area caused a dose dependent reduction of rectal temperature from 37 to 32.1 degrees C. Injection of the non-psychoactive analog, HU-211 which does not bind to brain cannabinoid receptor, did not affect body temperature. Injection of the adrenergic agonists, CGP-12177 and clonidine (beta, and alpha adrenergic agonists, respectively) abrogated the hypothermia induced by HU-210. Injection of the adrenergic antagonists, prazosin (alpha 1) and propranolol (beta) enhanced the hypothermic effect of HU-210. Intracerebral administration of IL-1 or PGE2 to rats pretreated with HU-210 caused a transient inhibition of the hypothermia. The ex vivo rate of basal or bacterial endotoxin-induced synthesis of PGE2 by different brain regions, including the preoptic area was not affected by HU-210 administration. These results suggest that the synthetic cannabinoid HU-210 acts in the preoptic area, probably via the brain cannabinoid receptor to induce hypothermia. The hypothermic effect can be antagonized by adrenergic agonists and enhanced by adrenergic antagonists. HU-210 does not interfere with the pyrogenic effect of IL-1 or PGE2.
Cannabis in cancer care.

PubMed

Abrams, D I; Guzman, M

2015-06-01

Cannabis has been used in medicine for thousands of years prior to achieving its current illicit substance status. Cannabinoids, the active components of Cannabis sativa, mimic the effects of the endogenous cannabinoids (endocannabinoids), activating specific cannabinoid receptors, particularly CB1 found predominantly in the central nervous system and CB2 found predominantly in cells involved with immune function. Delta-9-tetrahydrocannabinol, the main bioactive cannabinoid in the plant, has been available as a prescription medication approved for treatment of cancer chemotherapy-induced nausea and vomiting and anorexia associated with the AIDS wasting syndrome. Cannabinoids may be of benefit in the treatment of cancer-related pain, possibly synergistic with opioid analgesics. Cannabinoids have been shown to be of benefit in the treatment of HIV-related peripheral neuropathy, suggesting that they may be worthy of study in patients with other neuropathic symptoms. Cannabinoids have a favorable drug safety profile, but their medical use is predominantly limited by their psychoactive effects and their limited bioavailability. © 2015 American Society for Clinical Pharmacology and Therapeutics.
Plant cannabinoids: a neglected pharmacological treasure trove.

PubMed

Mechoulam, Raphael

2005-12-01

Most of the cannabinoids in Cannabis sativa L. have not been fully evaluated for their pharmacological activity. A publication in this issue presents evidence that a plant cannabinoid, Delta(9)-tetrahydrocannabivarin is a potent antagonist of anandamide, a major endogenous cannabinoid. It seems possible that many of the non-psychoactive constituents of this plant will be of biological interest.
Endocannabinoid system acts as a regulator of immune homeostasis in the gut.

PubMed

Acharya, Nandini; Penukonda, Sasi; Shcheglova, Tatiana; Hagymasi, Adam T; Basu, Sreyashi; Srivastava, Pramod K

2017-05-09

Endogenous cannabinoids (endocannabinoids) are small molecules biosynthesized from membrane glycerophospholipid. Anandamide (AEA) is an endogenous intestinal cannabinoid that controls appetite and energy balance by engagement of the enteric nervous system through cannabinoid receptors. Here, we uncover a role for AEA and its receptor, cannabinoid receptor 2 (CB2), in the regulation of immune tolerance in the gut and the pancreas. This work demonstrates a major immunological role for an endocannabinoid. The pungent molecule capsaicin (CP) has a similar effect as AEA; however, CP acts by engagement of the vanilloid receptor TRPV1, causing local production of AEA, which acts through CB2. We show that the engagement of the cannabinoid/vanilloid receptors augments the number and immune suppressive function of the regulatory CX3CR1 hi macrophages (Mϕ), which express the highest levels of such receptors among the gut immune cells. Additionally, TRPV1 -/- or CB2 -/- mice have fewer CX3CR1 hi Mϕ in the gut. Treatment of mice with CP also leads to differentiation of a regulatory subset of CD4 + cells, the Tr1 cells, in an IL-27-dependent manner in vitro and in vivo. In a functional demonstration, tolerance elicited by engagement of TRPV1 can be transferred to naïve nonobese diabetic (NOD) mice [model of type 1 diabetes (T1D)] by transfer of CD4 + T cells. Further, oral administration of AEA to NOD mice provides protection from T1D. Our study unveils a role for the endocannabinoid system in maintaining immune homeostasis in the gut/pancreas and reveals a conversation between the nervous and immune systems using distinct receptors.
Looking back at Cannabis research.

PubMed

Mechoulam, R

2000-09-01

Research leading to the isolation of the plant cannabinoids during the 1960 s and to the endogenous cannabinoids, during the 1990 s is described. Investigations on two non-psychotropic, synthetic cannabinoids, HU-211, a neuroprotective agent and HU-308, a specific CB2 agonist are presented.
Prospects for cannabinoid therapies in basal ganglia disorders.

PubMed

Fernández-Ruiz, Javier; Moreno-Martet, Miguel; Rodríguez-Cueto, Carmen; Palomo-Garo, Cristina; Gómez-Cañas, María; Valdeolivas, Sara; Guaza, Carmen; Romero, Julián; Guzmán, Manuel; Mechoulam, Raphael; Ramos, José A

2011-08-01

Cannabinoids are promising medicines to slow down disease progression in neurodegenerative disorders including Parkinson's disease (PD) and Huntington's disease (HD), two of the most important disorders affecting the basal ganglia. Two pharmacological profiles have been proposed for cannabinoids being effective in these disorders. On the one hand, cannabinoids like Δ(9) -tetrahydrocannabinol or cannabidiol protect nigral or striatal neurons in experimental models of both disorders, in which oxidative injury is a prominent cytotoxic mechanism. This effect could be exerted, at least in part, through mechanisms independent of CB(1) and CB(2) receptors and involving the control of endogenous antioxidant defences. On the other hand, the activation of CB(2) receptors leads to a slower progression of neurodegeneration in both disorders. This effect would be exerted by limiting the toxicity of microglial cells for neurons and, in particular, by reducing the generation of proinflammatory factors. It is important to mention that CB(2) receptors have been identified in the healthy brain, mainly in glial elements and, to a lesser extent, in certain subpopulations of neurons, and that they are dramatically up-regulated in response to damaging stimuli, which supports the idea that the cannabinoid system behaves as an endogenous neuroprotective system. This CB(2) receptor up-regulation has been found in many neurodegenerative disorders including HD and PD, which supports the beneficial effects found for CB(2) receptor agonists in both disorders. In conclusion, the evidence reported so far supports that those cannabinoids having antioxidant properties and/or capability to activate CB(2) receptors may represent promising therapeutic agents in HD and PD, thus deserving a prompt clinical evaluation. © 2011 The Authors. British Journal of Pharmacology © 2011 The British Pharmacological Society.
Plant cannabinoids: a neglected pharmacological treasure trove

PubMed Central

Mechoulam, Raphael

2005-01-01

Most of the cannabinoids in Cannabis sativa L. have not been fully evaluated for their pharmacological activity. A publication in this issue presents evidence that a plant cannabinoid, Δ9-tetrahydrocannabivarin is a potent antagonist of anandamide, a major endogenous cannabinoid. It seems possible that many of the non-psychoactive constituents of this plant will be of biological interest. PMID:16205721
Cannabinoid-related agents in the treatment of anxiety disorders: current knowledge and future perspectives

PubMed Central

Tambaro, Simone; Bortolato, Marco

2013-01-01

Rich evidence has shown that cannabis products exert a broad gamut of effects on emotional regulation. The main psychoactive ingredient of hemp, Δ9-tetrahydrocannabinol (THC), and its synthetic cannabinoid analogs have been reported to either attenuate or exacerbate anxiety and fear-related behaviors in humans and experimental animals. The heterogeneity of cannabis-induced psychological outcomes reflects a complex network of molecular interactions between the key neurobiological substrates of anxiety and fear and the endogenous cannabinoid system, mainly consisting of the arachidonic acid derivatives anandamide and 2-arachidonoylglycerol (2-AG) and two receptors, respectively termed CB1 and CB2. The high degree of interindividual variability in the responses to cannabis is contributed by a wide spectrum of factors, including genetic and environmental determinants, as well as differences in the relative concentrations of THC and other alkaloids (such as cannabidiol) within the plant itself. The present article reviews the currently available knowledge on the herbal, synthetic and endogenous cannabinoids with respect to the modulation of anxiety responses, and highlights the challenges that should be overcome to harness the therapeutic potential of some of these compounds, all the while limiting the side effects associated with cannabis consumption. PMID:22280339

The Cannabinoid Acids, Analogs and Endogenous Counterparts

PubMed Central

Burstein, Sumner H.

2015-01-01

The cannabinoid acids are a structurally heterogeneous group of compounds some of which are endogenous molecules and others that are metabolites of phytocannabinoids. The prototypic endogenous substance is N-arachidonoyl glycine (NAgly) that is closely related in structure to the cannabinoid agonist anandamide. The most studied phytocannabinoid is Δ9–THC-11-oic acid, the principal metabolite of Δ9–THC. Both types of acids have in common several biological actions such as low affinity for CB1, anti-inflammatory activity and analgesic properties. This suggests that there may be similarities in their mechanism of action, a point that is discussed in this review. Also presented are reports on analogs of the acids that provide opportunities for the development of novel therapeutic agents, such as ajulemic acid. PMID:24731541
Cannabinoids and Pain: Sites and Mechanisms of Action.

PubMed

Starowicz, Katarzyna; Finn, David P

2017-01-01

The endocannabinoid system, consisting of the cannabinoid 1 receptor (CB 1 R) and cannabinoid 2 receptor (CB 2 R), endogenous cannabinoid ligands (endocannabinoids), and metabolizing enzymes, is present throughout the pain pathways. Endocannabinoids, phytocannabinoids, and synthetic cannabinoid receptor agonists have antinociceptive effects in animal models of acute, inflammatory, and neuropathic pain. CB 1 R and CB 2 R located at peripheral, spinal, or supraspinal sites are important targets mediating these antinociceptive effects. The mechanisms underlying the analgesic effects of cannabinoids likely include inhibition of presynaptic neurotransmitter and neuropeptide release, modulation of postsynaptic neuronal excitability, activation of the descending inhibitory pain pathway, and reductions in neuroinflammatory signaling. Strategies to dissociate the psychoactive effects of cannabinoids from their analgesic effects have focused on peripherally restricted CB 1 R agonists, CB 2 R agonists, inhibitors of endocannabinoid catabolism or uptake, and modulation of other non-CB 1 R/non-CB 2 R targets of cannabinoids including TRPV1, GPR55, and PPARs. The large body of preclinical evidence in support of cannabinoids as potential analgesic agents is supported by clinical studies demonstrating their efficacy across a variety of pain disorders. © 2017 Elsevier Inc. All rights reserved.
The endocannabinoid system and the brain.

PubMed

Mechoulam, Raphael; Parker, Linda A

2013-01-01

The psychoactive constituent in cannabis, Δ(9)-tetrahydrocannabinol (THC), was isolated in the mid-1960s, but the cannabinoid receptors, CB1 and CB2, and the major endogenous cannabinoids (anandamide and 2-arachidonoyl glycerol) were identified only 20 to 25 years later. The cannabinoid system affects both central nervous system (CNS) and peripheral processes. In this review, we have tried to summarize research--with an emphasis on recent publications--on the actions of the endocannabinoid system on anxiety, depression, neurogenesis, reward, cognition, learning, and memory. The effects are at times biphasic--lower doses causing effects opposite to those seen at high doses. Recently, numerous endocannabinoid-like compounds have been identified in the brain. Only a few have been investigated for their CNS activity, and future investigations on their action may throw light on a wide spectrum of brain functions.
Prospects for cannabinoid therapies in basal ganglia disorders

PubMed Central

Fernández-Ruiz, Javier; Moreno-Martet, Miguel; Rodríguez-Cueto, Carmen; Palomo-Garo, Cristina; Gómez-Cañas, María; Valdeolivas, Sara; Guaza, Carmen; Romero, Julián; Guzmán, Manuel; Mechoulam, Raphael; Ramos, José A

2011-01-01

Cannabinoids are promising medicines to slow down disease progression in neurodegenerative disorders including Parkinson's disease (PD) and Huntington's disease (HD), two of the most important disorders affecting the basal ganglia. Two pharmacological profiles have been proposed for cannabinoids being effective in these disorders. On the one hand, cannabinoids like Δ9-tetrahydrocannabinol or cannabidiol protect nigral or striatal neurons in experimental models of both disorders, in which oxidative injury is a prominent cytotoxic mechanism. This effect could be exerted, at least in part, through mechanisms independent of CB1 and CB2 receptors and involving the control of endogenous antioxidant defences. On the other hand, the activation of CB2 receptors leads to a slower progression of neurodegeneration in both disorders. This effect would be exerted by limiting the toxicity of microglial cells for neurons and, in particular, by reducing the generation of proinflammatory factors. It is important to mention that CB2 receptors have been identified in the healthy brain, mainly in glial elements and, to a lesser extent, in certain subpopulations of neurons, and that they are dramatically up-regulated in response to damaging stimuli, which supports the idea that the cannabinoid system behaves as an endogenous neuroprotective system. This CB2 receptor up-regulation has been found in many neurodegenerative disorders including HD and PD, which supports the beneficial effects found for CB2 receptor agonists in both disorders. In conclusion, the evidence reported so far supports that those cannabinoids having antioxidant properties and/or capability to activate CB2 receptors may represent promising therapeutic agents in HD and PD, thus deserving a prompt clinical evaluation. LINKED ARTICLES This article is part of a themed issue on Cannabinoids in Biology and Medicine. To view the other articles in this issue visit http://dx.doi.org/10.1111/bph.2011.163.issue-7 PMID:21545415
Potential therapeutic agents derived from the cannabinoid nucleus.

PubMed

Pars, H G; Howes, J F

1977-01-01

Drugs derived from Cannabis sativa (Cannabinceae) were used until the 1940's for their stimulant and depressant effects for treating somatic and psychiatric illnesses. Renewed interest in marihuana research began in the 1970's and again pointed to the therapeutic potential of cannabinoids. Safer and more useful therapeutic agents may be generated from cannabinoids similarly to morphine, lysergic acid diethylamide, and cocaine which have structurally related analgesics, oxytoxics, and local anesthetics respectively. It has been shown that the C-ring in cannabinoids can be substituted with a variety of nitrogen and sulfur-containing rings without loss of CNS (central nervous system) activity. Cannabinoids have been shown to inhibit prostaglandin synthesis, intensify pressor effects of endogenous amines like norepinephrine, and enhance the stimulant effects of amphetamine. Cannabinoids' therapeutic potential lies in the areas of analgesics and anticonvulsants, and for use as a sedative-hypnotic, an antiglaucoma agent, an antiasthmatic agent, an antidiarrheal agent, and possibly as an anticancer and immunosuppressant agent.
Cannabis and cannabinoids: pharmacology and rationale for clinical use.

PubMed

Pertwee, R G

1999-10-01

It is now known that there are at least two types of cannabinoid receptors. These are CB1 receptors, present mainly on central and peripheral neurones, and CB2 receptors, present mainly on immune cells. Endogenous cannabinoid receptor agonists ('endocannabinoids') have also been identified. The discovery of this 'endogenous cannabinoid system' has led to the development of selective CB1 and CB2 receptor ligands and fueled renewed interest in the clinical potential of cannabinoids. Two cannabinoid CB1 receptor agonists are already used clinically, as antiemetics or as appetite stimulants. These are D 9 - tetrahydrocannabinol (THC) and nabilone. Other possible uses for CB1 receptor agonists include the suppression of muscle spasm/spasticity associated with multiple sclerosis or spinal cord injury, the relief of chronic pain and the management of glaucoma and bronchial asthma. CB1 receptor antagonists may also have clinical applications, e. g. as appetite suppressants and in the management of schizophrenia or disorders of cognition and memory. So too may CB2 receptor ligands and drugs that activate cannabinoid receptors indirectly by augmenting endocannabinoid levels at cannabinoid receptors. When taken orally, THC seems to undergo variable absorption and to have a narrow 'therapeutic window' (dose range in which it is effective without producing significant unwanted effects). This makes it difficult to predict an oral dose that will be both effective and tolerable to a patient and indicates a need for better cannabinoid formulations and modes of administration. For the therapeutic potential of cannabis or CB1 receptor agonists to be fully exploited, it will be important to establish objectively and conclusively (a) whether these agents have efficacy against selected symptoms that is of clinical significance and, if so, whether the benefits outweigh the risks, (b) whether cannabis has therapeutic advantages over individual cannabinoids, (c) whether there is a need for additional drug treatments to manage any of the disorders against which cannabinoids are effective, and (d) whether it will be possible to develop drugs that have reduced psychotropic activity and yet retain the ability to act through CB1 receptors to produce their sought-after effects. Copyright 1999 S. Karger GmbH, Freiburg
[Cognitive abnormalities and cannabis use].

PubMed

Solowij, Nadia; Pesa, Nicole

2010-05-01

Evidence that cannabis use impairs cognitive function in humans has been accumulating in recent decades. The purpose of this overview is to update knowledge in this area with new findings from the most recent literature. Literature searches were conducted using the Web of Science database up to February 2010. The terms searched were: "cannabi*" or "marijuana", and "cogniti*" or "memory" or "attention" or "executive function", and human studies were reviewed preferentially over the animal literature. Cannabis use impairs memory, attention, inhibitory control, executive functions and decision making, both during the period of acute intoxication and beyond, persisting for hours, days, weeks or more after the last use of cannabis. Pharmacological challenge studies in humans are elucidating the nature and neural substrates of cognitive changes associated with various cannabinoids. Long-term or heavy cannabis use appears to result in longer-lasting cognitive abnormalities and possibly structural brain alterations. Greater adverse cognitive effects are associated with cannabis use commencing in early adolescence. The endogenous cannabinoid system is involved in regulatory neural mechanisms that modulate processes underlying a range of cognitive functions that are impaired by cannabis. Deficits in human users most likely therefore reflect neuroadaptations and altered functioning of the endogenous cannabinoid system.
Endogenous cannabinoid receptor ligand induces the migration of human natural killer cells.

PubMed

Kishimoto, Seishi; Muramatsu, Mayumi; Gokoh, Maiko; Oka, Saori; Waku, Keizo; Sugiura, Takayuki

2005-02-01

2-Arachidonoylglycerol is an endogenous ligand for the cannabinoid receptors (CB1 and CB2). Evidence is gradually accumulating which shows that 2-arachidonoylglycerol plays important physiological roles in several mammalian tissues and cells, yet the details remain ambiguous. In this study, we first examined the effects of 2-arachidonoylglycerol on the motility of human natural killer cells. We found that 2-arachidonoylglycerol induces the migration of KHYG-1 cells (a natural killer leukemia cell line) and human peripheral blood natural killer cells. The migration of natural killer cells induced by 2-arachidonoylglycerol was abolished by treating the cells with SR144528, a CB2 receptor antagonist, suggesting that the CB2 receptor is involved in the 2-arachidonoylglycerol-induced migration. In contrast to 2-arachidonoylglycerol, anandamide, another endogenous cannabinoid receptor ligand, did not induce the migration. Delta9-tetrahydrocannabinol, a major psychoactive constituent of marijuana, also failed to induce the migration; instead, the addition of delta9-tetrahydrocannabinol together with 2-arachidonoylglycerol abolished the migration induced by 2-arachidonoylglycerol. It is conceivable that the endogenous ligand for the cannabinoid receptor, that is, 2-arachidonoylglycerol, affects natural killer cell functions such as migration, thereby contributing to the host-defense mechanism against infectious viruses and tumor cells.
Framework for sex differences in adolescent neurobiology: A focus on cannabinoids

PubMed Central

Viveros, Maria-Paz; Marco-López, Eva María; López-Gallardo, Meritxell; Garcia-Segura, Luis Miguel; Wagner, Edward J.

2017-01-01

This review highlights the salient findings that have furthered our understanding of how sex differences are initiated during development and maintained throughout life. First we discuss how gonadal steroid hormones organize the framework for sex differences within critical periods of development—namely, during those exposures which occur in utero and post-partum, as well as those which occur during puberty. Given the extensive precedence of sex differences in cannabinoid-regulated biology, we then focus on the disparities within the endogenous cannabinoid system, as well as those observed with exogenously administered cannabinoids. We start with how the expression of cannabinoid CB1 receptors is regulated throughout development. This is followed by a discussion of differential vulnerability to the pathological sequelae stemming from cannabinoid exposure during adolescence. Next we talk about sex differences in the interactions between cannabinoids and other drugs of abuse, followed by the organizational and activational roles of gonadal steroids in establishing and maintaining the sex dependence in the biological actions of cannabinoids. Finally, we discuss ways to utilize this knowledge to strategically target critical developmental windows of vulnerability/susceptibility and thereby implement more effective therapeutic interventions for afflictions that may be more prevalent in one sex vs. the other. PMID:20869396
Role of cannabis in digestive disorders.

PubMed

Goyal, Hemant; Singla, Umesh; Gupta, Urvashi; May, Elizabeth

2017-02-01

Cannabis sativa, a subspecies of the Cannabis plant, contains aromatic hydrocarbon compounds called cannabinoids. [INCREMENT]-Tetrahydrocannabinol is the most abundant cannabinoid and is the main psychotropic constituent. Cannabinoids activate two types of G-protein-coupled cannabinoid receptors: cannabinoid type 1 receptor and cannabinoid type 2 receptor. There has been ongoing interest and development in research to explore the therapeutic potential of cannabis. [INCREMENT]-Tetrahydrocannabinol exerts biological functions on the gastrointestinal (GI) tract. Cannabis has been used for the treatment of GI disorders such as abdominal pain and diarrhea. The endocannabinoid system (i.e. endogenous circulating cannabinoids) performs protective activities in the GI tract and presents a promising therapeutic target against various GI conditions such as inflammatory bowel disease (especially Crohn's disease), irritable bowel syndrome, and secretion and motility-related disorders. The present review sheds light on the role of cannabis in the gut, liver, and pancreas and also on other GI symptoms, such as nausea and vomiting, cannabinoid hyperemesis syndrome, anorexia, weight loss, and chronic abdominal pain. Although the current literature supports the use of marijuana for the treatment of digestive disorders, the clinical efficacy of cannabis and its constituents for various GI disorders remains unclear.
An Update on Non-CB1, Non-CB2 Cannabinoid Related G-Protein-Coupled Receptors

PubMed Central

Morales, Paula; Reggio, Patricia H.

2017-01-01

Abstract The endocannabinoid system (ECS) has been shown to be of great importance in the regulation of numerous physiological and pathological processes. To date, two Class A G-protein-coupled receptors (GPCRs) have been discovered and validated as the main therapeutic targets of this system: the cannabinoid receptor type 1 (CB1), which is the most abundant neuromodulatory receptor in the brain, and the cannabinoid receptor type 2 (CB2), predominantly found in the immune system among other organs and tissues. Endogenous cannabinoid receptor ligands (endocannabinoids) and the enzymes involved in their synthesis, cell uptake, and degradation have also been identified as part of the ECS. However, its complex pharmacology suggests that other GPCRs may also play physiologically relevant roles in this therapeutically promising system. In the last years, GPCRs such as GPR18 and GPR55 have emerged as possible missing members of the cannabinoid family. This categorization still stimulates strong debate due to the lack of pharmacological tools to validate it. Because of their close phylogenetic relationship, the Class A orphan GPCRs, GPR3, GPR6, and GPR12, have also been associated with the cannabinoids. Moreover, certain endo-, phyto-, and synthetic cannabinoid ligands have displayed activity at other well-established GPCRs, including the opioid, adenosine, serotonin, and dopamine receptor families. In addition, the cannabinoid receptors have also been shown to form dimers with other GPCRs triggering cross-talk signaling under specific conditions. In this mini review, we aim to provide insight into the non-CB1, non-CB2 cannabinoid-related GPCRs that have been reported thus far. We consider the physiological relevance of these molecular targets in modulating the ECS. PMID:29098189
Elucidating Cannabinoid Biology in Zebrafish (Danio rerio)

PubMed Central

Krug, Randall G.; Clark, Karl J.

2015-01-01

The number of annual cannabinoid users exceeds 100,000,000 globally and an estimated 9 % of these individuals will suffer from dependency. Although exogenous cannabinoids, like those contained in marijuana, are known to exert their effects by disrupting the endocannabinoid system, a dearth of knowledge exists about the potential toxicological consequences on public health. Conversely, the endocannabinoid system represents a promising therapeutic target for a plethora of disorders because it functions to endogenously regulate a vast repertoire of physiological functions. Accordingly, the rapidly expanding field of cannabinoid biology has sought to leverage model organisms in order to provide both toxicological and therapeutic insights about altered endocannabinoid signaling. The primary goal of this manuscript is to review the existing field of cannabinoid research in the genetically tractable zebrafish model—focusing on the cannabinoid receptor genes, cnr1 and cnr2, and the genes that produce enzymes for synthesis and degradation of the cognate ligands anandamide and 2-arachidonylglycerol. Consideration is also given to research that has studied the effects of exposure to exogenous phytocannabinoids and synthetic cannabinoids that are known to interact with cannabinoid receptors. These results are considered in the context of either endocannabinoid gene expression or endocannabinoid gene function, and are integrated with findings from rodent studies. This provides the framework for a discussion of how zebrafish may be leveraged in the future to provide novel toxicological and therapeutic insights in the field of cannabinoid biology, which has become increasingly significant given recent trends in cannabis legislation. PMID:26192460
The expanding field of cannabimimetic and related lipid mediators

PubMed Central

Bradshaw, Heather B; Walker, J Michael

2005-01-01

The discovery of the endogenous cannabimimetic lipid mediators, anandamide and 2-arachidonoyl glycerol, opened the door to the discovery of other endogenous lipid mediators similar in structure and function. The majority of these compounds do not bind appreciably to known cannabinoid receptors; yet some of them produce cannabimimetic effects while others exert actions through novel mechanisms that remain to be elucidated. This review explores the growing diversity of recently discovered putative lipid mediators and their relationship to the endogenous cannabinoid system. The possibility that there remain many unidentified signalling lipids coupled with the evidence that many of these yield bioactive metabolites due to actions of known enzymes (e.g. cyclooxygenases, lipoxygenases, cytochrome P450s) suggests the existence of a large and complex family of lipid mediators about which only little is known at this time. The elucidation of the biochemistry and pharmacology of these compounds may provide therapeutic targets for a variety of conditions including sleep dysfunction, eating disorders, cardiovascular disease, as well as inflammation and pain. PMID:15655504
The endocannabinoid system and multiple sclerosis.

PubMed

Baker, David; Pryce, Gareth

2008-01-01

Multiple sclerosis (MS) is a neurodegenerative disease that is characterised by repeated inflammatory/demyelinating events within the central nervous system (CNS). In addition to relapsing-remitting neurological insults, leading to loss of function, patients are often left with residual, troublesome symptoms such as spasticity and pain. These greatly diminish "quality of life" and have prompted some patients to self-medicate with and perceive benefit from cannabis. Recent advances in cannabinoid biology are beginning to support these anecdotal observations, notably the demonstration that spasticity is tonically regulated by the endogenous cannabinoid system. Recent clinical trials may indeed suggest that cannabis has some potential to relieve, pain, spasms and spasticity in MS. However, because the CB(1) cannabinoid receptor mediates both the positive and adverse effects of cannabis, therapy will invariably be associated with some unwanted, psychoactive effects. In an experimental model of MS, and in MS tissue, there are local perturbations of the endocannabinoid system in lesional areas. Stimulation of endocannabinoid activity in these areas either through increase of synthesis or inhibition of endocannabinoid degradation offers the positive therapeutic potential of the cannabinoid system whilst limiting adverse events by locally targeting the lesion. In addition, CB(1) and CB(2) cannabinoid receptor stimulation may also have anti-inflammatory and neuroprotective potential as the endocannabinoid system controls the level of neurodegeneration that occurs as a result of the inflammatory insults. Therefore cannabinoids may not only offer symptom control but may also slow the neurodegenerative disease progression that ultimately leads to the accumulation of disability.
The endogenous cannabinoid anandamide shares discriminative stimulus effects with ∆(9)-tetrahydrocannabinol in fatty acid amide hydrolase knockout mice.

PubMed

Walentiny, D Matthew; Gamage, Thomas F; Warner, Jonathan A; Nguyen, Thanh K; Grainger, Darren B; Wiley, Jenny L; Vann, Robert E

2011-04-10

The endogenous cannabinoid system has been noted for its therapeutic potential, as well as the psychoactivity of cannabinoids such as Δ9-tetrahydrocannabinol (THC). However, less is known about the psychoactivity of anandamide (AEA), an endocannabinoid ligand. Thus, the goals of this study were to establish AEA as a discriminative stimulus in transgenic mice lacking fatty acid amide hydrolase (i.e., FAAH -/- mice unable to rapidly metabolize AEA), evaluate whether THC or oleamide, a fatty acid amide, produced AEA-like responding, and assess for CB(1) mediation of AEA's discriminative stimulus. Mice readily discriminated between 6mg/kg AEA and vehicle in a two-lever drug discrimination task. AEA dose-dependently generalized to itself. THC elicited full AEA-like responding, whereas oleamide failed to substitute. The CB(1) antagonist rimonabant attenuated AEA- and THC-induced AEA-appropriate responding, demonstrating CB(1) mediation of AEA's discriminative stimulus. These findings suggest that, in the absence of FAAH, AEA produces intoxication comparable to THC, and consequently to marijuana. Copyright © 2011 Elsevier B.V. All rights reserved.
Atypical Responsiveness of the Orphan Receptor GPR55 to Cannabinoid Ligands*

PubMed Central

Kapur, Ankur; Zhao, Pingwei; Sharir, Haleli; Bai, Yushi; Caron, Marc G.; Barak, Larry S.; Abood, Mary E.

2009-01-01

The cannabinoid receptor 1 (CB1) and CB2 cannabinoid receptors, associated with drugs of abuse, may provide a means to treat pain, mood, and addiction disorders affecting widespread segments of society. Whether the orphan G-protein coupled receptor GPR55 is also a cannabinoid receptor remains unclear as a result of conflicting pharmacological studies. GPR55 has been reported to be activated by exogenous and endogenous cannabinoid compounds but surprisingly also by the endogenous non-cannabinoid mediator lysophosphatidylinositol (LPI). We examined the effects of a representative panel of cannabinoid ligands and LPI on GPR55 using a β-arrestin-green fluorescent protein biosensor as a direct readout of agonist-mediated receptor activation. Our data demonstrate that AM251 and SR141716A (rimonabant), which are cannabinoid antagonists, and the lipid LPI, which is not a cannabinoid receptor ligand, are GPR55 agonists. They possess comparable efficacy in inducing β-arrestin trafficking and, moreover, activate the G-protein-dependent signaling of protein kinase CβII. Conversely, the potent synthetic cannabinoid agonist CP55,940 acts as a GPR55 antagonist/partial agonist. CP55,940 blocks GPR55 internalization, the formation of β-arrestin GPR55 complexes, and the phosphorylation of ERK1/2; CP55,940 produces only a slight amount of protein kinase CβII membrane recruitment but does not stimulate membrane remodeling like LPI, AM251, or rimonabant. Our studies provide a paradigm for measuring the responsiveness of GPR55 to a variety of ligand scaffolds comprising cannabinoid and novel compounds and suggest that at best GPR55 is an atypical cannabinoid responder. The activation of GPR55 by rimonabant may be responsible for some of the off-target effects that led to its removal as a potential obesity therapy. PMID:19723626
Structural analogs of pyrazole and sulfonamide cannabinoids: Effects on acute food intake in mice

PubMed Central

Wiley, Jenny L.; Marusich, Julie A.; Zhang, Yanan; Fulp, Alan; Maitra, Rangan; Thomas, Brian F.; Mahadevan, Anu

2012-01-01

Obesity contributes to a multitude of serious health problems. Given the demonstrated role of the endogenous cannabinoid system in appetite regulation, the purpose of the present study was to evaluate structural analogs of two cannabinoids, rimonabant (cannabinoid CB1 receptor antagonist) and O-2050 (sulfonamide analog of Δ8-tetrahydrocannabinol), that showed appetite suppressant effects in previous studies. Structure–activity relationships of these two lead compounds were examined in several assays, including cannabinoid CB1 and CB2 receptor binding, food intake, and an in vivo test battery (locomotor activity, antinociception, ring immobility, and body temperature) in mice. Rimonabant and O-2050 reliably decreased feeding in mice; however, their analogs decreased feeding only at higher doses, even though some compounds had quite good cannabinoid CB1 binding affinity. Results of the in vivo test battery were inconsistent, with some of the compounds producing effects characteristic of cannabinoid agonists while other compounds were inactive or were antagonists against an active dose of Δ9-tetrahydrocannabinol. These results demonstrate that reduction of food intake is not a characteristic effect of pyrazole and sulfonamide cannabinoid analogs with favorable cannabinoid CB1 binding affinity, suggesting that development of these classes of cannabinoids for the treatment of obesity will require evaluation of their effects in a broad spectrum of pharmacological assays. PMID:22975289
[Cannabis and cannabinoid receptors: from pathophysiology to therapeutic options].

PubMed

Derkinderen, P; Valjent, E; Darcel, F; Damier, P; Girault, J-A

2004-07-01

Although cannabis has been used as a medicine for several centuries, the therapeutic properties of cannabis preparations (essentially haschich and marijuana) make them far most popular as a recreational drugs. Scientific studies on the effects of cannabis were advanced considerably by the identification in 1964 of cannabinoid D9-tetrahydrocannadinol (THC), recognized as the major active constituent of cannabis. Cloning of the centrally located CB1 receptor in 1990 and the identification of the first endogenous ligand of the CB1 receptor, anandamide, in 1992 further advanced our knowledge. Progress has incited further research on the biochemistry and pharmacology of the cannabinoids in numerous diseases of the central nervous system. In the laboratory animal, cannabinoids have demonstrated potential in motion disorders, demyelinizing disease, epilepsy, and as anti-tumor and neuroprotector agents. Several clinical studies are currently in progress, but therapeutic use of cannabinoids in humans couls be hindered by undesirable effects, particularly psychotropic effects. CB1 receptor antagonists also have interesting therapeutic potential.
Animal models of cannabinoid reward

PubMed Central

Panlilio, Leigh V; Justinova, Zuzana; Goldberg, Steven R

2010-01-01

The endogenous cannabinoid system is involved in numerous physiological and neuropsychological functions. Medications that target this system hold promise for the treatment of a wide variety of disorders. However, as reward is one of the most prominent of these functions, medications that activate this system must be evaluated for abuse potential. Meanwhile, cannabis is already being used chronically by millions of people, many of whom eventually seek treatment for cannabis dependence. Therefore, there is a need for procedures that can be used to: (i) better understand the mechanisms of cannabinoid reward; (ii) evaluate the abuse potential of new medications; and (iii) evaluate the effectiveness of medications developed for treating cannabis dependence. Animal models of cannabinoid reward provide a means of accomplishing these goals. In this review, we briefly describe and evaluate these models, their advantages and their shortcomings. Special emphasis is placed on intravenous cannabinoid self-administration in squirrel monkeys, a valid, reliable and flexible model that we have developed over the past decade. Although the conditions under which cannabinoid drugs have rewarding effects may be more restricted than with other drugs of abuse such as cocaine and heroin, work with these models indicates that cannabinoid reward involves similar brain mechanisms and produces the same kinds of reward-related behaviour. By continuing to use these animal models as tools in the development of new medications, it should be possible to take advantage of the potential benefits provided by the endocannabinoid system while minimizing its potential for harm. This article is part of a themed issue on Cannabinoids. To view the editorial for this themed issue visit http://dx.doi.org/10.1111/j.1476-5381.2010.00831.x PMID:20590560
2012 Division of Medicinal Chemistry Award Address: Trekking the Cannabinoid Road: A Personal Perspective

PubMed Central

Makriyannis, Alexandros

2014-01-01

My involvement with the field of cannabinoids spans close to three decades, and covers a major part of my scientific career. It also reflects the robust progress in this initially largely unexplored area of biology. During this period of time, I have witnessed the growth of modern cannabinoid biology, starting from the discovery of its two receptors and followed by the characterization of its endogenous ligands and the identification of the enzyme systems involved in their biosynthesis and biotransformation. I was fortunate enough to start at the beginning of this new era and participate in a number of the new discoveries. It has been a very exciting journey. By covering some key aspects of my work during this period of “modern cannabinoid research,” this perspective, in part historical, intends to give an account of how the field grew, the key discoveries, and the most promising directions for the future. PMID:24707904

Discovery of endocannabinoids and some random thoughts on their possible roles in neuroprotection and aggression.

PubMed

Mechoulam, R

2002-01-01

A short history of the discovery of the main plant cannabinoid, Delta(9)-tetrahydrocannabinol and of the endogenous cannabinoids anandamide, 2-arachidonoyl glycerol and 2-arachidonyl glyceryl ether (noladin ether) is presented. The role of the cannabinoids in neuroprotection, with emphasis on the endocannabinoids, is described. The unexpected production of aggression by Cannabis and cannabinoids under stressful conditions, published mainly in the past, is summarized. Copyright 2002 Elsevier Science Ltd. All rights reserved.
Betacaryophyllene - A phytocannabinoid as potential therapeutic modality for human sepsis?

PubMed

Meza, Angel; Lehmann, Christian

2018-01-01

Sepsis is a clinical condition resulting from a dysregulated immune response to an infection that leads to organ dysfunction. Despite numerous efforts to optimize treatment, sepsis remains to be the main cause of death in most intensive care units. The endogenous cannabinoid system (ECS) plays an important role in inflammation. Cannabinoid receptor 2 (CB2R) activation is immunosuppressive, which might be beneficial during the hyper-inflammatory phase of sepsis. Beta-caryophyllene (BCP) is a non-psychoactive natural cannabinoid (phytocannabinoid) found in Cannabis sativa and in essential oils of spices and food plants, that acts as a selective agonist of CB2R. We propose BCP administration as novel treatment to reduce hyper-inflammation in human sepsis. Copyright © 2017 Elsevier Ltd. All rights reserved.
Interactions between the endocannabinoid and nicotinic cholinergic systems: preclinical evidence and therapeutic perspectives.

PubMed

Scherma, Maria; Muntoni, Anna Lisa; Melis, Miriam; Fattore, Liana; Fadda, Paola; Fratta, Walter; Pistis, Marco

2016-05-01

Several lines of evidence suggest that endocannabinoid and nicotinic cholinergic systems are implicated in the regulation of different physiological processes, including reward, and in the neuropathological mechanisms of psychiatric diseases, such as addiction. A crosstalk between these two systems is substantiated by the overlapping distribution of cannabinoid and nicotinic acetylcholine receptors in many brain structures. We will review recent preclinical data showing how the endocannabinoid and nicotinic cholinergic systems interact bidirectionally at the level of the brain reward pathways, and how this interaction plays a key role in modulating nicotine and cannabinoid intake and dependence. Many behavioral and neurochemical effects of nicotine that are related to its addictive potential are reduced by pharmacological blockade or genetic deletion of type-1 cannabinoid receptors, inhibition of endocannabinoid uptake or metabolic degradation, and activation of peroxisome proliferator-activated-receptor-α. On the other hand, cholinergic antagonists at α7 nicotinic acetylcholine receptors as well as endogenous negative allosteric modulators of these receptors are effective in blocking dependence-related effects of cannabinoids. Pharmacological manipulation of the endocannabinoid system and endocannabinoid-like neuromodulators shows promise in the treatment of nicotine dependence and in relapse prevention. Likewise, drugs acting at nicotinic acetylcholine receptors might prove useful in the therapy of cannabinoid dependence. Research by Steven R. Goldberg has significantly contributed to the progress in this research field.
Endocannabinoids in brain plasticity: Cortical maturation, HPA axis function and behavior.

PubMed

Dow-Edwards, Diana; Silva, Lindsay

2017-01-01

Marijuana use during adolescence has reached virtually every strata of society. The general population has the perception that marijuana use is safe for mature people and therefore is also safe for developing adolescents. However, both clinical and preclinical research shows that marijuana use, particularly prior to age 16, could have long-term effects on cognition, anxiety and stress-related behaviors, mood disorders and substance abuse. These effects derive from the role of the endocannabinoid system, the endogenous cannabinoid system, in the development of cortex, amygdala, hippocampus and hypothalamus during adolescence. Endocannabinoids are necessary for normal neuronal excitation and inhibition through actions at glutamate and GABA terminals. Synaptic pruning at excitatory synapses and sparing of inhibitory synapses likely results in changes in the balance of excitation/inhibition in individual neurons and within networks; processes which are necessary for normal cortical development. The interaction between prefrontal cortex (PFC), amygdala and hippocampus is responsible for emotional memory, anxiety-related behaviors and drug abuse and all utilize the endogenous cannabinoid system to maintain homeostasis. Also, endocannabinoids are required for fast and slow feedback in the normal stress response, processes which mature during adolescence. Therefore, exogenous cannabinoids, such as marijuana, have the potential to alter the course of development of each of these major systems (limbic, hypothalamic-pituitary-adrenal (HPA) axis and neocortex) if used during the critical period of brain development, adolescence. This article is part of a Special Issue entitled SI: Adolescent plasticity. Copyright © 2016 Elsevier B.V. All rights reserved.
2-Arachidonyl glyceryl ether, an endogenous agonist of the cannabinoid CB1 receptor

PubMed Central

Hanuš, Lumír; Abu-Lafi, Saleh; Fride, Ester; Breuer, Aviva; Vogel, Zvi; Shalev, Deborah E.; Kustanovich, Irina; Mechoulam, Raphael

2001-01-01

Two types of endogenous cannabinoid-receptor agonists have been identified thus far. They are the ethanolamides of polyunsaturated fatty acids—arachidonoyl ethanolamide (anandamide) is the best known compound in the amide series—and 2-arachidonoyl glycerol, the only known endocannabinoid in the ester series. We report now an example of a third, ether-type endocannabinoid, 2-arachidonyl glyceryl ether (noladin ether), isolated from porcine brain. The structure of noladin ether was determined by mass spectrometry and nuclear magnetic resonance spectroscopy and was confirmed by comparison with a synthetic sample. It binds to the CB1 cannabinoid receptor (Ki = 21.2 ± 0.5 nM) and causes sedation, hypothermia, intestinal immobility, and mild antinociception in mice. It binds weakly to the CB2 receptor (Ki > 3 μM). PMID:11259648
The role of cannabinoid signaling in acute and chronic kidney diseases.

PubMed

Barutta, Federica; Bruno, Graziella; Mastrocola, Raffaella; Bellini, Stefania; Gruden, Gabriella

2018-04-26

The endogenous cannabinoids anandamide and 2-arachidonoylglycerol bind to the cannabinoid receptors of type 1 and 2. These receptors are also the binding sites for exogenous, both natural and synthetic, cannabinoids that are used for recreation purposes. Until recently, cannabinoids and cannabinoid receptors have attracted little interest among nephrologists; however, a full endocannabinoid system (ECS) is present in the kidney and it has recently emerged as an important player in the pathogenesis of diabetic nephropathy, drug nephrotoxicity, and progressive chronic kidney disease. This newly established role of the ECS in the kidney might have therapeutic relevance, as pharmacological modulation of the ECS has renoprotective effects in experimental animals, raising hope for future potential applications in humans. In addition, over the last years, there has been a number of reported cases of acute kidney injury (AKI) associated with the use of synthetic cannabinoids that appear to have higher potency and rate of toxicity than natural Cannabis. This poorly recognized cause of renal injury should be considered in the differential diagnosis of AKI, particularly in young people. In this review we provide an overview of preclinical evidence indicating a role of the ECS in renal disease and discuss potential future therapeutic applications. Moreover, we give a critical update of synthetic cannabinoid-induced AKI. Copyright © 2018 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.
Dual Influence of Endocannabinoids on Long-Term Potentiation of Synaptic Transmission

PubMed Central

Silva-Cruz, Armando; Carlström, Mattias; Ribeiro, Joaquim A.; Sebastião, Ana M.

2017-01-01

Cannabinoid receptor 1 (CB1R) is widely distributed in the central nervous system, in excitatory and inhibitory neurons, and in astrocytes. CB1R agonists impair cognition and prevent long-term potentiation (LTP) of synaptic transmission, but the influence of endogenously formed cannabinoids (eCBs) on hippocampal LTP remains ambiguous. Based on the knowledge that eCBs are released upon high frequency neuronal firing, we hypothesized that the influence of eCBs upon LTP could change according to the paradigm of LTP induction. We thus tested the influence of eCBs on hippocampal LTP using two θ-burst protocols that induce either a weak or a strong LTP. LTP induced by a weak-θ-burst protocol is facilitated while preventing the endogenous activation of CB1Rs. In contrast, the same procedures lead to inhibition of LTP induced by the strong-θ-burst protocol, suggestive of a facilitatory action of eCBs upon strong LTP. Accordingly, an inhibitor of the metabolism of the predominant eCB in the hippocampus, 2-arachidonoyl-glycerol (2-AG), facilitates strong LTP. The facilitatory action of endogenous CB1R activation does not require the activity of inhibitory A1 adenosine receptors, is not affected by inhibition of astrocytic metabolism, but involves inhibitory GABAergic transmission. The continuous activation of CB1Rs via exogenous cannabinoids, or by drugs known to prevent metabolism of the non-prevalent hippocampal eCB, anandamide, inhibited LTP. We conclude that endogenous activation of CB1Rs by physiologically formed eCBs exerts a fine-tune homeostatic control of LTP in the hippocampus, acting as a high-pass filter, therefore likely reducing the signal-to-noise ratio of synaptic strengthening. PMID:29311928
Sex-dependent effects of periadolescent exposure to the cannabinoid agonist CP-55,940 on morphine self-administration behaviour and the endogenous opioid system.

PubMed

Biscaia, Miguel; Fernández, Beatriz; Higuera-Matas, Alejandro; Miguéns, Miguel; Viveros, Maria-Paz; García-Lecumberri, Carmen; Ambrosio, Emilio

2008-04-01

Early cannabinoid consumption may predispose individuals to the misuse of addictive drugs later in life. However, there is a lack of experimental evidence as to whether cannabinoid exposure during adolescence might differently affect opiate reinforcing efficacy and the opioid system in adults of both sexes. Our aim was to examine whether periadolescent chronic exposure to the cannabinoid agonist CP-55,940 could exert sex-dependent effects on morphine reinforcing and the opioid system in adulthood. Morphine reinforcing was studied under a progressive ratio (PR) reinforcement schedule in adult male and female rats that previously acquired morphine self-administration under a fixed ratio 1 (FR1) schedule. Binding levels and functionality of mu-opioid receptors were also evaluated. Periadolescent cannabinoid exposure altered morphine self-administration and the opioid system in adult rats in a sex-dependent manner. CP-55,940-exposed males exhibited higher self-administration rates under a FR1, but not under a PR schedule. In females, CP-55,940 did not modify morphine self-administration under either schedule. Moreover, CP-55,940 also increased mu-opioid receptor levels in the subcallosal streak of pre-treated animals and decreased mu-opioid receptor functionality in the nucleus accumbens shell but again, only in males. Our data indicate that adult male rats exposed to the cannabinoid in adolescence self-administer more morphine than females, but only when the demands required by the schedule of reinforcement are low, which might be related to the decrease in mu-opioid receptor functionality in the NAcc-shell observed in these animals.
Differential Endocannabinoid Regulation of Extinction in Appetitive and Aversive Barnes Maze Tasks

ERIC Educational Resources Information Center

Harloe, John P.; Thorpe, Andrew J.; Lichtman, Aron H.

2008-01-01

CB[subscript 1] receptor-compromised animals show profound deficits in extinguishing learned behavior from aversive conditioning tasks, but display normal extinction learning in appetitive operant tasks. However, it is difficult to discern whether the differential involvement of the endogenous cannabinoid system on extinction results from the…
Cannabinoid CB1 Receptor Activation Mediates the Opposing Effects of Amphetamine on Impulsive Action and Impulsive Choice

PubMed Central

Wiskerke, Joost; Stoop, Nicky; Schetters, Dustin; Schoffelmeer, Anton N. M.; Pattij, Tommy

2011-01-01

It is well known that acute challenges with psychostimulants such as amphetamine affect impulsive behavior. We here studied the pharmacology underlying the effects of amphetamine in two rat models of impulsivity, the 5-choice serial reaction time task (5-CSRTT) and the delayed reward task (DRT), providing measures of inhibitory control, an aspect of impulsive action, and impulsive choice, respectively. We focused on the role of cannabinoid CB1 receptor activation in amphetamine-induced impulsivity as there is evidence that acute challenges with psychostimulants activate the endogenous cannabinoid system, and CB1 receptor activity modulates impulsivity in both rodents and humans. Results showed that pretreatment with either the CB1 receptor antagonist/inverse agonist SR141716A or the neutral CB1 receptor antagonist O-2050 dose-dependently improved baseline inhibitory control in the 5-CSRTT. Moreover, both compounds similarly attenuated amphetamine-induced inhibitory control deficits, suggesting that CB1 receptor activation by endogenously released cannabinoids mediates this aspect of impulsive action. Direct CB1 receptor activation by Δ9-Tetrahydrocannabinol (Δ9-THC) did, however, not affect inhibitory control. Although neither SR141716A nor O-2050 affected baseline impulsive choice in the DRT, both ligands completely prevented amphetamine-induced reductions in impulsive decision making, indicating that CB1 receptor activity may decrease this form of impulsivity. Indeed, acute Δ9-THC was found to reduce impulsive choice in a CB1 receptor-dependent way. Together, these results indicate an important, though complex role for cannabinoid CB1 receptor activity in the regulation of impulsive action and impulsive choice as well as the opposite effects amphetamine has on both forms of impulsive behavior. PMID:22016780
Acute resistance exercise induces antinociception by activation of the endocannabinoid system in rats.

PubMed

Galdino, Giovane; Romero, Thiago; Silva, José Felippe Pinho da; Aguiar, Daniele; Paula, Ana Maria de; Cruz, Jader; Parrella, Cosimo; Piscitelli, Fabiana; Duarte, Igor; Di Marzo, Vincenzo; Perez, Andrea

2014-09-01

Resistance exercise (RE) is also known as strength training, and it is performed to increase the strength and mass of muscles, bone strength, and metabolism. RE has been increasingly prescribed for pain relief. However, the endogenous mechanisms underlying this antinociceptive effect are still largely unexplored. Thus, we investigated the involvement of the endocannabinoid system in RE-induced antinociception. Male Wistar rats were submitted to acute RE in a weight-lifting model. The nociceptive threshold was measured by a mechanical nociceptive test (paw pressure) before and after exercise. To investigate the involvement of cannabinoid receptors and endocannabinoids in RE-induced antinociception, cannabinoid receptor inverse agonists, endocannabinoid metabolizing enzyme inhibitors, and an anandamide reuptake inhibitor were injected before RE. After RE, CB1 cannabinoid receptors were quantified in rat brain tissue by Western blot and immunofluorescence. In addition, endocannabinoid plasma levels were measured by isotope dilution-liquid chromatography mass spectrometry. RE-induced antinociception was prevented by preinjection with CB1 and CB2 cannabinoid receptor inverse agonists. By contrast, preadministration of metabolizing enzyme inhibitors and the anandamide reuptake inhibitor prolonged and enhanced this effect. RE also produced an increase in the expression and activation of CB1 cannabinoid receptors in rat brain tissue and in the dorsolateral and ventrolateral periaqueductal regions and an increase in endocannabinoid plasma levels. The present study suggests that a single session of RE activates the endocannabinoid system to induce antinociception.
The endogenous opioid system: a common substrate in drug addiction.

PubMed

Trigo, José Manuel; Martin-García, Elena; Berrendero, Fernando; Robledo, Patricia; Maldonado, Rafael

2010-05-01

Drug addiction is a chronic brain disorder leading to complex adaptive changes within the brain reward circuits that involve several neurotransmitters. One of the neurochemical systems that plays a pivotal role in different aspects of addiction is the endogenous opioid system (EOS). Opioid receptors and endogenous opioid peptides are largely distributed in the mesolimbic system and modulate dopaminergic activity within these reward circuits. Chronic exposure to the different prototypical drugs of abuse, including opioids, alcohol, nicotine, psychostimulants and cannabinoids has been reported to produce significant alterations within the EOS, which seem to play an important role in the development of the addictive process. In this review, we will describe the adaptive changes produced by different drugs of abuse on the EOS, and the current knowledge about the contribution of each component of this neurobiological system to their addictive properties.
Cannabinoids as therapeutic agents in cancer: current status and future implications

PubMed Central

Ganju, Ramesh K.

2014-01-01

The pharmacological importance of cannabinoids has been in study for several years. Cannabinoids comprise of (a) the active compounds of the Cannabis sativa plant, (b) endogenous as well as (c) synthetic cannabinoids. Though cannabinoids are clinically used for anti-palliative effects, recent studies open a promising possibility as anti-cancer agents. They have been shown to possess anti-proliferative and anti-angiogenic effects in vitro as well as in vivo in different cancer models. Cannabinoids regulate key cell signaling pathways that are involved in cell survival, invasion, angiogenesis, metastasis, etc. There is more focus on CB1 and CB2, the two cannabinoid receptors which are activated by most of the cannabinoids. In this review article, we will focus on a broad range of cannabinoids, their receptor dependent and receptor independent functional roles against various cancer types with respect to growth, metastasis, energy metabolism, immune environment, stemness and future perspectives in exploring new possible therapeutic opportunities. PMID:25115386
Endocannabinoid system in neurodegenerative disorders.

PubMed

Basavarajappa, Balapal S; Shivakumar, Madhu; Joshi, Vikram; Subbanna, Shivakumar

2017-09-01

Most neurodegenerative disorders (NDDs) are characterized by cognitive impairment and other neurological defects. The definite cause of and pathways underlying the progression of these NDDs are not well-defined. Several mechanisms have been proposed to contribute to the development of NDDs. These mechanisms may proceed concurrently or successively, and they differ among cell types at different developmental stages in distinct brain regions. The endocannabinoid system, which involves cannabinoid receptors type 1 (CB1R) and type 2 (CB2R), endogenous cannabinoids and the enzymes that catabolize these compounds, has been shown to contribute to the development of NDDs in several animal models and human studies. In this review, we discuss the functions of the endocannabinoid system in NDDs and converse the therapeutic efficacy of targeting the endocannabinoid system to rescue NDDs. © 2017 International Society for Neurochemistry.
Oxidation of the endogenous cannabinoid arachidonoyl ethanolamide by the cytochrome P450 monooxygenases: physiological and pharmacological implications.

PubMed

Snider, Natasha T; Walker, Vyvyca J; Hollenberg, Paul F

2010-03-01

Arachidonoyl ethanolamide (anandamide) is an endogenous amide of arachidonic acid and an important signaling mediator of the endocannabinoid system. Given its numerous roles in maintaining normal physiological function and modulating pathophysiological responses throughout the body, the endocannabinoid system is an important pharmacological target amenable to manipulation directly by cannabinoid receptor ligands or indirectly by drugs that alter endocannabinoid synthesis and inactivation. The latter approach has the possible advantage of more selectivity, thus there is the potential for fewer untoward effects like those that are traditionally associated with cannabinoid receptor ligands. In that regard, inhibitors of the principal inactivating enzyme for anandamide, fatty acid amide hydrolase (FAAH), are currently in development for the treatment of pain and inflammation. However, several pathways involved in anandamide synthesis, metabolism, and inactivation all need to be taken into account when evaluating the effects of FAAH inhibitors and similar agents in preclinical models and assessing their clinical potential. Anandamide undergoes oxidation by several human cytochrome P450 (P450) enzymes, including CYP3A4, CYP4F2, CYP4X1, and the highly polymorphic CYP2D6, forming numerous structurally diverse lipids, which are likely to have important physiological roles, as evidenced by the demonstration that a P450-derived epoxide of anandamide is a potent agonist for the cannabinoid receptor 2. The focus of this review is to emphasize the need for a better understanding of the P450-mediated pathways of the metabolism of anandamide, because these are likely to be important in mediating endocannabinoid signaling as well as the pharmacological responses to endocannabinoid-targeting drugs.
The therapeutic potential of cannabis and cannabinoids.

PubMed

Grotenhermen, Franjo; Müller-Vahl, Kirsten

2012-07-01

Cannabis-based medications have been a topic of intense study since the endogenous cannabinoid system was discovered two decades ago. In 2011, for the first time, a cannabis extract was approved for clinical use in Germany. Selective literature review. Cannabis-based medications exert their effects mainly through the activation of cannabinoid receptors (CB1 and CB2). More than 100 controlled clinical trials of cannabinoids or whole-plant preparations for various indications have been conducted since 1975. The findings of these trials have led to the approval of cannabis-based medicines (dronabinol, nabilone, and a cannabis extract [THC:CBD=1:1]) in several countries. In Germany, a cannabis extract was approved in 2011 for the treatment of moderate to severe refractory spasticity in multiple sclerosis. It is commonly used off label for the treatment of anorexia, nausea, and neuropathic pain. Patients can also apply for government permission to buy medicinal cannabis flowers for self-treatment under medical supervision. The most common side effects of cannabinoids are tiredness and dizziness (in more than 10% of patients), psychological effects, and dry mouth. Tolerance to these side effects nearly always develops within a short time. Withdrawal symptoms are hardly ever a problem in the therapeutic setting. There is now clear evidence that cannabinoids are useful for the treatment of various medical conditions.
Endocannabinoids and stress.

PubMed

Riebe, Caitlin J; Wotjak, Carsten T

2011-07-01

Endogenous cannabinoids play an important role in the physiology and behavioral expression of stress responses. Activation of the hypothalamic-pituitary-adrenal (HPA) axis, including the release of glucocorticoids, is the fundamental hormonal response to stress. Endocannabinoid (eCB) signaling serves to maintain HPA-axis homeostasis, by buffering basal activity as well as by mediating glucocorticoid fast feedback mechanisms. Following chronic stressor exposure, eCBs are also involved in physiological and behavioral habituation processes. Behavioral consequences of stress include fear and stress-induced anxiety as well as memory formation in the context of stress, involving contextual fear conditioning and inhibitory avoidance learning. Chronic stress can also lead to depression-like symptoms. Prominent in these behavioral stress responses is the interaction between eCBs and the HPA-axis. Future directions may differentiate among eCB signaling within various brain structures/neuronal subpopulations as well as between the distinct roles of the endogenous cannabinoid ligands. Investigation into the role of the eCB system in allostatic states and recovery processes may give insight into possible therapeutic manipulations of the system in treating chronic stress-related conditions in humans.
Distribution of the Endocannabinoid System in the Central Nervous System.

PubMed

Hu, Sherry Shu-Jung; Mackie, Ken

2015-01-01

The endocannabinoid system consists of endogenous cannabinoids (endocannabinoids), the enzymes that synthesize and degrade endocannabinoids, and the receptors that transduce the effects of endocannabinoids. Much of what we know about the function of endocannabinoids comes from studies that combine localization of endocannabinoid system components with physiological or behavioral approaches. This review will focus on the localization of the best-known components of the endocannabinoid system for which the strongest anatomical evidence exists.
Cannabinoids, cannabinoid receptors and tinnitus.

PubMed

Smith, Paul F; Zheng, Yiwen

2016-02-01

One hypothesis suggests that tinnitus is a form of sensory epilepsy, arising partly from neuronal hyperactivity in auditory regions of the brain such as the cochlear nucleus and inferior colliculus. Although there is currently no effective drug treatment for tinnitus, anti-epileptic drugs are used in some cases as a potential treatment option. There is increasing evidence to suggest that cannabinoid drugs, i.e. cannabinoid receptor agonists, can also have anti-epileptic effects, at least in some cases and in some parts of the brain. It has been reported that cannabinoid CB1 receptors and the endogenous cannabinoid, 2-arachidonylglycerol (2-AG), are expressed in the cochlear nucleus and that they are involved in the regulation of plasticity. This review explores the question of whether cannabinoid receptor agonists are likely to be pro- or anti-epileptic in the cochlear nucleus and therefore whether cannabinoids and Cannabis itself are likely to make tinnitus better or worse. Copyright © 2015 Elsevier B.V. All rights reserved.
R-Flurbiprofen Reduces Neuropathic Pain in Rodents by Restoring Endogenous Cannabinoids

PubMed Central

Marian, Claudiu; Häussler, Annett; Wijnvoord, Nina; Ziebell, Simone; Metzner, Julia; Koch, Marco; Myrczek, Thekla; Bechmann, Ingo; Kuner, Rohini; Costigan, Michael; Dehghani, Faramarz; Geisslinger, Gerd; Tegeder, Irmgard

2010-01-01

Background R-flurbiprofen, one of the enantiomers of flurbiprofen racemate, is inactive with respect to cyclooxygenase inhibition, but shows analgesic properties without relevant toxicity. Its mode of action is still unclear. Methodology/Principal Findings We show that R-flurbiprofen reduces glutamate release in the dorsal horn of the spinal cord evoked by sciatic nerve injury and thereby alleviates pain in sciatic nerve injury models of neuropathic pain in rats and mice. This is mediated by restoring the balance of endocannabinoids (eCB), which is disturbed following peripheral nerve injury in the DRGs, spinal cord and forebrain. The imbalance results from transcriptional adaptations of fatty acid amide hydrolase (FAAH) and NAPE-phospholipase D, i.e. the major enzymes involved in anandamide metabolism and synthesis, respectively. R-flurbiprofen inhibits FAAH activity and normalizes NAPE-PLD expression. As a consequence, R-Flurbiprofen improves endogenous cannabinoid mediated effects, indicated by the reduction of glutamate release, increased activity of the anti-inflammatory transcription factor PPARγ and attenuation of microglia activation. Antinociceptive effects are lost by combined inhibition of CB1 and CB2 receptors and partially abolished in CB1 receptor deficient mice. R-flurbiprofen does however not cause changes of core body temperature which is a typical indicator of central effects of cannabinoid-1 receptor agonists. Conclusion Our results suggest that R-flurbiprofen improves the endogenous mechanisms to regain stability after axonal injury and to fend off chronic neuropathic pain by modulating the endocannabinoid system and thus constitutes an attractive, novel therapeutic agent in the treatment of chronic, intractable pain. PMID:20498712

The Endocannabinoid System and Anxiety.

PubMed

Lisboa, S F; Gomes, F V; Terzian, A L B; Aguiar, D C; Moreira, F A; Resstel, L B M; Guimarães, F S

2017-01-01

The medical properties of Cannabis sativa is known for centuries. Since the discovery and characterization of the endogenous cannabinoid system, several studies have evaluated how cannabinoid compounds and, particularly, how the modulation of the endocannabinoid (eCB) system influences a wide range of functions, from metabolic to mental disorders. Cannabinoids and eCB system often exert opposite effects on several functions, such as anxiety. Although the mechanisms are not completely understood, evidence points to different factors influencing those effects. In this chapter, the recent advances in research about the relationship between eCB system and anxiety disorders in humans, as well as in animal models, will be discussed. The recent data addressing modulation of the eCBs in specific brain areas, such as the medial prefrontal cortex, amygdaloid complex, bed nucleus of stria terminalis, hippocampus, and dorsal periaqueductal gray, will be summarized. Finally, data from animal models addressing the mechanisms through which the eCB system modulates anxiety-related behavior dependent on stressful situations, such as the involvement of different receptors, distinct eCBs, modulation of neurotransmitters release, HPA axis and immune system activation, and plastic mechanisms, will also be discussed. © 2017 Elsevier Inc. All rights reserved.
Acute Resistance Exercise Induces Antinociception by Activation of the Endocannabinoid System in Rats

PubMed Central

Galdino, Giovane; Romero, Thiago; da Silva, José Felippe Pinho; Aguiar, Daniele; de Paula, Ana Maria; Cruz, Jader; Parrella, Cosimo; Piscitelli, Fabiana; Duarte, Igor; Di Marzo, Vincenzo; Perez, Andrea

2014-01-01

Background Resistance exercise (RE) is also known as strength training, and it is performed to increase the strength and mass of muscles, bone strength and metabolism. RE has been increasingly prescribed for pain relief. However, the endogenous mechanisms underlying this antinociceptive effect are still largely unexplored. Thus, we investigated the involvement of the endocannabinoid system in RE-induced antinociception. Methods Male Wistar rats were submitted to acute RE in a weight-lifting model. The nociceptive threshold was measured by a mechanical nociceptive test (paw pressure) before and after exercise. To investigate the involvement of cannabinoid receptors and endocannabinoids in RE-induced antinociception, cannabinoid receptor inverse agonists, endocannabinoid metabolizing enzyme inhibitors and an anandamide reuptake inhibitor were injected before RE. After RE, CB1 cannabinoid receptors were quantified in rat brain tissue by Western blot and immunofluorescence. In addition, endocannabinoid plasma levels were measured by isotope dilution-liquid chromatography mass spectrometry. Results RE-induced antinociception was prevented by preinjection with CB1 and CB2 cannabinoid receptor inverse agonists. By contrast, preadministration of metabolizing enzyme inhibitors and the anandamide reuptake inhibitor prolonged and enhanced this effect. RE also produced an increase in the expression and activation of CB1 cannabinoid receptors in rat brain tissue and in the dorsolateral and ventrolateral periaqueductal regions and an increase of endocannabinoid plasma levels. Conclusion The present study suggests that a single session of RE activates the endocannabinoid system to induce antinociception. PMID:24977916
Type 1 Cannabinoid Receptor Ligands Display Functional Selectivity in a Cell Culture Model of Striatal Medium Spiny Projection Neurons*

PubMed Central

Laprairie, Robert B.; Bagher, Amina M.; Kelly, Melanie E. M.; Dupré, Denis J.; Denovan-Wright, Eileen M.

2014-01-01

Modulation of type 1 cannabinoid receptor (CB1) activity has been touted as a potential means of treating addiction, anxiety, depression, and neurodegeneration. Different agonists of CB1 are known to evoke varied responses in vivo. Functional selectivity is the ligand-specific activation of certain signal transduction pathways at a receptor that can signal through multiple pathways. To understand cannabinoid-specific functional selectivity, different groups have examined the effect of individual cannabinoids on various signaling pathways in heterologous expression systems. In the current study, we compared the functional selectivity of six cannabinoids, including two endocannabinoids (2-arachidonyl glycerol (2-AG) and anandamide (AEA)), two synthetic cannabinoids (WIN55,212-2 and CP55,940), and two phytocannabinoids (cannabidiol (CBD) and Δ9-tetrahydrocannabinol (THC)) on arrestin2-, Gαi/o-, Gβγ-, Gαs-, and Gαq-mediated intracellular signaling in the mouse STHdhQ7/Q7 cell culture model of striatal medium spiny projection neurons that endogenously express CB1. In this system, 2-AG, THC, and CP55,940 were more potent mediators of arrestin2 recruitment than other cannabinoids tested. 2-AG, AEA, and WIN55,212-2, enhanced Gαi/o and Gβγ signaling, with 2-AG and AEA treatment leading to increased total CB1 levels. 2-AG, AEA, THC, and WIN55,212-2 also activated Gαq-dependent pathways. CP55,940 and CBD both signaled through Gαs. CP55,940, but not CBD, activated downstream Gαs pathways via CB1 targets. THC and CP55,940 promoted CB1 internalization and decreased CB1 protein levels over an 18-h period. These data demonstrate that individual cannabinoids display functional selectivity at CB1 leading to activation of distinct signaling pathways. To effectively match cannabinoids with therapeutic goals, these compounds must be screened for their signaling bias. PMID:25037227
From cannabis to the endocannabinoid system: refocussing attention on potential clinical benefits.

PubMed

Youssef, F F; Irving, A J

2012-06-01

Cannabis sativa is one of the oldest herbal remedies known to man. Over the past four thousand years, it has been used for the treatment of numerous diseases but due to its psychoactive properties, its current medicinal usage is highly restricted. In this review, we seek to highlight advances made over the last forty years in the understanding of the mechanisms responsible for the effects of cannabis on the human body and how these can potentially be utilized in clinical practice. During this time, the primary active ingredients in cannabis have been isolated, specific cannabinoid receptors have been discovered and at least five endogenous cannabinoid neurotransmitters (endocannabinoids) have been identified. Together, these form the framework of a complex endocannabinoid signalling system that has widespread distribution in the body and plays a role in regulating numerous physiological processes within the body. Cannabinoid ligands are therefore thought to display considerable therapeutic potential and the drive to develop compounds that can be targeted to specific neuronal systems at low enough doses so as to eliminate cognitive side effects remains the 'holy grail' of endocannabinoid research.
CB2 cannabinoid receptor agonist enantiomers HU-433 and HU-308: An inverse relationship between binding affinity and biological potency.

PubMed

Smoum, Reem; Baraghithy, Saja; Chourasia, Mukesh; Breuer, Aviva; Mussai, Naama; Attar-Namdar, Malka; Kogan, Natalya M; Raphael, Bitya; Bolognini, Daniele; Cascio, Maria G; Marini, Pietro; Pertwee, Roger G; Shurki, Avital; Mechoulam, Raphael; Bab, Itai

2015-07-14

Activation of the CB2 receptor is apparently an endogenous protective mechanism. Thus, it restrains inflammation and protects the skeleton against age-related bone loss. However, the endogenous cannabinoids, as well as Δ(9)-tetrahydrocannabinol, the main plant psychoactive constituent, activate both cannabinoid receptors, CB1 and CB2. HU-308 was among the first synthetic, selective CB2 agonists. HU-308 is antiosteoporotic and antiinflammatory. Here we show that the HU-308 enantiomer, designated HU-433, is 3-4 orders of magnitude more potent in osteoblast proliferation and osteoclast differentiation culture systems, as well as in mouse models, for the rescue of ovariectomy-induced bone loss and ear inflammation. HU-433 retains the HU-308 specificity for CB2, as shown by its failure to bind to the CB1 cannabinoid receptor, and has no activity in CB2-deficient cells and animals. Surprisingly, the CB2 binding affinity of HU-433 in terms of [(3)H]CP55,940 displacement and its effect on [(35)S]GTPγS accumulation is substantially lower compared with HU-308. A molecular-modeling analysis suggests that HU-433 and -308 have two different binding conformations within CB2, with one of them possibly responsible for the affinity difference, involving [(35)S]GTPγS and cAMP synthesis. Hence, different ligands may have different orientations relative to the same binding site. This situation questions the usefulness of universal radioligands for comparative binding studies. Moreover, orientation-targeted ligands have promising potential for the pharmacological activation of distinct processes.
CB2 cannabinoid receptor agonist enantiomers HU-433 and HU-308: An inverse relationship between binding affinity and biological potency

PubMed Central

Smoum, Reem; Baraghithy, Saja; Chourasia, Mukesh; Breuer, Aviva; Mussai, Naama; Attar-Namdar, Malka; Kogan, Natalya M.; Raphael, Bitya; Bolognini, Daniele; Cascio, Maria G.; Marini, Pietro; Pertwee, Roger G.; Shurki, Avital; Mechoulam, Raphael; Bab, Itai

2015-01-01

Activation of the CB2 receptor is apparently an endogenous protective mechanism. Thus, it restrains inflammation and protects the skeleton against age-related bone loss. However, the endogenous cannabinoids, as well as Δ9-tetrahydrocannabinol, the main plant psychoactive constituent, activate both cannabinoid receptors, CB1 and CB2. HU-308 was among the first synthetic, selective CB2 agonists. HU-308 is antiosteoporotic and antiinflammatory. Here we show that the HU-308 enantiomer, designated HU-433, is 3–4 orders of magnitude more potent in osteoblast proliferation and osteoclast differentiation culture systems, as well as in mouse models, for the rescue of ovariectomy-induced bone loss and ear inflammation. HU-433 retains the HU-308 specificity for CB2, as shown by its failure to bind to the CB1 cannabinoid receptor, and has no activity in CB2-deficient cells and animals. Surprisingly, the CB2 binding affinity of HU-433 in terms of [3H]CP55,940 displacement and its effect on [35S]GTPγS accumulation is substantially lower compared with HU-308. A molecular-modeling analysis suggests that HU-433 and -308 have two different binding conformations within CB2, with one of them possibly responsible for the affinity difference, involving [35S]GTPγS and cAMP synthesis. Hence, different ligands may have different orientations relative to the same binding site. This situation questions the usefulness of universal radioligands for comparative binding studies. Moreover, orientation-targeted ligands have promising potential for the pharmacological activation of distinct processes. PMID:26124120
Cannabinoid receptor signaling in progenitor/stem cell proliferation and differentiation.

PubMed

Galve-Roperh, Ismael; Chiurchiù, Valerio; Díaz-Alonso, Javier; Bari, Monica; Guzmán, Manuel; Maccarrone, Mauro

2013-10-01

Cannabinoids, the active components of cannabis (Cannabis sativa) extracts, have attracted the attention of human civilizations for centuries, much earlier than the discovery and characterization of their substrate of action, the endocannabinoid system (ECS). The latter is an ensemble of endogenous lipids, their receptors [in particular type-1 (CB1) and type-2 (CB2) cannabinoid receptors] and metabolic enzymes. Cannabinoid signaling regulates cell proliferation, differentiation and survival, with different outcomes depending on the molecular targets and cellular context involved. Cannabinoid receptors are expressed and functional from the very early developmental stages, when they regulate embryonic and trophoblast stem cell survival and differentiation, and thus may affect the formation of manifold adult specialized tissues derived from the three different germ layers (ectoderm, mesoderm and endoderm). In the ectoderm-derived nervous system, both CB1 and CB2 receptors are present in neural progenitor/stem cells and control their self-renewal, proliferation and differentiation. CB1 and CB2 show opposite patterns of expression, the former increasing and the latter decreasing along neuronal differentiation. Recently, endocannabinoid (eCB) signaling has also been shown to regulate proliferation and differentiation of mesoderm-derived hematopoietic and mesenchymal stem cells, with a key role in determining the formation of several cell types in peripheral tissues, including blood cells, adipocytes, osteoblasts/osteoclasts and epithelial cells. Here, we will review these new findings, which unveil the involvement of eCB signaling in the regulation of progenitor/stem cell fate in the nervous system and in the periphery. The developmental regulation of cannabinoid receptor expression and cellular/subcellular localization, together with their role in progenitor/stem cell biology, may have important implications in human health and disease. Copyright © 2013 Elsevier Ltd. All rights reserved.
Control of Inhibition by the Direct Action of Cannabinoids on GABAA Receptors.

PubMed

Golovko, Tatiana; Min, Rogier; Lozovaya, Natalia; Falconer, Caroline; Yatsenko, Natalia; Tsintsadze, Timur; Tsintsadze, Vera; Ledent, Catherine; Harvey, Robert J; Belelli, Delia; Lambert, Jeremy J; Rozov, Andrei; Burnashev, Nail

2015-09-01

Cannabinoids are known to regulate inhibitory synaptic transmission via activation of presynaptic G protein-coupled cannabinoid CB1 receptors (CB1Rs). Additionally, recent studies suggest that cannabinoids can also directly interact with recombinant GABAA receptors (GABAARs), potentiating currents activated by micromolar concentrations of γ-aminobutyric acid (GABA). However, the impact of this direct interaction on GABAergic inhibition in central nervous system is unknown. Here we report that currents mediated by recombinant GABAARs activated by high (synaptic) concentrations of GABA as well as GABAergic inhibitory postsynaptic currents (IPSCs) at neocortical fast spiking (FS) interneuron to pyramidal neuron synapses are suppressed by exogenous and endogenous cannabinoids in a CB1R-independent manner. This IPSC suppression may account for disruption of inhibitory control of pyramidal neurons by FS interneurons. At FS interneuron to pyramidal neuron synapses, endocannabinoids induce synaptic low-pass filtering of GABAAR-mediated currents evoked by high-frequency stimulation. The CB1R-independent suppression of inhibition is synapse specific. It does not occur in CB1R containing hippocampal cholecystokinin-positive interneuron to pyramidal neuron synapses. Furthermore, in contrast to synaptic receptors, the activity of extrasynaptic GABAARs in neocortical pyramidal neurons is enhanced by cannabinoids in a CB1R-independent manner. Thus, cannabinoids directly interact differentially with synaptic and extrasynaptic GABAARs, providing a potent novel context-dependent mechanism for regulation of inhibition. © The Author 2014. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.
Pharmacological blockade of either cannabinoid CB1 or CB2 receptors prevents both cocaine-induced conditioned locomotion and cocaine-induced reduction of cell proliferation in the hippocampus of adult male rat

PubMed Central

Blanco-Calvo, Eduardo; Rivera, Patricia; Arrabal, Sergio; Vargas, Antonio; Pavón, Francisco Javier; Serrano, Antonia; Castilla-Ortega, Estela; Galeano, Pablo; Rubio, Leticia; Suárez, Juan; Rodriguez de Fonseca, Fernando

2014-01-01

Addiction to major drugs of abuse, such as cocaine, has recently been linked to alterations in adult neurogenesis in the hippocampus. The endogenous cannabinoid system modulates this proliferative response as demonstrated by the finding that pharmacological activation/blockade of cannabinoid CB1 and CB2 receptors not only modulates neurogenesis but also modulates cell death in the brain. In the present study, we evaluated whether the endogenous cannabinoid system affects cocaine-induced alterations in cell proliferation. To this end, we examined whether pharmacological blockade of either CB1 (Rimonabant, 3 mg/kg) or CB2 receptors (AM630, 3 mg/kg) would affect cell proliferation [the cells were labeled with 5-bromo-2′-deoxyuridine (BrdU)] in the subventricular zone (SVZ) of the lateral ventricle and the dentate subgranular zone (SGZ). Additionally, we measured cell apoptosis (as monitored by the expression of cleaved caspase-3) and glial activation [by analyzing the expression of glial fibrillary acidic protein (GFAP) and Iba-1] in the striatum and hippocampus during acute and repeated (4 days) cocaine administration (20 mg/kg). The results showed that acute cocaine exposure decreased the number of BrdU-immunoreactive (ir) cells in the SVZ and SGZ. In contrast, repeated cocaine exposure reduced the number of BrdU-ir cells only in the SVZ. Both acute and repeated cocaine exposure increased the number of cleaved caspase-3-, GFAP- and Iba1-ir cells in the hippocampus, and this effect was counteracted by AM630 or Rimonabant, which increased the number of BrdU-, GFAP-, and Iba1-ir cells in the hippocampus. These results indicate that the changes in neurogenic, apoptotic and gliotic processes that were produced by repeated cocaine administration were normalized by pharmacological blockade of CB1 and CB2. The restorative effects of cannabinoid receptor blockade on hippocampal cell proliferation were associated with the prevention of the induction of conditioned locomotion but not with the prevention of cocaine-induced sensitization. PMID:24409127
The endocannabinoid system: a general view and latest additions

PubMed Central

Petrocellis, Luciano De; Cascio, Maria Grazia; Marzo, Vincenzo Di

2004-01-01

After the discovery, in the early 1990s, of specific G-protein-coupled receptors for marijuana's psychoactive principle Δ9-tetrahydrocannabinol, the cannabinoid receptors, and of their endogenous agonists, the endocannabinoids, a decade of investigations has greatly enlarged our understanding of this altogether new signalling system. Yet, while the finding of the endocannabinoids resulted in a new effort to reveal the mechanisms regulating their levels in the brain and peripheral organs under physiological and pathological conditions, more endogenous substances with a similar action, and more molecular targets for the previously discovered endogenous ligands, anandamide and 2-arachidonoylglycerol, or for some of their metabolites, were being proposed. As the scenario becomes subsequently more complicated, and the experimental tasks to be accomplished correspondingly more numerous, we briefly review in this article the latest ‘additions' to the endocannabinoid system together with earlier breakthroughs that have contributed to our present knowledge of the biochemistry and pharmacology of the endocannabinoids. PMID:14744801
SGIP1 alters internalization and modulates signaling of activated cannabinoid receptor 1 in a biased manner.

PubMed

Hájková, Alena; Techlovská, Šárka; Dvořáková, Michaela; Chambers, Jayne Nicole; Kumpošt, Jiří; Hubálková, Pavla; Prezeau, Laurent; Blahos, Jaroslav

2016-08-01

Many diseases of the nervous system are accompanied by alterations in synaptic functions. Synaptic plasticity mediated by the endogenous cannabinoid system involves the activation of the cannabinoid receptor 1 (CB1R). The principles of CB1R signaling must be understood in detail for its therapeutic exploration. We detected the Src homology 3-domain growth factor receptor-bound 2-like (endophilin) interacting protein 1 (SGIP1) as a novel CB1R partner. SGIP1 is functionally linked to clathrin-mediated endocytosis and its overexpression in animals leads to an energy regulation imbalance resulting in obesity. We report that SGIP1 prevents the endocytosis of activated CB1R and that it alters signaling via the CB1R in a biased manner. CB1R mediated G-protein activation is selectively influenced by SGIP1, β-arrestin associated signaling is changed profoundly, most likely as a consequence of the prevention of the receptor's internalization elicited by SGIP1. Copyright © 2016 The Authors. Published by Elsevier Ltd.. All rights reserved.
Nicotine-induced neuroprotection against ischemic injury involves activation of endocannabinoid system in rats.

PubMed

Chen, Yu; Nie, Huang; Tian, Li; Tong, Li; Yang, Lujia; Lao, Ning; Dong, Hailong; Sang, Hanfei; Xiong, Lize

2013-02-01

Nicotine has been reported to exert certain protective effect in the Parkinson's and Alzheimer's diseases. Whether it has a similar action in focal cerebral ischemia was unclear. In the present study, rats received either an injection of (-)-nicotine hydrogen tartrate salt (1.2 mg/kg, i.p.) or the vehicle 2 h before the 120 min middle cerebral artery occlusion. Neurological deficits and histological injury were assessed at 24 h after reperfusion. The content of endocannabinoids and the expression of cannabinoid receptor CB1 in brain tissues were determined at different time points after nicotine administration. Results showed that nicotine administration ameliorated neurological deficits and reduced infarct volume induced by cerebral ischemia in the rats. The neuroprotective effect was partially reversed by CB1 blockage. The content of the endocannabinoids N-arachidonylethanolamine and 2-arachidonoylglycerol, as well as the expression of cannabinoid receptor CB1 were up-regulated in brain tissues after nicotine delivery. These results suggest that endogenous cannabinoid system is involved in the nicotine-induced neuroprotection against transient focal cerebral ischemia.
Exposure to a Highly Caloric Palatable Diet during the Perinatal Period Affects the Expression of the Endogenous Cannabinoid System in the Brain, Liver and Adipose Tissue of Adult Rat Offspring

PubMed Central

Ramírez-López, María Teresa; Arco, Raquel; Decara, Juan; Vázquez, Mariam; Noemí Blanco, Rosario; Alén, Francisco; Suárez, Juan; Gómez de Heras, Raquel

2016-01-01

Recent studies have linked gestational exposure to highly caloric diets with a disrupted endogenous cannabinoid system (ECS). In the present study, we have extended these studies by analyzing the impact of the exposure to a palatable diet during gestation and lactation on a) the adult expression of endocannabinoid-related behaviors, b) the metabolic profile of adult offspring and c) the mRNA expression of the signaling machinery of the ECS in the hypothalamus, the liver and the adipose tissue of adult offspring of both sexes. Exposure to a palatable diet resulted in a) sex-dimorphic and perinatal diet specific feeding behaviors, including the differential response to the inhibitory effects of the cannabinoid receptor inverse agonist AM251, b) features of metabolic syndrome including increased adiposity, hyperleptinemia, hypertriglyceridemia and hypercholesterolemia and c) tissue and sex-specific changes in the expression of both CB1 and CB2 receptors and in that of the endocannabinoid-degrading enzymes FAAH and MAGL, being the adipose tissue the most affected organ analyzed. Since the effects were observed in adult animals that were weaned while consuming a normal diet, the present results indicate that the ECS is one of the targets of maternal programming of the offspring energy expenditure. These results clearly indicate that the maternal diet has long-term effects on the development of pups through multiple alterations of signaling homeostatic pathways that include the ECS. The potential relevance of these alterations for the current obesity epidemic is discussed. PMID:27806128
Cannabinoid receptor signalling in neurodegenerative diseases: a potential role for membrane fluidity disturbance

PubMed Central

Maccarrone, M; Bernardi, G; Agrò, A Finazzi; Centonze, D

2011-01-01

Type-1 cannabinoid receptor (CB1) is the most abundant G-protein-coupled receptor (GPCR) in the brain. CB1 and its endogenous agonists, the so-called ‘endocannabinoids (eCBs)’, belong to an ancient neurosignalling system that plays important functions in neurodegenerative and neuroinflammatory disorders like Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis and multiple sclerosis. For this reason, research on the therapeutic potential of drugs modulating the endogenous tone of eCBs is very intense. Several GPCRs reside within subdomains of the plasma membranes that contain high concentrations of cholesterol: the lipid rafts. Here, the hypothesis that changes in membrane fluidity alter function of the endocannabinoid system, as well as progression of particular neurodegenerative diseases, is described. To this end, the impact of membrane cholesterol on membrane properties and hence on neurodegenerative diseases, as well as on CB1 signalling in vitro and on CB1-dependent neurotransmission within the striatum, is discussed. Overall, present evidence points to the membrane environment as a critical regulator of signal transduction triggered by CB1, and calls for further studies aimed at better clarifying the contribution of membrane lipids to eCBs signalling. The results of these investigations might be exploited also for the development of novel therapeutics able to combat disorders associated with abnormal activity of CB1. LINKED ARTICLES This article is part of a themed issue on Cannabinoids in Biology and Medicine. To view the other articles in this issue visit http://dx.doi.org/10.1111/bph.2011.163.issue-7 PMID:21323908
Pain as a reward: changing the meaning of pain from negative to positive co-activates opioid and cannabinoid systems.

PubMed

Benedetti, Fabrizio; Thoen, Wilma; Blanchard, Catherine; Vighetti, Sergio; Arduino, Claudia

2013-03-01

Pain is a negative emotional experience that is modulated by a variety of psychological factors through different inhibitory systems. For example, endogenous opioids and cannabinoids have been found to be involved in stress and placebo analgesia. Here we show that when the meaning of the pain experience is changed from negative to positive through verbal suggestions, the opioid and cannabinoid systems are co-activated and these, in turn, increase pain tolerance. We induced ischemic arm pain in healthy volunteers, who had to tolerate the pain as long as possible. One group was informed about the aversive nature of the task, as done in any pain study. Conversely, a second group was told that the ischemia would be beneficial to the muscles, thus emphasizing the usefulness of the pain endurance task. We found that in the second group pain tolerance was significantly higher compared to the first one, and that this effect was partially blocked by the opioid antagonist naltrexone alone and by the cannabinoid antagonist rimonabant alone. However, the combined administration of naltrexone and rimonabant antagonized the increased tolerance completely. Our results indicate that a positive approach to pain reduces the global pain experience through the co-activation of the opioid and cannabinoid systems. These findings may have a profound impact on clinical practice. For example, postoperative pain, which means healing, can be perceived as less unpleasant than cancer pain, which means death. Therefore, the behavioral and/or pharmacological manipulation of the meaning of pain can represent an effective approach to pain management. Copyright © 2012 International Association for the Study of Pain. Published by Elsevier B.V. All rights reserved.
Neurobiological mechanisms involved in nicotine dependence and reward: participation of the endogenous opioid system

PubMed Central

Berrendero, Fernando; Robledo, Patricia; Trigo, José Manuel; Martín-García, Elena; Maldonado, Rafael

2010-01-01

Nicotine is the primary component of tobacco that maintains the smoking habit and develops addiction. The adaptive changes of nicotinic acetylcholine receptors produced by repeated exposure to nicotine play a crucial role in the establishment of dependence. However, other neurochemical systems also participate in the addictive effects of nicotine including glutamate, cannabinoids, GABA and opioids. This review will cover the involvement of these neurotransmitters in nicotine addictive properties, with a special emphasis on the endogenous opioid system. Thus, endogenous enkephalins and beta-endorphins acting on mu-opioid receptors are involved in nicotine rewarding effects, whereas opioid peptides derived from prodynorphin participate in nicotine aversive responses. An upregulation of mu-opioid receptors has been reported after chronic nicotine treatment that could counteract the development of nicotine tolerance, whereas the downregulation induced on kappa-opioid receptors seems to facilitate nicotine tolerance. Endogenous enkephalins acting on mu-opioid receptors also play a role in the development of physical dependence to nicotine. In agreement with these actions of the endogenous opioid system, the opioid antagonist naltrexone has shown to be effective for smoking cessation in certain subpopulations of smokers. PMID:20170672
Cannabinoid Receptor 2 Signaling in Neurodegenerative Disorders: From Pathogenesis to a Promising Therapeutic Target

PubMed Central

Cassano, Tommaso; Calcagnini, Silvio; Pace, Lorenzo; De Marco, Federico; Romano, Adele; Gaetani, Silvana

2017-01-01

As a consequence of an increasingly aging population, the number of people affected by neurodegenerative disorders, such as Alzheimer's disease, Parkinson's disease and Huntington's disease, is rapidly increasing. Although the etiology of these diseases has not been completely defined, common molecular mechanisms including neuroinflammation, excitotoxicity and mitochondrial dysfunction have been confirmed and can be targeted therapeutically. Moreover, recent studies have shown that endogenous cannabinoid signaling plays a number of modulatory roles throughout the central nervous system (CNS), including the neuroinflammation and neurogenesis. In particular, the up-regulation of type-2 cannabinoid (CB2) receptors has been found in a number of neurodegenerative disorders. Thus, the modulation of CB2 receptor signaling may represent a promising therapeutic target with minimal psychotropic effects that can be used to modulate endocannabinoid-based therapeutic approaches and to reduce neuronal degeneration. For these reasons this review will focus on the CB2 receptor as a promising pharmacological target in a number of neurodegenerative diseases. PMID:28210207
Cannabinoids and endocannabinoids in metabolic disorders with focus on diabetes.

PubMed

Di Marzo, Vincenzo; Piscitelli, Fabiana; Mechoulam, Raphael

2011-01-01

The cannabinoid receptors for Δ(9)-THC, and particularly, the CB(1) receptor, as well as its endogenous ligands, the endocannabinoids anandamide and 2-arachidonoylglycerol, are deeply involved in all aspects of the control of energy balance in mammals. While initially it was believed that this endocannabinoid signaling system would only facilitate energy intake, we now know that perhaps even more important functions of endocannabinoids and CB(1) receptors in this context are to enhance energy storage into the adipose tissue and reduce energy expenditure by influencing both lipid and glucose metabolism. Although normally well controlled by hormones and neuropeptides, both central and peripheral aspects of endocannabinoid regulation of energy balance can become dysregulated and contribute to obesity, dyslipidemia, and type 2 diabetes, thus raising the possibility that CB(1) antagonists might be used for the treatment of these metabolic disorders. On the other hand, evidence is emerging that some nonpsychotropic plant cannabinoids, such as cannabidiol, can be employed to retard β-cell damage in type 1 diabetes. These novel aspects of endocannabinoid research are reviewed in this chapter, with emphasis on the biological effects of plant cannabinoids and endocannabinoid receptor antagonists in diabetes.
Failure to extinguish fear and genetic variability in the human cannabinoid receptor 1.

PubMed

Heitland, I; Klumpers, F; Oosting, R S; Evers, D J J; Leon Kenemans, J; Baas, J M P

2012-09-25

Failure to extinguish fear can lead to persevering anxiety and has been postulated as an important mechanism in the pathogenesis of human anxiety disorders. In animals, it is well documented that the endogenous cannabinoid system has a pivotal role in the successful extinction of fear, most importantly through the cannabinoid receptor 1. However, no human studies have reported a translation of this preclinical evidence yet. Healthy medication-free human subjects (N=150) underwent a fear conditioning and extinction procedure in a virtual reality environment. Fear potentiation of the eyeblink startle reflex was measured to assess fear-conditioned responding, and subjective fear ratings were collected. Participants were genotyped for two polymorphisms located within the promoter region (rs2180619) and the coding region (rs1049353) of cannabinoid receptor 1. As predicted from the preclinical literature, acquisition and expression of conditioned fear did not differ between genotypes. Crucially, whereas both homozygote (G/G, N=23) and heterozygote (A/G, N=68) G-allele carriers of rs2180619 displayed robust extinction of fear, extinction of fear-potentiated startle was absent in A/A homozygotes (N=51). Additionally, this resistance to extinguish fear left A/A carriers of rs2180619 with significantly higher levels of fear-potentiated startle at the end of the extinction training. No effects of rs1049353 genotype were observed regarding fear acquisition and extinction. These results suggest for the first time involvement of the human endocannabinoid system in fear extinction. Implications are that genetic variability in this system may underlie individual differences in anxiety, rendering cannabinoid receptor 1 a potential target for novel pharmacological treatments of anxiety disorders.
Cardiovascular effects of marijuana and synthetic cannabinoids: the good, the bad, and the ugly.

PubMed

Pacher, Pal; Steffens, Sabine; Haskó, György; Schindler, Thomas H; Kunos, George

2018-03-01

Dysregulation of the endogenous lipid mediators endocannabinoids and their G-protein-coupled cannabinoid receptors 1 and 2 (CB 1 R and CB 2 R) has been implicated in a variety of cardiovascular pathologies. Activation of CB 1 R facilitates the development of cardiometabolic disease, whereas activation of CB 2 R (expressed primarily in immune cells) exerts anti-inflammatory effects. The psychoactive constituent of marijuana, Δ 9 -tetrahydrocannabinol (THC), is an agonist of both CB 1 R and CB 2 R, and exerts its psychoactive and adverse cardiovascular effects through the activation of CB 1 R in the central nervous and cardiovascular systems. The past decade has seen a nearly tenfold increase in the THC content of marijuana as well as the increased availability of highly potent synthetic cannabinoids for recreational use. These changes have been accompanied by the emergence of serious adverse cardiovascular events, including myocardial infarction, cardiomyopathy, arrhythmias, stroke, and cardiac arrest. In this Review, we summarize the role of the endocannabinoid system in cardiovascular disease, and critically discuss the cardiovascular consequences of marijuana and synthetic cannabinoid use. With the legalization of marijuana for medicinal purposes and/or recreational use in many countries, physicians should be alert to the possibility that the use of marijuana or its potent synthetic analogues might be the underlying cause of severe cardiovascular events and pathologies.

Presence and regulation of the endocannabinoid system in human dendritic cells.

PubMed

Matias, Isabel; Pochard, Pierre; Orlando, Pierangelo; Salzet, Michel; Pestel, Joel; Di Marzo, Vincenzo

2002-08-01

Cannabinoid receptors and their endogenous ligands, the endocannabinoids, have been detected in several blood immune cells, including monocytes/macrophages, basophils and lymphocytes. However, their presence in dendritic cells, which play a key role in the initiation and development of the immune response, has never been investigated. Here we have analyzed human dendritic cells for the presence of the endocannabinoids, anandamide and 2-arachidonoylglycerol (2-AG), the cannabinoid CB1 and CB2 receptors, and one of the enzymes mostly responsible for endocannabinoid hydrolysis, the fatty acid amide hydrolase (FAAH). By using a very sensitive liquid chromatography-atmospheric pressure chemical ionization-mass spectrometric (LC-APCI-MS) method, lipids extracted from immature dendritic cells were shown to contain 2-AG, anandamide and the anti-inflammatory anandamide congener, N-palmitoylethanolamine (PalEtn) (2.1 +/- 1.0, 0.14 +/- 0.02 and 8.2 +/- 3.9 pmol x 10(-7) cells, respectively). The amounts of 2-AG, but not anandamide or PalEtn, were significantly increased following cell maturation induced by bacterial lipopolysaccharide (LPS) or the allergen Der p 1 (2.8- and 1.9-fold, respectively). By using both RT-PCR and Western immunoblotting, dendritic cells were also found to express measurable amounts of CB1 and CB2 receptors and of FAAH. Cell maturation did not consistently modify the expression of these proteins, although in some cell preparations a decrease of the levels of both CB1 and CB2 mRNA transcripts was observed after LPS stimulation. These findings demonstrate for the first time that the endogenous cannabinoid system is present in human dendritic cells and can be regulated by cell activation.
Characterization of the intrinsic activity for a novel class of cannabinoid receptor ligands: Indole Quinuclidine analogues

PubMed Central

Franks, Lirit N.; Ford, Benjamin M.; Madadi, Nikhil R.; Penthala, Narsimha R.; Crooks, Peter A.; Prather, Paul L.

2014-01-01

Our laboratory recently reported that a group of novel indole quinuclidine analogues bind with nanomolar affinity to cannabinoid type-1 and type-2 receptors. This study characterized the intrinsic activity of these compounds by determining whether they exhibit agonist, antagonist, or inverse agonist activity at cannabinoid type-1 and/or type-2 receptors. Cannabinoid receptors activate Gi/Go-proteins that then proceed to inhibit activity of the downstream intracellular effector adenylyl cyclase. Therefore, intrinsic activity was quantified by measuring the ability of compounds to modulate levels of intracellular cAMP in intact cells. Concerning cannabinoid type-1 receptors endogenously expressed in Neuro2A cells, a single analogue exhibited agonist activity, while eight acted as neutral antagonists and two possessed inverse agonist activity. For cannabinoid type-2 receptors stably expressed in CHO cells, all but two analogues acted as agonists; these two exceptions exhibited inverse agonist activity. Confirming specificity at cannabinoid type-1 receptors, modulation of adenylyl cyclase activity by all proposed agonists and inverse agonists was blocked by co-incubation with the neutral cannabinoid type-1 antagonist O-2050. All proposed cannabinoid type-1 receptor antagonists attenuated adenylyl cyclase modulation by cannabinoid agonist CP-55,940. Specificity at cannabinoid type-2 receptors was confirmed by failure of all compounds to modulate adenylyl cyclase activity in CHO cells devoid of cannabinoid type-2 receptors. Further characterization of select analogues demonstrated concentration-dependent modulation of adenylyl cyclase activity with potencies similar to their respective affinities for cannabinoid receptors. Therefore, indole quinuclidines are a novel structural class of compounds exhibiting high affinity and a range of intrinsic activity at cannabinoid type-1 and type-2 receptors. PMID:24858620
Novel natural and synthetic ligands of the endocannabinoid system.

PubMed

Hanus, Lumír O; Mechoulam, Raphael

2010-01-01

In this review we describe recent advances in the chemistry of novel CB(1)/CB(2) agonists, CB(1) antagonists, selective CB(2) agonists, fatty acid amide hydrolase inibitors, monoglyceride (MGL) and diglyceride (DAGL) inhibitors and cannabinoid-type agonists and antagonists of non CB(1)/CB(2) receptors. In view of recent interest in the activities of fatty acid amides of amino acids (N-acyl amino acids) a list of this type of compounds was compiled and is presented as a Table. We conclude that further synthetic work based on both the plant cannabinoids and on the endocannabinoids may lead to novel therapeutics and that the identification and the elucidation of the biological profile of the myriad of endogenous N-acyl amino acids and related compounds may enhance the already wide spectrum of lipidomics.
A user’s guide to cannabinoid therapies in oncology

PubMed Central

Maida, V.; Daeninck, P.J.

2016-01-01

“Cannabinoid” is the collective term for a group of chemical compounds that either are derived from the Cannabis plant, are synthetic analogues, or occur endogenously. Although cannabinoids interact mostly at the level of the currently recognized cannabinoid receptors, they might have cross reactivity, such as at opioid receptors. Patients with malignant disease represent a cohort within health care that have some of the greatest unmet needs despite the availability of a plethora of guideline-driven disease-modulating treatments and pain and symptom management options. Cannabinoid therapies are varied and versatile, and can be offered as pharmaceuticals (nabilone, dronabinol, and nabiximols), dried botanical material, and edible organic oils infused with cannabis extracts. Cannabinoid therapy regimens can be creative, involving combinations of all of the aforementioned modalities. Patients with malignant disease, at all points of their disease trajectory, could be candidates for cannabinoid therapies whether as monotherapies or as adjuvants. The most studied and established roles for cannabinoid therapies include pain, chemotherapy-induced nausea and vomiting, and anorexia. Moreover, given their breadth of activity, cannabinoids could be used to concurrently optimize the management of multiple symptoms, thereby reducing overall polypharmacy. The use of cannabinoid therapies could be effective in improving quality of life and possibly modifying malignancy by virtue of direct effects and in improving compliance or adherence with disease-modulating treatments such as chemotherapy and radiation therapy. PMID:28050136
Tetrahydrocannabinol and endocannabinoids in feeding and appetite.

PubMed

Berry, Elliot M; Mechoulam, Raphael

2002-08-01

The physiological control of appetite and satiety, in which numerous neurotransmitters and neuropeptides play a role, is extremely complex. Here we describe the involvement of endocannabinoids in these processes. These endogenous neuromodulators enhance appetite in animals. The same effect is observed in animals and in humans with the psychotropic plant cannabinoid Delta(9)-tetrahydrocannabinol, which is an approved appetite-enhancing drug. The CB(1) cannabinoid receptor antagonist SR141716A blocks the effects on feeding produced by the endocannabinoids. If administered to mice pups, this antagonist blocks suckling. In obese humans, it causes weight reduction. Very little is known about the physiological and biochemical mechanisms involved in the effects of Delta(9)-tetrahydrocannabinol and the cannabinoids in feeding and appetite.
Marijuana, phytocannabinoids, the endocannabinoid system, and male fertility.

PubMed

du Plessis, Stefan S; Agarwal, Ashok; Syriac, Arun

2015-11-01

Marijuana has the highest consumption rate among all of the illicit drugs used in the USA, and its popularity as both a recreational and medicinal drug is increasing especially among men of reproductive age. Male factor infertility is on the increase, and the exposure to the cannabinoid compounds released by marijuana could be a contributing cause. The endocannabinoid system (ECS) is deeply involved in the complex regulation of male reproduction through the endogenous release of endocannabinoids and binding to cannabinoid receptors. Disturbing the delicate balance of the ECS due to marijuana use can negatively impact reproductive potential. Various in vivo and in vitro studies have reported on the empirical role that marijuana plays in disrupting the hypothalamus-pituitary-gonadal axis, spermatogenesis, and sperm function such as motility, capacitation, and the acrosome reaction. In this review, we highlight the latest evidence regarding the effect of marijuana use on male fertility and also provide a detailed insight into the ECS and its significance in the male reproductive system.
Cannabis in Pain Treatment: Clinical and Research Considerations.

PubMed

Savage, Seddon R; Romero-Sandoval, Alfonso; Schatman, Michael; Wallace, Mark; Fanciullo, Gilbert; McCarberg, Bill; Ware, Mark

2016-06-01

Cannabinoids show promise as therapeutic agents, particularly as analgesics, but their development and clinical use has been complicated by recognition of their botanical source, cannabis, as a substance of misuse. Although research into endogenous cannabinoid systems and potential cannabinoid pharmaceuticals is slowly increasing, there has been intense societal interest in making herbal (plant) cannabis available for medicinal use; 23 U.S. States and all Canadian provinces currently permit use in some clinical contexts. Whether or not individual professionals support the clinical use of herbal cannabis, all clinicians will encounter patients who elect to use it and therefore need to be prepared to advise them on cannabis-related clinical issues despite limited evidence to guide care. Expanded research on cannabis is needed to better determine the individual and public health effects of increasing use of herbal cannabis and to advance understanding of the pharmaceutical potential of cannabinoids as medications. This article reviews clinical, research, and policy issues related to herbal cannabis to support clinicians in thoughtfully advising and caring for patients who use cannabis, and it examines obstacles and opportunities to expand research on the health effects of herbal cannabis and cannabinoids. Herbal cannabis is increasingly available for clinical use in the United States despite continuing controversies over its efficacy and safety. This article explores important considerations in the use of plant Cannabis to better prepare clinicians to care for patients who use it, and identifies needed directions for research. Copyright © 2016 American Pain Society. Published by Elsevier Inc. All rights reserved.
Hemopressin Peptides as Modulators of the Endocannabinoid System and their Potential Applications as Therapeutic Tools.

PubMed

Macedonio, Giorgia; Stefanucci, Azzurra; Maccallini, Cristina; Mirzaie, Sako; Novellino, Ettore; Mollica, Adriano

2016-01-01

The endocannabinoid system (ECS) is activated when natural arachidonic acid derivatives (endogenous cannabinoids or endocannabinoids) bind as lipophilic messengers to cannabinoid receptors CB1 and CB2. The ECS comprises many hydrolytic enzymes responsible for the endocannabinoids cleavage. These hydrolases, such as fatty acid amide hydrolase (FAAH) and monoacylglyceride lipase (MAGL), are possible therapeutic targets for the development of new drugs as indirect cannabinoid agonists. Recently, a new family of endocannabinoid modulators was discovered; the lead structure of this family is the nonapeptide hemopressin produced from enzymatic cleavage of the α-chain of hemoglobin and acting as negative allosteric modulator of CB1. Hemopressin shows several physiological effects, e.g., antinociception, hypophagy, and hypotension. However, it is still a matter of debate whether this peptide, isolated from the brain of rats, is a real neuromodulator of the ECS. Recent evidence indicates that hemopressin could be a by-product formed by chemical degradation of a longer peptide RVD-hemopressin during the extraction from the brain homolysate. Indeed, RVD-hemopressin is more active than hemopressin in certain biological tests and may bind to the same subsite as Rimonabant, which is an inverse agonist of CB1 and a μ-opioid receptor antagonist. These findings have stimulated several studies to verify this hypothesis and to evaluate possible therapeutic applications of hemopressin, its peptidic derivatives, and synthetic analogues, opening new perspectives to the development of novel cannabinoid drugs.
[Short-and long-term effects of cannabinoids on memory, cognition and mental illness].

PubMed

Sagie, Shira; Eliasi, Yehuda; Livneh, Ido; Bart, Yosi; Monovich, Einat

2013-12-01

Marijuana is considered the most commonly used drug in the world, with estimated millions of users. There is dissent in the medical world about the positive and negative effects of marijuana, and recently, a large research effort has been directed to that domain. The main influencing drug ingredient is THC, which acts on the cannabinoid system and binds to the CB1 receptor. The discovery of the receptor led to the finding of an endogenous ligand, anandamide, and another receptor-CB2. The researchers also discovered that cannabinoids have extensive biological activity, and its short and long-term effects may cause cognitive and emotional deficiencies. Findings show that the short-term effects, such as shortterm memory and verbal Learning, are reversible. However, despite the accumulation of evidence about long-term cognitive damage due to cannabis use, it is difficult to find unequivocal results, arising from the existence of many variables such as large differences between cannabis users, frequency of use, dosage and endogenous brain compensation. Apart from cognitive damage, current studies investigate how marijuana affects mental illness: a high correlation between cannabis use and schizophrenia was found and a high risk to undergo a psychotic attack. Furthermore, patients with schizophrenia who used cannabis showed a selective neuro-psychological disruption, and similar cognitive deficiencies and brain morphological changes were found among healthy cannabis users and schizophrenia patients. In contrast to the negative effects of marijuana including addiction, there are the medical uses: reducing pain, anxiety and nausea, increasing appetite and an anti-inflammatory activity. Medicalization of marijuana encourages frequent use, which may elevate depression.
The Endocannabinoid System as an Emerging Target of Pharmacotherapy

PubMed Central

PACHER, PÁL; BÁTKAI, SÁNDOR; KUNOS, GEORGE

2008-01-01

The recent identification of cannabinoid receptors and their endogenous lipid ligands has triggered an exponential growth of studies exploring the endocannabinoid system and its regulatory functions in health and disease. Such studies have been greatly facilitated by the introduction of selective cannabinoid receptor antagonists and inhibitors of endocannabinoid metabolism and transport, as well as mice deficient in cannabinoid receptors or the endocannabinoid-degrading enzyme fatty acid amidohydrolase. In the past decade, the endocannabinoid system has been implicated in a growing number of physiological functions, both in the central and peripheral nervous systems and in peripheral organs. More importantly, modulating the activity of the endocannabinoid system turned out to hold therapeutic promise in a wide range of disparate diseases and pathological conditions, ranging from mood and anxiety disorders, movement disorders such as Parkinson’s and Huntington’s disease, neuropathic pain, multiple sclerosis and spinal cord injury, to cancer, atherosclerosis, myocardial infarction, stroke, hypertension, glaucoma, obesity/metabolic syndrome, and osteoporosis, to name just a few. An impediment to the development of cannabinoid medications has been the socially unacceptable psychoactive properties of plant-derived or synthetic agonists, mediated by CB1 receptors. However, this problem does not arise when the therapeutic aim is achieved by treatment with a CB1 receptor antagonist, such as in obesity, and may also be absent when the action of endocannabinoids is enhanced indirectly through blocking their metabolism or transport. The use of selective CB2 receptor agonists, which lack psychoactive properties, could represent another promising avenue for certain conditions. The abuse potential of plant-derived cannabinoids may also be limited through the use of preparations with controlled composition and the careful selection of dose and route of administration. The growing number of preclinical studies and clinical trials with compounds that modulate the endocannabinoid system will probably result in novel therapeutic approaches in a number of diseases for which current treatments do not fully address the patients’ need. Here, we provide a comprehensive overview on the current state of knowledge of the endocannabinoid system as a target of pharmacotherapy. PMID:16968947
Reduced levels of the endocannabinoid arachidonylethanolamide (AEA) in hair in patients with borderline personality disorder - a pilot study.

PubMed

Wingenfeld, Katja; Dettenborn, Lucia; Kirschbaum, Clemens; Gao, Wei; Otte, Christian; Roepke, Stefan

2018-03-16

Endocannabinoids are involved in depressive and anxious symptoms and might play a role in stress-associated psychiatric disorders. While alterations in the endogenous cannabinoid system have been repeatedly found in patients with posttraumatic stress disorder (PTSD), this system has been mostly neglected in borderline personality disorder (BPD). However, there is first evidence for elevated serum levels of the endocannabinoids arachidonylethanolamide (AEA) and 2-arachidonyl-sn-glycerol (2-AG) in BPD patients compared to healthy controls and PTSD patients. In this study, hair endocannabinoids were analyzed, reflecting long-term endocannabinoid concentrations. We assessed AEA concentrations as well as 2-AG and the 2-AG main isomer 1-AG (1-AG/2-AG) in hair in women with BPD (n = 15) and age- and education-matched healthy women (n = 16). We found significantly reduced log AEA in BPD patients compared to healthy women (p = .03) but no differences in log 1-AG/2-AG concentrations. In addition, there was no association between 1-AG/2-AG and hair cortisol, but we found a non-significant correlation between hair concentrations of AEA and cortisol (p = .06). Our data indicate altered long-term release of endogenous cannabinoids in women with BPD depending on type of endocannabinoid. AEA has been suggested to modulate the basal activity of the endocannabinoid system and seems to attenuate depressive and anxious symptoms. Thus, chronically reduced AEA might contribute to psychiatric symptoms in BPD.
Circulating Endocannabinoid Concentrations and Sexual Arousal in Women

PubMed Central

Klein, Carolin; Hill, Matthew N.; Chang, Sabrina C.H.; Hillard, Cecilia J.; Gorzalka, Boris B.

2013-01-01

Introduction Several lines of evidence point to the potential role of the endocannabinoid system in female sexual functioning. These include results from studies describing the subjective effects of exogenous cannabinoids on sexual functioning in humans and the observable effects of exogenous cannabinoids on sexual functioning in other species, as well as results from studies investigating the location of cannabinoid receptors in the brain and periphery, and the effects of cannabinoid receptor activation on neurotransmitters implicated in sexual functioning. While these lines of research suggest a role for the endocannabinoid system in female sexual functioning, no studies investigating the relationship between concentrations of endogenous cannabinoids (i.e., arachidonoylethanolamide [AEA] and 2-arachidonoylglycerol [2-AG]) and sexual functioning have been conducted in any species. Aim To measure circulating endocannabinoid concentrations in relation to subjective and physiological indices of sexual arousal in women (n = 21). Methods Serum endocannabinoid (AEA and 2-AG) concentrations were measured immediately prior to, and immediately following, viewing of neutral (control) and erotic (experimental) film stimuli in a repeated measures design. Physiological sexual arousal was measured via vaginal photoplethysmography. Subjective sexual arousal was measured both continuously and non-continuously. Pearson’s correlations were used to investigate the relationships between endocannabinoid concentrations and sexual arousal. Main Outcome Measures Changes in AEA and 2-AG concentrations from pre- to post-film and in relation to physiological and subjective indices of sexual arousal. Results Results revealed a significant relationship between endocannabinoid concentrations and female sexual arousal, whereby increases in both physiological and subjective indices of sexual arousal were significantly associated with decreases in AEA, and increases in subjective indices of sexual arousal were significantly associated with decreases in 2-AG. Conclusions These findings support the hypothesis that the endocannabinoid system is involved in female sexual functioning, with implications for furthering understanding of the biological mechanisms underlying female sexual functioning. PMID:22462722
The endocannabinoid system and its therapeutic exploitation in multiple sclerosis: Clues for other neuroinflammatory diseases.

PubMed

Chiurchiù, Valerio; van der Stelt, Mario; Centonze, Diego; Maccarrone, Mauro

2018-01-01

Multiple sclerosis is the most common inflammatory demyelinating disease of the central nervous system, caused by an autoimmune response against myelin that eventually leads to progressive neurodegeneration and disability. Although the knowledge on its underlying neurobiological mechanisms has considerably improved, there is a still unmet need for new treatment options, especially for the progressive forms of the disease. Both preclinical and clinical data suggest that cannabinoids, derived from the Cannabis sativa plant, may be used to control symptoms such as spasticity and chronic pain, whereas only preclinical data indicate that these compounds and their endogenous counterparts, i.e. the endocannabinoids, may also exert neuroprotective effects and slow down disease progression. Here, we review the preclinical and clinical studies that could explain the therapeutic action of cannabinoid-based medicines, as well as the medical potential of modulating endocannabinoid signaling in multiple sclerosis, with a link to other neuroinflammatory disorders that share common hallmarks and pathogenetic features. Copyright © 2017 The Authors. Published by Elsevier Ltd.. All rights reserved.
Clinical Effects of Synthetic Cannabinoid Receptor Agonists Compared with Marijuana in Emergency Department Patients with Acute Drug Overdose.

PubMed

Zaurova, Milana; Hoffman, Robert S; Vlahov, David; Manini, Alex F

2016-12-01

Synthetic cannabinoid receptor agonists (SCRAs) are heterogeneous compounds originally intended as probes of the endogenous cannabinoid system or as potential therapeutic agents. We assessed the clinical toxicity associated with recent SCRA use in a large cohort of drug overdose patients. This subgroup analysis of a large (n = 3739) drug overdose cohort study involved consecutive ED patients at two urban teaching hospitals collected between 2009 and 2013. Clinical characteristics of patients with the exposure to SCRAs (SRCA subgroup) were compared with those from patients who smoked traditional cannabinoids (marijuana subgroup). Data included demographics, exposure details, vital signs, mental status, and basic chemistries gathered as part of routine clinical care. Study outcomes included altered mental status and cardiotoxicity. Eighty-seven patients reported exposure to any cannabinoid, of whom 17 reported SCRAs (17 cases, 70 controls, mean age 38.9 years, 77 % males, 31 % Hispanic). There were no significant differences between SRCA and marijuana with respect to demographics (age, gender, and race/ethnicity), exposure history (suicidality, misuse, and intent), vital signs, or serum chemistries. Mental status varied between SRCA and marijuana, with agitation significantly more likely in SCRA subgroup (OR = 3.8, CI = 1.2-11.9). Cardiotoxicity was more pronounced in the SCRA subgroup with dysrhythmia significantly more likely (OR = 9.2, CI = 1.0-108). In the first clinical study comparing the adverse effects of SCRA overdose vs. marijuana controls in an ED population, we found that SCRA overdoses had significantly pronounced neurotoxicity and cardiotoxicity compared with marijuana.
Peripheral cannabinoid receptor, CB2, regulates bone mass

PubMed Central

Ofek, Orr; Karsak, Meliha; Leclerc, Nathalie; Fogel, Meirav; Frenkel, Baruch; Wright, Karen; Tam, Joseph; Attar-Namdar, Malka; Kram, Vardit; Shohami, Esther; Mechoulam, Raphael; Zimmer, Andreas; Bab, Itai

2006-01-01

The endogenous cannabinoids bind to and activate two G protein-coupled receptors, the predominantly central cannabinoid receptor type 1 (CB1) and peripheral cannabinoid receptor type 2 (CB2). Whereas CB1 mediates the cannabinoid psychotropic, analgesic, and orectic effects, CB2 has been implicated recently in the regulation of liver fibrosis and atherosclerosis. Here we show that CB2-deficient mice have a markedly accelerated age-related trabecular bone loss and cortical expansion, although cortical thickness remains unaltered. These changes are reminiscent of human osteoporosis and may result from differential regulation of trabecular and cortical bone remodeling. The CB2–/– phenotype is also characterized by increased activity of trabecular osteoblasts (bone-forming cells), increased osteoclast (the bone-resorbing cell) number, and a markedly decreased number of diaphyseal osteoblast precursors. CB2 is expressed in osteoblasts, osteocytes, and osteoclasts. A CB2-specific agonist that does not have any psychotropic effects enhances endocortical osteoblast number and activity and restrains trabecular osteoclastogenesis, apparently by inhibiting proliferation of osteoclast precursors and receptor activator of NF-κB ligand expression in bone marrow-derived osteoblasts/stromal cells. The same agonist attenuates ovariectomy-induced bone loss and markedly stimulates cortical thickness through the respective suppression of osteoclast number and stimulation of endocortical bone formation. These results demonstrate that the endocannabinoid system is essential for the maintenance of normal bone mass by osteoblastic and osteoclastic CB2 signaling. Hence, CB2 offers a molecular target for the diagnosis and treatment of osteoporosis, the most prevalent degenerative disease in developed countries. PMID:16407142
Triphasic blood pressure responses to cannabinoids: do we understand the mechanism?

PubMed Central

Malinowska, Barbara; Baranowska-Kuczko, Marta; Schlicker, Eberhard

2012-01-01

The cannabinoids comprise three major classes of substances, including compounds derived from the cannabis plant (e.g. Δ9-tetrahydrocannabinol and the chemically related substances CP55940 and HU210), endogenously formed (e.g. anandamide) and synthetic compounds (e.g. WIN55212-2). Beyond their psychotropic effects, cannabinoids have complex effects on blood pressure, including biphasic changes of Δ9-tetrahydrocannabinol and WIN55212-2 and an even triphasic effect of anandamide. The differing pattern of blood pressure changes displayed by the three types of compounds is not really surprising since, although they share an agonistic effect at cannabinoid CB1 and CB2 receptors, some compounds have additional effects. In particular, anandamide is known for its pleiotropic effects, and there is overwhelming evidence that anandamide influences blood pressure via (i) CB1 receptors, (ii) TRPV1 receptors, (iii) endothelial cannabinoid receptors and (iv) degradation products. This review is dedicated to the description of the effects of externally added cannabinoids on cardiovascular parameters in vivo. First, the cardiovascular effects of cannabinoids in anaesthetized animals will be highlighted since most data have been generated in experiments of that type. The text will follow the three phases of anandamide on blood pressure, and we will check to which extent cardiovascular changes elicited by other cannabinoids show overlap with those effects or differ. The second part will be dedicated to the cardiovascular effects of the cannabinoids in conscious animals. In the third part, cardiovascular effects in humans will be discussed, and similarities and differences with respect to the data from animals will be examined. PMID:22022923
Specific attentional dysfunction in adults following early start of cannabis use.

PubMed

Ehrenreich, H; Rinn, T; Kunert, H J; Moeller, M R; Poser, W; Schilling, L; Gigerenzer, G; Hoehe, M R

1999-03-01

The present study tested the hypothesis that chronic interference by cannabis with endogenous cannabinoid systems during peripubertal development causes specific and persistent brain alterations in humans. As an index of cannabinoid action, visual scanning, along with other attentional functions, was chosen. Visual scanning undergoes a major maturation process around age 12-15 years and, in addition, the visual system is known to react specifically and sensitively to cannabinoids. From 250 individuals consuming cannabis regularly, 99 healthy pure cannabis users were selected. They were free of any other past or present drug abuse, or history of neuropsychiatric disease. After an interview, physical examination, analysis of routine laboratory parameters, plasma/urine analyses for drugs, and MMPI testing, users and respective controls were subjected to a computer-assisted attention test battery comprising visual scanning, alertness, divided attention, flexibility, and working memory. Of the potential predictors of test performance within the user group, including present age, age of onset of cannabis use, degree of acute intoxication (THC+THCOH plasma levels), and cumulative toxicity (estimated total life dose), an early age of onset turned out to be the only predictor, predicting impaired reaction times exclusively in visual scanning. Early-onset users (onset before age 16; n = 48) showed a significant impairment in reaction times in this function, whereas late-onset users (onset after age 16; n = 51) did not differ from controls (n = 49). These data suggest that beginning cannabis use during early adolescence may lead to enduring effects on specific attentional functions in adulthood. Apparently, vulnerable periods during brain development exist that are subject to persistent alterations by interfering exogenous cannabinoids.
Role of Cannabinoids in Gastrointestinal Mucosal Defense and Inflammation

PubMed Central

Gyires, Klára; Zádori, Zoltán S.

2016-01-01

Modulating the activity of the endocannabinoid system influences various gastrointestinal physiological and pathophysiological processes, and cannabinoid receptors as well as regulatory enzymes responsible for the synthesis or degradation of endocannabinoids representing potential targets to reduce the development of gastrointestinal mucosal lesions, hemorrhage and inflammation. Direct activation of CB1 receptors by plant-derived, endogenous or synthetic cannabinoids effectively reduces both gastric acid secretion and gastric motor activity, and decreases the formation of gastric mucosal lesions induced by stress, pylorus ligation, nonsteroidal anti-inflammatory drugs (NSAIDs) or alcohol, partly by peripheral, partly by central mechanisms. Similarly, indirect activation of cannabinoid receptors through elevation of endocannabinoid levels by globally acting or peripherally restricted inhibitors of their metabolizing enzymes (FAAH, MAGL) or by inhibitors of their cellular uptake reduces the gastric mucosal lesions induced by NSAIDs in a CB1 receptor-dependent fashion. Dual inhibition of FAAH and cyclooxygenase enzymes induces protection against both NSAID-induced gastrointestinal damage and intestinal inflammation. Moreover, in intestinal inflammation direct or indirect activation of CB1 and CB2 receptors exerts also multiple beneficial effects. Namely, activation of both CB receptors was shown to ameliorate intestinal inflammation in various murine colitis models, to decrease visceral hypersensitivity and abdominal pain, as well as to reduce colitis-associated hypermotility and diarrhea. In addition, CB1 receptors suppress secretory processes and also modulate intestinal epithelial barrier functions. Thus, experimental data suggest that the endocannabinoid system represents a promising target in the treatment of inflammatory bowel diseases, and this assumption is also confirmed by preliminary clinical studies. PMID:26935536
CB1 receptor mediated analgesia from the Nucleus Reticularis Gigantocellularis pars alpha is activated in an animal model of neuropathic pain.

PubMed

Monhemius, R; Azami, J; Green, D L; Roberts, M H

2001-07-20

Cannabinoids are known to suppress responses to noxious stimulation in animals and man. Recent research has suggested a role for endogenous cannabinoids in the descending inhibition of dorsal horn cells via a supraspinal site of action. We have recently demonstrated [J. Physiol. 506(2) (1998) 459] that the nucleus reticularis gigantocellularis pars alpha (GiA) is a major source of such descending modulation, and importantly, that this system is activated in response to noxious stimulation. We have therefore investigated the role of CB1 receptor activation in mediating the antinociceptive effects of activation of GiA in models of acute and chronic pain. Microinjections (0.5 microl 60% DMSO) of either WIN 55,212-2 (5 microg, selective CB1 agonist), SR141716A (50 microg, competitive CB1 antagonist), both compounds together, or vehicle alone into GiA were performed prior to these tests in a randomised, blind manner. In control animals, WIN 55,212-2 markedly increased withdrawal latencies in the tail flick test and reduced responses to subcutaneous formalin. These effects were blocked by co-administration of SR141716A. These data suggest that activation of cannabinoid CB1 receptor subtypes in GiA leads to behavioural analgesia. In animals with partial sciatic nerve ligation, microinjection of drugs and injection of formalin were performed contralaterally to the site of ligation. Partial sciatic nerve ligation significantly reduced behavioural responses to contralaterally applied formalin. Microinjection of SR141716A to GiA reversed this inhibition of responses to formalin in animals with partial sciatic nerve ligation. These data provide evidence that endogenous CB1 receptor ligands are involved in GiA mediated antinociception, and that this system is important for the modulation of nociceptive transmission in an animal model of chronic neuropathic pain.
The emerging role of the endocannabinoid system in the pathogenesis and treatment of kidney diseases.

PubMed

Tam, Joseph

2016-05-01

Endocannabinoids (eCBs) are endogenous lipid ligands that bind to cannabinoid receptors that also mediate the effects of marijuana. The eCB system is comprised of eCBs, anandamide, and 2-arachidonoyl glycerol, their cannabinoid-1 and cannabinoid-2 receptors (CB1 and CB2, respectively), and the enzymes involved in their biosynthesis and degradation. It is present in both the central nervous system and peripheral organs including the kidney. The current review focuses on the role of the eCB system in normal kidney function and various diseases, such as diabetes and obesity, that directly contributes to the development of renal pathologies. Normally, activation of the CB1 receptor regulates renal vascular hemodynamics and stimulates the transport of ions and proteins in different nephron compartments. In various mouse and rat models of obesity and type 1 and 2 diabetes mellitus, eCBs generated in various renal cells activate CB1 receptors and contribute to the development of oxidative stress, inflammation, and renal fibrosis. These effects can be chronically ameliorated by CB1 receptor blockers. In contrast, activation of the renal CB2 receptors reduces the deleterious effects of these chronic diseases. Because the therapeutic potential of globally acting CB1 receptor antagonists in these conditions is limited due to their neuropsychiatric adverse effects, the recent development of peripherally restricted CB1 receptor antagonists may represent a novel pharmacological approach in treating renal diseases.

Non-psychotropic plant cannabinoids: new therapeutic opportunities from an ancient herb.

PubMed

Izzo, Angelo A; Borrelli, Francesca; Capasso, Raffaele; Di Marzo, Vincenzo; Mechoulam, Raphael

2009-10-01

Delta(9)-tetrahydrocannabinol binds cannabinoid (CB(1) and CB(2)) receptors, which are activated by endogenous compounds (endocannabinoids) and are involved in a wide range of physiopathological processes (e.g. modulation of neurotransmitter release, regulation of pain perception, and of cardiovascular, gastrointestinal and liver functions). The well-known psychotropic effects of Delta(9)-tetrahydrocannabinol, which are mediated by activation of brain CB(1) receptors, have greatly limited its clinical use. However, the plant Cannabis contains many cannabinoids with weak or no psychoactivity that, therapeutically, might be more promising than Delta(9)-tetrahydrocannabinol. Here, we provide an overview of the recent pharmacological advances, novel mechanisms of action, and potential therapeutic applications of such non-psychotropic plant-derived cannabinoids. Special emphasis is given to cannabidiol, the possible applications of which have recently emerged in inflammation, diabetes, cancer, affective and neurodegenerative diseases, and to Delta(9)-tetrahydrocannabivarin, a novel CB(1) antagonist which exerts potentially useful actions in the treatment of epilepsy and obesity.
International Union of Basic and Clinical Pharmacology. LXXIX. Cannabinoid Receptors and Their Ligands: Beyond CB1 and CB2

PubMed Central

Howlett, A. C.; Abood, M. E.; Alexander, S. P. H.; Di Marzo, V.; Elphick, M. R.; Greasley, P. J.; Hansen, H. S.; Kunos, G.; Mackie, K.; Mechoulam, R.; Ross, R. A.

2010-01-01

There are at least two types of cannabinoid receptors (CB1 and CB2). Ligands activating these G protein-coupled receptors (GPCRs) include the phytocannabinoid Δ9-tetrahydrocannabinol, numerous synthetic compounds, and endogenous compounds known as endocannabinoids. Cannabinoid receptor antagonists have also been developed. Some of these ligands activate or block one type of cannabinoid receptor more potently than the other type. This review summarizes current data indicating the extent to which cannabinoid receptor ligands undergo orthosteric or allosteric interactions with non-CB1, non-CB2 established GPCRs, deorphanized receptors such as GPR55, ligand-gated ion channels, transient receptor potential (TRP) channels, and other ion channels or peroxisome proliferator-activated nuclear receptors. From these data, it is clear that some ligands that interact similarly with CB1 and/or CB2 receptors are likely to display significantly different pharmacological profiles. The review also lists some criteria that any novel “CB3” cannabinoid receptor or channel should fulfil and concludes that these criteria are not currently met by any non-CB1, non-CB2 pharmacological receptor or channel. However, it does identify certain pharmacological targets that should be investigated further as potential CB3 receptors or channels. These include TRP vanilloid 1, which possibly functions as an ionotropic cannabinoid receptor under physiological and/or pathological conditions, and some deorphanized GPCRs. Also discussed are 1) the ability of CB1 receptors to form heteromeric complexes with certain other GPCRs, 2) phylogenetic relationships that exist between CB1/CB2 receptors and other GPCRs, 3) evidence for the existence of several as-yet-uncharacterized non-CB1, non-CB2 cannabinoid receptors; and 4) current cannabinoid receptor nomenclature. PMID:21079038
International Union of Basic and Clinical Pharmacology. LXXIX. Cannabinoid receptors and their ligands: beyond CB₁ and CB₂.

PubMed

Pertwee, R G; Howlett, A C; Abood, M E; Alexander, S P H; Di Marzo, V; Elphick, M R; Greasley, P J; Hansen, H S; Kunos, G; Mackie, K; Mechoulam, R; Ross, R A

2010-12-01

There are at least two types of cannabinoid receptors (CB(1) and CB(2)). Ligands activating these G protein-coupled receptors (GPCRs) include the phytocannabinoid Δ(9)-tetrahydrocannabinol, numerous synthetic compounds, and endogenous compounds known as endocannabinoids. Cannabinoid receptor antagonists have also been developed. Some of these ligands activate or block one type of cannabinoid receptor more potently than the other type. This review summarizes current data indicating the extent to which cannabinoid receptor ligands undergo orthosteric or allosteric interactions with non-CB(1), non-CB(2) established GPCRs, deorphanized receptors such as GPR55, ligand-gated ion channels, transient receptor potential (TRP) channels, and other ion channels or peroxisome proliferator-activated nuclear receptors. From these data, it is clear that some ligands that interact similarly with CB(1) and/or CB(2) receptors are likely to display significantly different pharmacological profiles. The review also lists some criteria that any novel "CB(3)" cannabinoid receptor or channel should fulfil and concludes that these criteria are not currently met by any non-CB(1), non-CB(2) pharmacological receptor or channel. However, it does identify certain pharmacological targets that should be investigated further as potential CB(3) receptors or channels. These include TRP vanilloid 1, which possibly functions as an ionotropic cannabinoid receptor under physiological and/or pathological conditions, and some deorphanized GPCRs. Also discussed are 1) the ability of CB(1) receptors to form heteromeric complexes with certain other GPCRs, 2) phylogenetic relationships that exist between CB(1)/CB(2) receptors and other GPCRs, 3) evidence for the existence of several as-yet-uncharacterized non-CB(1), non-CB(2) cannabinoid receptors; and 4) current cannabinoid receptor nomenclature.
Depression in Parkinson's disease is related to a genetic polymorphism of the cannabinoid receptor gene (CNR1).

PubMed

Barrero, F J; Ampuero, I; Morales, B; Vives, F; de Dios Luna Del Castillo, J; Hoenicka, J; García Yébenes, J

2005-01-01

Depression is a common symptom in Parkinson's disease (PD) and it is present in up to 40% of the patients. The cause of depression in PD is thought to be related to disturbance of monoamine neurotransmission. The endogenous cannabinoid system mediates different brain processes that play a role in the control of behaviour and emotions. Cannabinoid function may be altered in neuropsychiatry diseases, directly or through interactions with monoamine, GABA and glutamate systems. For this reason, we have investigated whether there is a genetic risk factor for depression in PD linked to the polymorphisms of CB1 receptor gene. Depression was more frequent in patients with PD than in controls with osteoarthritis. The presence of depression did not correlate with the stage of the disease but it was more frequent in patients with pure akinetic syndrome than in those with tremoric or mixed type PD. The CB1 receptor gene polymorphism (AAT)n is considered to modify the transcription of the gene and, therefore, it may have functional relevance. We analysed the length of the polymorphic triplet (AAT)n of the gene that encodes CB1 (CNR1) receptor in 89 subjects (48 PD patients and 41 controls). In patients with PD, the presence of two long alleles, with more than 16 repeated AAT trinucleotides in the CNR1 gene, was associated with a reduced prevalence of depression (Fisher's exact test: P=0.003). This association did not reach significant differences in the control group, but the number of control individuals with depression was too small to allow for statistical analysis. Since the alleles with long expansions may have functional impact in cannabinoid neurotransmission, our data suggest that the pharmacological manipulation of cannabinoid neurotransmission could open a new therapeutic approach for the treatment of depression in PD and possibly in other conditions.
Cannabinoids, inflammation, and fibrosis.

PubMed

Zurier, Robert B; Burstein, Sumner H

2016-11-01

Cannabinoids apparently act on inflammation through mechanisms different from those of agents such as nonsteroidal anti-inflammatory drugs (NSAIDs). As a class, the cannabinoids are generally free from the adverse effects associated with NSAIDs. Their clinical development thus provides a new approach to treatment of diseases characterized by acute and chronic inflammation and fibrosis. A concise survey of the anti-inflammatory actions of the phytocannabinoids Δ 9 -tetrahydrocannabinol (THC), cannabidiol, cannabichromene, and cannabinol is presented. Mention is also made of the noncannabinoid plant components and pyrolysis products, followed by a discussion of 3 synthetic preparations-Cesamet (nabilone; Meda Pharmaceuticals, Somerset, NJ, USA), Marinol (dronabinol; THC; AbbVie, Inc., North Chicago, IL, USA), and Sativex (Cannabis extract; GW Pharmaceuticals, Cambridge United Kingdom)-that have anti-inflammatory effects. A fourth synthetic cannabinoid, ajulemic acid (AJA; CT-3; Resunab; Corbus Pharmaceuticals, Norwood, MA, USA), is discussed in greater detail because it represents the most recent advance in this area and is currently undergoing 3 phase 2 clinical trials by Corbus Pharmaceuticals. The endogenous cannabinoids, including the closely related lipoamino acids, are then discussed. The review concludes with a presentation of a possible mechanism for the anti-inflammatory and antifibrotic actions of these substances. Thus, several cannabinoids may be considered candidates for development as anti-inflammatory and antifibrotic agents. Of special interest is their possible use for treatment of chronic inflammation, a major unmet medical need.-Zurier, R. B., Burstein, S. H. Cannabinoids, inflammation, and fibrosis. © FASEB.
Psychomotor performance in relation to acute oral administration of Delta9-tetrahydrocannabinol and standardized cannabis extract in healthy human subjects.

PubMed

Roser, Patrik; Gallinat, Jürgen; Weinberg, Gordon; Juckel, Georg; Gorynia, Inge; Stadelmann, Andreas M

2009-08-01

Abnormalities in psychomotor performance are a consistent finding in schizophrenic patients as well as in chronic cannabis users. The high levels of central cannabinoid (CB(1)) receptors in the basal ganglia, the cerebral cortex and the cerebellum indicate their implication in the regulation of motor activity. Based on the close relationship between cannabis use, the endogenous cannabinoid system and motor disturbances found in schizophrenia, we expected that administration of cannabinoids may change pattern of psychomotor activity like in schizophrenic patients. This prospective, double-blind, placebo-controlled cross-over study investigated the acute effects of cannabinoids on psychomotor performance in 24 healthy right-handed volunteers (age 27.9 +/- 2.9 years, 12 male) by comparing Delta(9)-tetrahydrocannabinol (Delta(9)-THC) and standardized cannabis extract containing Delta(9)-THC and cannabidiol. Psychomotor performance was assessed by using a finger tapping test series. Cannabis extract, but not Delta(9)-THC, revealed a significant reduction of right-hand tapping frequencies that was also found in schizophrenia. As to the pure Delta(9)-THC condition, left-hand tapping frequencies were correlated with the plasma concentrations of the Delta(9)-THC metabolite 11-OH-THC. These effects are thought to be related to cannabinoid actions on CB(1) receptors in the basal ganglia, the cerebral cortex and the cerebellum. Our data further demonstrate that acute CB(1) receptor activation under the cannabis extract condition may also affect intermanual coordination (IMC) as an index of interhemispheric transfer. AIR-Scale scores as a measure of subjective perception of intoxication were dose-dependently related to IMC which was shown by an inverted U-curve. This result may be due to functional changes involving GABAergic and glutamatergic neurotransmission within the corpus callosum.
The effect of the palmitoylethanolamide analogue, palmitoylallylamide (L-29) on pain behaviour in rodent models of neuropathy.

PubMed

Wallace, V C J; Segerdahl, A R; Lambert, D M; Vandevoorde, S; Blackbeard, J; Pheby, T; Hasnie, F; Rice, A S C

2007-08-01

Cannabinoids are associated with analgesia in acute and chronic pain states. A spectrum of central cannabinoid (CB(1)) receptor-mediated motor and psychotropic side effects limit their therapeutic potential. Here, we investigate the analgesic effect of the palmitoylethanolamide (PEA) analogue, palmitoylallylamide (L-29), which via inhibition of fatty acid amide hydrolase (FAAH) may potentiate endocannabinoids thereby avoiding psychotropic side effects. The in vivo analysis of the effect of L-29 on measures of pain behaviour in three rat models of neuropathic pain. Systemically administered L-29 (10 mg kg(-1)) reduced hypersensitivity to mechanical and thermal stimuli in the partial sciatic nerve injury (PSNI) model of neuropathic pain; and mechanical hypersensitivity in a model of antiretroviral (ddC)-associated hypersensitivity and a model of varicella zoster virus (VZV)-associated hypersensitivity. The effects of L-29 were comparable to those of gabapentin (50 mg kg(-1)). The CB(1) receptor antagonist SR141716a (1 mg kg(-1)) and the CB(2) receptor antagonist SR144528 (1 mg kg(-1)) reduced the effect of L-29 on hypersensitivity in the PSNI and ddC models, but not in the VZV model. The peroxisome proliferator-activated receptor-alpha antagonist, MK-886 (1 mg kg(-1)), partially attenuated the effect of L-29 on hypersensitivity in the PSNI model. L-29 (10 mg kg(-1)) significantly attenuated thigmotactic behaviour in the open field arena without effect on locomotor activity. L-29 produces analgesia in a range of neuropathic pain models. This presents L-29 as a novel analgesic compound that may target the endogenous cannabinoid system while avoiding undesirable side effects associated with direct cannabinoid receptor activation.
Monoacylglycerol lipase (MGLL) polymorphism rs604300 interacts with childhood adversity to predict cannabis dependence symptoms and amygdala habituation: Evidence from an endocannabinoid system-level analysis

PubMed Central

Carey, Caitlin E.; Agrawal, Arpana; Zhang, Bo; Conley, Emily D.; Degenhardt, Louisa; Heath, Andrew C.; Li, Daofeng; Lynskey, Michael T.; Martin, Nicholas G.; Montgomery, Grant W.; Wang, Ting; Bierut, Laura J.; Hariri, Ahmad R.; Nelson, Elliot C.; Bogdan, Ryan

2015-01-01

Despite evidence for heritable variation in cannabis involvement and the discovery of cannabinoid receptors and their endogenous ligands, no consistent patterns have emerged from candidate endocannabinoid (eCB) genetic association studies of cannabis involvement. Given interactions between eCB and stress systems and associations between childhood stress and cannabis involvement, it may be important to consider childhood adversity in the context of eCB-related genetic variation. We employed a system-level gene-based analysis of data from the Comorbidity and Trauma Study (N = 1,558) to examine whether genetic variation in 6 eCB genes (anabolism: DAGLA, DAGLB, NAPEPLD, catabolism: MGLL, FAAH, binding: CNR1; SNPs N = 65) and childhood sexual abuse (CSA) predicts cannabis dependence symptoms. Significant interactions with CSA emerged for MGLL at the gene-level (p = .009), and for rs604300 within MGLL (ΔR2 = .007, p < .001), the latter of which survived SNP-level Bonferroni correction and was significant in an additional sample with similar directional effects (N = 859; ΔR2 = .005, p = .026). Furthermore, in a third sample (N = 312), there was evidence that rs604300 genotype interacts with early life adversity to predict threat-related basolateral amygdala habituation, a neural phenotype linked to the eCB system and addiction (ΔR2 = .013, p = .047). Rs604300 may be related to epigenetic modulation of MGLL expression. These results are consistent with rodent models implicating 2-arachidonoylglycerol (2-AG), an endogenous cannabinoid metabolized by the enzyme encoded by MGLL, in the etiology of stress adaptation related to cannabis dependence, but require further replication. PMID:26595473
Detection of Cyclooxygenase-2-Derived Oxygenation Products of the Endogenous Cannabinoid 2-Arachidonoylglycerol in Mouse Brain.

PubMed

Morgan, Amanda J; Kingsley, Philip J; Mitchener, Michelle M; Altemus, Megan; Patrick, Toni A; Gaulden, Andrew D; Marnett, Lawrence J; Patel, Sachin

2018-05-09

Cyclooxygenase-2 (COX-2) catalyzes the formation of prostaglandins, which are involved in immune regulation, vascular function, and synaptic signaling. COX-2 also inactivates the endogenous cannabinoid (eCB) 2-arachidonoylglycerol (2-AG) via oxygenation of its arachidonic acid backbone to form a variety of prostaglandin glyceryl esters (PG-Gs). Although this oxygenation reaction is readily observed in vitro and in intact cells, detection of COX-2-derived 2-AG oxygenation products has not been previously reported in neuronal tissue. Here we show that 2-AG is metabolized in the brain of transgenic COX-2-overexpressing mice and mice treated with lipopolysaccharide to form multiple species of PG-Gs that are detectable only when monoacylglycerol lipase is concomitantly blocked. Formation of these PG-Gs is prevented by acute pharmacological inhibition of COX-2. These data provide evidence that neuronal COX-2 is capable of oxygenating 2-AG to form a variety PG-Gs in vivo and support further investigation of the physiological functions of PG-Gs.
Endocannabinoids in the Retina: From Marijuana to Neuroprotection

PubMed Central

Yazulla, Stephen

2008-01-01

The active component of the marijuana plant Cannabis sativa, Δ9-tetrahydrocannabinol (THC), produces numerous beneficial effects, including analgesia, appetite stimulation and nausea reduction, in addition to its psychotropic effects. THC mimics the action of endogenous fatty acid derivatives, referred to as endocannabinoids. The effects of THC and the endocannabinoids are mediated largely by metabotropic receptors that are distributed throughout the nervous and peripheral organ systems. There is great interest in endocannabinoids for their role in neuroplasticity as well as for therapeutic use in numerous conditions, including pain, stroke, cancer, obesity, osteoporosis, fertility, neurodegenerative diseases, multiple sclerosis, glaucoma and inflammatory diseases, among others. However, there has been relatively far less research on this topic in the eye and retina compared with the brain and other organ systems. The purpose of this review is to introduce the “cannabinergic” field to the retinal community. All of the fundamental work on cannabinoids has been performed in non-retinal preparations, necessitating extensive dependence on this literature for background. Happily, the retinal cannabinoid system has much in common with other regions of the central nervous system. For example, there is general agreement that cannabinoids suppress dopamine release and presynaptically reduce transmitter release from cones and bipolar cells. How these effects relate to light and dark adaptation, receptive field formation, temporal properties of ganglion cells or visual perception are unknown. The presence of multiple endocannabinoids, degradative enzymes with their bioactive metabolites, and receptors provides a broad spectrum of opportunities for basic research and to identify targets for therapeutic application to retinal diseases. PMID:18725316
Endocannabinoids in the retina: from marijuana to neuroprotection.

PubMed

Yazulla, Stephen

2008-09-01

The active component of the marijuana plant Cannabis sativa, Delta9-tetrahydrocannabinol (THC), produces numerous beneficial effects, including analgesia, appetite stimulation and nausea reduction, in addition to its psychotropic effects. THC mimics the action of endogenous fatty acid derivatives, referred to as endocannabinoids. The effects of THC and the endocannabinoids are mediated largely by metabotropic receptors that are distributed throughout the nervous and peripheral organ systems. There is great interest in endocannabinoids for their role in neuroplasticity as well as for therapeutic use in numerous conditions, including pain, stroke, cancer, obesity, osteoporosis, fertility, neurodegenerative diseases, multiple sclerosis, glaucoma and inflammatory diseases, among others. However, there has been relatively far less research on this topic in the eye and retina compared with the brain and other organ systems. The purpose of this review is to introduce the "cannabinergic" field to the retinal community. All of the fundamental works on cannabinoids have been performed in non-retinal preparations, necessitating extensive dependence on this literature for background. Happily, the retinal cannabinoid system has much in common with other regions of the central nervous system. For example, there is general agreement that cannabinoids suppress dopamine release and presynaptically reduce transmitter release from cones and bipolar cells. How these effects relate to light and dark adaptations, receptive field formation, temporal properties of ganglion cells or visual perception are unknown. The presence of multiple endocannabinoids, degradative enzymes with their bioactive metabolites, and receptors provides a broad spectrum of opportunities for basic research and to identify targets for therapeutic application to retinal diseases.
Lipopolysaccharide-induced murine embryonic resorption involves changes in endocannabinoid profiling and alters progesterone secretion and inflammatory response by a CB1-mediated fashion.

PubMed

Wolfson, Manuel L; Correa, Fernando; Leishman, Emma; Vercelli, Claudia; Cymeryng, Cora; Blanco, Julieta; Bradshaw, Heather B; Franchi, Ana María

2015-08-15

Genital tract infections are a common complication of human pregnancy that can result in miscarriage. We have previously shown that a lipopolysaccharide (LPS) induces embryonic resorption in a murine model of inflammatory miscarriage. This is accompanied by a dramatic decrease in systemic progesterone levels associated with a robust pro-inflammatory response that results in embryo resorption. Here, we tested the hypothesis that the endogenous cannabinoid system (eCS), through cannabinoid receptor 1 (CB1), plays a role in regulating progesterone levels and, therefore, the pro-inflammatory response. We show that LPS treatment in pregnant mice causes significant changes in the eCS ligands, which are reversed by progesterone treatment. We further show the CB1-KO mice maintain higher plasma progesterone levels after LPS treatment, which is associated with a feebler uterine inflammatory response and a significant drop in embryo resorption. These data suggest that manipulation of CB1 receptors and/or ligands is a potential therapeutic avenue to decrease infection-induced miscarriage. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.
Interaction between the cholecystokinin and endogenous cannabinoid systems in cued fear expression and extinction retention.

PubMed

Bowers, Mallory E; Ressler, Kerry J

2015-02-01

Post-traumatic stress disorder (PTSD) is thought to develop, in part, from improper inhibition of fear. Accordingly, one of the most effective treatment strategies for PTSD is exposure-based psychotherapy. Ideally, neuroscience would inform adjunct therapies that target the neurotransmitter systems involved in extinction processes. Separate studies have implicated the cholecystokinin (CCK) and endocannabinoid systems in fear; however, there is a high degree of anatomical colocalization between the cannabinoid 1 receptor (Cnr1) and CCK in the basolateral amygdala (BLA), a brain region critical for emotion regulation. Although most research has focused on GABA and GABAergic plasticity as the mechanism by which Cnr1 mediates fear inhibition, we hypothesize that a functional interaction between Cnr1 and CCKB receptor (CCKBR) is critical for fear extinction processes. In this study, systemic pharmacological manipulation of the cannabinoid system modulated cued fear expression in C57BL/6J mice after consolidation of auditory fear conditioning. Knockout of the CCKBR, however, had no effect on fear- or anxiety-like behaviors. Nonetheless, administration of a Cnr1 antagonist increased freezing behavior during a cued fear expression test in wild-type subjects, but had no effect on freezing behavior in CCKBR knockout littermates. In addition, we found that Cnr1-positive fibers form perisomatic clusters around CCKBR-positive cell bodies in the BLA. These CCKBR-positive cells comprise a molecularly heterogenous population of excitatory and inhibitory neurons. These findings provide novel evidence that Cnr1 contributes to cued fear expression via an interaction with the CCK system. Dysfunctional Cnr1-CCKBR interactions might contribute to the etiology of, or result from, fear-related psychiatric disease.
Non-psychotropic analgesic drugs from the endocannabinoid system: "magic bullet" or "multiple-target" strategies?

PubMed

Starowicz, Katarzyna; Di Marzo, Vincenzo

2013-09-15

The exploitation of preparations of Cannabis sativa to combat pain seems to date back to time immemorial, although their psychotropic effects, which are at the bases of their recreational use and limit their therapeutic use, are at least as ancient. Indeed, it has always been different to tease apart the unwanted central effects from the therapeutic benefits of Δ⁹-tetrahydrocannabinol (THC), the main psychotropic component of cannabis. The discovery of the cannabinoid receptors and of their endogenous ligands, the endocannabinoids, which, unlike THC, play a pro-homeostatic function in a tissue- and time-selective manner, offered the opportunity to develop new analgesics from synthetic inhibitors of endocannabinoid inactivation. The advantages of this approach over direct activation of cannabinoid receptors as a therapeutic strategy against neuropathic and inflammatory pain are discussed here along with its potential complications. These latter have been such that clinical success has been achieved so far more rapidly with naturally occurring THC or endocannabinoid structural analogues acting at a plethora of cannabinoid-related and -unrelated molecular targets, than with selective inhibitors of endocannabinoid enzymatic hydrolysis, thus leading to revisit the potential usefulness of "multi-target" versus "magic bullet" compounds as new analgesics. © 2013 Elsevier B.V. All rights reserved.
Endogenous and Synthetic Cannabinoids as Therapeutics in Retinal Disease.

PubMed

Kokona, Despina; Georgiou, Panagiota-Christina; Kounenidakis, Mihalis; Kiagiadaki, Foteini; Thermos, Kyriaki

2016-01-01

The functional significance of cannabinoids in ocular physiology and disease has been reported some decades ago. In the early 1970s, subjects who smoked Cannabis sativa developed lower intraocular pressure (IOP). This led to the isolation of phytocannabinoids from this plant and the study of their therapeutic effects in glaucoma. The main treatment of this disease to date involves the administration of drugs mediating either the decrease of aqueous humour synthesis or the increase of its outflow and thus reduces IOP. However, the reduction of IOP is not sufficient to prevent visual field loss. Retinal diseases, such as glaucoma and diabetic retinopathy, have been defined as neurodegenerative diseases and characterized by ischemia-induced excitotoxicity and loss of retinal neurons. Therefore, new therapeutic strategies must be applied in order to target retinal cell death, reduction of visual acuity, and blindness. The aim of the present review is to address the neuroprotective and therapeutic potential of cannabinoids in retinal disease.
Cocaine-Induced Endocannabinoid Mobilization in the Ventral Tegmental Area.

PubMed

Wang, Huikun; Treadway, Tyler; Covey, Daniel P; Cheer, Joseph F; Lupica, Carl R

2015-09-29

Cocaine is a highly addictive drug that acts upon the brain's reward circuitry via the inhibition of monoamine uptake. Endogenous cannabinoids (eCB) are lipid molecules released from midbrain dopamine (DA) neurons that modulate cocaine's effects through poorly understood mechanisms. We find that cocaine stimulates release of the eCB, 2-arachidonoylglycerol (2-AG), in the rat ventral midbrain to suppress GABAergic inhibition of DA neurons, through activation of presynaptic cannabinoid CB1 receptors. Cocaine mobilizes 2-AG via inhibition of norepinephrine uptake and promotion of a cooperative interaction between Gq/11-coupled type-1 metabotropic glutamate and α1-adrenergic receptors to stimulate internal calcium stores and activate phospholipase C. The disinhibition of DA neurons by cocaine-mobilized 2-AG is also functionally relevant because it augments DA release in the nucleus accumbens in vivo. Our results identify a mechanism through which the eCB system can regulate the rewarding and addictive properties of cocaine. Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.
The future of type 1 cannabinoid receptor allosteric ligands.

PubMed

Alaverdashvili, Mariam; Laprairie, Robert B

2018-02-01

Allosteric modulation of the type 1 cannabinoid receptor (CB1R) holds great therapeutic potential. This is because allosteric modulators do not possess intrinsic efficacy, but instead augment (positive allosteric modulation) or diminish (negative allosteric modulation) the receptor's response to endogenous ligand. Consequently, CB1R allosteric modulators have an effect ceiling which allows for the tempering of CB1R signaling without the desensitization, tolerance, dependence, and psychoactivity associated with orthosteric compounds. Pain, movement disorders, epilepsy, obesity are all potential therapeutic targets for CB1R allosteric modulation. Several challenges exist for the development of CB1R allosteric modulators, such as receptor subtype specificity, translation to in vivo systems, and mixed allosteric/agonist/inverse agonist activity. Despite these challenges, elucidation of crystal structures of CB1R and compound design based on structure-activity relationships will advance the field. In this review, we will cover recent progress for CB1R allosteric modulators and discuss the future promise of this research.
Adolescent brain maturation, the endogenous cannabinoid system and the neurobiology of cannabis-induced schizophrenia.

PubMed

Bossong, Matthijs G; Niesink, Raymond J M

2010-11-01

Cannabis use during adolescence increases the risk of developing psychotic disorders later in life. However, the neurobiological processes underlying this relationship are unknown. This review reports the results of a literature search comprising various neurobiological disciplines, ultimately converging into a model that might explain the neurobiology of cannabis-induced schizophrenia. The article briefly reviews current insights into brain development during adolescence. In particular, the role of the excitatory neurotransmitter glutamate in experience-dependent maturation of specific cortical circuitries is examined. The review also covers recent hypotheses regarding disturbances in strengthening and pruning of synaptic connections in the prefrontal cortex, and the link with latent psychotic disorders. In the present model, cannabis-induced schizophrenia is considered to be a distortion of normal late postnatal brain maturation. Distortion of glutamatergic transmission during critical periods may disturb prefrontal neurocircuitry in specific brain areas. Our model postulates that adolescent exposure to Δ9-tetrahydrocannabinol (THC), the primary psychoactive substance in cannabis, transiently disturbs physiological control of the endogenous cannabinoid system over glutamate and GABA release. As a result, THC may adversely affect adolescent experience-dependent maturation of neural circuitries within prefrontal cortical areas. Depending on dose, exact time window and duration of exposure, this may ultimately lead to the development of psychosis or schizophrenia. The proposed model provides testable hypotheses which can be addressed in future studies, including animal experiments, reanalysis of existing epidemiological data, and prospective epidemiological studies in which the role of the dose-time-effect relationship should be central. Copyright © 2010 Elsevier Ltd. All rights reserved.
Behavioral evidence for the interaction of oleamide with multiple neurotransmitter systems.

PubMed

Fedorova, I; Hashimoto, A; Fecik, R A; Hedrick, M P; Hanus, L O; Boger, D L; Rice, K C; Basile, A S

2001-10-01

While the endogenous fatty acid amide oleamide has hypnotic properties, neither the breadth of its behavioral actions nor the mechanism(s) by which these behaviors may be mediated has been elucidated. Therefore, the effects of oleamide on the performance of rats in tests of motor function, analgesia, and anxiety were investigated. Oleamide reduced the distance traveled in the open field (ED50 = 14, 10-19 mg/kg, mean, 95% confidence interval), induced analgesia and hypothermia, but did not cause catalepsy. Moreover, a dose of oleamide without effect on motor function was anxiolytic in the social interaction test and elevated plus-maze. These actions of a single dose of oleamide lasted for 30 to 60 min. While rats became tolerant to oleamide following 8 days of repeated administration, oleamide is a poor inducer of physical dependence. Pretreatment with antagonists of the serotonin (5HT)1A, 5HT2C, and vanilloid receptors did not modify oleamide's effects. However, the cannabinoid receptor antagonist SR 141716A inhibited oleamide-induced analgesia in the tail-flick assay, the gamma-aminobutyric acid (GABA)A receptor antagonist bicuculline reversed the analgesia and hypothermia, and the dopamine D2 receptor antagonist L 741626 blocked oleamide's locomotor and analgesic actions. Interestingly, oleamide analogs resistant to hydrolysis by fatty acid amide hydrolase (FAAH) maintained but did not show increased behavioral potency or duration of action, whereas two FAAH inhibitors produced analogous behavioral effects. Thus, oleamide induces behaviors reminiscent of the actions of endogenous cannabinoids, but the involvement of GABAergic and dopaminergic systems, either directly or indirectly, in the actions of oleamide cannot be ruled out.
[Neuro-skeletal biology and its importance for clinical osteology].

PubMed

Zofková, I

2012-01-01

Bone remodeling is determined by function of two basic cell forms--bone resorbing osteoclasts and bone formation activating osteoblasts. Both cells are under control of a variety of endogenic and environmental factors, which ensure balance between bone resorption and bone formation. This article reviews the neuro-hormonal factors with osteoanabolic (central isoform of serotonin, melatonin, cannabinoids, beta 1 adrenergic system, oxytocin, ACTH and TSH) or osteocatabolic effects (neuropeptide Y, neuromedin U, beta2 adrenergic system). The dual effects of the beta-adrenergic system, serotonin and leptin are also discussed. The goal of studies focused on neuro-skeletal interaction is to synthesize new molecules, which can modify osteo-anabolic or osteo-catabolic pathways.

The CB2 cannabinoid agonist AM-1241 prolongs survival in a transgenic mouse model of amyotrophic lateral sclerosis when initiated at symptom onset

PubMed Central

Shoemaker, Jennifer L.; Seely, Kathryn A.; Reed, Ronald L.; Crow, John P.; Prather, Paul L.

2010-01-01

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by progressive motor neuron loss, paralysis and death within 2–5 years of diagnosis. Currently, no effective pharmacological agents exist for the treatment of this devastating disease. Neuroinflammation may accelerate the progression of ALS. Cannabinoids produce anti-inflammatory actions via cannabinoid receptor 1 (CB1) and cannabinoid receptor 2 (CB2), and delay the progression of neuroinflammatory diseases. Additionally, CB2 receptors, which normally exist primarily in the periphery, are dramatically up-regulated in inflamed neural tissues associated with CNS disorders. In G93A-SOD1 mutant mice, the most well-characterized animal model of ALS, endogenous cannabinoids are elevated in spinal cords of symptomatic mice. Furthermore, treatment with non-selective cannabinoid partial agonists prior to, or upon, symptom appearance minimally delays disease onset and prolongs survival through undefined mechanisms. We demonstrate that mRNA, receptor binding and function of CB2, but not CB1, receptors are dramatically and selectively up-regulated in spinal cords of G93A-SOD1 mice in a temporal pattern paralleling disease progression. More importantly, daily injections of the selective CB2 agonist AM-1241, initiated at symptom onset, increase the survival interval after disease onset by 56%. Therefore, CB2 agonists may slow motor neuron degeneration and preserve motor function, and represent a novel therapeutic modality for treatment of ALS. PMID:17241118
CB2 receptors in reproduction

PubMed Central

Maccarrone, M

2007-01-01

Cannabinoids have been always identified as harmful drugs because of their negative effects on male and female reproduction. The discovery of the ‘endocannabinoid system (ECS)', composed of bioactive lipids (endocannabinoids), their receptors and their metabolic enzymes, and the generation of mouse models missing cannabinoid receptors or other elements of the ECS, has enabled a wealth of information on the significance of endocannabinoid signalling in multiple reproductive events: Sertoli cell survival, spermatogenesis, placentation, fertilization, preimplantation embryo development, implantation and postimplantation embryonic growth. These studies have also opened new perspectives in clinical applications, pointing to the ECS as a new target for correcting infertility and for improving reproductive health in humans. This review will focus on the involvement of type-2 cannabinoid (CB2) receptors in reproductive biology, covering both the male and female sides. It will also discuss the potential relevance of the immunological activity of CB2 at the maternal/foetal interface, as well as the distinctiveness of CB2 versus type-1 cannabinoid (CB1) receptors that might be exploited for a receptor subtype-specific regulation of fertility. In this context, the different signalling pathways triggered by CB1 and CB2 (especially those controlling the intracellular tone of nitric oxide), the different activation of CB1 and CB2 by endogenous agonists (like anandamide and 2-arachidonoylglycerol) and the different localization of CB1 and CB2 within membrane subdomains, termed ‘lipid rafts', will be discussed. It is hoped that CB2-dependent endocannabinoid signalling might become a useful target for correcting infertility, in both men and women. PMID:17828289
Cannabidiol for neurodegenerative disorders: important new clinical applications for this phytocannabinoid?

PubMed Central

Fernández-Ruiz, Javier; Sagredo, Onintza; Pazos, M Ruth; García, Concepción; Pertwee, Roger; Mechoulam, Raphael; Martínez-Orgado, José

2013-01-01

Cannabidiol (CBD) is a phytocannabinoid with therapeutic properties for numerous disorders exerted through molecular mechanisms that are yet to be completely identified. CBD acts in some experimental models as an anti-inflammatory, anticonvulsant, anti-oxidant, anti-emetic, anxiolytic and antipsychotic agent, and is therefore a potential medicine for the treatment of neuroinflammation, epilepsy, oxidative injury, vomiting and nausea, anxiety and schizophrenia, respectively. The neuroprotective potential of CBD, based on the combination of its anti-inflammatory and anti-oxidant properties, is of particular interest and is presently under intense preclinical research in numerous neurodegenerative disorders. In fact, CBD combined with Δ9-tetrahydrocannabinol is already under clinical evaluation in patients with Huntington's disease to determine its potential as a disease-modifying therapy. The neuroprotective properties of CBD do not appear to be exerted by the activation of key targets within the endocannabinoid system for plant-derived cannabinoids like Δ9-tetrahydrocannabinol, i.e. CB1 and CB2 receptors, as CBD has negligible activity at these cannabinoid receptors, although certain activity at the CB2 receptor has been documented in specific pathological conditions (i.e. damage of immature brain). Within the endocannabinoid system, CBD has been shown to have an inhibitory effect on the inactivation of endocannabinoids (i.e. inhibition of FAAH enzyme), thereby enhancing the action of these endogenous molecules on cannabinoid receptors, which is also noted in certain pathological conditions. CBD acts not only through the endocannabinoid system, but also causes direct or indirect activation of metabotropic receptors for serotonin or adenosine, and can target nuclear receptors of the PPAR family and also ion channels. PMID:22625422
DIFFERENTIAL EFFECTS OF SINGLE VERSUS REPEATED ALCOHOL WITHDRAWAL ON THE EXPRESSION OF ENDOCANNABINOID SYSTEM-RELATED GENES IN THE RAT AMYGDALA

PubMed Central

Serrano, Antonia; Rivera, Patricia; Pavon, Francisco J.; Decara, Juan; Suárez, Juan; de Fonseca, Fernando Rodriguez; Parsons, Loren H.

2011-01-01

Background Endogenous cannabinoids such as anandamide and 2-arachidonoylglycerol (2-AG) exert important regulatory influences on neuronal signaling, participate in short- and long-term forms of neuroplasticity, and modulate stress responses and affective behavior in part through the modulation of neurotransmission in the amygdala. Alcohol consumption alters brain endocannabinoid levels, and alcohol dependence is associated with dysregulated amygdalar function, stress responsivity and affective control. Methods The consequence of long-term alcohol consumption on the expression of genes related to endocannabinoid signaling was investigated using quantitative RT-PCR analyses of amygdala tissue. Two groups of ethanol-exposed rats were generated by maintenance on an ethanol liquid diet (10%): one group received continuous access to ethanol for 15 days, while the second group was given intermittent access to the ethanol diet (5 days/week for 3 weeks). Control subjects were maintained on an isocaloric ethanol-free liquid diet. To provide an initial profile of acute withdrawal amygdala tissue was harvested following either 6 or 24 hours of ethanol withdrawal. Results Acute ethanol withdrawal was associated with significant changes in mRNA expression for various components of the endogenous cannabinoid system in the amygdala. Specifically, reductions in mRNA expression for the primary clearance routes for anandamide and 2-AG (FAAH and MAGL, respectively) were evident, as were reductions in mRNA expression for CB1, CB2 and GPR55 receptors. Although similar alterations in FAAH mRNA were evident following either continuous or intermittent ethanol exposure, alterations in MAGL and cannabinoid receptor-related mRNA (e.g. CB1, CB2, GPR55) were more pronounced following intermittent exposure. In general, greater withdrawal-associated deficits in mRNA expression were evident following 24 versus 6 hours of withdrawal. No significant changes in mRNA expression for enzymes involved in 2-AG biosynthesis (e.g. DAGL-α/β) were found in any condition. Conclusions These findings suggest that ethanol dependence and withdrawal are associated with dysregulated endocannabinoid signaling in the amygdala. These alterations may contribute to withdrawal-related dysregulation of amygdalar neurotransmission. PMID:22141465
Endocannabinoid system and mood disorders: priming a target for new therapies.

PubMed

Micale, Vincenzo; Di Marzo, Vincenzo; Sulcova, Alexandra; Wotjak, Carsten T; Drago, Filippo

2013-04-01

The endocannabinoid system (ECS), comprising two G protein-coupled receptors (the cannabinoid receptors 1 and 2 [CB1 and CB2] for marijuana's psychoactive principle ∆(9)-tetrahydrocannabinol [∆(9)-THC]), their endogenous small lipid ligands (namely anandamide [AEA] and 2-arachidonoylglycerol [2-AG], also known as endocannabinoids), and the proteins for endocannabinoid biosynthesis and degradation, has been suggested as a pro-homeostatic and pleiotropic signaling system activated in a time- and tissue-specific way during physiopathological conditions. In the brain activation of this system modulates the release of excitatory and inhibitory neurotransmitters and of cytokines from glial cells. As such, the ECS is strongly involved in neuropsychiatric disorders, particularly in affective disturbances such as anxiety and depression. It has been proposed that synthetic molecules that inhibit endocannabinoid degradation can exploit the selectivity of endocannabinoid action, thus activating cannabinoid receptors only in those tissues where there is perturbed endocannabinoid turnover due to the disorder, and avoiding the potential side effects of direct CB1 and CB2 activation. However, the realization that endocannabinoids, and AEA in particular, also act at other molecular targets, and that these mediators can be deactivated by redundant pathways, has recently led to question the efficacy of such approach, thus opening the way to new multi-target therapeutic strategies, and to the use of non-psychotropic cannabinoids, such as cannabidiol (CBD), which act via several parallel mechanisms, including indirect interactions with the ECS. The state of the art of the possible therapeutic use of endocannabinoid deactivation inhibitors and phytocannabinoids in mood disorders is discussed in this review article. Copyright © 2012 Elsevier Inc. All rights reserved.
Endocannabinoids concentrations in plasma associated with feed efficiency and carcass composition of beef steers

USDA-ARS?s Scientific Manuscript database

Endocannabinoids, including anandamide (AEA) and 2-arachidonoylglycerol (2-AG), are a class of endogenous lipid mediators that activate cannabinoids receptors and may be involved in the control of feed intake and energy metabolism. The objective of this study was to quantify AEA and 2-AG in plasma a...
Endocannabinoid concentrations in plasma associated with feed efficiency and carcass composition on crossbreed steers

USDA-ARS?s Scientific Manuscript database

Endocannabinoids, including anandamide (AEA) and 2-arachidonoylglycerol (2-AG), are a class of endogenous lipid mediators that activate cannabinoids receptors and may be involved in the control of feed intake and energy metabolism. The objective of this study was to quantify AEA and 2-AG in plasma a...
Endogenous cannabinoids induce fever through the activation of CB1 receptors

PubMed Central

Fraga, D; Zanoni, CIS; Rae, GA; Parada, CA; Souza, GEP

2009-01-01

Background and purpose: The effects of centrally administered cannabinoids on body core temperature (Tc) and the contribution of endogenous cannabinoids to thermoregulation and fever induced by lipopolysaccharide (LPS) (Sigma Chem. Co., St. Louis, MO, USA) were investigated. Experimental approach: Drug-induced changes in Tc of male Wistar rats were recorded over 6 h using a thermistor probe (Yellow Springs Instruments 402, Dayton, OH, USA) inserted into the rectum. Key results: Injection of anandamide [(arachidonoylethanolamide (AEA); Tocris, Ellisville, MO, USA], 0.01–1 µg i.c.v. or 0.1–100 ng intra-hypothalamic (i.h.), induced graded increases in Tc (peaks 1.5 and 1.6°C at 4 h after 1 µg i.c.v. or 10 ng i.h.). The effect of AEA (1 µg, i.c.v.) was preceded by decreases in tail skin temperature and heat loss index (values at 1.5 h: vehicle 0.62, AEA 0.48). Bell-shaped curves were obtained for the increase in Tc induced by the fatty acid amide hydrolase inhibitor [3-(3-carbamoylphenyl)phenyl] N-cyclohexylcarbamate (Cayman Chemical Co., Ann Arbor, MI, USA) (0.001–1 ng i.c.v.; peak 1.9°C at 5 h after 0.1 ng) and arachidonyl-2-chloroethylamide (ACEA; Tocris) (selective CB1 agonist; 0.001–1 µg i.c.v.; peak 1.4°C 5 h after 0.01 µg), but (R,S)-(+)-(2-Iodo-5-nitrobenzoyl)-[1-(1-methyl-piperidin-2-ylmethyl)-1H-indole-3-yl] methanone (Tocris) (selective CB2 agonist) had no effect on Tc. AEA-induced fever was unaffected by i.c.v. pretreatment with 6-Iodo-2-methyl-1-[2-(4-morpholinyl)ethyl]-1H-indole-3-yl](4-methoxyphenyl) methanone (Tocris) (selective CB2 antagonist), but reduced by i.c.v. pretreatment with N-(piperidin-1-yl)-5-(4-iodophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide (AM251; Tocris) (selective CB1 antagonist). AM251 also reduced the fever induced by ACEA or LPS. Conclusions and implications: The endogenous cannabinoid AEA induces an integrated febrile response through activation of CB1 receptors. Endocannabinoids participate in the development of the febrile response to LPS constituting a target for antipyretic therapy. PMID:19681872
The endocannabinoid system in brain reward processes.

PubMed

Solinas, M; Goldberg, S R; Piomelli, D

2008-05-01

Food, drugs and brain stimulation can serve as strong rewarding stimuli and are all believed to activate common brain circuits that evolved in mammals to favour fitness and survival. For decades, endogenous dopaminergic and opioid systems have been considered the most important systems in mediating brain reward processes. Recent evidence suggests that the endogenous cannabinoid (endocannabinoid) system also has an important role in signalling of rewarding events. First, CB(1) receptors are found in brain areas involved in reward processes, such as the dopaminergic mesolimbic system. Second, activation of CB(1) receptors by plant-derived, synthetic or endogenous CB(1) receptor agonists stimulates dopaminergic neurotransmission, produces rewarding effects and increases rewarding effects of abused drugs and food. Third, pharmacological or genetic blockade of CB(1) receptors prevents activation of dopaminergic neurotransmission by several addictive drugs and reduces rewarding effects of food and these drugs. Fourth, brain levels of the endocannabinoids anandamide and 2-arachidonoylglycerol are altered by activation of reward processes. However, the intrinsic activity of the endocannabinoid system does not appear to play a facilitatory role in brain stimulation reward and some evidence suggests it may even oppose it. The influence of the endocannabinoid system on brain reward processes may depend on the degree of activation of the different brain areas involved and might represent a mechanism for fine-tuning dopaminergic activity. Although involvement of the various components of the endocannabinoid system may differ depending on the type of rewarding event investigated, this system appears to play a major role in modulating reward processes.
On the pharmacological properties of Delta9-tetrahydrocannabinol (THC).

PubMed

Costa, Barbara

2007-08-01

Cannabis is one of the first plants used as medicine, and the notion that it has potentially valuable therapeutic properties is a matter of current debate. The isolation of its main constituent, Delta9-tetrahydrocannabinol (THC), and the discovery of the endocannabinoid system (cannabinoid receptors CB1 and CB2 and their endogenous ligands) made possible studies concerning the pharmacological activity of cannabinoids. This paper reviews some of the most-important findings in the field of THC pharmacology. Clinical trials, anecdotal reports, and experiments employing animal models strongly support the idea that THC and its derivatives exhibit a wide variety of therapeutic applications. However, the psychotropic effects observed in laboratory animals and the adverse reactions reported during human trials, as well as the risk of tolerance development and potential dependence, limit the application of THC in therapy. Nowadays, researchers focus on other therapeutic strategies by which the endocannabinoid system might be modulated to clinical advantage (inhibitor or activator of endocannabinoid biosynthesis, cellular uptake, or metabolism). However, emerging evidence highlights the beneficial effects of the whole cannabis extract over those observed with single components, indicating cannabis-based medicines as new perspective to revisit the pharmacology of this plant.
Endocannabinoids Acting at Cannabinoid-1 Receptors Regulate Cardiovascular Function in Hypertension

PubMed Central

Bátkai, Sándor; Pacher, Pál; Osei-Hyiaman, Douglas; Radaeva, Svetlana; Liu, Jie; Harvey-White, Judith; Offertáler, László; Mackie, Ken; Audrey Rudd, M.; Bukoski, Richard D.; Kunos, George

2009-01-01

Background Endocannabinoids are novel lipid mediators with hypotensive and cardiodepressor activity. Here, we examined the possible role of the endocannabinergic system in cardiovascular regulation in hypertension. Methods and Results In spontaneously hypertensive rats (SHR), cannabinoid-1 receptor (CB1) antagonists increase blood pressure and left ventricular contractile performance. Conversely, preventing the degradation of the endocannabinoid anandamide by an inhibitor of fatty acid amidohydrolase reduces blood pressure, cardiac contractility, and vascular resistance to levels in normotensive rats, and these effects are prevented by CB1 antagonists. Similar changes are observed in 2 additional models of hypertension, whereas in normotensive control rats, the same parameters remain unaffected by any of these treatments. CB1 agonists lower blood pressure much more in SHR than in normotensive Wistar-Kyoto rats, and the expression of CB1 is increased in heart and aortic endothelium of SHR compared with Wistar-Kyoto rats. Conclusions We conclude that endocannabinoids tonically suppress cardiac contractility in hypertension and that enhancing the CB1-mediated cardiodepressor and vasodilator effects of endogenous anandamide by blocking its hydrolysis can normalize blood pressure. Targeting the endocannabinoid system offers novel therapeutic strategies in the treatment of hypertension. PMID:15451779
Cell-specific STORM superresolution imaging reveals nanoscale organization of cannabinoid signaling

PubMed Central

Szabó, Szilárd I.; Szabadits, Eszter; Pintér, Balázs; Woodhams, Stephen G.; Henstridge, Christopher M.; Balla, Gyula Y.; Nyilas, Rita; Varga, Csaba; Lee, Sang-Hun; Matolcsi, Máté; Cervenak, Judit; Kacskovics, Imre; Watanabe, Masahiko; Sagheddu, Claudia; Melis, Miriam; Pistis, Marco; Soltesz, Ivan; Katona, István

2014-01-01

A major challenge in neuroscience is to determine the nanoscale position and quantity of signaling molecules in a cell-type-, and subcellular compartment-specific manner. We therefore developed a novel approach combining cell-specific physiological and anatomical characterization with superresolution imaging, and studied the molecular and structural parameters shaping the physiological properties of synaptic endocannabinoid signaling in the mouse hippocampus. We found that axon terminals of perisomatically-projecting GABAergic interneurons possess increased CB1 receptor number, active-zone complexity, and receptor/effector ratio compared to dendritically-projecting interneurons, in agreement with higher efficiency of cannabinoid signaling at somatic versus dendritic synapses. Furthermore, chronic Δ9-tetrahydrocannabinol administration, which reduces cannabinoid efficacy on GABA release, evoked dramatic CB1-downregulation in a dose-dependent manner. Full receptor recovery required several weeks after cessation of Δ9-tetrahydrocannabinol treatment. These findings demonstrate that cell-type-specific nanoscale analysis of endogenous protein distribution is possible in brain circuits, and identify novel molecular properties controlling endocannabinoid signaling and cannabis-induced cognitive dysfunction. PMID:25485758
Endogenous and Synthetic Cannabinoids as Therapeutics in Retinal Disease

PubMed Central

Kokona, Despina; Georgiou, Panagiota-Christina; Kounenidakis, Mihalis; Kiagiadaki, Foteini; Thermos, Kyriaki

2016-01-01

The functional significance of cannabinoids in ocular physiology and disease has been reported some decades ago. In the early 1970s, subjects who smoked Cannabis sativa developed lower intraocular pressure (IOP). This led to the isolation of phytocannabinoids from this plant and the study of their therapeutic effects in glaucoma. The main treatment of this disease to date involves the administration of drugs mediating either the decrease of aqueous humour synthesis or the increase of its outflow and thus reduces IOP. However, the reduction of IOP is not sufficient to prevent visual field loss. Retinal diseases, such as glaucoma and diabetic retinopathy, have been defined as neurodegenerative diseases and characterized by ischemia-induced excitotoxicity and loss of retinal neurons. Therefore, new therapeutic strategies must be applied in order to target retinal cell death, reduction of visual acuity, and blindness. The aim of the present review is to address the neuroprotective and therapeutic potential of cannabinoids in retinal disease. PMID:26881135
Cannabidiol for neurodegenerative disorders: important new clinical applications for this phytocannabinoid?

PubMed

Fernández-Ruiz, Javier; Sagredo, Onintza; Pazos, M Ruth; García, Concepción; Pertwee, Roger; Mechoulam, Raphael; Martínez-Orgado, José

2013-02-01

Cannabidiol (CBD) is a phytocannabinoid with therapeutic properties for numerous disorders exerted through molecular mechanisms that are yet to be completely identified. CBD acts in some experimental models as an anti-inflammatory, anticonvulsant, anti-oxidant, anti-emetic, anxiolytic and antipsychotic agent, and is therefore a potential medicine for the treatment of neuroinflammation, epilepsy, oxidative injury, vomiting and nausea, anxiety and schizophrenia, respectively. The neuroprotective potential of CBD, based on the combination of its anti-inflammatory and anti-oxidant properties, is of particular interest and is presently under intense preclinical research in numerous neurodegenerative disorders. In fact, CBD combined with Δ(9)-tetrahydrocannabinol is already under clinical evaluation in patients with Huntington's disease to determine its potential as a disease-modifying therapy. The neuroprotective properties of CBD do not appear to be exerted by the activation of key targets within the endocannabinoid system for plant-derived cannabinoids like Δ(9)-tetrahydrocannabinol, i.e. CB(1) and CB(2) receptors, as CBD has negligible activity at these cannabinoid receptors, although certain activity at the CB(2) receptor has been documented in specific pathological conditions (i.e. damage of immature brain). Within the endocannabinoid system, CBD has been shown to have an inhibitory effect on the inactivation of endocannabinoids (i.e. inhibition of FAAH enzyme), thereby enhancing the action of these endogenous molecules on cannabinoid receptors, which is also noted in certain pathological conditions. CBD acts not only through the endocannabinoid system, but also causes direct or indirect activation of metabotropic receptors for serotonin or adenosine, and can target nuclear receptors of the PPAR family and also ion channels. © 2012 The Authors. British Journal of Clinical Pharmacology © 2012 The British Pharmacological Society.
Fatty Acid Amide Hydrolase (FAAH) Inhibition Enhances Memory Acquisition through Activation of PPAR-alpha Nuclear Receptors

ERIC Educational Resources Information Center

Mazzola, Carmen; Medalie, Julie; Scherma, Maria; Panlilio, Leigh V.; Solinas, Marcello; Tanda, Gianluigi; Drago, Filippo; Cadet, Jean Lud; Goldberg, Steven R.; Yasar, Sevil

2009-01-01

Inhibitors of fatty acid amide hydrolase (FAAH) increase endogenous levels of anandamide (a cannabinoid CB[subscript 1]-receptor ligand) and oleoylethanolamide and palmitoylethanolamide (OEA and PEA, ligands for alpha-type peroxisome proliferator-activated nuclear receptors, PPAR-alpha) when and where they are naturally released in the brain.…
Endogenous Cannabinoids Trigger the Depolarization-Induced Suppression of Excitation in the Lateral Amygdala

ERIC Educational Resources Information Center

Kodirov, Sodikdjon A.; Jasiewicz, Julia; Amirmahani, Parisa; Psyrakis, Dimitrios; Bonni, Kathrin; Wehrmeister, Michael; Lutz, Beat

2010-01-01

The amygdala is a key area of the brain where the emotional memories are stored throughout the lifespan. It is well established that synapses in the lateral nucleus of amygdala (LA) can undergo long-term potentiation, a putative cellular correlate of learning and memory. However, a type of short-term synaptic plasticity, known as…
The administration of endocannabinoid uptake inhibitors OMDM-2 or VDM-11 promotes sleep and decreases extracellular levels of dopamine in rats.

PubMed

Murillo-Rodríguez, Eric; Palomero-Rivero, Marcela; Millán-Aldaco, Diana; Di Marzo, Vincenzo

2013-01-17

The family of the endocannabinoid system comprises endogenous lipids (such as anandamide [ANA]), receptors (CB(1)/CB(2) cannabinoid receptors), metabolic enzymes (fatty acid amide hydrolase [FAAH]) and a putative membrane transporter (anandamide membrane transporter [AMT]). Although the role of ANA, FAAH or the CB(1) cannabinoid receptor in sleep modulation has been reported, the effects of the inhibition of AMT on sleep remain unclear. In the present study, we show that microdialysis perfusion in rats of AMT inhibitors, (9Z)-N-[1-((R)-4-hydroxbenzyl)-2-hydroxyethyl]-9-octadecenamide (OMDM-2) or N-(4-hydroxy-2-methylphenyl)-5Z,8Z,11Z,14Z-eicosatetraenamide (VDM-11; 10, 20 or 30 μM; each compound) delivered into the paraventricular thalamic nucleus (PVA) increased sleep and decreased waking. In addition, the infusion of compounds reduced the extracellular levels of dopamine collected from nucleus accumbens. Taken together, these findings illustrate a critical role of AMT in sleep modulation. Copyright © 2012 Elsevier Inc. All rights reserved.
N-arachidonoyl L-serine, an endocannabinoid-like brain constituent with vasodilatory properties.

PubMed

Milman, Garry; Maor, Yehoshua; Abu-Lafi, Saleh; Horowitz, Michal; Gallily, Ruth; Batkai, Sandor; Mo, Fong-Ming; Offertaler, Laszlo; Pacher, Pal; Kunos, George; Mechoulam, Raphael

2006-02-14

The endocannabinoid N-arachidonoyl ethanolamine (anandamide), found both in the CNS and in the periphery, plays a role in numerous physiological systems. One might expect that the chemically related N-arachidonoyl-L-serine (ARA-S) could also be formed alongside anandamide. We have now isolated ARA-S from bovine brain and elucidated its structure by comparison with synthetic ARA-S. Contrary to anandamide, ARA-S binds very weakly to cannabinoid CB1 and CB2 or vanilloid TRPV1 (transient receptor potential vanilloid 1) receptors. However, it produces endothelium-dependent vasodilation of rat isolated mesenteric arteries and abdominal aorta and stimulates phosphorylation of p44/42 mitogen-activated protein (MAP) kinase and protein kinase B/Akt in cultured endothelial cells. ARA-S also suppresses LPS-induced formation of TNF-alpha in a murine macrophage cell line and in wild-type mice, as well as in mice deficient in CB1 or CB2 receptors. Many of these effects parallel those reported for abnormal cannabidiol (Abn-CBD), a synthetic agonist of a putative novel cannabinoid-type receptor. Hence, ARA-S may represent an endogenous agonist for this receptor.
Exceptionally potent inhibitors of fatty acid amide hydrolase: The enzyme responsible for degradation of endogenous oleamide and anandamide

PubMed Central

Boger, Dale L.; Sato, Haruhiko; Lerner, Aaron E.; Hedrick, Michael P.; Fecik, Robert A.; Miyauchi, Hiroshi; Wilkie, Gordon D.; Austin, Bryce J.; Patricelli, Matthew P.; Cravatt, Benjamin F.

2000-01-01

The development of exceptionally potent inhibitors of fatty acid amide hydrolase (FAAH), the enzyme responsible for the degradation of oleamide (an endogenous sleep-inducing lipid), and anandamide (an endogenous ligand for cannabinoid receptors) is detailed. The inhibitors may serve as useful tools to clarify the role of endogenous oleamide and anandamide and may prove to be useful therapeutic agents for the treatment of sleep disorders or pain. The combination of several features—an optimal C12–C8 chain length, π-unsaturation introduction at the corresponding arachidonoyl Δ8,9/Δ11,12 and oleoyl Δ9,10 location, and an α-keto N4 oxazolopyridine with incorporation of a second weakly basic nitrogen provided FAAH inhibitors with Kis that drop below 200 pM and are 102–103 times more potent than the corresponding trifluoromethyl ketones. PMID:10805767
Δ9-Tetrahydrocannabinol attenuates allogeneic host-versus-graft response and delays skin graft rejection through activation of cannabinoid receptor 1 and induction of myeloid-derived suppressor cells

PubMed Central

Sido, Jessica M.; Nagarkatti, Prakash S.; Nagarkatti, Mitzi

2015-01-01

Immune cells have been shown to express cannabinoid receptors and to produce endogenous ligands. Moreover, activation of cannabinoid receptors on immune cells has been shown to trigger potent immunosuppression. Despite such studies, the role of cannabinoids in transplantation, specifically to prevent allograft rejection, has not, to our knowledge, been investigated previously. In the current study, we tested the effect of THC on the suppression of HvGD as well as rejection of skin allografts. To this end, we studied HvGD by injecting H-2k splenocytes into H-2b mice and analyzing the immune response in the draining ingLNs. THC treatment significantly reduced T cell proliferation and activation in draining LNs of the recipient mice and decreased early stage rejection-indicator cytokines, including IL-2 and IFN-γ. THC treatment also increased the allogeneic skin graft survival. THC treatment in HvGD mice led to induction of MDSCs. Using MDSC depletion studies as well as adoptive transfer experiments, we found that THC-induced MDSCs were necessary for attenuation of HvGD. Additionally, using pharmacological inhibitors of CB1 and CB2 receptors and CB1 and CB2 knockout mice, we found that THC was working preferentially through CB1. Together, our research shows, for the first time to our knowledge, that targeting cannabinoid receptors may provide a novel treatment modality to attenuate HvGD and prevent allograft rejection. PMID:26034207

Milk intake and survival in newborn cannabinoid CB1 receptor knockout mice: evidence for a "CB3" receptor.

PubMed

Fride, Ester; Foox, Anat; Rosenberg, Elana; Faigenboim, Moran; Cohen, Vickey; Barda, Lena; Blau, Hannah; Mechoulam, Raphael

2003-02-07

Cannabinoids, whether plant-derived, synthetic or endogenous, have been shown to stimulate appetite in the adult organism. We have reported previously that cannabinoid receptors play a critical role during the early suckling period: The selective cannabinoid CB(1) receptor antagonist N-(piperidiny-1-yl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide (SR141617A) permanently prevented milk ingestion in a dose-dependent manner, when administered to (Sabra, albino) mouse pups, within 1 day of birth. As a consequence, these pups died within the first week of life. We now generalize this finding to a different strain of mice (C57BL/6). Further, we show that cannabinoid CB(1) receptor blockade (20 mg/kg SR141716A) must occur within 24 h after birth as injection of SR141716A into 2- or 5-day-old pups had a much smaller effect or no effect at all, respectively. Cannabinoid CB(1) receptor knockout mice did not ingest milk on the first day of life, similarly to SR141716A-treated normal pups, as measured by the appearance of "milkbands". However, the knockout pups started to display milkbands from day 2 of life. Survival rates of cannabinoid CB(1) receptor knockout mice were affected significantly, but to a lesser extent than normal pups, by the administration of SR141716A. Daily administration of the endocannabinoid 2-arachidonoyl glycerol, or the synthetic agonists (R)-(+)-[2,3-dihydro-5-methyl-3-(4-morpholinylmethyl)pyrrolo[1,2,3-de]-1,4-benzoxazin-6-yl]-1-naphthalenylmethanone (WIN55,212-2, 5 mg/kg) or (-)-cis-3-[2-Hydroxy4-(1,1-dimethylheptyl) phenyl]-trans-4-(3-hydroxypropyl)cyclohexanol (CP55,940, 5 or 20 mg/kg) did not promote survival or weight gain in CB(1)(-/-) pups. Our data support previous evidence for a critical role of cannabinoid CB(1) receptors for the initiation of suckling. Further, the present observations support the existence of an unknown cannabinoid receptor, with partial control over milk ingestion in newborns. Our data also suggest that the CB(1)(-/-) neonates possess a compensatory mechanism which helps them overcome the lack of cannabinoid CB(1) receptors.
Endo-cannabinoids system and the toxicity of cannabinoids with a biotechnological approach

PubMed Central

Niaz, Kamal; Khan, Fazlullah; Maqbool, Faheem; Momtaz, Saeideh; Ismail Hassan, Fatima; Nobakht-Haghighi, Navid; Rahimifard, Mahban; Abdollahi, Mohammad

2017-01-01

Cannabinoids have shown diverse and critical effects on the body systems, which alter the physiological functions. Synthetic cannabinoids are comparatively innovative misuse drugs with respect to their nature of synthesis. Synthetic cannabinoids therapy in healthy, chain smokers, and alcoholic individuals cause damage to the immune and nervous system, eventually leading to intoxication throughout the body. Relevant studies were retrieved using major electronic databases such as PubMed, EMBASE, Medline, Scopus, and Google Scholar. The extensive use of Cannabis Sativa L. (C. Sativa) and its derivatives/analogues such as the nonpsychoactive dimethyl heptyl homolog (CBG-DMH), and tetrahydrocannabivarin (THCV) amongst juveniles and adults have been enhanced in recent years. Cannabinoids play a crucial role in the induction of respiratory, reproductive, immune and carcinogenic effects; however, potential data about mutagenic and developmental effects are still insufficient. The possible toxicity associated with the prolong use of cannabinoids acts as a tumor promoter in animal models and humans. Particular synthetic cannabinoids and analogues have low affinity for CB1 or CB2 receptors, while some synthetic members like Δ9-THC have high affinity towards these receptors. Cannabinoids and their derivatives have a direct or indirect association with acute and long-term toxicity. To reduce/attenuate cannabinoids toxicity, pharmaceutical biotechnology and cloning methods have opened a new window to develop cannabinoids encoding the gene tetrahydrocannabinolic acid (THCA) synthase. Plant revolution and regeneration hindered genetic engineering in C. Sativa. The genetic culture suspension of C. Sativa can be transmuted by the use of Agrobacterium tumefaciens to overcome its toxicity. The main aim of the present review was to collect evidence of the endo-cannabinoid system (ECS), cannabinoids toxicity, and the potential biotechnological approach of cannabinoids synthesis. PMID:28827985
Potential antipsychotic properties of central cannabinoid (CB1) receptor antagonists.

PubMed

Roser, Patrik; Vollenweider, Franz X; Kawohl, Wolfram

2010-03-01

Delta(9)-Tetrahydrocannabinol (Delta(9)-THC), the principal psychoactive constituent of the Cannabis sativa plant, and other agonists at the central cannabinoid (CB(1)) receptor may induce characteristic psychomotor effects, psychotic reactions and cognitive impairment resembling schizophrenia. These effects of Delta(9)-THC can be reduced in animal and human models of psychopathology by two exogenous cannabinoids, cannabidiol (CBD) and SR141716. CBD is the second most abundant constituent of Cannabis sativa that has weak partial antagonistic properties at the CB(1) receptor. CBD inhibits the reuptake and hydrolysis of anandamide, the most important endogenous CB(1) receptor agonist, and exhibits neuroprotective antioxidant activity. SR141716 is a potent and selective CB(1) receptor antagonist. Since both CBD and SR141716 can reverse many of the biochemical, physiological and behavioural effects of CB(1) receptor agonists, it has been proposed that both CBD and SR141716 have antipsychotic properties. Various experimental studies in animals, healthy human volunteers, and schizophrenic patients support this notion. Moreover, recent studies suggest that cannabinoids such as CBD and SR141716 have a pharmacological profile similar to that of atypical antipsychotic drugs. In this review, both preclinical and clinical studies investigating the potential antipsychotic effects of both CBD and SR141716 are presented together with the possible underlying mechanisms of action.
The diverse CB1 and CB2 receptor pharmacology of three plant cannabinoids: Δ9-tetrahydrocannabinol, cannabidiol and Δ9-tetrahydrocannabivarin

PubMed Central

Pertwee, R G

2007-01-01

Cannabis sativa is the source of a unique set of compounds known collectively as plant cannabinoids or phytocannabinoids. This review focuses on the manner with which three of these compounds, (−)-trans-Δ9-tetrahydrocannabinol (Δ9-THC), (−)-cannabidiol (CBD) and (−)-trans-Δ9-tetrahydrocannabivarin (Δ9-THCV), interact with cannabinoid CB1 and CB2 receptors. Δ9-THC, the main psychotropic constituent of cannabis, is a CB1 and CB2 receptor partial agonist and in line with classical pharmacology, the responses it elicits appear to be strongly influenced both by the expression level and signalling efficiency of cannabinoid receptors and by ongoing endogenous cannabinoid release. CBD displays unexpectedly high potency as an antagonist of CB1/CB2 receptor agonists in CB1- and CB2-expressing cells or tissues, the manner with which it interacts with CB2 receptors providing a possible explanation for its ability to inhibit evoked immune cell migration. Δ9-THCV behaves as a potent CB2 receptor partial agonist in vitro. In contrast, it antagonizes cannabinoid receptor agonists in CB1-expressing tissues. This it does with relatively high potency and in a manner that is both tissue and ligand dependent. Δ9-THCV also interacts with CB1 receptors when administered in vivo, behaving either as a CB1 antagonist or, at higher doses, as a CB1 receptor agonist. Brief mention is also made in this review, first of the production by Δ9-THC of pharmacodynamic tolerance, second of current knowledge about the extent to which Δ9-THC, CBD and Δ9-THCV interact with pharmacological targets other than CB1 or CB2 receptors, and third of actual and potential therapeutic applications for each of these cannabinoids. PMID:17828291
Endocannabinoid 2-arachidonoylglycerol protects inflammatory insults from sulfur dioxide inhalation via cannabinoid receptors in the brain.

PubMed

Li, Ben; Chen, Minjun; Guo, Lin; Yun, Yang; Li, Guangke; Sang, Nan

2017-01-01

Sulfur dioxide (SO 2 ) pollution in the atmospheric environment causes brain inflammatory insult and inflammatory-related microvasculature dysfunction. However, there are currently no effective medications targeting the harmful outcomes from chemical inhalation. Endocannabinoids (eCBs) are involved in neuronal protection against inflammation-induced neuronal injury. The 2-arachidonoylglycerol (2-AG), the most abundant eCBs and a full agonist for cannabinoid receptors (CB1 and CB2), is also capable of suppressing proinflammatory stimuli and improving microvasculature dysfunction. Here, we indicated that endogenous 2-AG protected against neuroinflammation in response to SO 2 inhalation by inhibiting the activation of microglia and astrocytes and attenuating the overexpression of inflammatory cytokines, including tumor necrosis factor alpha (TNF-a), interleukin (IL)-1β, and inducible nitric oxide synthase (iNOS). In addition, endogenous 2-AG prevented cerebral vasculature dysfunction following SO 2 inhalation by inhibiting endothelin 1 (ET-1), vascular cell adhesion molecule-1 (VCAM-1) and intercellular adhesion molecule 1 (ICAM-1) expression, elevating endothelial nitric oxide synthase (eNOS) level, and restoring the imbalance between thromboxane A2 (TXA2) and prostaglandin I2 (PGI2). In addition, the action of endogenous 2-AG on the suppression of inflammatory insult and inflammatory-related microvasculature dysfunction appeared to be mainly mediated by CB1 and CB2 receptors. Our results provided a mechanistic basis for the development of new therapeutic approaches for protecting brain injuries from SO 2 inhalation. Copyright © 2016. Published by Elsevier B.V.
Cannabinoid antagonist SLV326 induces convulsive seizures and changes in the interictal EEG in rats

PubMed Central

de Bruin, Natasja; Heijink, Liesbeth; Kruse, Chris; Vinogradova, Lyudmila; Lüttjohann, Annika; van Luijtelaar, Gilles; van Rijn, Clementina M.

2017-01-01

Cannabinoid CB1 antagonists have been investigated for possible treatment of e.g. obesity-related disorders. However, clinical application was halted due to their symptoms of anxiety and depression. In addition to these adverse effects, we have shown earlier that chronic treatment with the CB1 antagonist rimonabant may induce EEG-confirmed convulsive seizures. In a regulatory repeat-dose toxicity study violent episodes of “muscle spasms” were observed in Wistar rats, daily dosed with the CB1 receptor antagonist SLV326 during 5 months. The aim of the present follow-up study was to investigate whether these violent movements were of an epileptic origin. In selected SLV326-treated and control animals, EEG and behavior were monitored for 24 hours. 25% of SLV326 treated animals showed 1 to 21 EEG-confirmed generalized convulsive seizures, whereas controls were seizure-free. The behavioral seizures were typical for a limbic origin. Moreover, interictal spikes were found in 38% of treated animals. The frequency spectrum of the interictal EEG of the treated rats showed a lower theta peak frequency, as well as lower gamma power compared to the controls. These frequency changes were state-dependent: they were only found during high locomotor activity. It is concluded that long term blockade of the endogenous cannabinoid system can provoke limbic seizures in otherwise healthy rats. Additionally, SLV326 alters the frequency spectrum of the EEG when rats are highly active, suggesting effects on complex behavior and cognition. PMID:28151935
Characterization of endocannabinoids and related acylethanolamides in the synovial fluid of dogs with osteoarthritis: a pilot study.

PubMed

Valastro, Carmela; Campanile, Debora; Marinaro, Mariarosaria; Franchini, Delia; Piscitelli, Fabiana; Verde, Roberta; Di Marzo, Vincenzo; Di Bello, Antonio

2017-11-06

Cannabis-based drugs have been shown to be effective in inflammatory diseases. A number of endocannabinoids including N- arachidonoylethanolamide (anandamide, AEA) and 2-arachidonyl glycerol (2-AG) with activity at the cannabinoid receptors (CBR) CBR1 and CBR2, have been identified. Other structurally related endogenous fatty acid compounds such as oleoylethanolamide (OEA) and palmitoyl ethanolamide (PEA) have been identified in biological tissues. These compounds do not bind to CBR but might be involved in facilitating the actions of directly acting endocannabinoids and thus are commonly termed "entourage" compounds due to their ability to modulate the endocannabinoid system. The aim of this study was to evaluate the presence of endocannabinoids and entourage compounds in the synovial fluid of dogs with osteoarthritis subjected to arthrotomy of the knee joint. Cytokines and cytology were studied as well. AEA, 2-AG, OEA and PEA were all present in the synovial fluid of arthritic knees and in the contralateral joints; in addition, a significant increase of OEA and 2AG levels were noted in SF from OA knees when compared to the contralateral joints. The identification and quantification of endocannabinoids and entourage compounds levels in synovial fluids from dogs with OA of the knee is reported for the first time. Our data are instrumental for future studies involving a greater number of dogs. Cannabinoids represent an emerging and innovative pharmacological tool for the treatment of OA and further studies are warranted to evaluate the effectiveness of cannabinoids in veterinary medicine.
Endocannabinoid and cannabinoid-like fatty acid amide levels correlate with pain-related symptoms in patients with IBS-D and IBS-C: a pilot study.

PubMed

Fichna, Jakub; Wood, Jodianne T; Papanastasiou, Malvina; Vadivel, Subramanian K; Oprocha, Piotr; Sałaga, Maciej; Sobczak, Marta; Mokrowiecka, Anna; Cygankiewicz, Adam I; Zakrzewski, Piotr K; Małecka-Panas, Ewa; Krajewska, Wanda M; Kościelniak, Piotr; Makriyannis, Alexandros; Storr, Martin A

2013-01-01

Irritable bowel syndrome (IBS) is a functional gastrointestinal (GI) disorder, associated with alterations of bowel function, abdominal pain and other symptoms related to the GI tract. Recently the endogenous cannabinoid system (ECS) was shown to be involved in the physiological and pathophysiological control of the GI function. The aim of this pilot study was to investigate whether IBS defining symptoms correlate with changes in endocannabinoids or cannabinoid like fatty acid levels in IBS patients. AEA, 2-AG, OEA and PEA plasma levels were determined in diarrhoea-predominant (IBS-D) and constipation-predominant (IBS-C) patients and were compared to healthy subjects, following the establishment of correlations between biolipid contents and disease symptoms. FAAH mRNA levels were evaluated in colonic biopsies from IBS-D and IBS-C patients and matched controls. Patients with IBS-D had higher levels of 2AG and lower levels of OEA and PEA. In contrast, patients with IBS-C had higher levels of OEA. Multivariate analysis found that lower PEA levels are associated with cramping abdominal pain. FAAH mRNA levels were lower in patients with IBS-C. IBS subtypes and their symptoms show distinct alterations of endocannabinoid and endocannabinoid-like fatty acid levels. These changes may partially result from reduced FAAH expression. The here reported changes support the notion that the ECS is involved in the pathophysiology of IBS and the development of IBS symptoms.
Cell-specific STORM super-resolution imaging reveals nanoscale organization of cannabinoid signaling.

PubMed

Dudok, Barna; Barna, László; Ledri, Marco; Szabó, Szilárd I; Szabadits, Eszter; Pintér, Balázs; Woodhams, Stephen G; Henstridge, Christopher M; Balla, Gyula Y; Nyilas, Rita; Varga, Csaba; Lee, Sang-Hun; Matolcsi, Máté; Cervenak, Judit; Kacskovics, Imre; Watanabe, Masahiko; Sagheddu, Claudia; Melis, Miriam; Pistis, Marco; Soltesz, Ivan; Katona, István

2015-01-01

A major challenge in neuroscience is to determine the nanoscale position and quantity of signaling molecules in a cell type- and subcellular compartment-specific manner. We developed a new approach to this problem by combining cell-specific physiological and anatomical characterization with super-resolution imaging and studied the molecular and structural parameters shaping the physiological properties of synaptic endocannabinoid signaling in the mouse hippocampus. We found that axon terminals of perisomatically projecting GABAergic interneurons possessed increased CB1 receptor number, active-zone complexity and receptor/effector ratio compared with dendritically projecting interneurons, consistent with higher efficiency of cannabinoid signaling at somatic versus dendritic synapses. Furthermore, chronic Δ(9)-tetrahydrocannabinol administration, which reduces cannabinoid efficacy on GABA release, evoked marked CB1 downregulation in a dose-dependent manner. Full receptor recovery required several weeks after the cessation of Δ(9)-tetrahydrocannabinol treatment. These findings indicate that cell type-specific nanoscale analysis of endogenous protein distribution is possible in brain circuits and identify previously unknown molecular properties controlling endocannabinoid signaling and cannabis-induced cognitive dysfunction.
Inhibitors of Fatty Acid Amide Hydrolase and Monoacylglycerol Lipase: New Targets for Future Antidepressants.

PubMed

Ogawa, Shintaro; Kunugi, Hiroshi

2015-01-01

Cannabis and analogs of Δ<sup>9</sup>-tetrahydrocannabinol have been used for therapeutic purposes, but their therapeutic use remains limited because of various adverse effects. Endogenous cannabinoids have been discovered, and dysregulation of endocannabinoid signaling is implicated in the pathophysiology of major depressive disorder (MDD). Recently, endocannabinoid hydrolytic enzymes such as fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL) have become new therapeutic targets in the treatment of MDD. Several FAAH or MAGL inhibitors are reported to have no cannabimimetic side effects and, therefore, are new potential therapeutic options for patients with MDD who are resistant to first-line antidepressants (selective serotonin and serotonin-norepinephrine reuptake inhibitors). In this review, we focus on the possible relationships between MDD and the endocannabinoid system as well as the inhibitors' therapeutic potential. MAGL inhibitors may reduce inflammatory responses through activation of cannabinoid receptor type 2. In the hypothalamic-pituitary-adrenal axis, repeated FAAH inhibitor administration may be beneficial for reducing circulating glucocorticoid levels. Both FAAH and MAGL inhibitors may contribute to dopaminergic system regulation. Recently, several new inhibitors have been developed with strong potency and selectivity. FAAH inhibitor, MAGL inhibitor, or dual blocker use would be promising new treatments for MDD. Further pre-clinical studies and clinical trials using these inhibitors are warranted.
From Phytocannabinoids to Cannabinoid Receptors and Endocannabinoids: Pleiotropic Physiological and Pathological Roles Through Complex Pharmacology.

PubMed

Ligresti, Alessia; De Petrocellis, Luciano; Di Marzo, Vincenzo

2016-10-01

Apart from having been used and misused for at least four millennia for, among others, recreational and medicinal purposes, the cannabis plant and its most peculiar chemical components, the plant cannabinoids (phytocannabinoids), have the merit to have led humanity to discover one of the most intriguing and pleiotropic endogenous signaling systems, the endocannabinoid system (ECS). This review article aims to describe and critically discuss, in the most comprehensive possible manner, the multifaceted aspects of 1) the pharmacology and potential impact on mammalian physiology of all major phytocannabinoids, and not only of the most famous one Δ(9)-tetrahydrocannabinol, and 2) the adaptive pro-homeostatic physiological, or maladaptive pathological, roles of the ECS in mammalian cells, tissues, and organs. In doing so, we have respected the chronological order of the milestones of the millennial route from medicinal/recreational cannabis to the ECS and beyond, as it is now clear that some of the early steps in this long path, which were originally neglected, are becoming important again. The emerging picture is rather complex, but still supports the belief that more important discoveries on human physiology, and new therapies, might come in the future from new knowledge in this field. Copyright © 2016 the American Physiological Society.
Phytocannabinoids for Cancer Therapeutics: Recent Updates and Future Prospects.

PubMed

Patil, K R; Goyal, S N; Sharma, C; Patil, C R; Ojha, S

2015-01-01

Phytocannabinoids (pCBs) are lipid-soluble phytochemicals present in the plant, Cannabis sativa L. and non-cannabis plants which have a long history in recreation and traditional medicine. The plant and the constituents isolated were central in the discovery of the endocannabinoid system (ECS), the most new target for drug discovery. The ECS includes two G-protein-coupled receptors; the cannabinoid receptors-1 and -2 (CB1 and CB2) for marijuana's psychoactive principle Δ(9)-tetrahydrocannabinol (Δ(9)-THC), their endogenous small lipid ligands; namely anandamide (AEA) and 2-arachidonoylglycerol (2-AG), also known as endocannabinoids and the enzymes for endocannabinoid biosynthesis and degradation such as fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL). The ECS has been suggested as a pro-homeostatic and pleiotropic signaling system activated in a time- and tissue-specific way during pathological conditions including cancer. Targeting the CB1 receptors becomes a concern because of adverse psychotropic reactions. Hence, targeting the CB2 receptors or the endocannabinoid metabolizing enzymes by pCBs obtained from plants lacking psychotropic adverse reactions has garnered interest in drug discovery. These pCBs derived from plants appear safe and effective with a wider access and availability. In the recent years, several pCBs derived other than non-cannabinoid plants have been reported to bind to and functionally interact with cannabinoid receptors and appear promising candidate for drug development including cancer therapeutics. Several of them also targets the endocannabinoid metabolizing enzymes that control endocannabinoid levels. In this article, we summarize and critically discuss the updates and future prospects of the pCBs as novel and promising candidates for cancer therapeutics.
The influence of cannabinoids on learning and memory processes of the dorsal striatum.

PubMed

Goodman, Jarid; Packard, Mark G

2015-11-01

Extensive evidence indicates that the mammalian endocannabinoid system plays an integral role in learning and memory. Our understanding of how cannabinoids influence memory comes predominantly from studies examining cognitive and emotional memory systems mediated by the hippocampus and amygdala, respectively. However, recent evidence suggests that cannabinoids also affect habit or stimulus-response (S-R) memory mediated by the dorsal striatum. Studies implementing a variety of maze tasks in rats indicate that systemic or intra-dorsolateral striatum infusions of cannabinoid receptor agonists or antagonists impair habit memory. In mice, cannabinoid 1 (CB1) receptor knockdown can enhance or impair habit formation, whereas Δ(9)THC tolerance enhances habit formation. Studies in human cannabis users also suggest an enhancement of S-R/habit memory. A tentative conclusion based on the available data is that acute disruption of the endocannabinoid system with either agonists or antagonists impairs, whereas chronic cannabinoid exposure enhances, dorsal striatum-dependent S-R/habit memory. CB1 receptors are required for multiple forms of striatal synaptic plasticity implicated in memory, including short-term and long-term depression. Interactions with the hippocampus-dependent memory system may also have a role in some of the observed effects of cannabinoids on habit memory. The impairing effect often observed with acute cannabinoid administration argues for cannabinoid-based treatments for human psychopathologies associated with a dysfunctional habit memory system (e.g. post-traumatic stress disorder and drug addiction/relapse). In addition, the enhancing effect of repeated cannabinoid exposure on habit memory suggests a novel neurobehavioral mechanism for marijuana addiction involving the dorsal striatum-dependent memory system. Copyright © 2015 Elsevier Inc. All rights reserved.
Endocannabinoid system dysfunction in mood and related disorders.

PubMed

Ashton, C H; Moore, P B

2011-10-01

The endocannabinoid (EC) system is widely distributed throughout the brain and modulates many functions. It is involved in mood and related disorders, and its activity may be modified by exogenous cannabinoids. This article examines the therapeutic potential of cannabinoids in psychiatric disorders. An overview is presented of the literature focussed on the functions of the EC system, its dysfunction in mood disorders and the therapeutic potential of exogenous cannabinoids. We propose (hypothesize) that the EC system, which is homoeostatic in cortical excitation and inhibition, is dysfunctional in mood and related disorders. Anandamide, tetrahydrocannabinol (THC) and cannabidiol (CBD) variously combine antidepressant, antipsychotic, anxiolytic, analgesic, anticonvulsant actions, suggesting a therapeutic potential in mood and related disorders. Currently, cannabinoids find a role in pain control. Post mortem and other studies report EC system abnormalities in depression, schizophrenia and suicide. Abnormalities in the cannabinoid-1 receptor (CNR1) gene that codes for cannabinoid-1 (CB1) receptors are reported in psychiatric disorders. However, efficacy trials of cannabinoids in psychiatric disorders are limited but offer some encouragement. Research is needed to elucidate the role of the EC system in psychiatric disorders and for clinical trials with THC, CBD and synthetic cannabinoids to assess their therapeutic potential. © 2011 John Wiley & Sons A/S.
The Endocannabinoid System in the Retina: From Physiology to Practical and Therapeutic Applications.

PubMed

Schwitzer, Thomas; Schwan, Raymund; Angioi-Duprez, Karine; Giersch, Anne; Laprevote, Vincent

2016-01-01

Cannabis is one of the most prevalent drugs used in industrialized countries. The main effects of Cannabis are mediated by two major exogenous cannabinoids: ∆9-tetrahydroxycannabinol and cannabidiol. They act on specific endocannabinoid receptors, especially types 1 and 2. Mammals are endowed with a functional cannabinoid system including cannabinoid receptors, ligands, and enzymes. This endocannabinoid signaling pathway is involved in both physiological and pathophysiological conditions with a main role in the biology of the central nervous system. As the retina is a part of the central nervous system due to its embryonic origin, we aim at providing the relevance of studying the endocannabinoid system in the retina. Here, we review the distribution of the cannabinoid receptors, ligands, and enzymes in the retina and focus on the role of the cannabinoid system in retinal neurobiology. This review describes the presence of the cannabinoid system in critical stages of retinal processing and its broad involvement in retinal neurotransmission, neuroplasticity, and neuroprotection. Accordingly, we support the use of synthetic cannabinoids as new neuroprotective drugs to prevent and treat retinal diseases. Finally, we argue for the relevance of functional retinal measures in cannabis users to evaluate the impact of cannabis use on human retinal processing.
Acute and Delayed Systemic Treatment with Cannabinoid Receptor 2 Agonists to Prevent or Treat/Reverse Osteoporosis in a Mouse Model of SCI

DTIC Science & Technology

2017-08-01

AWARD NUMBER: W81XWH-16-1-0349 TITLE: Acute and Delayed Systemic Treatment with Cannabinoid Receptor 2 Agonists to Prevent or Treat/Reverse...REPORT TYPE Annual 3. DATES COVERED 1 Aug 2016 - 31 Jul 2017 4. TITLE AND SUBTITLE Acute and Delayed Systemic Treatment with Cannabinoid Receptor 2...for the cannabinoid-2 receptor, when systemically delivered, can prevent the onset of osteoporosis in mice when delivered during the acute phase of
“Redundancy” of Endocannabinoid Inactivation: New Challenges and Opportunities for Pain Control

PubMed Central

2012-01-01

Redundancy of metabolic pathways and molecular targets is a typical feature of all lipid mediators, and endocannabinoids, which were originally defined as endogenous agonists at cannabinoid CB1 and CB2 receptors, are no exception. In particular, the two most studied endocannabinoids, anandamide and 2-arachidonoylglycerol, are inactivated through alternative biochemical routes, including hydrolysis and oxidation, and more than one enzyme might be used even for the same type of inactivating reaction. These enzymes also recognize as substrates other concurrent lipid mediators, whereas, in turn, endocannabinoids might interact with noncannabinoid receptors with subcellular distribution and ultimate biological actions either similar to or completely different from those of cannabinoid receptors. Even splicing variants of endocannabinoid hydrolyzing enzymes, such as FAAH-1, might play distinct roles in endocannabinoid inactivation. Finally, the products of endocannabinoid catabolism may have their own targets, with biological roles different from those of cannabinoid receptors. These peculiarities of endocannabinoid signaling have complicated the use of inhibitors of its inactivation mechanisms as a safer and more efficacious alternative to the direct targeting of cannabinoid receptors for the treatment of several pathological conditions, including pain. However, new strategies, including the rediscovery of “dirty drugs”, and the use of certain natural products (including non-THC cannabis constituents), are emerging that might allow us to make a virtue of necessity and exploit endocannabinoid redundancy to develop new analgesics. PMID:22860203
Synergistic interaction of the cannabinoid and death receptor systems - a potential target for future cancer therapies?

PubMed

Keresztes, Attila; Streicher, John M

2017-10-01

Cannabinoid receptors have been shown to interact with other receptors, including tumor necrosis factor receptor superfamily (TNFRS) members, to induce cancer cell death. When cannabinoids and death-inducing ligands (including TNF-related apoptosis-inducing ligand) are administered together, they have been shown to synergize and demonstrate enhanced antitumor activity in vitro. Certain cannabinoid ligands have been shown to sensitize cancer cells and synergistically interact with members of the TNFRS, thus suggesting that the combination of cannabinoids with death receptor (DR) ligands induces additive or synergistic tumor cell death. This review summarizes recent findings on the interaction of the cannabinoid and DR systems and suggests possible clinical co-application of cannabinoids and DR ligands in the treatment of various malignancies. © 2017 Federation of European Biochemical Societies.
N-arachidonoyl l-serine, an endocannabinoid-like brain constituent with vasodilatory properties

PubMed Central

Milman, Garry; Maor, Yehoshua; Abu-Lafi, Saleh; Horowitz, Michal; Gallily, Ruth; Batkai, Sandor; Mo, Fong-Ming; Offertaler, Laszlo; Pacher, Pal; Kunos, George; Mechoulam, Raphael

2006-01-01

The endocannabinoid N-arachidonoyl ethanolamine (anandamide), found both in the CNS and in the periphery, plays a role in numerous physiological systems. One might expect that the chemically related N-arachidonoyl-l-serine (ARA-S) could also be formed alongside anandamide. We have now isolated ARA-S from bovine brain and elucidated its structure by comparison with synthetic ARA-S. Contrary to anandamide, ARA-S binds very weakly to cannabinoid CB1 and CB2 or vanilloid TRPV1 (transient receptor potential vanilloid 1) receptors. However, it produces endothelium-dependent vasodilation of rat isolated mesenteric arteries and abdominal aorta and stimulates phosphorylation of p44/42 mitogen-activated protein (MAP) kinase and protein kinase B/Akt in cultured endothelial cells. ARA-S also suppresses LPS-induced formation of TNF-α in a murine macrophage cell line and in wild-type mice, as well as in mice deficient in CB1 or CB2 receptors. Many of these effects parallel those reported for abnormal cannabidiol (Abn-CBD), a synthetic agonist of a putative novel cannabinoid-type receptor. Hence, ARA-S may represent an endogenous agonist for this receptor. PMID:16467152
Cannabinoids and Vanilloids in Schizophrenia: Neurophysiological Evidence and Directions for Basic Research.

PubMed

Ruggiero, Rafael N; Rossignoli, Matheus T; De Ross, Jana B; Hallak, Jaime E C; Leite, Joao P; Bueno-Junior, Lezio S

2017-01-01

Much of our knowledge of the endocannabinoid system in schizophrenia comes from behavioral measures in rodents, like prepulse inhibition of the acoustic startle and open-field locomotion, which are commonly used along with neurochemical approaches or drug challenge designs. Such methods continue to map fundamental mechanisms of sensorimotor gating, hyperlocomotion, social interaction, and underlying monoaminergic, glutamatergic, and GABAergic disturbances. These strategies will require, however, a greater use of neurophysiological tools to better inform clinical research. In this sense, electrophysiology and viral vector-based circuit dissection, like optogenetics, can further elucidate how exogenous cannabinoids worsen (e.g., tetrahydrocannabinol, THC) or ameliorate (e.g., cannabidiol, CBD) schizophrenia symptoms, like hallucinations, delusions, and cognitive deficits. Also, recent studies point to a complex endocannabinoid-endovanilloid interplay, including the influence of anandamide (endogenous CB 1 and TRPV 1 agonist) on cognitive variables, such as aversive memory extinction. In fact, growing interest has been devoted to TRPV 1 receptors as promising therapeutic targets. Here, these issues are reviewed with an emphasis on the neurophysiological evidence. First, we contextualize imaging and electrographic findings in humans. Then, we present a comprehensive review on rodent electrophysiology. Finally, we discuss how basic research will benefit from further combining psychopharmacological and neurophysiological tools.

The Endocannabinoid System in the Baboon (Papio SPP.) as a Complex Framework for Developmental Pharmacology

PubMed Central

Rodriguez-Sanchez, Iram P.; Guindon, Josee; Ruiz, Marco; Tejero, Maria E.; Hubbard, Gene; Martinez-De-Villarreal, Laura E.; Barrera-Saldaña, Hugo A.; Dick, Edward J.; Commuzzie, Anthony G; Schlabritz-Loutsevitch, Natalia E

2017-01-01

Introduction The consumption of marijuana (exogenous cannabinoid) almost doubled in adults during last decade. Consumption of exogenous cannabinoids interferes with the endogenous cannabinoid (or “endocannabinoid” (eCB)) system (ECS), which comprises N-arachidonylethanolamide (anandamide, AEA), 2-arachidonoyl glycerol (2-AG), endocannabinoid receptors (cannabinoid receptors 1 and 2 (CB1R and CB2R), encoded by CNR1 and CNR2, respectively), and synthesizing/degrading enzymes (FAAH, fatty-acid amide hydrolase; MAGL, monoacylglycerol lipase; DAGL-α, diacylglycerol lipase-alpha). Reports regarding the toxic and therapeutic effects of pharmacological compounds targeting the ECS are sometimes contradictory. This may be caused by the fact that structure of the eCBs varies in the species studied. Objectives First: to clone and characterize the cDNAs of selected members of ECS in a non-human primate (baboon, Papio spp.), and second: to compare those cDNA sequences to known human structural variants (single nucleotide polymorphisms and haplotypes). Materials and methods Polymerase chain reaction-amplified gene products from baboon tissues were transformed into Escherichia coli. Amplicon-positive clones were sequenced, and the obtained sequences were conceptually translated into amino-acid sequences using the genetic code. Results Among the ECS members, CNR1 was the best conserved gene between humans and baboons. The phenotypes associated with mutations in the untranslated regions of this gene in humans have not been described in baboons. One difference in the structure of CNR2 between humans and baboons was detected in the region with the only known clinically relevant polymorphism in a human receptor. All of the differences in the amino-acid structure of DAGL-α between humans and baboons were located in the hydroxylase domain, close to phosphorylation sites. None of the differences in the amino-acid structure of MAGL observed between baboons and humans were located in the area critical for enzyme function. Conclusion The evaluation of the data, obtained in non-human primate model of cannabis-related developmental exposure should take into consideration possible evolutionary-determined species-specific differences in the CB1R expression, CB2R transduction pathway, and FAAH and DAGLα substrate-enzyme interactions. PMID:27327781
The endocannabinoid system in the baboon (Papio spp.) as a complex framework for developmental pharmacology.

PubMed

Rodriguez-Sanchez, Iram P; Guindon, Josee; Ruiz, Marco; Tejero, M Elizabeth; Hubbard, Gene; Martinez-de-Villarreal, Laura E; Barrera-Saldaña, Hugo A; Dick, Edward J; Comuzzie, Anthony G; Schlabritz-Loutsevitch, Natalia E

The consumption of marijuana (exogenous cannabinoid) almost doubled in adults during last decade. Consumption of exogenous cannabinoids interferes with the endogenous cannabinoid (or "endocannabinoid" (eCB)) system (ECS), which comprises N-arachidonylethanolamide (anandamide, AEA), 2-arachidonoyl glycerol (2-AG), endocannabinoid receptors (cannabinoid receptors 1 and 2 (CB1R and CB2R), encoded by CNR1 and CNR2, respectively), and synthesizing/degrading enzymes (FAAH, fatty-acid amide hydrolase; MAGL, monoacylglycerol lipase; DAGL-α, diacylglycerol lipase-alpha). Reports regarding the toxic and therapeutic effects of pharmacological compounds targeting the ECS are sometimes contradictory. This may be caused by the fact that structure of the eCBs varies in the species studied. First: to clone and characterize the cDNAs of selected members of ECS in a non-human primate (baboon, Papio spp.), and second: to compare those cDNA sequences to known human structural variants (single nucleotide polymorphisms and haplotypes). Polymerase chain reaction-amplified gene products from baboon tissues were transformed into Escherichia coli. Amplicon-positive clones were sequenced, and the obtained sequences were conceptually translated into amino-acid sequences using the genetic code. Among the ECS members, CNR1 was the best conserved gene between humans and baboons. The phenotypes associated with mutations in the untranslated regions of this gene in humans have not been described in baboons. One difference in the structure of CNR2 between humans and baboons was detected in the region with the only known clinically relevant polymorphism in a human receptor. All of the differences in the amino-acid structure of DAGL-α between humans and baboons were located in the hydroxylase domain, close to phosphorylation sites. None of the differences in the amino-acid structure of MAGL observed between baboons and humans were located in the area critical for enzyme function. The evaluation of the data, obtained in non-human primate model of cannabis-related developmental exposure should take into consideration possible evolutionary-determined species-specific differences in the CB1R expression, CB2R transduction pathway, and FAAH and DAGLα substrate-enzyme interactions. Copyright © 2016 Elsevier Inc. All rights reserved.
The Endocannabinoid System in the Retina: From Physiology to Practical and Therapeutic Applications

PubMed Central

Schwitzer, Thomas; Schwan, Raymund; Angioi-Duprez, Karine; Giersch, Anne; Laprevote, Vincent

2016-01-01

Cannabis is one of the most prevalent drugs used in industrialized countries. The main effects of Cannabis are mediated by two major exogenous cannabinoids: ∆9-tetrahydroxycannabinol and cannabidiol. They act on specific endocannabinoid receptors, especially types 1 and 2. Mammals are endowed with a functional cannabinoid system including cannabinoid receptors, ligands, and enzymes. This endocannabinoid signaling pathway is involved in both physiological and pathophysiological conditions with a main role in the biology of the central nervous system. As the retina is a part of the central nervous system due to its embryonic origin, we aim at providing the relevance of studying the endocannabinoid system in the retina. Here, we review the distribution of the cannabinoid receptors, ligands, and enzymes in the retina and focus on the role of the cannabinoid system in retinal neurobiology. This review describes the presence of the cannabinoid system in critical stages of retinal processing and its broad involvement in retinal neurotransmission, neuroplasticity, and neuroprotection. Accordingly, we support the use of synthetic cannabinoids as new neuroprotective drugs to prevent and treat retinal diseases. Finally, we argue for the relevance of functional retinal measures in cannabis users to evaluate the impact of cannabis use on human retinal processing. PMID:26881099
The arguments for and against cannabinoids application in glaucomatous retinopathy.

PubMed

Panahi, Yunes; Manayi, Azadeh; Nikan, Marjan; Vazirian, Mahdi

2017-02-01

Glaucoma represents several optic neuropathies leading to irreversible blindness through progressive retinal ganglion cell (RGC) loss. Reduction of intraocular pressure (IOP) is known as the only modifiable factor in the treatment of this disorder. Application of exogenous cannabinoids to lower IOP has attracted attention of scientists as potential agents for the treatment of glaucoma. Accordingly, neuroprotective effect of these agents has been recently described through modulation of endocannabinoid system in the eye. In the present work, pertinent information regarding ocular endocannabinoid system, mechanism of exogenous cannabinoids interaction with the ocular endocannabinoid system to reduce IOP, and neuroprotection property of cannabinoids will be discussed according to current scientific literature. In addition to experimental studies, bioavailability of cannabinoids, clinical surveys, and adverse effects of application of cannabinoids in glaucoma will be reviewed. Copyright © 2016 Elsevier Masson SAS. All rights reserved.
The role of the endocannabinoid system in the brain-gut axis

PubMed Central

Sharkey, Keith A.; Wiley, John W.

2016-01-01

The actions of cannabis are mediated by receptors that are part of an endogenous cannabinoid system. The endocannabinoid system (ECS) consists of the naturally occurring ligands N-arachidonoylethanolamine (anandamide) and 2-arachidonoylglycerol (2-AG), their biosynthetic and degradative enzymes, and the cannabinoid receptors CB1 and CB2. The ECS is a widely distributed transmitter system that controls gut functions peripherally and centrally. It is an important physiologic regulator of gastrointestinal motility. Polymorphisms in the gene encoding CB1 (CNR1) have been associated with some forms of irritable bowel syndrome. The ECS is involved in the control of nausea and vomiting and visceral sensation. The homeostatic role of the ECS also extends to the control of intestinal inflammation. We review the mechanisms by which the ECS links stress and visceral pain. CB1 in sensory ganglia controls visceral sensation, and transcription of CNR1 is modified through epigenetic processes under conditions of chronic stress. These processes might link stress with abdominal pain. The ECS is also involved centrally in the manifestation of stress, and endocannabinoid signaling reduces the activity of hypothalamic–pituitary–adrenal pathways via actions in specific brain regions—notably the prefrontal cortex, amygdala, and hypothalamus. Agents that modulate the ECS are in early stages of development for treatment of gastrointestinal diseases. Increasing our understanding of the ECS will greatly advance our knowledge of interactions between the brain and gut and could lead to new treatments for gastrointestinal disorders. PMID:27133395
The Role of the Endocannabinoid System in the Brain-Gut Axis.

PubMed

Sharkey, Keith A; Wiley, John W

2016-08-01

The actions of cannabis are mediated by receptors that are part of an endogenous cannabinoid system. The endocannabinoid system (ECS) consists of the naturally occurring ligands N-arachidonoylethanolamine (anandamide) and 2-arachidonoylglycerol (2-AG), their biosynthetic and degradative enzymes, and the cannabinoid (CB) receptors CB1 and CB2. The ECS is a widely distributed transmitter system that controls gut functions peripherally and centrally. It is an important physiologic regulator of gastrointestinal motility. Polymorphisms in the gene encoding CB1 (CNR1) have been associated with some forms of irritable bowel syndrome. The ECS is involved in the control of nausea and vomiting and visceral sensation. The homeostatic role of the ECS also extends to the control of intestinal inflammation. We review the mechanisms by which the ECS links stress and visceral pain. CB1 in sensory ganglia controls visceral sensation, and transcription of CNR1 is modified through epigenetic processes under conditions of chronic stress. These processes might link stress with abdominal pain. The ECS is also involved centrally in the manifestation of stress, and endocannabinoid signaling reduces the activity of hypothalamic-pituitary-adrenal pathways via actions in specific brain regions, notably the prefrontal cortex, amygdala, and hypothalamus. Agents that modulate the ECS are in early stages of development for treatment of gastrointestinal diseases. Increasing our understanding of the ECS will greatly advance our knowledge of interactions between the brain and gut and could lead to new treatments for gastrointestinal disorders. Copyright © 2016. Published by Elsevier Inc.
High Times for Painful Blues: The Endocannabinoid System in Pain-Depression Comorbidity

PubMed Central

Fitzgibbon, Marie; Finn, David P.

2016-01-01

Depression and pain are two of the most debilitating disorders worldwide and have an estimated cooccurrence of up to 80%. Comorbidity of these disorders is more difficult to treat, associated with significant disability and impaired health-related quality of life than either condition alone, resulting in enormous social and economic cost. Several neural substrates have been identified as potential mediators in the association between depression and pain, including neuroanatomical reorganization, monoamine and neurotrophin depletion, dysregulation of the hypothalamo-pituitary-adrenal axis, and neuroinflammation. However, the past decade has seen mounting evidence supporting a role for the endogenous cannabinoid (endocannabinoid) system in affective and nociceptive processing, and thus, alterations in this system may play a key role in reciprocal interactions between depression and pain. This review will provide an overview of the preclinical evidence supporting an interaction between depression and pain and the evidence supporting a role for the endocannabinoid system in this interaction. PMID:26342110
Endocannabinoids and neuropathic pain: focus on neuron-glia and endocannabinoid-neurotrophin interactions.

PubMed

Luongo, Livio; Maione, Sabatino; Di Marzo, Vincenzo

2014-02-01

Although originally described as a signalling system encompassing the cannabinoid CB1 and CB2 receptors, their endogenous agonists (the endocannabinoids), and metabolic enzymes regulating the levels of such agonists, the endocannabinoid system is now viewed as being more complex, and including metabolically related endocannabinoid-like mediators and their molecular targets as well. The function and dysfunction of this complex signalling system in the molecular and cellular mechanisms of pain transduction and control has been widely studied over the last two decades. In this review article, we describe some of the latest advances in our knowledge on the role of the endocannabinoid system, in its most recent and wider conception, in pain pathways, by focusing on: (1) neuron-glia interactions; and (2) emerging data on endocannabinoid cross-talk with neurotrophins, such as nerve growth factor and brain-derived neurotrophic factor. © 2014 Federation of European Neuroscience Societies and John Wiley & Sons Ltd.
Oleamide: a fatty acid amide signaling molecule in the cardiovascular system?

PubMed

Hiley, C Robin; Hoi, Pui Man

2007-01-01

Oleamide (cis-9,10-octadecenoamide), a fatty acid primary amide discovered in the cerebrospinal fluid of sleep-deprived cats, has a variety of actions that give it potential as a signaling molecule, although these actions have not been extensively investigated in the cardiovascular system. The synthetic pathway probably involves synthesis of oleoylglycine and then conversion to oleamide by peptidylglycine alpha-amidating monooxygenase (PAM); breakdown of oleamide is by fatty acid amide hydrolase (FAAH). Oleamide interacts with voltage-gated Na(+) channels and allosterically with GABA(A) and 5-HT(7) receptors as well as having cannabinoid-like actions. The latter have been suggested to be due to potentiation of the effects of endocannabinoids such as anandamide by inhibiting FAAH-mediated hydrolysis. This might underlie an "entourage effect" whereby co-released endogenous nonagonist congeners of endocannabinoids protect the active molecule from hydrolysis by FAAH. However, oleamide has direct agonist actions at CB(1) cannabinoid receptors and also activates the TRPV1 vanilloid receptor. Other actions include inhibition of gap-junctional communication, and this might give oleamide a role in myocardial development. Many of these actions are absent from the trans isomer of 9,10-octadecenoamide. One of the most potent actions of oleamide is vasodilation. In rat small mesenteric artery the response does not involve CB(1) cannabinoid receptors but another pertussis toxin-sensitive, G protein-coupled receptor, as yet unidentified. This receptor is sensitive to rimonabant and O-1918, an antagonist at the putative "abnormal-cannabidiol" or endothelial "anandamide" receptors. Vasodilation is mediated by endothelium-derived nitric oxide, endothelium-dependent hyperpolarization, and also through activation of TRPV1 receptors. A physiological role for oleamide in the heart and circulation has yet to be demonstrated, as has production by cells of the cardiovascular system, but this molecule has a range of actions that could give it considerable modulatory power.
Neuropeptide Regulation of Fear and Anxiety: Implications of Cholecystokinin, Endogenous Opioids, and Neuropeptide Y

PubMed Central

Bowers, Mallory E.; Choi, Dennis C.; Ressler, Kerry J.

2012-01-01

The neural circuitry of fear likely underlies anxiety and fear-related disorders such as specific and social phobia, panic disorder, and posttraumatic stress disorder. The primary pharmacological treatments currently utilized for these disorders include benzodiazepines, which act on the GABAergic receptor system, and antidepressants, which modulate the monamine systems. However, recent work on the regulation of fear neural circuitry suggests that specific neuropeptide modulation of this system is of critical importance. Recent reviews have examined the roles of the hypothalamic-pituitary-adrenal axis neuropeptides as well as the roles of neurotrophic factors in regulating fear. The present review, instead, will focus on three neuropeptide systems which have received less attention in recent years but which are clearly involved in regulating fear and its extinction. The endogenous opioid system, particularly activating the μ opioid receptors, has been demonstrated to regulate fear expression and extinction, possibly through functioning as an error signal within the amygdala to mark unreinforced conditioned stimuli. The cholecystokinin (CCK) system initially led to much excitement through its potential role in panic disorder. More recent work in the CCK neuropeptide pathway suggests that it may act in concordance with the endogenous cannabinoid system in the modulation of fear inhibition and extinction. Finally, older as well as very recent data suggests that neuropeptide Y (NPY) may play a very interesting role in counteracting stress effects, enhancing extinction, and enhancing resilience in fear and stress preclinical models. Future work in understanding the mechanisms of neuropeptide functioning, particularly within well-known behavioral circuits, are likely to provide fascinating new clues into the understanding of fear behavior as well as suggesting novel therapeutics for treating disorders of anxiety and fear dysregulation. PMID:22429904
The endocannabinoid system in normal and pathological brain ageing

PubMed Central

Bilkei-Gorzo, Andras

2012-01-01

The role of endocannabinoids as inhibitory retrograde transmitters is now widely known and intensively studied. However, endocannabinoids also influence neuronal activity by exerting neuroprotective effects and regulating glial responses. This review centres around this less-studied area, focusing on the cellular and molecular mechanisms underlying the protective effect of the cannabinoid system in brain ageing. The progression of ageing is largely determined by the balance between detrimental, pro-ageing, largely stochastic processes, and the activity of the homeostatic defence system. Experimental evidence suggests that the cannabinoid system is part of the latter system. Cannabinoids as regulators of mitochondrial activity, as anti-oxidants and as modulators of clearance processes protect neurons on the molecular level. On the cellular level, the cannabinoid system regulates the expression of brain-derived neurotrophic factor and neurogenesis. Neuroinflammatory processes contributing to the progression of normal brain ageing and to the pathogenesis of neurodegenerative diseases are suppressed by cannabinoids, suggesting that they may also influence the ageing process on the system level. In good agreement with the hypothesized beneficial role of cannabinoid system activity against brain ageing, it was shown that animals lacking CB1 receptors show early onset of learning deficits associated with age-related histological and molecular changes. In preclinical models of neurodegenerative disorders, cannabinoids show beneficial effects, but the clinical evidence regarding their efficacy as therapeutic tools is either inconclusive or still missing. PMID:23108550
The endocannabinoid system in normal and pathological brain ageing.

PubMed

Bilkei-Gorzo, Andras

2012-12-05

The role of endocannabinoids as inhibitory retrograde transmitters is now widely known and intensively studied. However, endocannabinoids also influence neuronal activity by exerting neuroprotective effects and regulating glial responses. This review centres around this less-studied area, focusing on the cellular and molecular mechanisms underlying the protective effect of the cannabinoid system in brain ageing. The progression of ageing is largely determined by the balance between detrimental, pro-ageing, largely stochastic processes, and the activity of the homeostatic defence system. Experimental evidence suggests that the cannabinoid system is part of the latter system. Cannabinoids as regulators of mitochondrial activity, as anti-oxidants and as modulators of clearance processes protect neurons on the molecular level. On the cellular level, the cannabinoid system regulates the expression of brain-derived neurotrophic factor and neurogenesis. Neuroinflammatory processes contributing to the progression of normal brain ageing and to the pathogenesis of neurodegenerative diseases are suppressed by cannabinoids, suggesting that they may also influence the ageing process on the system level. In good agreement with the hypothesized beneficial role of cannabinoid system activity against brain ageing, it was shown that animals lacking CB1 receptors show early onset of learning deficits associated with age-related histological and molecular changes. In preclinical models of neurodegenerative disorders, cannabinoids show beneficial effects, but the clinical evidence regarding their efficacy as therapeutic tools is either inconclusive or still missing.
Leptin receptor deficiency is associated with upregulation of cannabinoid 1 receptors in limbic brain regions.

PubMed

Thanos, Panayotis K; Ramalhete, Roberto C; Michaelides, Michael; Piyis, Yianni K; Wang, Gene-Jack; Volkow, Nora D

2008-09-01

Leptin receptor dysfunction results in overeating and obesity. Leptin regulates hypothalamic signaling that underlies the motivation to hyperphagia, but the interaction between leptin and cannabinoid signaling is poorly understood. We evaluated the role of cannabinoid 1 receptors (CB(1)R) in overeating and the effects of food deprivation on CB(1)R in the brain. One-month-old Zucker rats were divided into unrestricted and restricted (fed 70% of unrestricted rats) diet groups and maintained until adulthood (4 months). Levels of relative binding sites of CB(1)R (CB(1)R binding levels) were assessed using [(3)H] SR141716A in vitro autoradiography. These levels were higher (except cerebellum and hypothalamus) at 4 months than at 1 month of age. One month CB(1)R binding levels for most brain regions did not differ between Ob and Lean (Le) rats (except in frontal and cingulate cortices in Le and in the hypothalamus in Ob). Four month Ob rats had higher CB(1)R binding levels than Le in most brain regions and food restriction was associated with higher CB(1)R levels in all brain regions in Ob, but not in Le rats. CB(1)R binding levels increased between adolescence and young adulthood which we believe was influenced by leptin and food availability. The high levels of CB(1)R in Ob rats suggest that leptin's inhibition of food-intake is in part mediated by downregulation of CB(1)R and that leptin interferes with CB(1)R upregulation under food-deprivation conditions. These results are consistent with prior findings showing increased levels of endogenous cannabinoids in the Ob rats corroborating the regulation of cannabinoid signaling by leptin. Published 2008 Wiley-Liss, Inc.
Leptin Receptor Deficiency is Associated With Upregulation of Cannabinoid 1 Receptors in Limbic Brain Regions

PubMed Central

THANOS, PANAYOTIS K.; RAMALHETE, ROBERTO C.; MICHAELIDES, MICHAEL; PIYIS, YIANNI K.; WANG, GENE-JACK; VOLKOW, NORA D.

2009-01-01

Leptin receptor dysfunction results in overeating and obesity. Leptin regulates hypothalamic signaling that underlies the motivation to hyperphagia, but the interaction between leptin and cannabinoid signaling is poorly understood. We evaluated the role of cannabinoid 1 receptors (CB1R) in overeating and the effects of food deprivation on CB1R in the brain. One-month-old Zucker rats were divided into unrestricted and restricted (fed 70% of unrestricted rats) diet groups and maintained until adulthood (4 months). Levels of relative binding sites of CB1R (CB1R binding levels) were assessed using [3H] SR141716A in vitro autoradiography. These levels were higher (except cerebellum and hypothalamus) at 4 months than at 1 month of age. One month CB1R binding levels for most brain regions did not differ between Ob and Lean (Le) rats (except in frontal and cingulate cortices in Le and in the hypothalamus in Ob). Four month Ob rats had higher CB1R binding levels than Le in most brain regions and food restriction was associated with higher CB1R levels in all brain regions in Ob, but not in Le rats. CB1R binding levels increased between adolescence and young adulthood which we believe was influenced by leptin and food availability. The high levels of CB1R in Ob rats suggest that leptin's inhibition of food-intake is in part mediated by downregulation of CB1R and that leptin interferes with CB1R upregulation under food-deprivation conditions. These results are consistent with prior findings showing increased levels of endogenous cannabinoids in the Ob rats corroborating the regulation of cannabinoid signaling by leptin. PMID:18563836
Endocannabinoids as physiological regulators of colonic propulsion in mice.

PubMed

Pinto, Luisa; Izzo, Angelo A; Cascio, Maria Grazia; Bisogno, Tiziana; Hospodar-Scott, Karen; Brown, David R; Mascolo, Nicola; Di Marzo, Vincenzo; Capasso, Francesco

2002-07-01

Activation of enteric cannabinoid CB1 receptors inhibits motility in the small intestine; however, it is not known whether endogenous cannabinoids (anandamide and 2-arachidonylglycerol) play a physiologic role in regulating intestinal motility. In the present study, we investigated the possible involvement of endocannabinoids in regulating intestinal propulsion in the mouse colon in vivo. Intestinal motility was studied measuring the expulsion of a glass bead inserted into the distal colon; endocannabinoid levels were measured by isotope-dilution gas chromatography-mass spectrometry; anandamide amidohydrolase activity was measured by specific enzyme assays. CB1 receptors were localized by immunohistochemistry. Anandamide, WIN 55,212-2, cannabinol (nonselective cannabinoid agonists), and ACEA (a selective CB1 agonist) inhibited colonic propulsion; this effect was counteracted by SR141716A, a CB1 receptor antagonist. Administered alone, SR141716A increased motility, whereas the inhibitor of anandamide cellular reuptake, VDM11, decreased motility. High amounts of 2-arachidonylglycerol and particularly anandamide were found in the colon, together with a high activity of anandamide amidohydrolase. CB1 receptor immunoreactivity was colocalized to a subpopulation of choline acetyltransferase-immunoreactive neurons and fiber bundles in the myenteric plexus. We conclude that endocannabinoids acting on myenteric CB1 receptors tonically inhibit colonic propulsion in mice.
Marijuana and cannabinoid regulation of brain reward circuits.

PubMed

Lupica, Carl R; Riegel, Arthur C; Hoffman, Alexander F

2004-09-01

The reward circuitry of the brain consists of neurons that synaptically connect a wide variety of nuclei. Of these brain regions, the ventral tegmental area (VTA) and the nucleus accumbens (NAc) play central roles in the processing of rewarding environmental stimuli and in drug addiction. The psychoactive properties of marijuana are mediated by the active constituent, Delta(9)-THC, interacting primarily with CB1 cannabinoid receptors in a large number of brain areas. However, it is the activation of these receptors located within the central brain reward circuits that is thought to play an important role in sustaining the self-administration of marijuana in humans, and in mediating the anxiolytic and pleasurable effects of the drug. Here we describe the cellular circuitry of the VTA and the NAc, define the sites within these areas at which cannabinoids alter synaptic processes, and discuss the relevance of these actions to the regulation of reinforcement and reward. In addition, we compare the effects of Delta(9)-THC with those of other commonly abused drugs on these reward circuits, and we discuss the roles that endogenous cannabinoids may play within these brain pathways, and their possible involvement in regulating ongoing brain function, independently of marijuana consumption. We conclude that, whereas Delta(9)-THC alters the activity of these central reward pathways in a manner that is consistent with other abused drugs, the cellular mechanism through which this occurs is likely different, relying upon the combined regulation of several afferent pathways to the VTA.
ENDOCANNABINOID INFLUENCE IN DRUG REINFORCEMENT, DEPENDENCE AND ADDICTION-RELATED BEHAVIORS

PubMed Central

Serrano, Antonia; Parsons, Loren H.

2011-01-01

The endogenous cannabinoid system is an important regulatory system involved in physiological homeostasis. Endocannabinoid signaling is known to modulate neural development, immune function, metabolism, synaptic plasticity and emotional state. Accumulating evidence also implicates brain endocannabinoid signaling in the etiology of drug addiction which is characterized by compulsive drug seeking, loss of control in limiting drug intake, emergence of a negative emotional state in the absence of drug use and a persistent vulnerability toward relapse to drug use during protracted abstinence. In this review we discuss the effects of drug intake on brain endocannabinoid signaling, evidence implicating the endocannabinoid system in the motivation for drug consumption, and drug-induced alterations in endocannabinoid function that may contribute to various aspects of addiction including dysregulated synaptic plasticity, increased stress responsivity, negative affective states, drug craving and relapse to drug taking. Current knowledge of genetic variants in endocannabinoid signaling associated with addiction is also discussed. PMID:21798285
Cannabinoids and Viral Infections

PubMed Central

Reiss, Carol Shoshkes

2010-01-01

Exogenous cannabinoids or receptor antagonists may influence many cellular and systemic host responses. The anti-inflammatory activity of cannabinoids may compromise host inflammatory responses to acute viral infections, but may be beneficial in persistent infections. In neurons, where innate antiviral/pro-resolution responses include the activation of NOS-1, inhibition of Ca2+ activity by cannabinoids, increased viral replication and disease. This review examines the effect(s) of cannabinoids and their antagonists in viral infections. PMID:20634917
Elevation of endogenous anandamide impairs LTP, learning, and memory through CB1 receptor signaling in mice.

PubMed

Basavarajappa, Balapal S; Nagre, Nagaraja N; Xie, Shan; Subbanna, Shivakumar

2014-07-01

In rodents, many exogenous and endogenous cannabinoids, such as anandamide (AEA) and 2-arachidonyl glycerol (2-AG), have been shown to play an important role in certain hippocampal memory processes. However, the mechanisms by which endogenous AEA regulate this processes are not well understood. Here the effects of AEA on long-term potentiation (LTP), hippocampal-dependent learning and memory tasks, pERK1/2, pCaMKIV, and pCREB signaling events in both cannabinoid receptor type 1 (CB1R) wild-type (WT) and knockout (KO) mice were assessed following administration of URB597, an inhibitor of the fatty acid amide hydrolase (FAAH). Acute administration of URB597 enhanced AEA levels without affecting the levels of 2-AG or CB1R in the hippocampus and neocortex as compared to vehicle. In hippocampal slices, URB597 impaired LTP in CB1R WT but not in KO littermates. URB597 impaired object recognition, spontaneous alternation and spatial memory in the Y-maze test in CB1R WT mice but not in KO mice. Furthermore, URB597 enhanced ERK phosphorylation in WT without affecting total ERK levels in WT or KO mice. URB597 impaired CaMKIV and CREB phosphorylation in WT but not in KO mice. CB1R KO mice have a lower pCaMKIV/CaMKIV ratio and higher pCREB/CREB ratio as compared to WT littermates. Our results indicate that pharmacologically elevated AEA impair LTP, learning and memory and inhibit CaMKIV and CREB phosphorylation, via the activation of CB1Rs. Collectively, these findings also suggest that pharmacological elevation of AEA beyond normal concentrations is also detrimental for the underlying physiological responses. © 2014 Wiley Periodicals, Inc.
Involvement of the cannabinoid CB2 receptor and its endogenous ligand 2-arachidonoylglycerol in oxazolone-induced contact dermatitis in mice.

PubMed

Oka, Saori; Wakui, Junichi; Ikeda, Shinobu; Yanagimoto, Shin; Kishimoto, Seishi; Gokoh, Maiko; Nasui, Miwako; Sugiura, Takayuki

2006-12-15

The possible involvement of 2-arachidonoylglycerol (2-AG), an endogenous ligand for the cannabinoid receptors (CB1 and CB2), in contact dermatitis in mouse ear was investigated. We found that the level of 2-AG was markedly elevated in the ear following a challenge with oxazolone in sensitized mice. Of note, the swelling following the challenge was suppressed by either the administration of SR144528, a CB2 receptor antagonist, immediately after sensitization, or the administration of SR144528 upon the challenge. The effect of AM251, a CB1 receptor antagonist, was marginal in either case. It seems apparent, therefore, that the CB2 receptor and its endogenous ligand 2-AG are closely involved in both the sensitization phase and the elicitation phase of oxazolone-induced contact dermatitis. In line with this, we found that Langerhans cells (MHC class II(+)) contain a substantial amount of CB2 receptor mRNA, whereas keratinocytes (MHC class II(-)) do not. We also obtained evidence that the expression of mRNAs for proinflammatory cytokines following a challenge with oxazolone was markedly suppressed by treatment with SR144528. We next examined whether the CB2 receptor and 2-AG participate in chronic contact dermatitis accompanied by the infiltration of tissues by eosinophils. The amount of 2-AG in mouse ear dramatically increased following repeated challenge with oxazolone. Importantly, treatment with SR144528 attenuated both the recruitment of eosinophils and ear swelling in chronic contact dermatitis induced by repeated challenge with oxazolone. These results strongly suggest that the CB2 receptor and 2-AG play important stimulative roles in the sensitization, elicitation, and exacerbation of allergic inflammation.

Cannabis, Cannabinoids, and Cerebral Metabolism: Potential Applications in Stroke and Disorders of the Central Nervous System.

PubMed

Latorre, Julius Gene S; Schmidt, Elena B

2015-09-01

No compound has generated more attention in both the scientific and recently in the political arena as much as cannabinoids. These diverse groups of compounds referred collectively as cannabinoids have both been vilified due to its dramatic and potentially harmful psychotropic effects and glorified due to its equally dramatic and potential application in a number of acute and chronic neurological conditions. Previously illegal to possess, cannabis, the plant where natural form of cannabinoids are derived, is now accepted in a growing number of states for medicinal purpose, and some even for recreational use, increasing opportunities for more scientific experimentation. The purpose of this review is to summarize the growing body of literature on cannabinoids and to present an overview of our current state of knowledge of the human endocannabinoid system in the hope of defining the future of cannabinoids and its potential applications in disorders of the central nervous system, focusing on stroke.
Cannabinoids therapeutic use: what is our current understanding following the introduction of THC, THC:CBD oromucosal spray and others?

PubMed

Maccarrone, Mauro; Maldonado, Rafael; Casas, Miguel; Henze, Thomas; Centonze, Diego

2017-04-01

The complexity of the endocannabinoid (eCB) system is becoming better understood and new drivers of eCB signaling are emerging. Modulation of the activities of the eCB system can be therapeutic in a number of diseases. Research into the eCB system has been paralleled by the development of agents that interact with cannabinoid receptors. In this regard it should be remembered that herbal cannabis contains a myriad of active ingredients, and the individual cannabinoids have quite distinct biological activities requiring independent studies. Areas covered: This article reviews the most important current data involving the eCB system in relation to human diseases, to reflect the present (based mainly on the most used prescription cannabinoid medicine, THC/CBD oromucosal spray) and potential future uses of cannabinoid-based therapy. Expert commentary: From the different therapeutic possibilities, THC/CBD oromucosal spray has been in clinical use for approximately five years in numerous countries world-wide for the management of multiple sclerosis (MS)-related moderate to severe resistant spasticity. Clinical trials have confirmed its efficacy and tolerability. Other diseases in which different cannabinoids are currently being investigated include various pain states, Alzheimer's disease, Parkinson's disease, Huntington's disease and epilepsy. The continued characterization of individual cannabinoids in different diseases remains important.
A Review of the Therapeutic Antitumor Potential of Cannabinoids.

PubMed

Bogdanović, Višnja; Mrdjanović, Jasminka; Borišev, Ivana

2017-11-01

The aim of this review is to discuss cannabinoids from a preclinical and clinical oncological perspective and provide the audience with a concise, retrospective overview of the most significant findings concerning the potential use of cannabinoids in cancer treatment. A literature survey of medical and scientific databases was conducted with a focus on the biological and medical potential of cannabinoids in cancer treatment. Cannabis sativa is a plant rich in more than 100 types of cannabinoids. Besides exogenous plant cannabinoids, mammalian endocannabinoids and synthetic cannabinoid analogues have been identified. Cannabinoid receptors type 1 (CB1) and type 2 (CB2) have been isolated and characterized from mammalian cells. Through cannabinoid receptor and non-receptor signaling pathways, cannabinoids show specific cytotoxicity against tumor cells, while protecting healthy tissue from apoptosis. The dual antiproliferative and proapoptotic effects of cannabinoids and associated signaling pathways have been investigated on a large panel of cancer cell lines. Cannabinoids also display potent anticancer activity against tumor xenografts, including tumors that express high resistance to standard chemotherapeutics. Few studies have investigated the possible synergistic effects of cannabinoids with standard oncology therapies, and are based on the preclinically confirmed concept of "cannabinoid sensitizers." Also, clinical trials aimed to confirm the antineoplastic activity of cannabinoids have only been evaluated on a small number of subjects, with no consensus conclusions regarding their effectiveness. A large number of cannabinoid compounds have been discovered, developed, and used to study the effects of cannabinoids on cancers in model systems. However, few clinical trials have been conducted on the use of cannabinoids in the treatment of cancers in humans. Further studies require extensive monitoring of the effects of cannabinoids alone or in combination with standard anticancer strategies. With such knowledge, cannabinoids could become a therapy of choice in contemporary oncology.
The Role of the Brain's Endocannabinoid System in Pain and Its Modulation by Stress.

PubMed

Corcoran, Louise; Roche, Michelle; Finn, David P

2015-01-01

Stress has a complex, bidirectional modulatory influence on pain. Stress may either reduce (stress-induced analgesia) or exacerbate (stress-induced hyperalgesia) pain depending on the nature, duration, and intensity of the stressor. The endogenous cannabinoid (endocannabinoid) system is present throughout the neuroanatomical pathways that mediate and modulate responses to painful stimuli. The specific role of the endocannabinoid system in the brain in pain and the modulation of pain by stress is reviewed herein. We first provide a brief overview of the endocannabinoid system, followed by a review of the evidence that the brain's endocannabinoid system modulates pain. We provide a comprehensive evaluation of the role of the endocannabinoid system supraspinally, and particularly in the rostral ventromedial medulla, periaqueductal gray, amygdala, and prefrontal cortex, in pain, stress-induced analgesia, and stress-induced hyperalgesia. Increased understanding of endocannabinoid-mediated regulation of pain and its modulation by stress will inform the development of novel therapeutic approaches for pain and its comorbidity with stress-related disorders. © 2015 Elsevier Inc. All rights reserved.
Mustard vesicants alter expression of the endocannabinoid system in mouse skin

DOE Office of Scientific and Technical Information (OSTI.GOV)

Wohlman, Irene M.; Composto, Gabriella M.

Vesicants including sulfur mustard (SM) and nitrogen mustard (NM) are bifunctional alkylating agents that cause skin inflammation, edema and blistering. This is associated with alterations in keratinocyte growth and differentiation. Endogenous cannabinoids, including N-arachidonoylethanolamine (anandamide, AEA) and 2-arachidonoyl glycerol (2-AG), are important in regulating inflammation, keratinocyte proliferation and wound healing. Their activity is mediated by binding to cannabinoid receptors 1 and 2 (CB1 and CB2), as well as peroxisome proliferator-activated receptor alpha (PPARα). Levels of endocannabinoids are regulated by fatty acid amide hydrolase (FAAH). We found that CB1, CB2, PPARα and FAAH were all constitutively expressed in mouse epidermis andmore » dermal appendages. Topical administration of NM or SM, at concentrations that induce tissue injury, resulted in upregulation of FAAH, CB1, CB2 and PPARα, a response that persisted throughout the wound healing process. Inhibitors of FAAH including a novel class of vanillyl alcohol carbamates were found to be highly effective in suppressing vesicant-induced inflammation in mouse skin. Taken together, these data indicate that the endocannabinoid system is important in regulating skin homeostasis and that inhibitors of FAAH may be useful as medical countermeasures against vesicants. - Highlights: • Sulfur mustard and nitrogen mustard are potent skin vesicants. • The endocannabinoid system regulates keratinocyte growth and differentiation. • Vesicants are potent inducers of the endocannabinoid system in mouse skin. • Endocannabinoid proteins upregulated are FAAH, CB1, CB2 and PPARα. • FAAH inhibitors suppress vesicant-induced inflammation in mouse skin.« less
Social defeat leads to changes in the endocannabinoid system: An overexpression of calreticulin and motor impairment in mice.

PubMed

Tomas-Roig, J; Piscitelli, F; Gil, V; Del Río, J A; Moore, T P; Agbemenyah, H; Salinas-Riester, G; Pommerenke, C; Lorenzen, S; Beißbarth, T; Hoyer-Fender, S; Di Marzo, V; Havemann-Reinecke, U

2016-04-15

Prolonged and sustained stimulation of the hypothalamo-pituitary-adrenal axis have adverse effects on numerous brain regions, including the cerebellum. Motor coordination and motor learning are essential for animal and require the regulation of cerebellar neurons. The G-protein-coupled cannabinoid CB1 receptor coordinates synaptic transmission throughout the CNS and is of highest abundance in the cerebellum. Accordingly, the aim of this study was to investigate the long-lasting effects of chronic psychosocial stress on motor coordination and motor learning, CB1 receptor expression, endogenous cannabinoid ligands and gene expression in the cerebellum. After chronic psychosocial stress, motor coordination and motor learning were impaired as indicated the righting reflex and the rota-rod. The amount of the endocannabinoid 2-AG increased while CB1 mRNA and protein expression were downregulated after chronic stress. Transcriptome analysis revealed 319 genes differentially expressed by chronic psychosocial stress in the cerebellum; mainly involved in synaptic transmission, transmission of nerve impulse, and cell-cell signaling. Calreticulin was validated as a stress candidate gene. The present study provides evidence that chronic stress activates calreticulin and might be one of the pathological mechanisms underlying the motor coordination and motor learning dysfunctions seen in social defeat mice. Copyright © 2016 Elsevier B.V. All rights reserved.
Cannabinoids and Vanilloids in Schizophrenia: Neurophysiological Evidence and Directions for Basic Research

PubMed Central

Ruggiero, Rafael N.; Rossignoli, Matheus T.; De Ross, Jana B.; Hallak, Jaime E. C.; Leite, Joao P.; Bueno-Junior, Lezio S.

2017-01-01

Much of our knowledge of the endocannabinoid system in schizophrenia comes from behavioral measures in rodents, like prepulse inhibition of the acoustic startle and open-field locomotion, which are commonly used along with neurochemical approaches or drug challenge designs. Such methods continue to map fundamental mechanisms of sensorimotor gating, hyperlocomotion, social interaction, and underlying monoaminergic, glutamatergic, and GABAergic disturbances. These strategies will require, however, a greater use of neurophysiological tools to better inform clinical research. In this sense, electrophysiology and viral vector-based circuit dissection, like optogenetics, can further elucidate how exogenous cannabinoids worsen (e.g., tetrahydrocannabinol, THC) or ameliorate (e.g., cannabidiol, CBD) schizophrenia symptoms, like hallucinations, delusions, and cognitive deficits. Also, recent studies point to a complex endocannabinoid-endovanilloid interplay, including the influence of anandamide (endogenous CB1 and TRPV1 agonist) on cognitive variables, such as aversive memory extinction. In fact, growing interest has been devoted to TRPV1 receptors as promising therapeutic targets. Here, these issues are reviewed with an emphasis on the neurophysiological evidence. First, we contextualize imaging and electrographic findings in humans. Then, we present a comprehensive review on rodent electrophysiology. Finally, we discuss how basic research will benefit from further combining psychopharmacological and neurophysiological tools. PMID:28680405
Δ9-Tetrahydrocannabinol and Endocannabinoid Degradative Enzyme Inhibitors Attenuate Intracranial Self-Stimulation in Mice

PubMed Central

Grim, Travis W.; Owens, Robert A.; Lazenka, Matthew F.; Sim-Selley, Laura J.; Abdullah, Rehab A.; Niphakis, Micah J.; Vann, Robert E.; Cravatt, Benjamin F.; Wiley, Jenny L.; Negus, S. Stevens; Lichtman, Aron H.

2015-01-01

A growing body of evidence implicates endogenous cannabinoids as modulators of the mesolimbic dopamine system and motivated behavior. Paradoxically, the reinforcing effects of Δ9-tetrahydrocannabinol (THC), the primary psychoactive constituent of cannabis, have been difficult to detect in preclinical rodent models. In this study, we investigated the impact of THC and inhibitors of the endocannabinoid hydrolytic enzymes fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL) on operant responding for electrical stimulation of the medial forebrain bundle [intracranial self-stimulation (ICSS)], which is known to activate the mesolimbic dopamine system. These drugs were also tested in assays of operant responding for food reinforcement and spontaneous locomotor activity. THC and the MAGL inhibitor JZL184 (4-[bis(1,3-benzodioxol-5-yl)hydroxymethyl]-1-piperidinecarboxylic acid 4-nitrophenyl ester) attenuated operant responding for ICSS and food, and also reduced spontaneous locomotor activity. In contrast, the FAAH inhibitor PF-3845 (N-3-pyridinyl-4-[[3-[[5-(trifluoromethyl)-2-pyridinyl]oxy]phenyl]methyl]-1-piperidinecarboxamide) was largely without effect in these assays. Consistent with previous studies showing that combined inhibition of FAAH and MAGL produces a substantially greater cannabimimetic profile than single enzyme inhibition, the dual FAAH-MAGL inhibitor SA-57 (4-[2-(4-chlorophenyl)ethyl]-1-piperidinecarboxylic acid 2-(methylamino)-2-oxoethyl ester) produced a similar magnitude of ICSS depression as that produced by THC. ICSS attenuation by JZL184 was associated with increased brain levels of 2-arachidonoylglycerol (2-AG), whereas peak effects of SA-57 were associated with increased levels of both N-arachidonoylethanolamine (anandamide) and 2-AG. The cannabinoid receptor type 1 receptor antagonist rimonabant, but not the cannabinoid receptor type 2 receptor antagonist SR144528, blocked the attenuating effects of THC, JZL184, and SA-57 on ICSS. Thus, THC, MAGL inhibition, and dual FAAH-MAGL inhibition not only reduce ICSS, but also decrease other reinforced and nonreinforced behaviors. PMID:25398241
Δ9-tetrahydrocannabinol and endocannabinoid degradative enzyme inhibitors attenuate intracranial self-stimulation in mice.

PubMed

Wiebelhaus, Jason M; Grim, Travis W; Owens, Robert A; Lazenka, Matthew F; Sim-Selley, Laura J; Abdullah, Rehab A; Niphakis, Micah J; Vann, Robert E; Cravatt, Benjamin F; Wiley, Jenny L; Negus, S Stevens; Lichtman, Aron H

2015-02-01

A growing body of evidence implicates endogenous cannabinoids as modulators of the mesolimbic dopamine system and motivated behavior. Paradoxically, the reinforcing effects of Δ(9)-tetrahydrocannabinol (THC), the primary psychoactive constituent of cannabis, have been difficult to detect in preclinical rodent models. In this study, we investigated the impact of THC and inhibitors of the endocannabinoid hydrolytic enzymes fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL) on operant responding for electrical stimulation of the medial forebrain bundle [intracranial self-stimulation (ICSS)], which is known to activate the mesolimbic dopamine system. These drugs were also tested in assays of operant responding for food reinforcement and spontaneous locomotor activity. THC and the MAGL inhibitor JZL184 (4-[bis(1,3-benzodioxol-5-yl)hydroxymethyl]-1-piperidinecarboxylic acid 4-nitrophenyl ester) attenuated operant responding for ICSS and food, and also reduced spontaneous locomotor activity. In contrast, the FAAH inhibitor PF-3845 (N-3-pyridinyl-4-[[3-[[5-(trifluoromethyl)-2-pyridinyl]oxy]phenyl]methyl]-1-piperidinecarboxamide) was largely without effect in these assays. Consistent with previous studies showing that combined inhibition of FAAH and MAGL produces a substantially greater cannabimimetic profile than single enzyme inhibition, the dual FAAH-MAGL inhibitor SA-57 (4-[2-(4-chlorophenyl)ethyl]-1-piperidinecarboxylic acid 2-(methylamino)-2-oxoethyl ester) produced a similar magnitude of ICSS depression as that produced by THC. ICSS attenuation by JZL184 was associated with increased brain levels of 2-arachidonoylglycerol (2-AG), whereas peak effects of SA-57 were associated with increased levels of both N-arachidonoylethanolamine (anandamide) and 2-AG. The cannabinoid receptor type 1 receptor antagonist rimonabant, but not the cannabinoid receptor type 2 receptor antagonist SR144528, blocked the attenuating effects of THC, JZL184, and SA-57 on ICSS. Thus, THC, MAGL inhibition, and dual FAAH-MAGL inhibition not only reduce ICSS, but also decrease other reinforced and nonreinforced behaviors. Copyright © 2014 by The American Society for Pharmacology and Experimental Therapeutics.
Cannabinoids and Dementia: A Review of Clinical and Preclinical Data

PubMed Central

Walther, Sebastian; Halpern, Michael

2010-01-01

The endocannabinoid system has been shown to be associated with neurodegenerative diseases and dementia. We review the preclinical and clinical data on cannabinoids and four neurodegenerative diseases: Alzheimer’s disease (AD), Huntington’s disease (HD), Parkinson’s disease (PD) and vascular dementia (VD). Numerous studies have demonstrated an involvement of the cannabinoid system in neurotransmission, neuropathology and neurobiology of dementias. In addition, several candidate compounds have demonstrated efficacy in vitro. However, some of the substances produced inconclusive results in vivo. Therefore, only few trials have aimed to replicate the effects seen in animal studies in patients. Indeed, the literature on cannabinoid administration in patients is scarce. While preclinical findings suggest causal treatment strategies involving cannabinoids, clinical trials have only assessed the suitability of cannabinoid receptor agonists, antagonists and cannabidiol for the symptomatic treatment of dementia. Further research is needed, including in vivo models of dementia and human studies. PMID:27713372
Cannabinoid-based medicines for neurological disorders--clinical evidence.

PubMed

Wright, Stephen

2007-08-01

Whereas the cannabis plant has a long history of medicinal use, it is only in recent years that a sufficient understanding of the pharmacology of the main plant constituents has allowed for a better understanding of the most rational therapeutic targets. The distribution of cannabinoid receptors, both within the nervous system and without, and the development of pharmacological tools to investigate their function has lead to a substantial increase in efforts to develop cannabinoids as therapeutic agents. Concomitant with these efforts, the understanding of the pharmacology of plant cannabinoids at receptor and other systems distinct from the cannabinoid receptors suggests that the therapeutic applications of plant-derived cannabinoids (and presumably their synthetic derivatives also) may be diverse. This review aims to discuss the clinical evidence investigating the use of medicines derived, directly or indirectly, from plant cannabinoids with special reference to neurological disorders. Published studies suggest that the oral administration of cannabinoids may not be the preferred route of administration and that plant extracts show greater evidence of efficacy than synthetic compounds. One of these, Sativex (GW Pharmaceuticals), was approved as a prescription medicine in Canada in 2005 and is currently under regulatory review in the EU.
Designing microorganisms for heterologous biosynthesis of cannabinoids

PubMed Central

Carvalho, Ângela; Hansen, Esben Halkjær; Kayser, Oliver; Stehle, Felix

2017-01-01

Abstract During the last decade, the use of medical Cannabis has expanded globally and legislation is getting more liberal in many countries, facilitating the research on cannabinoids. The unique interaction of cannabinoids with the human endocannabinoid system makes these compounds an interesting target to be studied as therapeutic agents for the treatment of several medical conditions. However, currently there are important limitations in the study, production and use of cannabinoids as pharmaceutical drugs. Besides the main constituent tetrahydrocannabinolic acid, the structurally related compound cannabidiol is of high interest as drug candidate. From the more than 100 known cannabinoids reported, most can only be extracted in very low amounts and their pharmacological profile has not been determined. Today, cannabinoids are isolated from the strictly regulated Cannabis plant, and the supply of compounds with sufficient quality is a major problem. Biotechnological production could be an attractive alternative mode of production. Herein, we explore the potential use of synthetic biology as an alternative strategy for synthesis of cannabinoids in heterologous hosts. We summarize the current knowledge surrounding cannabinoids biosynthesis and present a comprehensive description of the key steps of the genuine and artificial pathway, systems biotechnology needs and platform optimization. PMID:28582498
Designing microorganisms for heterologous biosynthesis of cannabinoids.

PubMed

Carvalho, Ângela; Hansen, Esben Halkjær; Kayser, Oliver; Carlsen, Simon; Stehle, Felix

2017-06-01

During the last decade, the use of medical Cannabis has expanded globally and legislation is getting more liberal in many countries, facilitating the research on cannabinoids. The unique interaction of cannabinoids with the human endocannabinoid system makes these compounds an interesting target to be studied as therapeutic agents for the treatment of several medical conditions. However, currently there are important limitations in the study, production and use of cannabinoids as pharmaceutical drugs. Besides the main constituent tetrahydrocannabinolic acid, the structurally related compound cannabidiol is of high interest as drug candidate. From the more than 100 known cannabinoids reported, most can only be extracted in very low amounts and their pharmacological profile has not been determined. Today, cannabinoids are isolated from the strictly regulated Cannabis plant, and the supply of compounds with sufficient quality is a major problem. Biotechnological production could be an attractive alternative mode of production. Herein, we explore the potential use of synthetic biology as an alternative strategy for synthesis of cannabinoids in heterologous hosts. We summarize the current knowledge surrounding cannabinoids biosynthesis and present a comprehensive description of the key steps of the genuine and artificial pathway, systems biotechnology needs and platform optimization. © FEMS 2017.
Antitumorigenic targets of cannabinoids - current status and implications.

PubMed

Ramer, Robert; Hinz, Burkhard

2016-10-01

Molecular structures of the endocannabinoid system have gained interest as potential pharmacotherapeutical targets for systemic cancer treatment. The present review covers the contribution of the endocannabinoid system to cancer progression. Particular focus will be set on the accumulating preclinical data concerning antimetastatic, anti-invasive and anti-angiogenic mechanisms induced by cannabinoids. The main goal of targeting endocannabinoid structures for systemic anticancer treatment is the comparatively good safety profile of cannabinoid compounds. In addition, antitumorigenic mechanisms of cannabinoids are not restricted to a single molecular cascade but involve multiple effects on various levels of cancer progression such as angiogenesis and metastasis. Particularly the latter effect has gained interest for pharmacological interventions. Thus, drugs aiming at the endocannabinoid system may represent potential 'antimetastatics' for an upgrade of a future armamentarium against cancer diseases.
Peripheral cannabinoid-1 receptor blockade restores hypothalamic leptin signaling.

PubMed

Tam, Joseph; Szanda, Gergő; Drori, Adi; Liu, Ziyi; Cinar, Resat; Kashiwaya, Yoshihiro; Reitman, Marc L; Kunos, George

2017-10-01

In visceral obesity, an overactive endocannabinoid/CB 1 receptor (CB 1 R) system promotes increased caloric intake and decreases energy expenditure, which are mitigated by global or peripheral CB 1 R blockade. In mice with diet-induced obesity (DIO), inhibition of food intake by the peripherally restricted CB 1 R antagonist JD5037 could be attributed to endogenous leptin due to the rapid reversal of hyperleptinemia that maintains leptin resistance, but the signaling pathway engaged by leptin has remained to be determined. We analyzed the hypothalamic circuitry targeted by leptin following chronic treatment of DIO mice with JD5037. Leptin treatment or an increase in endogenous leptin following fasting/refeeding induced STAT3 phosphorylation in neurons in the arcuate nucleus (ARC) in lean and JD5037-treated DIO mice, but not in vehicle-treated DIO animals. Co-localization of pSTAT3 in leptin-treated mice was significantly less common with NPY + than with POMC + ARC neurons. The hypophagic effect of JD5037 was absent in melanocortin-4 receptor (MC4R) deficient obese mice or DIO mice treated with a MC4R antagonist, but was maintained in NPY -/- mice kept on a high-fat diet. Peripheral CB 1 R blockade in DIO restores sensitivity to endogenous leptin, which elicits hypophagia via the re-activation of melanocortin signaling in the ARC. Copyright © 2017 The Authors. Published by Elsevier GmbH.. All rights reserved.
Endocannabinoid signaling in neurotoxicity and neuroprotection.

PubMed

Pope, C; Mechoulam, R; Parsons, L

2010-09-01

The cannabis plant and products produced from it, such as marijuana and hashish, have been used for centuries for their psychoactive properties. The mechanism for how Delta(9)-tetrahydrocannabinol (THC), the active constituent of cannabis, elicits these neurological effects remained elusive until relatively recently, when specific G-protein coupled receptors were discovered that appeared to mediate cellular actions of THC. Shortly after discovery of these specific receptors, endogenous ligands (endocannabinoids) were identified. Since that time, an extensive number of papers have been published on the endocannabinoid signaling system, a widespread neuromodulatory mechanism that influences neurotransmission throughout the nervous system. This paper summarizes presentations given at the 12th International Neurotoxicology Association meeting that described the potential role of endocannabinoids in the expression of neurotoxicity. Dr. Raphael Mechoulam first gave an overview of the discovery of exogenous and endogenous cannabinoids and their potential for neuroprotection in a variety of conditions. Dr. Larry Parsons then described studies suggesting that endocannabinoid signaling may play a selective role in drug reinforcement. Dr. Carey Pope presented information on the role that endocannabinoid signaling may have in the expression of cholinergic toxicity following anticholinesterase exposures. Together, these presentations highlighted the diverse types of neurological insults that may be modulated by endocannabinoids and drugs/toxicants which might influence endocannabinoid signaling pathways. Copyright © 2009 Elsevier Inc. All rights reserved.
ENDOCANNABINOID SIGNALING IN NEUROTOXICITY AND NEUROPROTECTION

PubMed Central

Pope, C.; Mechoulam, R.; Parsons, L.

2010-01-01

The cannabis plant and products produced from it, such as marijuana and hashish, have been used for centuries for their psychoactive properties. The mechanism for how Δ9 -tetrahydrocannabinol (THC), the active constituent of cannabis, elicits these neurological effects remained elusive until relatively recently, when specific G-protein coupled receptors were discovered that appeared to mediate cellular actions of THC. Shortly after discovery of these specific receptors, endogenous ligands (endocannabinoids) were identified. Since that time, an extensive number of papers have been published on the endocannabinoid signaling system, a widespread neuromodulatory mechanism that influences neurotransmission throughout the nervous system. This paper summarizes presentations given at the 12th International Neurotoxicology Association meeting that described the potential role of endocannabinoids in the expression of neurotoxicity. Dr. Raphael Mechoulam first gave an overview of the discovery of exogenous and endogenous cannabinoids and their potential for neuroprotection in a variety of conditions. Dr. Larry Parsons then described studies suggesting that endocannabinoid signaling may play a selective role in drug reinforcement. Dr. Carey Pope presented information on the role that endocannabinoid signaling may have in the expression of cholinergic toxicity following anticholinesterase exposures. Together, these presentations highlighted the diverse types of neurological insults that may be modulated by endocannabinoids and drugs/toxicants which might influence endocannabinoid signaling pathways. PMID:19969019
The Endocannabinoid System as a Target for Treatment of Breast Cancer

DTIC Science & Technology

2011-08-01

cannabinoids with radiation in MCF-7, MDA-MB-231, and 4T1 breast tumor cell lines. Interestingly, the high efficacy synthetic cannabinoid agonist...tumorgenesis in FAAH (-/-) mice vs. wild type mice; and 2) the synthetic cannabinoid receptor agonist WIN55,212-2 in combination with radiation or adriamycin...THC (the primary active psychoactive constituent present in marijuana ), cannabidiol (CBD: a marijuana -derived cannabinoid that lacks psychomimetic
Reinforcing and neurochemical effects of cannabinoid CB1 receptor agonists, but not cocaine, are altered by an adenosine A2A receptor antagonist.

PubMed

Justinová, Zuzana; Ferré, Sergi; Redhi, Godfrey H; Mascia, Paola; Stroik, Jessica; Quarta, Davide; Yasar, Sevil; Müller, Christa E; Franco, Rafael; Goldberg, Steven R

2011-07-01

Several recent studies suggest functional and molecular interactions between striatal adenosine A(2A) and cannabinoid CB(1) receptors. Here, we demonstrate that A(2A) receptors selectively modulate reinforcing effects of cannabinoids. We studied effects of A(2A) receptor blockade on the reinforcing effects of delta-9-tetrahydrocannabinol (THC) and the endogenous CB(1) receptor ligand anandamide under a fixed-ratio schedule of intravenous drug injection in squirrel monkeys. A low dose of the selective adenosine A(2A) receptor antagonist MSX-3 (1 mg/kg) caused downward shifts of THC and anandamide dose-response curves. In contrast, a higher dose of MSX-3 (3 mg/kg) shifted THC and anandamide dose-response curves to the left. MSX-3 did not modify cocaine or food pellet self-administration. Also, MSX-3 neither promoted reinstatement of extinguished drug-seeking behavior nor altered reinstatement of drug-seeking behavior by non-contingent priming injections of THC. Finally, using in vivo microdialysis in freely-moving rats, a behaviorally active dose of MSX-3 significantly counteracted THC-induced, but not cocaine-induced, increases in extracellular dopamine levels in the nucleus accumbens shell. The significant and selective results obtained with the lower dose of MSX-3 suggest that adenosine A(2A) antagonists acting preferentially at presynaptic A(2A) receptors might selectively reduce reinforcing effects of cannabinoids that lead to their abuse. However, the appearance of potentiating rather than suppressing effects on cannabinoid reinforcement at the higher dose of MSX-3 would likely preclude the use of such a compound as a medication for cannabis abuse. Adenosine A(2A) antagonists with more selectivity for presynaptic versus postsynaptic receptors could be potential medications for treatment of cannabis abuse. Addiction Biology © 2010 Society for the Study of Addiction. No claim to original US government works.
Anxiety, Stress, and Fear Response in Mice With Reduced Endocannabinoid Levels.

PubMed

Jenniches, Imke; Ternes, Svenja; Albayram, Onder; Otte, David M; Bach, Karsten; Bindila, Laura; Michel, Kerstin; Lutz, Beat; Bilkei-Gorzo, Andras; Zimmer, Andreas

2016-05-15

Disruption of the endocannabinoid system through pharmacological or genetic invalidation of cannabinoid CB1 receptors has been linked to depression in humans and depression-like behaviors in mice. The two main endogenous cannabinoids, anandamide and 2-arachidonoyl glycerol (2-AG), are produced on demand from phospholipids. The pathways and enzymes involved in endocannabinoid biosynthesis thus play a major role in regulating the activity of this system. This study investigates the role of the main 2-AG producing enzyme diacylglycerol lipase α (DAGL-α). We generated and used knockout mice lacking DAGL-α (Dagla(-/-)) to assess the behavioral consequences of reduced endocannabinoid levels in the brain. We performed different behavior tests to determine anxiety- and depression-related behavioral changes in Dagla(-/-) mice. We also analyzed expression of genes related to the endocannabinoid system via real-time polymerase chain reaction and used the mitotic marker 5-bromo-2'-deoxyuridine to analyze adult neurogenesis. Dagla(-/-) animals show an 80% reduction of brain 2-AG levels but also a reduction in cortical and amygdalar anandamide. The behavioral changes induced by Dagla deletion include a reduced exploration of the central area of the open field, a maternal neglect behavior, a fear extinction deficit, increased behavioral despair, increased anxiety-related behaviors in the light/dark box, and reduced hippocampal neurogenesis. Some of these behavioral changes resemble those observed in animals lacking the CB1 receptor. Our findings demonstrate that the deletion of Dagla adversely affects the emotional state of animals and results in enhanced anxiety, stress, and fear responses. Copyright © 2016 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.

Cannabinoids in the Cardiovascular System.

PubMed

Ho, Wing S V; Kelly, Melanie E M

2017-01-01

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 CB 1 and CB 2 receptors or non-CB 1/2 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. © 2017 Elsevier Inc. All rights reserved.
Signal Peptide and Denaturing Temperature are Critical Factors for Efficient Mammalian Expression and Immunoblotting of Cannabinoid Receptors*

PubMed Central

WANG, Chenyun; WANG, Yingying; WANG, Miao; CHEN, Jiankui; YU, Nong; SONG, Shiping; KAMINSKI, Norbert E.; ZHANG, Wei

2013-01-01

Summary Many researchers employed mammalian expression system to artificially express cannabinoid receptors, but immunoblot data that directly prove efficient protein expression can hardly be seen in related research reports. In present study, we demonstrated cannabinoid receptor protein was not able to be properly expressed with routine mammalian expression system. This inefficient expression was rescued by endowing an exogenous signal peptide ahead of cannabinoid receptor peptide. In addition, the artificially synthesized cannabinoid receptor was found to aggregate under routine sample denaturing temperatures (i.e., ≥95°C), forming a large molecular weight band when analyzed by immunoblotting. Only denaturing temperatures ≤75°C yielded a clear band at the predicted molecular weight. Collectively, we showed that efficient mammalian expression of cannabinoid receptors need a signal peptide sequence, and described the requirement for a low sample denaturing temperature in immunoblot analysis. These findings provide very useful information for efficient mammalian expression and immunoblotting of membrane receptors. PMID:22528237
Peripherally Restricted Cannabinoids for the Treatment of Pain.

PubMed

Romero-Sandoval, E Alfonso; Asbill, Scott; Paige, Candler A; Byrd-Glover, Kiara

2015-10-01

The use of cannabinoids for the treatment of chronic diseases has increased in the United States, with 23 states having legalized the use of marijuana. Although currently available cannabinoid compounds have shown effectiveness in relieving symptoms associated with numerous diseases, the use of cannabis or cannabinoids is still controversial mostly due to their psychotropic effects (e.g., euphoria, laughter) or central nervous system (CNS)-related undesired effects (e.g., tolerance, dependence). A potential strategy to use cannabinoids for medical conditions without inducing psychotropic or CNS-related undesired effects is to avoid their actions in the CNS. This approach could be beneficial for conditions with prominent peripheral pathophysiologic mechanisms (e.g., painful diabetic neuropathy, chemotherapy-induced neuropathy). In this article, we discuss the scientific evidence to target the peripheral cannabinoid system as an alternative to cannabis use for medical purposes, and we review the available literature to determine the pros and cons of potential strategies that can be used to this end. © 2015 Pharmacotherapy Publications, Inc.
Current Perspectives on Biotechnological Cannabinoid Production in Plants.

PubMed

Schachtsiek, Julia; Warzecha, Heribert; Kayser, Oliver; Stehle, Felix

2018-03-01

The plant Cannabis sativa contains a number of psychoactive chemical compounds, the cannabinoids, which possess a significant pharmaceutical potential. Recently, the usage of Cannabis for medicinal purposes was legalized in many countries. Thus, the study on the influence of different cannabinoids in combination with other Cannabis -derived compounds with respect to the treatment of various diseases becomes increasingly important. Besides the production of distinct cannabinoids in a heterologous host, like tobacco or yeast, transgenic Cannabis plants would be a suitable alternative to modify and therefore optimize the cannabinoid profile. This perspective highlights the current efforts on Cannabis cell culture systems, in vitro propagation, and transformation of the plant and reveals the resulting opportunities concerning biotechnological production of cannabinoids. Furthermore, alternative platform organisms for the heterologous production of cannabinoids, like tobacco, are considered and evaluated. Georg Thieme Verlag KG Stuttgart · New York.
Focus on cannabinoids and synthetic cannabinoids.

PubMed

Le Boisselier, R; Alexandre, J; Lelong-Boulouard, V; Debruyne, D

2017-02-01

The recent emergence of a multitude of synthetic cannabinoids (SCs) has generated a wealth of new information, suggesting the usefulness of state-of-the-art on lato sensu cannabinoids. By modulating a plurality of neurotransmission pathways, the endocannabinoid system is involved in many physiological processes that are increasingly explored. SCs desired and adverse effects are considered to be more intense than those observed with cannabis smoking, which is partly explained by the full agonist activity and higher affinity for cannabinoid receptors. Neurological and cardiovascular side effects observed after cannabinoid poisoning generally respond to conventional supportive care, but severe outcomes may occur in a minority of cases, mainly observed with SCs. The likelihood of severe abuse and addiction produced by SCs are of concern for the scientific community also interested in the potential therapeutic value of cannabinoids. © 2016 American Society for Clinical Pharmacology and Therapeutics.
Cannabinoid-Induced Changes in the Activity of Electron Transport Chain Complexes of Brain Mitochondria.

PubMed

Singh, Namrata; Hroudová, Jana; Fišar, Zdeněk

2015-08-01

The aim of this study was to investigate changes in the activity of individual mitochondrial respiratory chain complexes (I, II/III, IV) and citrate synthase induced by pharmacologically different cannabinoids. In vitro effects of selected cannabinoids on mitochondrial enzymes were measured in crude mitochondrial fraction isolated from pig brain. Both cannabinoid receptor agonists, Δ(9)-tetrahydrocannabinol, anandamide, and R-(+)-WIN55,212-2, and antagonist/inverse agonists of cannabinoid receptors, AM251, and cannabidiol were examined in pig brain mitochondria. Different effects of these cannabinoids on mitochondrial respiratory chain complexes and citrate synthase were found. Citrate synthase activity was decreased only by Δ(9)-tetrahydrocannabinol and AM251. Significant increase in the complex I activity was induced by anandamide. At micromolar concentration, all the tested cannabinoids inhibited the activity of electron transport chain complexes II/III and IV. Stimulatory effect of anandamide on activity of complex I may participate on distinct physiological effects of endocannabinoids compared to phytocannabinoids or synthetic cannabinoids. Common inhibitory effect of cannabinoids on activity of complex II/III and IV confirmed a non-receptor-mediated mechanism of cannabinoid action on individual components of system of oxidative phosphorylation.
Systemic administration of WIN 55,212-2 increases norepinephrine release in the rat frontal cortex.

PubMed

Oropeza, V C; Page, M E; Van Bockstaele, E J

2005-06-07

Cannabinoid agonists modulate a variety of behavioral functions by activating cannabinoid receptors that are widely distributed throughout the central nervous system. In the present study, norepinephrine efflux was assessed in the frontal cortex of rats that received a systemic administration of the cannabinoid agonist, WIN 55,212-2. The synthetic cannabinoid agonist dose-dependently increased the release of norepinephrine in this brain region. Pretreatment with the cannabinoid receptor antagonist, SR 141716A, blocked the increase in norepinephrine release. To identify sites of cellular activation, immunocytochemical detection of c-Fos was combined with detection of the catecholamine synthesizing enzyme, tyrosine hydroxylase (TH), in the brainstem nucleus locus coeruleus (LC), a region that is the sole source of norepinephrine to the frontal cortex. Systemic administration of WIN 55,212-2 significantly increased the number of c-Fos immunoreactive cells within TH-containing neurons in the LC compared to vehicle-treated rats. Pretreatment with SR 141716A inhibited the WIN 55,212-2 induced c-Fos expression, while the antagonist alone did not affect c-Fos expression. Taken together, these data indicate that systemically administered cannabinoid agonists stimulate norepinephrine release in the frontal cortex by activating noradrenergic neurons in the coeruleo-frontal cortex pathway. These effects may partially underlie changes in attention, arousal and anxiety observed following exposure to cannabis-based drugs.
Emerging Role of (Endo)Cannabinoids in Migraine.

PubMed

Leimuranta, Pinja; Khiroug, Leonard; Giniatullin, Rashid

2018-01-01

In this mini-review, we summarize recent discoveries and present new hypotheses on the role of cannabinoids in controlling trigeminal nociceptive system underlying migraine pain. Individual sections of this review cover key aspects of this topic, such as: (i) the current knowledge on the endocannabinoid system (ECS) with emphasis on expression of its components in migraine related structures; (ii) distinguishing peripheral from central site of action of cannabinoids, (iii) proposed mechanisms of migraine pain and control of nociceptive traffic by cannabinoids at the level of meninges and in brainstem, (iv) therapeutic targeting in migraine of monoacylglycerol lipase and fatty acid amide hydrolase, enzymes which control the level of endocannabinoids; (v) dual (possibly opposing) actions of cannabinoids via anti-nociceptive CB1 and CB2 and pro-nociceptive TRPV1 receptors. We explore the cannabinoid-mediated mechanisms in the frame of the Clinical Endocannabinoid Deficiency (CECD) hypothesis, which implies reduced tone of endocannabinoids in migraine patients. We further discuss the control of cortical excitability by cannabinoids via inhibition of cortical spreading depression (CSD) underlying the migraine aura. Finally, we present our view on perspectives of Cannabis-derived (extracted or synthetized marijuana components) or novel endocannabinoid therapeutics in migraine treatment.
Cannabinoid-induced effects on the nociceptive system: a neurophysiological study in patients with secondary progressive multiple sclerosis.

PubMed

Conte, Antonella; Bettolo, Chiara Marini; Onesti, Emanuela; Frasca, Vittorio; Iacovelli, Elisa; Gilio, Francesca; Giacomelli, Elena; Gabriele, Maria; Aragona, Massimiliano; Tomassini, Valentina; Pantano, Patrizia; Pozzilli, Carlo; Inghilleri, Maurizio

2009-05-01

Although clinical studies show that cannabinoids improve central pain in patients with multiple sclerosis (MS) neurophysiological studies are lacking to investigate whether they also suppress these patients' electrophysiological responses to noxious stimulation. The flexion reflex (FR) in humans is a widely used technique for assessing the pain threshold and for studying spinal and supraspinal pain pathways and the neurotransmitter system involved in pain control. In a randomized, double-blind, placebo-controlled, cross-over study we investigated cannabinoid-induced changes in RIII reflex variables (threshold, latency and area) in a group of 18 patients with secondary progressive MS. To investigate whether cannabinoids act indirectly on the nociceptive reflex by modulating lower motoneuron excitability we also evaluated the H-reflex size after tibial nerve stimulation and calculated the H wave/M wave (H/M) ratio. Of the 18 patients recruited and randomized 17 completed the study. After patients used a commercial delta-9-tetrahydrocannabinol (THC) and cannabidiol mixture as an oromucosal spray the RIII reflex threshold increased and RIII reflex area decreased. The visual analogue scale score for pain also decreased, though not significantly. Conversely, the H/M ratio measured before patients received cannabinoids remained unchanged after therapy. In conclusion, the cannabinoid-induced changes in the RIII reflex threshold and area in patients with MS provide objective neurophysiological evidence that cannabinoids modulate the nociceptive system in patients with MS.
Molecular characterization of an enzyme that degrades neuromodulatory fatty-acid amides.

PubMed

Cravatt, B F; Giang, D K; Mayfield, S P; Boger, D L; Lerner, R A; Gilula, N B

1996-11-07

Endogenous neuromodulatory molecules are commonly coupled to specific metabolic enzymes to ensure rapid signal inactivation. Thus, acetylcholine is hydrolysed by acetylcholine esterase and tryptamine neurotransmitters like serotonin are degraded by monoamine oxidases. Previously, we reported the structure and sleep-inducing properties of cis-9-octadecenamide, a lipid isolated from the cerebrospinal fluid of sleep-deprived cats. cis-9-Octadecenamide, or oleamide, has since been shown to affect serotonergic systems and block gap-junction communication in glial cells (our unpublished results). We also identified a membrane-bound enzyme activity that hydrolyses oleamide to its inactive acid, oleic acid. We now report the mechanism-based isolation, cloning and expression of this enzyme activity, originally named oleamide hydrolase, from rat liver plasma membranes. We also show that oleamide hydrolase converts anandamide, a fatty-acid amide identified as the endogenous ligand for the cannabinoid receptor, to arachidonic acid, indicating that oleamide hydrolase may serve as the general inactivating enzyme for a growing family of bioactive signalling molecules, the fatty-acid amides. Therefore we will hereafter refer to oleamide hydrolase as fatty-acid amide hydrolase, in recognition of the plurality of fatty-acid amides that the enzyme can accept as substrates.
The Cannabinoid System and Pain

PubMed Central

Woodhams, Stephen G.; Chapman, Victoria; Finn, David P.; Hohmann, Andrea G.; Neugebauer, Volker

2018-01-01

Chronic pain states are highly prevalent and yet poorly controlled by currently available analgesics, representing an enormous clinical, societal, and economic burden. Existing pain medications have significant limitations and adverse effects including tolerance, dependence, gastrointestinal dysfunction, cognitive impairment, and a narrow therapeutic window, making the search for novel analgesics ever more important. In this article, we review the role of an important endogenous pain control system, the endocannabinoid (EC) system, in the sensory, emotional, and cognitive aspects of pain. Herein, we briefly cover the discovery of the EC system and its role in pain processing pathways, before concentrating on three areas of current major interest in EC pain research; 1. Pharmacological enhancement of endocannabinoid activity (via blockade of EC metabolism or allosteric modulation of CB1 receptors); 2. The EC System and stress-induced modulation of pain; and 3. The EC system & medial prefrontal cortex (mPFC) dysfunction in pain states. Whilst we focus predominantly on the preclinical data, we also include extensive discussion of recent clinical failures of endocannabinoid-related therapies, the future potential of these approaches, and important directions for future research on the EC system and pain. PMID:28625720
Psychotropic and nonpsychotropic cannabis derivatives inhibit human 5-HT(3A) receptors through a receptor desensitization-dependent mechanism.

PubMed

Xiong, W; Koo, B-N; Morton, R; Zhang, L

2011-06-16

Δ⁹ tetrahydrocannabinol (THC) and cannabidiol (CBD) are the principal psychoactive and nonpsychoactive components of cannabis. While most THC-induced behavioral effects are thought to depend on endogenous cannabinoid 1 (CB1) receptors, the molecular targets for CBD remain unclear. Here, we report that CBD and THC inhibited the function of human 5-HT(3A) receptors (h5-HT(3A)Rs) expressed in HEK 293 cells. The magnitude of THC and CBD inhibition was maximal 5 min after a continuous incubation with cannabinoids. The EC₅₀ values for CBD and THC-induced inhibition were 110 nM and 322 nM, respectively in HEK 293 cells expressing h5-HT(3A)Rs. In these cells, CBD and THC did not stimulate specific [³⁵S]-GTP-γs binding in membranes, suggesting that the inhibition by cannabinoids is unlikely mediated by a G-protein dependent mechanism. On the other hand, both CBD and THC accelerated receptor desensitization kinetics without significantly changing activation time. The extent of cannabinoid inhibition appeared to depend on receptor desensitization. Reducing receptor desensitization by nocodazole, 5-hydroxyindole and a point-mutation in the large cytoplasmic domain of the receptor significantly decreased CBD-induced inhibition. Similarly, the magnitude of THC and CBD-induced inhibition varied with the apparent desensitization rate of h5-HT(3A)Rs expressed in Xenopus oocytes. For instance, with increasing amount of h5-HT(3A)R cRNA injected into the oocytes, the receptor desensitization rate at steady state decreased. THC and CBD-induced inhibition was correlated with the change in the receptor desensitization rate. Thus, CBD and THC inhibit h5-HT(3A) receptors through a mechanism that is dependent on receptor desensitization. Published by Elsevier Ltd.
Psychotropic and Nonpsychotropic Cannabis Derivatives Inhibit Human 5-HT3A receptors through a Receptor Desensitization-Dependent Mechanism

PubMed Central

Xiong, Wei; Koo, Bon-Nyeo; Morton, Russell; Zhang, Li

2011-01-01

Δ9 tetrahydrocannabinol (THC) and cannabidiol (CBD) are the principal psychoactive and non-psychoactive components of cannabis. While most THC-induced behavioral effects are thought to depend on endogenous cannabinoid 1 (CB1) receptors, the molecular targets for CBD remain unclear. Here, we report that CBD and THC inhibited the function of human 5-HT3A receptors (h5-HT3ARs) expressed in HEK 293 cells. The magnitude of THC and CBD inhibition was maximal 5 min after a continuous incubation with cannabinoids. The EC50 values for CBD and THC-induced inhibition were 110 nM and 322 nM respectively in HEK 293 cells expressing h5-HT3ARs. In these cells, CBD and THC did not stimulate specific [35S]-GTP-γs binding in membranes, suggesting that the inhibition by cannabinoids is unlikely mediated by a G-protein dependent mechanism. On the other hand, both CBD and THC accelerated receptor desensitization kinetics without significantly changing activation time. The extent of cannabinoid inhibition appeared to depend on receptor desensitization. Reducing receptor desensitization by nocodazole, 5-hydroxyindole and a point-mutation in the large cytoplasmic domain of the receptor significantly decreased CBD-induced inhibition. Similarly, the magnitude of THC and CBD-induced inhibition varied with the apparent desensitization rate of h5-HT3ARs expressed in Xenopus oocytes. For instance, with increasing amount of h5-HT3AR cRNA injected into the oocytes, the receptor desensitization rate at steady state decreased. THC and CBD-induced inhibition was correlated with the change in the receptor desensitization rate. Thus, CBD and THC inhibit h5-HT3A receptors through a mechanism that is dependent on receptor desensitization. PMID:21477640
The palmitoylethanolamide family: a new class of anti-inflammatory agents?

PubMed

Lambert, Didier M; Vandevoorde, Severine; Jonsson, Kent-Olov; Fowler, Christopher J

2002-03-01

The discovery of anandamide as an endogenous ligand for the cannabinoid receptors has led to a resurgence of interest in the fatty acid amides. However, N-palmitoylethanolamine (PEA), a shorter and fully saturated analogue of anandamide, has been known since the fifties. This endogenous compound is a member of the N-acylethanolamines, found in most mammalian tissues. PEA is accumulated during inflammation and has been demonstrated to have a number of anti-inflammatory effects, including beneficial effects in clinically relevant animal models of inflammatory pain. It is now engaged in phase II clinical development, and two studies regarding the treatment of chronic lumbosciatalgia and multiple sclerosis are in progress. However, its precise mechanism of action remains debated. In the present review, the biochemical and pharmacological properties of PEA are discussed, in particular with respect to its analgesic and anti-inflammatory properties.
Modulation of NMDA and AMPA-Mediated Synaptic Transmission by CB1 Receptors in Frontal Cortical Pyramidal Cells

PubMed Central

Li, Qiang; Yan, Haidun; Wilson, Wilkie A.; Swartzwelder, H. Scott

2010-01-01

Although the endogenous cannabinoid system modulates a variety of physiological and pharmacological processes, the specific role of cannabinoid CB1 receptors in the modulation of glutamatergic neurotransmission and neural plasticity is not well understood. Using whole-cell patch clamp recording techniques, evoked or spontaneous excitatory postsynaptic currents (eEPSCs or sEPSCs) were recorded from visualized, layer II/III pyramidal cells in frontal cortical slices from rat brain. Bath application of the CB1 receptor agonist, WIN 55212-2 (WIN), reduced the amplitude of NMDA receptor-mediated EPSCs in a concentration-dependent manner. When co-applied with the specific CB1 antagonists, AM251 or AM281, WIN did not suppress NMDA receptor mediated EPSCs. WIN also reduced the amplitude of evoked AMPA receptor-mediated EPSCs, an effect that was also reversed by AM251. Both the frequency and amplitude of spontaneous AMPA receptor-mediated EPSCs were significantly reduced by WIN. In contrast, WIN reduced the frequency, but not the amplitude of miniature EPSCs, suggesting that the suppression of glutmatergic activity by CB1 receptors in the frontal neocortex is mediated by a pre-synaptic mechanism. Taken together, these data indicate a critical role for endocannabinoid signaling in the regulation of excitatory synaptic transmission in frontal neocortex, and suggest a possible neuronal mechanism whereby THC regulates cortical function. PMID:20420813
Cannabinoid Receptor 2 Participates in Amyloid-β Processing in a Mouse Model of Alzheimer's Disease but Plays a Minor Role in the Therapeutic Properties of a Cannabis-Based Medicine.

PubMed

Aso, Ester; Andrés-Benito, Pol; Carmona, Margarita; Maldonado, Rafael; Ferrer, Isidre

2016-01-01

The endogenous cannabinoid system represents a promising therapeutic target to modify neurodegenerative pathways linked to Alzheimer's disease (AD). The aim of the present study was to evaluate the specific contribution of CB2 receptor to the progression of AD-like pathology and its role in the positive effect of a cannabis-based medicine (1:1 combination of Δ9-tetrahidrocannabinol and cannabidiol) previously demonstrated to be beneficial in the AβPP/PS1 transgenic model of the disease. A new mouse strain was generated by crossing AβPP/PS1 transgenic mice with CB2 knockout mice. Results show that lack of CB2 exacerbates cortical Aβ deposition and increases the levels of soluble Aβ40. However, CB2 receptor deficiency does not affect the viability of AβPP/PS1 mice, does not accelerate their memory impairment, does not modify tau hyperphosphorylation in dystrophic neurites associated to Aβ plaques, and does not attenuate the positive cognitive effect induced by the cannabis-based medicine in these animals. These findings suggest a minor role for the CB2 receptor in the therapeutic effect of the cannabis-based medicine in AβPP/PS1 mice, but also constitute evidence of a link between CB2 receptor and Aβ processing.
Cannabinoids suppress inflammatory and neuropathic pain by targeting α3 glycine receptors

PubMed Central

Xiong, Wei; Cui, Tanxing; Cheng, Kejun; Yang, Fei; Chen, Shao-Rui; Willenbring, Dan; Guan, Yun; Pan, Hui-Lin; Ren, Ke; Xu, Yan

2012-01-01

Certain types of nonpsychoactive cannabinoids can potentiate glycine receptors (GlyRs), an important target for nociceptive regulation at the spinal level. However, little is known about the potential and mechanism of glycinergic cannabinoids for chronic pain treatment. We report that systemic and intrathecal administration of cannabidiol (CBD), a major nonpsychoactive component of marijuana, and its modified derivatives significantly suppress chronic inflammatory and neuropathic pain without causing apparent analgesic tolerance in rodents. The cannabinoids significantly potentiate glycine currents in dorsal horn neurons in rat spinal cord slices. The analgesic potency of 11 structurally similar cannabinoids is positively correlated with cannabinoid potentiation of the α3 GlyRs. In contrast, the cannabinoid analgesia is neither correlated with their binding affinity for CB1 and CB2 receptors nor with their psychoactive side effects. NMR analysis reveals a direct interaction between CBD and S296 in the third transmembrane domain of purified α3 GlyR. The cannabinoid-induced analgesic effect is absent in mice lacking the α3 GlyRs. Our findings suggest that the α3 GlyRs mediate glycinergic cannabinoid-induced suppression of chronic pain. These cannabinoids may represent a novel class of therapeutic agents for the treatment of chronic pain and other diseases involving GlyR dysfunction. PMID:22585736
The cannabinoid anticonvulsant effect on pentylenetetrazole-induced seizure is potentiated by ultra-low dose naltrexone in mice.

PubMed

Bahremand, Arash; Shafaroodi, Hamed; Ghasemi, Mehdi; Nasrabady, Sara Ebrahimi; Gholizadeh, Shervin; Dehpour, Ahmad Reza

2008-09-01

Cannabinoid compounds are anticonvulsant since they have inhibitory effects at micromolar doses, which are mediated by activated receptors coupling to G(i/o) proteins. Surprisingly, both the analgesic and anticonvulsant effects of opioids are enhanced by ultra-low doses (nanomolar to picomolar) of the opioid antagonist naltrexone and as opioid and cannabinoid systems interact, it has been shown that ultra-low dose naltrexone also enhances cannabinoid-induced antinociception. Thus, concerning the seizure modulating properties of both classes of receptors this study investigated whether the ultra-low dose opioid antagonist naltrexone influences cannabinoid anticonvulsant effects. The clonic seizure threshold was tested in separate groups of male NMRI mice following injection of vehicle, the cannabinoid selective agonist arachidonyl-2-chloroethylamide (ACEA) and ultra-low doses of the opioid receptor antagonist naltrexone and a combination of ACEA and naltrexone doses in a model of clonic seizure induced by pentylenetetrazole (PTZ). Systemic injection of ultra-low doses of naltrexone (1pg/kg to 1ng/kg, i.p.) significantly potentiated the anticonvulsant effect of ACEA (1mg/kg, i.p.). Moreover, the very low dose of naltrexone (500pg/kg) unmasked a strong anticonvulsant effect for very low doses of ACEA (10 and 100microg/kg). A similar potentiation by naltrexone (500pg/kg) of anticonvulsant effects of non-effective dose of ACEA (1mg/kg) was also observed in the generalized tonic-clonic model of seizure. The present data indicate that the interaction between opioid and cannabinoid systems extends to ultra-low dose levels and ultra-low doses of opioid receptor antagonist in conjunction with very low doses of cannabinoids may provide a potent strategy to modulate seizure susceptibility.
Decreased CB receptor binding and cannabinoid signaling in three brain regions of a rat model of schizophrenia.

PubMed

Szűcs, Edina; Dvorácskó, Szabolcs; Tömböly, Csaba; Büki, Alexandra; Kékesi, Gabriella; Horváth, Gyöngyi; Benyhe, Sándor

2016-10-28

Schizophrenia is a serious mental health disorder characterized by several behavioral and biochemicel abnormalities. In a previous study we have shown that mu-opioid (MOP) receptor signaling is impaired in specific brain regions of our three-hit animal model of schizophrenia. Since the cannabinoid system is significantly influenced in schizophrenic patients, in the present work we investigated cannabinoid (CB) receptor binding and G-protein activation in cortical, subcortical and cerebellar regions of control and 'schizophrenic' rats. Cannabinoid agonist (WIN-55,212-2 mesylate) mediated G-protein activation was consistently decreased in all areas tested, and the difference was extremely significant in membranes prepared from the cerebellum. Interestingly, the cerebellar activity of WIN-55,212-2 stimulated G-proteins was substantially higher than those of cerebral cortex and subcortical region in control animals, indicating a primordial role of the cannabinoid system in the cerebellum. At the level of radioligand binding, the affinities of the CB receptors were also markedly decreased in the model animals. Capacity of the [ 3 H]WIN-55,212-2 binding was only higher in the cerebellum of 'schizophrenic' model rats. Taken together, in all three brain areas of model rats both cannabinoid receptor binding and cannabinoid agonist-mediated G-protein activation were regularly decreased. Our results revealed that besides the opioids, the endocannabinoid - cannabis receptor system also shows impairment in our rat model, increasing its face validity and translational utility. Copyright © 2016. Published by Elsevier Ireland Ltd.
The synthetic cannabinoid WIN55,212-2 attenuates hyperalgesia and allodynia in a rat model of neuropathic pain

PubMed Central

Bridges, Daniel; Ahmad, Kamran; Rice, Andrew S C

2001-01-01

The analgesic properties of the synthetic cannabinoid WIN55,212-2 were investigated in a model of neuropathic pain. In male Wistar rats, bilateral hind limb withdrawal thresholds to cold, mechanical and noxious thermal stimuli were measured. Following this, unilateral L5 spinal nerve ligation was performed. Seven days later, sensory thresholds were reassessed and the development of allodynia to cold and mechanical stimuli and hyperalgesia to a noxious thermal stimulus confirmed.The effect of WIN55,212-2 (0.1 – 5.0 mg kg−1, i.p.) on the signs of neuropathy was then determined; there was a dose related reversal of all three signs of painful neuropathy at doses which did not generally alter sensory thresholds in the contralateral unligated limb. This effect was prevented by co-administration of the CB1 receptor antagonist SR141716a, but not by co-administration of the CB2 receptor antagonist SR144528, suggesting this action of WIN55,212-2 is mediated via the CB1 receptor. Administration of SR141716a alone had no affect on the observed allodynia and hyperalgesia, which does not support the concept of an endogenous analgesic tone.These data indicate that cannabinoids may have therapeutic potential in neuropathic pain, and that this effect is mediated through the CB1 receptor. PMID:11399676

Cannabinoid receptor-specific mechanisms to alleviate pain in sickle cell anemia via inhibition of mast cell activation and neurogenic inflammation.

PubMed

Vincent, Lucile; Vang, Derek; Nguyen, Julia; Benson, Barbara; Lei, Jianxun; Gupta, Kalpna

2016-05-01

Sickle cell anemia is a manifestation of a single point mutation in hemoglobin, but inflammation and pain are the insignia of this disease which can start in infancy and continue throughout life. Earlier studies showed that mast cell activation contributes to neurogenic inflammation and pain in sickle mice. Morphine is the common analgesic treatment but also remains a major challenge due to its side effects and ability to activate mast cells. We, therefore, examined cannabinoid receptor-specific mechanisms to mitigate mast cell activation, neurogenic inflammation and hyperalgesia, using HbSS-BERK sickle and cannabinoid receptor-2-deleted sickle mice. We show that cannabinoids mitigate mast cell activation, inflammation and neurogenic inflammation in sickle mice via both cannabinoid receptors 1 and 2. Thus, cannabinoids influence systemic and neural mechanisms, ameliorating the disease pathobiology and hyperalgesia in sickle mice. This study provides 'proof of principle' for the potential of cannabinoid/cannabinoid receptor-based therapeutics to treat several manifestations of sickle cell anemia. Copyright© Ferrata Storti Foundation.
Cannabinoids Modulate Neuronal Activity and Cancer by CB1 and CB2 Receptor-Independent Mechanisms

PubMed Central

Soderstrom, Ken; Soliman, Eman; Van Dross, Rukiyah

2017-01-01

Cannabinoids include the active constituents of Cannabis or are molecules that mimic the structure and/or function of these Cannabis-derived molecules. Cannabinoids produce many of their cellular and organ system effects by interacting with the well-characterized CB1 and CB2 receptors. However, it has become clear that not all effects of cannabinoid drugs are attributable to their interaction with CB1 and CB2 receptors. Evidence now demonstrates that cannabinoid agents produce effects by modulating activity of the entire array of cellular macromolecules targeted by other drug classes, including: other receptor types; ion channels; transporters; enzymes, and protein- and non-protein cellular structures. This review summarizes evidence for these interactions in the CNS and in cancer, and is organized according to the cellular targets involved. The CNS represents a well-studied area and cancer is emerging in terms of understanding mechanisms by which cannabinoids modulate their activity. Considering the CNS and cancer together allow identification of non-cannabinoid receptor targets that are shared and divergent in both systems. This comparative approach allows the identified targets to be compared and contrasted, suggesting potential new areas of investigation. It also provides insight into the diverse sources of efficacy employed by this interesting class of drugs. Obtaining a comprehensive understanding of the diverse mechanisms of cannabinoid action may lead to the design and development of therapeutic agents with greater efficacy and specificity for their cellular targets. PMID:29066974
Acute Poisonings from Synthetic Cannabinoids - 50 U.S. Toxicology Investigators Consortium Registry Sites, 2010-2015.

PubMed

Riederer, Anne M; Campleman, Sharan L; Carlson, Robert G; Boyer, Edward W; Manini, Alex F; Wax, Paul M; Brent, Jeffrey A

2016-07-15

Recent reports suggest that acute intoxications by synthetic cannabinoids are increasing in the United States (1,2). Synthetic cannabinoids, which were research compounds in the 1980s, are now produced overseas; the first shipment recognized to contain synthetic cannabinoids was seized at a U.S. border in 2008 (3). Fifteen synthetic cannabinoids are Schedule I controlled substances (3), but enforcement is hampered by the continual introduction of new chemical compounds (1,3). Studies of synthetic cannabinoids indicate higher cannabinoid receptor binding affinities, effects two to 100 times more potent than Δ(9)-tetrahydrocannabinol (the principal psychoactive constituent of cannabis), noncannabinoid receptor binding, and genotoxicity (4,5). Acute synthetic cannabinoid exposure reportedly causes a range of mild to severe neuropsychiatric, cardiovascular, renal, and other effects (4,6,7); chronic use might lead to psychosis (6,8). During 2010-2015, physicians in the Toxicology Investigators Consortium (ToxIC) treated 456 patients for synthetic cannabinoid intoxications; 277 of the 456 patients reported synthetic cannabinoids as the sole toxicologic agent. Among these 277 patients, the most common clinical signs of intoxication were neurologic (agitation, central nervous system depression/coma, and delirium/toxic psychosis). Relative to all cases logged by 50 different sites in the ToxIC Case Registry, there was a statistically significant association between reporting year and the annual proportion of synthetic cannabinoid cases. In 2015, reported cases of synthetic cannabinoid intoxication increased at several ToxIC sites, corroborating reported upward trends in the numbers of such cases (1,2) and underscoring the need for prevention.
21 CFR 862.3870 - Cannabinoid test system.

Code of Federal Regulations, 2011 CFR

2011-04-01

... 21 Food and Drugs 8 2011-04-01 2011-04-01 false Cannabinoid test system. 862.3870 Section 862.3870 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) MEDICAL DEVICES CLINICAL CHEMISTRY AND CLINICAL TOXICOLOGY DEVICES Clinical Toxicology Test Systems § 862...
21 CFR 862.3870 - Cannabinoid test system.

Code of Federal Regulations, 2012 CFR

2012-04-01

... 21 Food and Drugs 8 2012-04-01 2012-04-01 false Cannabinoid test system. 862.3870 Section 862.3870 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) MEDICAL DEVICES CLINICAL CHEMISTRY AND CLINICAL TOXICOLOGY DEVICES Clinical Toxicology Test Systems § 862...
21 CFR 862.3870 - Cannabinoid test system.

Code of Federal Regulations, 2013 CFR

2013-04-01

... 21 Food and Drugs 8 2013-04-01 2013-04-01 false Cannabinoid test system. 862.3870 Section 862.3870 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) MEDICAL DEVICES CLINICAL CHEMISTRY AND CLINICAL TOXICOLOGY DEVICES Clinical Toxicology Test Systems § 862...
21 CFR 862.3870 - Cannabinoid test system.

Code of Federal Regulations, 2014 CFR

2014-04-01

... 21 Food and Drugs 8 2014-04-01 2014-04-01 false Cannabinoid test system. 862.3870 Section 862.3870 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) MEDICAL DEVICES CLINICAL CHEMISTRY AND CLINICAL TOXICOLOGY DEVICES Clinical Toxicology Test Systems § 862...
Synthetic cannabinoids: the multi-organ failure and metabolic derangements associated with getting high.

PubMed

Sherpa, Dolkar; Paudel, Bishow M; Subedi, Bishnu H; Chow, Robert Dobbin

2015-01-01

Synthetic cannabinoids (SC), though not detected with routine urine toxicology screening, can cause severe metabolic derangements and widespread deleterious effects in multiple organ systems. The diversity of effects is related to the wide distribution of cannabinoid receptors in multiple organ systems. Both cannabinoid-receptor-mediated and non-receptor-mediated effects can result in severe cardiovascular, renal, and neurologic manifestations. We report the case of a 45-year-old African American male with ST-elevation myocardial infarction, subarachnoid hemorrhage, reversible cardiomyopathy, acute rhabdomyolysis, and severe metabolic derangement associated with the use of K2, an SC. Though each of these complications has been independently associated with SCs, the combination of these effects in a single patient has not been heretofore reported. This case demonstrates the range and severity of complications associated with the recreational use of SCs. Though now banned in the United States, use of systemic cannabinoids is still prevalent, especially among adolescents. Clinicians should be aware of their continued use and the potential for harm. To prevent delay in diagnosis, tests to screen for these substances should be made more readily available.
Cannabinoids and brain injury: therapeutic implications.

PubMed

Mechoulam, Raphael; Panikashvili, David; Shohami, Esther

2002-02-01

Mounting in vitro and in vivo data suggest that the endocannabinoids anandamide and 2-arachidonoyl glycerol, as well as some plant and synthetic cannabinoids, have neuroprotective effects following brain injury. Cannabinoid receptor agonists inhibit glutamatergic synaptic transmission and reduce the production of tumour necrosis factor-alpha and reactive oxygen intermediates, which are factors in causing neuronal damage. The formation of the endocannabinoids anandamide and 2-arachidonoyl glycerol is strongly enhanced after brain injury, and there is evidence that these compounds reduce the secondary damage incurred. Some plant and synthetic cannabinoids, which do not bind to the cannabinoid receptors, have also been shown to be neuroprotective, possibly through their direct effect on the excitatory glutamate system and/or as antioxidants.
Methods of the pharmacological imaging of the cannabinoid system (PhICS) study: towards understanding the role of the brain endocannabinoid system in human cognition.

PubMed

van Hell, Hendrika H; Bossong, Matthijs G; Jager, Gerry; Kahn, René S; Ramsey, Nick F

2011-03-01

Various lines of (pre)clinical research indicate that cannabinoid agents carry the potential for therapeutic application to reduce symptoms in several psychiatric disorders. However, direct testing of the involvement of cannabinoid brain systems in psychiatric syndromes is essential for further development. In the Pharmacological Imaging of the Cannabinoid System (PhICS) study, the involvement of the endocannabinoid system in cognitive brain function is assessed by comparing acute effects of the cannabinoid agonist Δ9-tetrahydrocannabinol (THC) on brain function between healthy controls and groups of psychiatric patients showing cognitive dysfunction. This article describes the objectives and methods of the PhICS study and presents preliminary results of the administration procedure on subjective and neurophysiological parameters. Core elements in the methodology of PhICS are the administration method (THC is administered by inhalation using a vaporizing device) and a comprehensive use of pharmacological magnetic resonance imaging (phMRI) combining several types of MRI scans including functional MRI (fMRI), Arterial Spin Labeling (ASL) to measure brain perfusion, and resting-state fMRI. Additional methods like neuropsychological testing further specify the exact role of the endocannabinoid system in regulating cognition. Preliminary results presented in this paper indicate robust behavioral and subjective effects of THC. In addition, fMRI paradigms demonstrate activation of expected networks of brain regions in the cognitive domains of interest. The presented administration and assessment protocol provides a basis for further research on the involvement of the endocannabionoid systems in behavior and in psychopathology, which in turn may lead to development of therapeutic opportunities of cannabinoid ligands. Copyright © 2011 John Wiley & Sons, Ltd.
Endocannabinoid Signaling Regulates Sleep Stability.

PubMed

Pava, Matthew J; Makriyannis, Alexandros; Lovinger, David M

2016-01-01

The hypnogenic properties of cannabis have been recognized for centuries, but endogenous cannabinoid (endocannabinoid) regulation of vigilance states is poorly characterized. We report findings from a series of experiments in mice measuring sleep with polysomnography after various systemic pharmacological manipulations of the endocannabinoid system. Rapid, unbiased scoring of vigilance states was achieved using an automated algorithm that we devised and validated. Increasing endocannabinoid tone with a selective inhibitor of monoacyglycerol lipase (JZL184) or fatty acid amide hydrolase (AM3506) produced a transient increase in non-rapid eye movement (NREM) sleep due to an augmentation of the length of NREM bouts (NREM stability). Similarly, direct activation of type 1 cannabinoid (CB1) receptors with CP47,497 increased NREM stability, but both CP47,497 and JZL184 had a secondary effect that reduced NREM sleep time and stability. This secondary response to these drugs was similar to the early effect of CB1 blockade with the antagonist/inverse agonist AM281, which fragmented NREM sleep. The magnitude of the effects produced by JZL184 and AM281 were dependent on the time of day this drug was administered. While activation of CB1 resulted in only a slight reduction in gamma power, CB1 blockade had dramatic effects on broadband power in the EEG, particularly at low frequencies. However, CB1 blockade did not significantly reduce the rebound in NREM sleep following total sleep deprivation. These results support the hypothesis that endocannabinoid signaling through CB1 is necessary for NREM stability but it is not necessary for sleep homeostasis.
Endocannabinoid Signaling Regulates Sleep Stability

PubMed Central

Pava, Matthew J.; Makriyannis, Alexandros; Lovinger, David M.

2016-01-01

The hypnogenic properties of cannabis have been recognized for centuries, but endogenous cannabinoid (endocannabinoid) regulation of vigilance states is poorly characterized. We report findings from a series of experiments in mice measuring sleep with polysomnography after various systemic pharmacological manipulations of the endocannabinoid system. Rapid, unbiased scoring of vigilance states was achieved using an automated algorithm that we devised and validated. Increasing endocannabinoid tone with a selective inhibitor of monoacyglycerol lipase (JZL184) or fatty acid amide hydrolase (AM3506) produced a transient increase in non-rapid eye movement (NREM) sleep due to an augmentation of the length of NREM bouts (NREM stability). Similarly, direct activation of type 1 cannabinoid (CB1) receptors with CP47,497 increased NREM stability, but both CP47,497 and JZL184 had a secondary effect that reduced NREM sleep time and stability. This secondary response to these drugs was similar to the early effect of CB1 blockade with the antagonist/inverse agonist AM281, which fragmented NREM sleep. The magnitude of the effects produced by JZL184 and AM281 were dependent on the time of day this drug was administered. While activation of CB1 resulted in only a slight reduction in gamma power, CB1 blockade had dramatic effects on broadband power in the EEG, particularly at low frequencies. However, CB1 blockade did not significantly reduce the rebound in NREM sleep following total sleep deprivation. These results support the hypothesis that endocannabinoid signaling through CB1 is necessary for NREM stability but it is not necessary for sleep homeostasis. PMID:27031992
Modulation of sweet taste sensitivities by endogenous leptin and endocannabinoids in mice

PubMed Central

Niki, Mayu; Jyotaki, Masafumi; Yoshida, Ryusuke; Yasumatsu, Keiko; Shigemura, Noriatsu; DiPatrizio, Nicholas V; Piomelli, Daniele; Ninomiya, Yuzo

2015-01-01

Leptin is an anorexigenic mediator that reduces food intake by acting on hypothalamic receptor Ob-Rb. In contrast, endocannabinoids are orexigenic mediators that act via cannabinoid CB1 receptors in hypothalamus, limbic forebrain, and brainstem. In the peripheral taste system, leptin administration selectively inhibits behavioural, taste nerve and taste cell responses to sweet compounds. Opposing the action of leptin, endocannabinoids enhance sweet taste responses. However, potential roles of endogenous leptin and endocannabinoids in sweet taste remain unclear. Here, we used pharmacological antagonists (Ob-Rb: L39A/D40A/F41A (LA), CB1: AM251) and examined the effects of their blocking activation of endogenous leptin and endocannabinoid signalling on taste responses in lean control, leptin receptor deficient db/db, and diet-induced obese (DIO) mice. Lean mice exhibited significant increases in chorda tympani (CT) nerve responses to sweet compounds after LA administration, while they showed no significant changes in CT responses after AM251. In contrast, db/db mice showed clear suppression of CT responses to sweet compounds after AM251, increased endocannabinoid (2-arachidonoyl-sn-glycerol (2-AG)) levels in the taste organ, and enhanced expression of a biosynthesizing enzyme (diacylglycerol lipase α (DAGLα)) of 2-AG in taste cells. In DIO mice, the LA effect was gradually decreased and the AM251 effect was increased during the course of obesity. Taken together, our results suggest that circulating leptin, but not local endocannabinoids, may be a dominant modulator for sweet taste in lean mice; however, endocannabinoids may become more effective modulators of sweet taste under conditions of deficient leptin signalling, possibly due to increased production of endocannabinoids in taste tissue. Key points Potential roles of endogenous leptin and endocannabinoids in sweet taste were examined by using pharmacological antagonists and mouse models including leptin receptor deficient (db/db) and diet-induced obese (DIO) mice. Chorda tympani (CT) nerve responses of lean mice to sweet compounds were increased after administration of leptin antagonist (LA) but not affected by administration of cannabinoid receptor antagonist (AM251). db/db mice showed clear suppression of CT responses to sweet compounds after AM251, increased endocannabinoid levels in the taste organ, and enhanced expression of a biosynthesizing enzyme of endocannabinoids in taste cells. The effect of LA was gradually decreased and that of AM251 was increased during the course of obesity in DIO mice. These findings suggest that circulating leptin, but not local endocannabinoids, is a dominant modulator for sweet taste in lean mice and endocannabinoids become more effective modulators of sweet taste under conditions of deficient leptin signalling. PMID:25728242
Cannabinoids as therapeutic agents in cardiovascular disease: a tale of passions and illusions

PubMed Central

Mendizábal, V E; Adler-Graschinsky, E

2007-01-01

In addition to their classical known effects, such as analgesia, impairment of cognition and learning and appetite enhancement, cannabinoids have also been related to the regulation of cardiovascular responses and implicated in cardiovascular pathology. Elevated levels of endocannabinoids have been related to the extreme hypotension associated with various forms of shock as well as to the cardiovascular abnormalities that accompany cirrhosis. In contrast, cannabinoids have also been associated with beneficial effects on the cardiovascular system, such as a protective role in atherosclerosis progression and in cerebral and myocardial ischaemia. In addition, it has also been suggested that the pharmacological manipulation of the endocannabinoid system may offer a novel approach to antihypertensive therapy. During the last decades, the tremendous increase in the understanding of the molecular basis of cannabinoid activity has encouraged many pharmaceutical companies to develop more potent synthetic cannabinoid analogues and antagonists, leading to an explosion of basic research and clinical trials. Consequently. not only the synthetic THC dronabinol (Marinol) and the synthetic THC analogue nabilone (Cesamet) have been approved in the United States, but also the standardized cannabis extract (Sativex) in Canada. At least three strategies can be foreseen in the future clinical use of cannabinoid-based drugs: (a) the use of CB1 receptor antagonists, such as the recently approved rimonabant (b) the use of CB2-selective agonists, and (c) the use of inhibitors of endocannabinoid degradation. In this context, the present review examines the effects of cannabinoids and of the pharmacological manipulation of the endocannabinoid system, in cardiovascular pathophysiology. PMID:17450170
[Drug Dependence and Cytotoxicity of Law-evading Drugs: Their Identities Explored from Basic Research].

PubMed

Funada, Masahiko

2016-01-01

Cases of people experiencing disturbed consciousness or dyspnea, causing traffic accidents, or requiring ambulance transport to hospital due to abuse of law-evading chemical substances have become a serious social problem in Japan. Most law-evading herbal products are marketed as incense or herbs and consist of finely chopped, dry vegetative matter mixed with chemical substances (drugs). Analysis of the chemical substances in these herbal products has demonstrated that they contain synthetic cannabinoids. Because there are many cannabinoid compounds, even if a particular drug is regulated, similar compounds that differ only slightly in structure may be added in their place. Therefore a cat-and-mouse game exists between regulations on chemical substances and their propagation. This paper summarizes the pharmacological actions and dangers of chemical substances contained in law-evading herbal products by focusing on synthetic cannabinoids, as a group of chemical substances contained in these products. Furthermore, comprehensive designations of synthetic cannabinoids have been introduced as a new method of regulation that emphasizes the similarity of chemical structures; this paper also outlines the comprehensive designations. We established a psychic-dependence liability and cytotoxicity screening system for synthetic cannabinoids using animals (behavioral analysis in vivo) and cell cultures (cytotoxicity analysis in vitro). With our drug-screening system, we were able rapidly to evaluate and quantify psychic-dependence liabilities and cytotoxicity of synthetic cannabinoids contained in law-evading herbal products. These scientific data using our screening system contributed to the establishment of legislation for comprehensive designations of synthetic cannabinoids.
Anti-inflammatory effect of cannabinoid agonist WIN55, 212 on mouse experimental colitis is related to inhibition of p38MAPK

PubMed Central

Feng, Ya-Jing; Li, Yong-Yu; Lin, Xu-Hong; Li, Kun; Cao, Ming-Hua

2016-01-01

AIM To investigate the anti-inflammatory effect and the possible mechanisms of an agonist of cannabinoid (CB) receptors, WIN55-212-2 (WIN55), in mice with experimental colitis, so as to supply experimental evidence for its clinical use in future. METHODS We established the colitis model in C57BL/6 mice by replacing the animals’ water supply with 4% dextran sulfate sodium (DSS) for 7 consecutive days. A colitis scoring system was used to evaluate the severity of colon local lesion. The plasma levels of proinflammatory cytokines, such as tumor necrosis factor-alpha (TNF-α) and interleukin-6 (IL-6), and the myeloperoxidase (MPO) activity in colon tissue were measured. The expressions of cannabinoid receptors, claudin-1 protein, p38 mitogen-activated protein kinase (p38MAPK) and its phosphorylated form (p-p38) in colon tissue were determined by immunohistochemistry and Western blot. In addition, the effect of SB203580 (SB), an inhibitor of p38, was investigated in parallel experiments, and the data were compared with those from intervention groups of WIN55 and SB alone or used together. RESULTS The results demonstrated that WIN55 or SB treatment alone or together improved the pathological changes in mice with DSS colitis, decreased the plasma levels of TNF-α, and IL-6, and MPO activity in colon. The enhanced expression of claudin-1 and the inhibited expression of p-p38 in colon tissues were found in the WIN55-treated group. Besides, the expression of CB1 and CB2 receptors was enhanced in the colon after the induction of DSS colitis, but reduced when p38MAPK was inhibited. CONCLUSION These results confirmed the anti-inflammatory effect and protective role of WIN55 on the mice with experimental colitis, and revealed that this agent exercises its action at least partially by inhibiting p38MAPK. Furthermore, the results showed that SB203580, affected the expression of CB1 and CB2 receptors in the mouse colon, suggesting a close linkage and cross-talk between the p38MAPK signaling pathway and the endogenous CB system. PMID:27920472
Notes from the Field: Increase in Reported Adverse Health Effects Related to Synthetic Cannabinoid Use - United States, January-May 2015.

PubMed

Law, Royal; Schier, Josh; Martin, Colleen; Chang, Arthur; Wolkin, Amy

2015-06-12

On April 6, 2015, CDC received notification of an increase in telephone calls to U.S. poison centers related to synthetic cannabinoid use. Monthly calls to all poison centers are tracked by the National Poison Data System, which reported that adverse health effects or concerns about possible adverse health effects related to synthetic cannabinoid use increased 330% from 349 in January 2015 to 1,501 in April 2015. Synthetic cannabinoids include various psychoactive chemicals or a mixture of such chemicals that are sprayed onto plant material, which is then often smoked or ingested to achieve a "high." These products are sold under a variety of names (e.g., synthetic marijuana, spice, K2, black mamba, and crazy clown) and can be sold in retail outlets as herbal products. Law enforcement agencies have regulated a number of these substances; however, manufacturers of synthetic cannabinoids frequently change the formulation to avoid detection and regulation. After the initial notification, CDC analyzed information from the National Poison Data System on reported adverse health effects related to synthetic cannabinoid use for the period January-May 2015.
CANNABINOID AND OPIOID MODULATION OF SOCIAL PLAY BEHAVIOR IN ADOLESCENT RATS: DIFFERENTIAL BEHAVIORAL MECHANISMS

PubMed Central

Trezza, Viviana; Vanderschuren, Louk J.M.J.

2008-01-01

We have recently shown that the pharmacological mechanisms through which cannabinoid and opioid drugs influence social play behavior in adolescent rats can be partially dissociated. Here, we characterize the effects of the direct cannabinoid agonist WIN55,212-2, the indirect cannabinoid agonist URB597 and the opioid agonist morphine on social play at the behavioral level. By treating either one or both partners of the test dyad, we show that these drugs differentially affect play solicitation and play responsiveness. By testing these drugs in animals which were either familiar or unfamiliar to the test cage, we show that environmental factors differentially modulate the effects of cannabinoid and opioid drugs on social play. These results support and extend our previous findings suggesting that, although cannabinoid and opioid systems interact in the modulation of social play behavior in adolescent rats, they do so through partially dissociable behavioral and pharmacological mechanisms. PMID:18434104
A Personal Retrospective: Elevating Anandamide (AEA) by Targeting Fatty Acid Amide Hydrolase (FAAH) and the Fatty Acid Binding Proteins (FABPs).

PubMed

Deutsch, Dale G

2016-01-01

This perspective was adapted from a Career Achievement Award talk given at the International Cannabinoid Research Society Symposium in Bukovina, Poland on June 27, 2016. As a biochemist working in the neurosciences, I was always fascinated with neurotransmitter inactivation. In 1993 we identified an enzyme activity that breaks down anandamide. We called the enzyme anandamide amidase, now called FAAH. We and other laboratories developed FAAH inhibitors that were useful reagents that also proved to have beneficial physiological effects and until recently, new generations of inhibitors were in clinical trials. Nearly all neurotransmitters are water soluble and as such, require a transmembrane protein transporter to pass through the lipid membrane for inactivation inside the cell. However, using model systems, we and others have shown that this is unnecessary for anandamide, an uncharged hydrophobic molecule that readily diffuses across the cellular membrane. Interestingly, its uptake is driven by the concentration gradient resulting from its breakdown mainly by FAAH localized in the endoplasmic reticulum. We identified the FABPs as intracellular carriers that "solubilize" anandamide, transporting anandamide to FAAH. Compounds that bind to FABPs block AEA breakdown, raising its level. The cannabinoids (THC and CBD) also were discovered to bind FABPs and this may be one of the mechanisms by which CBD works in childhood epilepsy, raising anandamide levels. Targeting FABPs may be advantageous since they have some tissue specificity and do not require reactive serine hydrolase inhibitors, as does FAAH, with potential for off-target reactions. At the International Cannabis Research Society Symposium in 1992, Raphe Mechoulam revealed that his laboratory isolated an endogenous lipid molecule that binds to the CB1 receptor (cannabinoid receptor type 1) and this became the milestone paper published in December of that year describing anandamide (AEA, Devane et al., 1992). As to be expected, this discovery raised the issues of AEA's synthesis and breakdown.
A Personal Retrospective: Elevating Anandamide (AEA) by Targeting Fatty Acid Amide Hydrolase (FAAH) and the Fatty Acid Binding Proteins (FABPs)

PubMed Central

Deutsch, Dale G.

2016-01-01

This perspective was adapted from a Career Achievement Award talk given at the International Cannabinoid Research Society Symposium in Bukovina, Poland on June 27, 2016. As a biochemist working in the neurosciences, I was always fascinated with neurotransmitter inactivation. In 1993 we identified an enzyme activity that breaks down anandamide. We called the enzyme anandamide amidase, now called FAAH. We and other laboratories developed FAAH inhibitors that were useful reagents that also proved to have beneficial physiological effects and until recently, new generations of inhibitors were in clinical trials. Nearly all neurotransmitters are water soluble and as such, require a transmembrane protein transporter to pass through the lipid membrane for inactivation inside the cell. However, using model systems, we and others have shown that this is unnecessary for anandamide, an uncharged hydrophobic molecule that readily diffuses across the cellular membrane. Interestingly, its uptake is driven by the concentration gradient resulting from its breakdown mainly by FAAH localized in the endoplasmic reticulum. We identified the FABPs as intracellular carriers that “solubilize” anandamide, transporting anandamide to FAAH. Compounds that bind to FABPs block AEA breakdown, raising its level. The cannabinoids (THC and CBD) also were discovered to bind FABPs and this may be one of the mechanisms by which CBD works in childhood epilepsy, raising anandamide levels. Targeting FABPs may be advantageous since they have some tissue specificity and do not require reactive serine hydrolase inhibitors, as does FAAH, with potential for off-target reactions. At the International Cannabis Research Society Symposium in 1992, Raphe Mechoulam revealed that his laboratory isolated an endogenous lipid molecule that binds to the CB1 receptor (cannabinoid receptor type 1) and this became the milestone paper published in December of that year describing anandamide (AEA, Devane et al., 1992). As to be expected, this discovery raised the issues of AEA's synthesis and breakdown. PMID:27790143

Anti-nociceptive interactions between opioids and a cannabinoid receptor 2 agonist in inflammatory pain

PubMed Central

Hale, David E; Guindon, Josée; Morgan, Daniel J

2017-01-01

The cannabinoid 1 receptor and cannabinoid 2 receptor can both be targeted in the treatment of pain; yet, they have some important differences. Cannabinoid 1 receptor is expressed at high levels in the central nervous system, whereas cannabinoid 2 receptor is found predominantly, although not exclusively, outside the central nervous system. The objective of this study was to investigate potential interactions between cannabinoid 2 receptor and the mu-opioid receptor in pathological pain. The low level of adverse side effects and lack of tolerance for cannabinoid 2 receptor agonists are attractive pharmacotherapeutic traits. This study assessed the anti-nociceptive effects of a selective cannabinoid 2 receptor agonist (JWH-133) in pathological pain using mice subjected to inflammatory pain using the formalin test. Furthermore, we examined several ways in which JWH-133 may interact with morphine. JWH-133 produces dose-dependent anti-nociception during both the acute and inflammatory phases of the formalin test. This was observed in both male and female mice. However, a maximally efficacious dose of JWH-133 (1 mg/kg) was not associated with somatic withdrawal symptoms, motor impairment, or hypothermia. After eleven once-daily injections of 1 mg/JWH-133, no tolerance was observed in the formalin test. Cross-tolerance for the anti-nociceptive effects of JWH-133 and morphine were assessed to gain insight into physiologically relevant cannabinoid 2 receptor and mu-opioid receptor interaction. Mice made tolerant to the effects of morphine exhibited a lower JWH-133 response in both phases of the formalin test compared to vehicle-treated morphine-naïve animals. However, repeated daily JWH-133 administration did not cause cross-tolerance for morphine, suggesting opioid and cannabinoid 2 receptor cross-tolerance is unidirectional. However, preliminary data suggest co-administration of JWH-133 with morphine modestly attenuates morphine tolerance. Isobolographic analysis revealed that co-administration of JWH-133 and morphine has an additive effect on anti-nociception in the formalin test. Overall these findings show that cannabinoid 2 receptor may functionally interact with mu-opioid receptor to modulate anti-nociception in the formalin test. PMID:28879802
Local Delivery of Cannabinoid-Loaded Microparticles Inhibits Tumor Growth in a Murine Xenograft Model of Glioblastoma Multiforme

PubMed Central

Gil-Alegre, Maria Esther; Torres, Sofía; García-Taboada, Elena; Aberturas, María del Rosario; Molpeceres, Jesús

2013-01-01

Cannabinoids, the active components of marijuana and their derivatives, are currently investigated due to their potential therapeutic application for the management of many different diseases, including cancer. Specifically, Δ9-Tetrahydrocannabinol (THC) and Cannabidiol (CBD) – the two major ingredients of marijuana – have been shown to inhibit tumor growth in a number of animal models of cancer, including glioma. Although there are several pharmaceutical preparations that permit the oral administration of THC or its analogue nabilone or the oromucosal delivery of a THC- and CBD-enriched cannabis extract, the systemic administration of cannabinoids has several limitations in part derived from the high lipophilicity exhibited by these compounds. In this work we analyzed CBD- and THC-loaded poly-ε-caprolactone microparticles as an alternative delivery system for long-term cannabinoid administration in a murine xenograft model of glioma. In vitro characterization of THC- and CBD-loaded microparticles showed that this method of microencapsulation facilitates a sustained release of the two cannabinoids for several days. Local administration of THC-, CBD- or a mixture (1∶1 w:w) of THC- and CBD-loaded microparticles every 5 days to mice bearing glioma xenografts reduced tumour growth with the same efficacy than a daily local administration of the equivalent amount of those cannabinoids in solution. Moreover, treatment with cannabinoid-loaded microparticles enhanced apoptosis and decreased cell proliferation and angiogenesis in these tumours. Our findings support that THC- and CBD-loaded microparticles could be used as an alternative method of cannabinoid delivery in anticancer therapies. PMID:23349970
Local delivery of cannabinoid-loaded microparticles inhibits tumor growth in a murine xenograft model of glioblastoma multiforme.

PubMed

Hernán Pérez de la Ossa, Dolores; Lorente, Mar; Gil-Alegre, Maria Esther; Torres, Sofía; García-Taboada, Elena; Aberturas, María Del Rosario; Molpeceres, Jesús; Velasco, Guillermo; Torres-Suárez, Ana Isabel

2013-01-01

Cannabinoids, the active components of marijuana and their derivatives, are currently investigated due to their potential therapeutic application for the management of many different diseases, including cancer. Specifically, Δ(9)-Tetrahydrocannabinol (THC) and Cannabidiol (CBD) - the two major ingredients of marijuana - have been shown to inhibit tumor growth in a number of animal models of cancer, including glioma. Although there are several pharmaceutical preparations that permit the oral administration of THC or its analogue nabilone or the oromucosal delivery of a THC- and CBD-enriched cannabis extract, the systemic administration of cannabinoids has several limitations in part derived from the high lipophilicity exhibited by these compounds. In this work we analyzed CBD- and THC-loaded poly-ε-caprolactone microparticles as an alternative delivery system for long-term cannabinoid administration in a murine xenograft model of glioma. In vitro characterization of THC- and CBD-loaded microparticles showed that this method of microencapsulation facilitates a sustained release of the two cannabinoids for several days. Local administration of THC-, CBD- or a mixture (1:1 w:w) of THC- and CBD-loaded microparticles every 5 days to mice bearing glioma xenografts reduced tumour growth with the same efficacy than a daily local administration of the equivalent amount of those cannabinoids in solution. Moreover, treatment with cannabinoid-loaded microparticles enhanced apoptosis and decreased cell proliferation and angiogenesis in these tumours. Our findings support that THC- and CBD-loaded microparticles could be used as an alternative method of cannabinoid delivery in anticancer therapies.
Involvement of cannabinoid system in the nucleus accumbens on delay-based decision making in the rat.

PubMed

Fatahi, Zahra; Sadeghi, Bahman; Haghparast, Abbas

2018-01-30

The nucleus accumbens (NAc) plays a fundamental role in decision making and anticipation of reward. In addition, exogenous cannabinoids affect the behavior of humans and animals including disruption of short-term memory and cognitive impairments. Therefore, in this study, cannabinoid agonist and antagonist were administrated into the NAc to determine the effect of cannabinoid activation in the entire NAc on delay-based decision making. Rats were trained on a cost-benefit T-maze decision making task in which the animals were well-trained to choose between a small/immediate reward and a large/delay reward. After training, the animals were implanted with guide cannulae in the NAc. On test day, they received cannabinoid agonist (Win 55,212-2; 10, 50 and 100μM) and/or antagonist (AM251; 45μM) into the NAc. Percentage of high reward choice and latency of reward achievement were evaluated. Results showed that cannabinoid agonist administration caused a decrease in high reward choice such that rats selected small/immediate reward instead of large/delay reward. Moreover, in agonist-treated animals latency of reward achievement increased. Effects of cannabinoid activation on delay-based decision making with equivalent delays demonstrated that if the delay was equated on both arm goals, animals still had a preference for the high/delay reward, showing the results was not caused by an impairment of spatial preference or memory. These finding clarified that cannabinoid system activation in the entire NAc plays a critical role in the regulation of delay-based decision making. Copyright © 2017 Elsevier B.V. All rights reserved.
Cannabinoids: is there a potential treatment role in epilepsy?

PubMed

Blair, Robert E; Deshpande, Laxmikant S; DeLorenzo, Robert J

2015-01-01

Cannabinoids have been used medicinally for centuries, and in the last decade, attention has focused on their broad therapeutic potential particularly in seizure management. While some cannabinoids have demonstrated anticonvulsant activity in experimental studies, their efficacy for managing clinical seizures has not been fully established. This commentary will touch on our understanding of the brain endocannabinoid system's regulation of synaptic transmission in both physiological and pathophysiological conditions, and review the findings from both experimental and clinical studies on the effectiveness of cannabinoids to suppress epileptic seizures. At present, there is preliminary evidence that non-psychoactive cannabinoids may be useful as anticonvulsants, but additional clinical trials are needed to fully evaluate the efficacy and safety of these compounds for the treatment of epilepsy.
[The mechanism of action of cannabis and cannabinoids].

PubMed

Scholten, W K

2006-01-21

The effect ofcannabis can be explained on the basis of the function of the cannabinoid receptor system, which consists of CB receptors (CB1, CB2), endoligands to activate these receptors and an enzyme--fatty acid amidohydrolase--to metabolize the endoligands. The endoligands of the cannabinoid receptor system are arachidonic acid-like substances, and are called endocannabinoids. Indications exist that the body also contains arachidonic acid-like substances that inhibit fatty acid amido hydrolase. Various cannabinoids have diverse effects on the receptors, functioning as agonists, antagonists or partial antagonists, as well as affecting the vanilloid receptor. Many known effects ofcannabis can be explained on the basis of this mechanism of action as can the use ofcannabis in various conditions including multiple sclerosis, Parkinson's disease, glaucoma, nausea, vomiting and rheumatoid arthritis.
15 years of genetic approaches in vivo for addiction research: Opioid receptor and peptide gene knockout in mouse models of drug abuse.

PubMed

Charbogne, Pauline; Kieffer, Brigitte L; Befort, Katia

2014-01-01

The endogenous opioid system is expressed throughout the brain reinforcement circuitry, and plays a major role in reward processing, mood control and the development of addiction. This neuromodulator system is composed of three receptors, mu, delta and kappa, interacting with a family of opioid peptides derived from POMC (β-endorphin), preproenkephalin (pEnk) and preprodynorphin (pDyn) precursors. Knockout mice targeting each gene of the opioid system have been created almost two decades ago. Extending classical pharmacology, these mutant mice represent unique tools to tease apart the specific role of each opioid receptor and peptide in vivo, and a powerful approach to understand how the opioid system modulates behavioral effects of drugs of abuse. The present review summarizes these studies, with a focus on major drugs of abuse including morphine/heroin, cannabinoids, psychostimulants, nicotine or alcohol. Genetic data, altogether, set the mu receptor as the primary target for morphine and heroin. In addition, this receptor is essential to mediate rewarding properties of non-opioid drugs of abuse, with a demonstrated implication of β-endorphin for cocaine and nicotine. Delta receptor activity reduces levels of anxiety and depressive-like behaviors, and facilitates morphine-context association. pEnk is involved in these processes and delta/pEnk signaling likely regulates alcohol intake. The kappa receptor mainly interacts with pDyn peptides to limit drug reward, and mediate dysphoric effects of cannabinoids and nicotine. Kappa/dynorphin activity also increases sensitivity to cocaine reward under stressful conditions. The opioid system remains a prime candidate to develop successful therapies in addicted individuals, and understanding opioid-mediated processes at systems level, through emerging genetic and imaging technologies, represents the next challenging goal and a promising avenue in addiction research. This article is part of a Special Issue entitled 'NIDA 40th Anniversary Issue'. Copyright © 2013 Elsevier Ltd. All rights reserved.
Cannabis and cognitive dysfunction: parallels with endophenotypes of schizophrenia?

PubMed

Solowij, Nadia; Michie, Patricia T

2007-01-01

Currently, there is a lot of interest in cannabis use as a risk factor for the development of schizophrenia. Cognitive dysfunction associated with long-term or heavy cannabis use is similar in many respects to the cognitive endophenotypes that have been proposed as vulnerability markers of schizophrenia. In this overview, we examine the similarities between these in the context of the neurobiology underlying cognitive dysfunction, particularly implicating the endogenous cannabinoid system, which plays a significant role in attention, learning and memory, and in general, inhibitory regulatory mechanisms in the brain. Closer examination of the cognitive deficits associated with specific parameters of cannabis use and interactions with neurodevelopmental stages and neural substrates will better inform our understanding of the nature of the association between cannabis use and psychosis. The theoretical and clinical significance of further research in this field is in enhancing our understanding of underlying pathophysiology and improving the provision of treatments for substance use and mental illness.
The Antitumor Activity of Plant-Derived Non-Psychoactive Cannabinoids.

PubMed

McAllister, Sean D; Soroceanu, Liliana; Desprez, Pierre-Yves

2015-06-01

As a therapeutic agent, most people are familiar with the palliative effects of the primary psychoactive constituent of Cannabis sativa (CS), Δ(9)-tetrahydrocannabinol (THC), a molecule active at both the cannabinoid 1 (CB1) and cannabinoid 2 (CB2) receptor subtypes. Through the activation primarily of CB1 receptors in the central nervous system, THC can reduce nausea, emesis and pain in cancer patients undergoing chemotherapy. During the last decade, however, several studies have now shown that CB1 and CB2 receptor agonists can act as direct antitumor agents in a variety of aggressive cancers. In addition to THC, there are many other cannabinoids found in CS, and a majority produces little to no psychoactivity due to the inability to activate cannabinoid receptors. For example, the second most abundant cannabinoid in CS is the non-psychoactive cannabidiol (CBD). Using animal models, CBD has been shown to inhibit the progression of many types of cancer including glioblastoma (GBM), breast, lung, prostate and colon cancer. This review will center on mechanisms by which CBD, and other plant-derived cannabinoids inefficient at activating cannabinoid receptors, inhibit tumor cell viability, invasion, metastasis, angiogenesis, and the stem-like potential of cancer cells. We will also discuss the ability of non-psychoactive cannabinoids to induce autophagy and apoptotic-mediated cancer cell death, and enhance the activity of first-line agents commonly used in cancer treatment.
The antitumor activity of plant-derived non-psychoactive cannabinoids

PubMed Central

McAllister, Sean D.; Soroceanu, Liliana; Desprez, Pierre-Yves

2015-01-01

As a therapeutic agent, most people are familiar with the palliative effects of the primary psychoactive constituent of Cannabis sativa (CS), Δ9-tetrahydrocannabinol (THC), a molecule active at both the cannabinoid 1 (CB1) and cannabinoid 2 (CB2) receptor subtypes. Through the activation primarily of CB1 receptors in the central nervous system, THC can reduce nausea, emesis and pain in cancer patients undergoing chemotherapy. During the last decade, however, several studies have now shown that CB1 and CB2 receptor agonists can act as direct antitumor agents in a variety of aggressive cancers. In addition to THC, there are many other cannabinoids found in CS, and a majority produces little to no psychoactivity due to the inability to activate cannabinoid receptors. For example, the second most abundant cannabinoid in CS is the non-psychoactive cannabidiol (CBD). Using animal models, CBD has been shown to inhibit the progression of many types of cancer including glioblastoma (GBM), breast, lung, prostate and colon cancer. This review will center on mechanisms by which CBD, and other plant-derived cannabinoids inefficient at activating cannabinoid receptors, inhibit tumor cell viability, invasion, metastasis, angiogenesis, and the stem-like potential of cancer stem cells. We will also discuss the ability of non-psychoactive cannabinoids to induce autophagy and apoptotic-mediated cancer cell death, and enhance the activity of first-line agents commonly used in cancer treatment. PMID:25916739
Cannabis and alcohol--a close friendship.

PubMed

Mechoulam, Raphael; Parker, Linda

2003-06-01

Cannabinoids and alcohol activate the same reward pathways, and the cannabinoid CB(1) receptor system plays an important role in regulating the positive reinforcing properties of alcohol. Indeed, both cannabinoids and alcohol cause the release of dopamine in the nucleus accumbens. Recent research suggests that ethanol preference, which is dependent on CB(1) receptors, is higher in young mice than in old mice, and higher in female mice than in male mice.
Chronic cannabis use is associated with impaired fear extinction in humans.

PubMed

Papini, Santiago; Ruglass, Lesia M; Lopez-Castro, Teresa; Powers, Mark B; Smits, Jasper A J; Hien, Denise A

2017-01-01

The use of fear conditioning and extinction paradigms to examine intermediate phenotypes of anxiety and stress-related disorders has facilitated the identification of neurobiological mechanisms that underlie specific components of abnormal psychological functioning. Across species, acute pharmacologic manipulation of the endogenous cannabinoid system has provided evidence of its critical role in fear extinction, but the effects of chronic cannabis on extinction are relatively understudied. In rats, chronic cannabinoid administration impairs fear extinction in a drug-free state. Here we examine whether chronic cannabis use is associated with impaired fear extinction in humans. Participants were healthy chronic cannabis users (n = 20) and nonuser controls with minimal lifetime cannabis use (n = 20) matched on age, sex, and race who all screened negative for psychiatric disorders. A 2-day differential fear conditioning paradigm was used to test the hypothesis that chronic cannabis use would be associated with impaired extinction of the skin conductance response. Consistent with hypotheses, chronic cannabis use was associated with reduced within-session extinction of skin conductance response on Day 1 (d = 0.78), and between-session extinction on Day 2 (d = 0.76). Unexpectedly, cannabis use was also associated with reduced subjective differentiation between threat and safety stimuli during conditioning. Replication and translation of findings are necessary to test potential mechanisms directly and examine whether impairments can be reversed pharmacologically or after a period of cannabis abstinence. (PsycINFO Database Record (c) 2017 APA, all rights reserved).
Cannabinoid-induced autophagy regulates suppressor of cytokine signaling-3 in intestinal epithelium

PubMed Central

Koay, Luan C.; Rigby, Rachael J.

2014-01-01

Autophagy is a catabolic process involved in homeostatic and regulated cellular protein recycling and degradation via the lysosomal degradation pathway. Emerging data associate impaired autophagy, increased activity in the endocannabinoid system, and upregulation of suppressor of cytokine signaling-3 (SOCS3) protein expression during intestinal inflammation. We have investigated whether these three processes are linked. By assessing the impact of the phytocannabinoid cannabidiol (CBD), the synthetic cannabinoid arachidonyl-2′-chloroethylamide (ACEA), and the endocannabinoid N-arachidonoylethanolamine (AEA) on autophagosome formation, we explored whether these actions were responsible for cyclic SOCS3 protein levels. Our findings show that all three cannabinoids induce autophagy in a dose-dependent manner in fully differentiated Caco-2 cells, a model of mature intestinal epithelium. ACEA and AEA induced canonical autophagy, which was cannabinoid type 1 receptor-mediated. In contrast, CBD was able to bypass the cannabinoid type 1 receptor and the canonical pathway to induce autophagy, albeit to a lesser extent. Functionally, all three cannabinoids reduced SOCS3 protein expression, which was reversed by blocking early and late autophagy. In conclusion, the regulatory protein SOCS3 is regulated by autophagy, and cannabinoids play a role in this process, which could be important when therapeutic applications for the cannabinoids in inflammatory conditions are considered. PMID:24833710
Cannabinoids and Epilepsy.

PubMed

Rosenberg, Evan C; Tsien, Richard W; Whalley, Benjamin J; Devinsky, Orrin

2015-10-01

Cannabis has been used for centuries to treat seizures. Recent anecdotal reports, accumulating animal model data, and mechanistic insights have raised interest in cannabis-based antiepileptic therapies. In this study, we review current understanding of the endocannabinoid system, characterize the pro- and anticonvulsive effects of cannabinoids [e.g., Δ9-tetrahydrocannabinol and cannabidiol (CBD)], and highlight scientific evidence from pre-clinical and clinical trials of cannabinoids in epilepsy. These studies suggest that CBD avoids the psychoactive effects of the endocannabinoid system to provide a well-tolerated, promising therapeutic for the treatment of seizures, while whole-plant cannabis can both contribute to and reduce seizures. Finally, we discuss results from a new multicenter, open-label study using CBD in a population with treatment-resistant epilepsy. In all, we seek to evaluate our current understanding of cannabinoids in epilepsy and guide future basic science and clinical studies.
Human Laboratory Studies on Cannabinoids and Psychosis.

PubMed

Sherif, Mohamed; Radhakrishnan, Rajiv; D'Souza, Deepak Cyril; Ranganathan, Mohini

2016-04-01

Some of the most compelling evidence supporting an association between cannabinoid agonists and psychosis comes from controlled laboratory studies in humans. Randomized, double-blind, placebo-controlled, crossover laboratory studies demonstrate that cannabinoid agonists, including phytocannabinoids and synthetic cannabinoids, produce a wide range of positive, negative, and cognitive symptoms and psychophysiologic deficits in healthy human subjects that resemble the phenomenology of schizophrenia. These effects are time locked to drug administration, are dose related, and are transient and rarely necessitate intervention. The magnitude of effects is similar to the effects of ketamine but qualitatively distinct from other psychotomimetic drugs, including ketamine, amphetamine, and salvinorin A. Cannabinoid agonists have also been shown to transiently exacerbate symptoms in individuals with schizophrenia in laboratory studies. Patients with schizophrenia are more vulnerable than healthy control subjects to the acute behavioral and cognitive effects of cannabinoid agonists and experience transient exacerbation of symptoms despite treatment with antipsychotic medications. Furthermore, laboratory studies have failed to demonstrate any "beneficial" effects of cannabinoid agonists in individuals with schizophrenia-challenging the cannabis self-medication hypothesis. Emerging evidence suggests that polymorphisms of several genes related to dopamine metabolism (e.g., COMT, DAT1, and AKT1) may moderate the effects of cannabinoid agonists in laboratory studies. Cannabinoid agonists induce dopamine release, although the magnitude of release does not appear to be commensurate to the magnitude and spectrum of their acute psychotomimetic effects. Interactions between the endocannabinoid, gamma-aminobutyric acid, and glutamate systems and their individual and interactive effects on neural oscillations provide a plausible mechanism underlying the psychotomimetic effects of cannabinoids. Copyright © 2016. Published by Elsevier Inc.
Neuroprotective antioxidants from marijuana.

PubMed

Hampson, A J; Grimaldi, M; Lolic, M; Wink, D; Rosenthal, R; Axelrod, J

2000-01-01

Cannabidiol and other cannabinoids were examined as neuroprotectants in rat cortical neuron cultures exposed to toxic levels of the neurotransmitter, glutamate. The psychotropic cannabinoid receptor agonist delta 9-tetrahydrocannabinol (THC) and cannabidiol, (a non-psychoactive constituent of marijuana), both reduced NMDA, AMPA and kainate receptor mediated neurotoxicities. Neuroprotection was not affected by cannabinoid receptor antagonist, indicating a (cannabinoid) receptor-independent mechanism of action. Glutamate toxicity can be reduced by antioxidants. Using cyclic voltametry and a fenton reaction based system, it was demonstrated that Cannabidiol, THC and other cannabinoids are potent antioxidants. As evidence that cannabinoids can act as an antioxidants in neuronal cultures, cannabidiol was demonstrated to reduce hydroperoxide toxicity in neurons. In a head to head trial of the abilities of various antioxidants to prevent glutamate toxicity, cannabidiol was superior to both alpha-tocopherol and ascorbate in protective capacity. Recent preliminary studies in a rat model of focal cerebral ischemia suggest that cannabidiol may be at least as effective in vivo as seen in these in vitro studies.
Involvement of the Endocannabinoid System in the Development and Treatment of Breast Cancer

DTIC Science & Technology

2012-02-01

maximally efficacious synthetic cannabinoid that would ensure full activation of the cannabinoid receptors (1,2). We also expanded the spectrum of...of the data failed to demonstrate significance (fig 2A, B and C). We then expanded these experiments to the synthetic cannabinoid CP55,940 (CP55...radiation treatment in various breast cancer cell lines has the capacity to enhance the inhibition of tumor growth. Marijuana and its related
Involvement of the Endocannabinoid System in the Development and Treatment of Breast Cancer

DTIC Science & Technology

2013-02-01

looking at the interaction of the synthetic cannabinoid WIN55,212-2 and ionizing radiation has led to preliminary results implicating a novel site of...we found that the various cannabinoids do not interfere with the anti-proliferative effects of either treatment; furthermore, the synthetic ...aminoalkylindole series, is one of the most highly studied synthetic cannabinoids. It has been shown to produce the full spectrum of psychoactive effects
Cannabinoids for treating inflammatory bowel diseases: where are we and where do we go?

PubMed

Hasenoehrl, Carina; Storr, Martin; Schicho, Rudolf

2017-04-01

Fifty years after the discovery of Δ 9 -tetrahydrocannabinol (THC) as the psychoactive component of Cannabis, we are assessing the possibility of translating this herb into clinical treatment of inflammatory bowel diseases (IBDs). Here, a discussion on the problems associated with a potential treatment is given. From first surveys and small clinical studies in patients with IBD we have learned that Cannabis is frequently used to alleviate diarrhea, abdominal pain, and loss of appetite. Single ingredients from Cannabis, such as THC and cannabidiol, commonly described as cannabinoids, are responsible for these effects. Synthetic cannabinoid receptor agonists are also termed cannabinoids, some of which, like dronabinol and nabilone, are already available with a narcotic prescription. Areas covered: Recent data on the effects of Cannabis/cannabinoids in experimental models of IBD and in clinical trials with IBD patients have been reviewed using a PubMed database search. A short background on the endocannabinoid system is also provided. Expert commentary: Cannabinoids could be helpful for certain symptoms of IBD, but there is still a lack of clinical studies to prove efficacy, tolerability and safety of cannabinoid-based medication for IBD patients, leaving medical professionals without evidence and guidelines.
Cannabinoids for treating inflammatory bowel diseases: where are we and where do we go?

PubMed Central

Hasenoehrl, Carina; Storr, Martin; Schicho, Rudolf

2017-01-01

ABSTRACT Introduction: Fifty years after the discovery of Δ9-tetrahydrocannabinol (THC) as the psychoactive component of Cannabis, we are assessing the possibility of translating this herb into clinical treatment of inflammatory bowel diseases (IBDs). Here, a discussion on the problems associated with a potential treatment is given. From first surveys and small clinical studies in patients with IBD we have learned that Cannabis is frequently used to alleviate diarrhea, abdominal pain, and loss of appetite. Single ingredients from Cannabis, such as THC and cannabidiol, commonly described as cannabinoids, are responsible for these effects. Synthetic cannabinoid receptor agonists are also termed cannabinoids, some of which, like dronabinol and nabilone, are already available with a narcotic prescription. Areas covered: Recent data on the effects of Cannabis/cannabinoids in experimental models of IBD and in clinical trials with IBD patients have been reviewed using a PubMed database search. A short background on the endocannabinoid system is also provided. Expert commentary: Cannabinoids could be helpful for certain symptoms of IBD, but there is still a lack of clinical studies to prove efficacy, tolerability and safety of cannabinoid-based medication for IBD patients, leaving medical professionals without evidence and guidelines. PMID:28276820

Cannabinoids and glucocorticoids modulate emotional memory after stress.

PubMed

Akirav, Irit

2013-12-01

Bidirectional and functional relationships between glucocorticoids and the endocannabinoid system have been demonstrated. Here, I review the interaction between the endocannabinoid and glucocorticoid/stress systems. Specifically, stress is known to produce rapid changes in endocannabinoid signaling in stress-responsive brain regions. In turn, the endocannabinoid system plays an important role in the downregulation and habituation of hypothalamic-pituitary-adrenocortical (HPA) axis activity in response to stress. Glucocorticoids also recruit the endocannabinoid system to exert rapid negative feedback control of the HPA axis during stress. It became increasingly clear, however, that cannabinoid CB1 receptors are also abundantly expressed in the basolateral amygdala (BLA) and other limbic regions where they modulate emotional arousal effects on memory. Enhancing cannabinoids signaling using exogenous CB1 receptor agonists prevent the effects of acute stress on emotional memory. I propose a model suggesting that the ameliorating effects of exogenously administered cannabinoids on emotional learning after acute stress are mediated by the decrease in the activity of the HPA axis via GABAergic mechanisms in the amygdala. Copyright © 2013 Elsevier Ltd. All rights reserved.
Modulation of the Endocannabinoid System: Vulnerability Factor and New Treatment Target for Stimulant Addiction

PubMed Central

Olière, Stéphanie; Jolette-Riopel, Antoine; Potvin, Stéphane; Jutras-Aswad, Didier

2013-01-01

Cannabis is one of the most widely used illicit substance among users of stimulants such as cocaine and amphetamines. Interestingly, increasing recent evidence points toward the involvement of the endocannabinoid system (ECBS) in the neurobiological processes related to stimulant addiction. This article presents an up-to-date review with deep insights into the pivotal role of the ECBS in the neurobiology of stimulant addiction and the effects of its modulation on addictive behaviors. This article aims to: (1) review the role of cannabis use and ECBS modulation in the neurobiological substrates of psychostimulant addiction and (2) evaluate the potential of cannabinoid-based pharmacological strategies to treat stimulant addiction. A growing number of studies support a critical role of the ECBS and its modulation by synthetic or natural cannabinoids in various neurobiological and behavioral aspects of stimulants addiction. Thus, cannabinoids modulate brain reward systems closely involved in stimulants addiction, and provide further evidence that the cannabinoid system could be explored as a potential drug discovery target for treating addiction across different classes of stimulants. PMID:24069004
Endocannabinergic modulation of interleukin-1β in mouse hippocampus under basal conditions and after in vivo systemic lipopolysaccharide stimulation.

PubMed

Csölle, Cecília; Sperlágh, Beáta

2011-01-01

Cannabinoids play an important role in the suppression of proinflammatory cytokine production in the periphery and brain. In this study, we explored whether endogenous activation of cannabinoid (CB) 1 receptors (CB1Rs) affects interleukin (IL)-1β levels in the mouse hippocampus under basal conditions and following stimulation with in vivo bacterial lipopolysaccharide (LPS, 250 μg/kg i.p.). IL-1β levels were determined in the hippocampi of wild-type (WT), CB1R-/- and P2X₇ receptor (P2X₇R)-/- mice using an ELISA kit. Basal but not LPS-induced IL-1β levels were downregulated when CB1R function was abrogated by genetic deletion, suggesting that endocannabinoids contributed to basal IL-1β content in the mouse hippocampus. AM251 (3 mg/kg i.p.), an antagonist of CB1Rs, also inhibited basal IL-1β protein in WT but not in CB1R-/- mice. In the absence of P2X₇R, LPS-induced IL-1β production was lower, while the inhibitory effect of CB1R antagonists on basal IL-1β was significantly attenuated. The LPS-induced elevation in IL-1β production was decreased in the presence of AM251 and AM281, with no significant difference between WT and P2X₇R-/- mice. CB1Rs are responsible for the modulation of basal IL-1β levels in the hippocampus, while the effects of CB1 antagonists on systemic LPS-induced IL-1β concentrations are independent of CB1Rs. Copyright © 2011 S. Karger AG, Basel.
Involvement of cannabinoid receptors in infrasonic noise-induced neuronal impairment.

PubMed

Ma, Lei; He, Hua; Liu, Xuedong; Zhang, Guangyun; Li, Li; Yan, Song; Li, Kangchu; Shi, Ming

2015-08-01

Excessive exposure to infrasound, a kind of low-frequency but high-intensity sound noise generated by heavy transportations and machineries, can cause vibroacoustic disease which is a progressive and systemic disease, and finally results in the dysfunction of central nervous system. Our previous studies have demonstrated that glial cell-mediated inflammation may contribute to infrasound-induced neuronal impairment, but the underlying mechanisms are not fully understood. Here, we show that cannabinoid (CB) receptors may be involved in infrasound-induced neuronal injury. After exposure to infrasound at 16 Hz and 130 dB for 1-14 days, the expression of CB receptors in rat hippocampi was gradually but significantly decreased. Their expression levels reached the minimum after 7- to 14-day exposure during which the maximum number of apoptotic cells was observed in the CA1. 2-Arachidonoylglycerol (2-AG), an endogenous agonist for CB receptors, reduced the number of infrasound-triggered apoptotic cells, which, however, could be further increased by CB receptor antagonist AM251. In animal behavior performance test, 2-AG ameliorated the infrasound-impaired learning and memory abilities of rats, whereas AM251 aggravated the infrasound-impaired learning and memory abilities of rats. Furthermore, the levels of proinflammatory cytokines tumor necrosis factor alpha and interleukin-1β in the CA1 were upregulated after infrasound exposure, which were attenuated by 2-AG but further increased by AM251. Thus, our results provide the first evidence that CB receptors may be involved in infrasound-induced neuronal impairment possibly by affecting the release of proinflammatory cytokines. © The Author 2015. Published by ABBS Editorial Office in association with Oxford University Press on behalf of the Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences.
A Lipid Pathway for Ligand Binding Is Necessary for a Cannabinoid G Protein-coupled Receptor*

PubMed Central

Hurst, Dow P.; Grossfield, Alan; Lynch, Diane L.; Feller, Scott; Romo, Tod D.; Gawrisch, Klaus; Pitman, Michael C.; Reggio, Patricia H.

2010-01-01

Recent isothiocyanate covalent labeling studies have suggested that a classical cannabinoid, (−)-7′-isothiocyanato-11-hydroxy-1′,1′dimethylheptyl-hexahydrocannabinol (AM841), enters the cannabinoid CB2 receptor via the lipid bilayer (Pei, Y., Mercier, R. W., Anday, J. K., Thakur, G. A., Zvonok, A. M., Hurst, D., Reggio, P. H., Janero, D. R., and Makriyannis, A. (2008) Chem. Biol. 15, 1207–1219). However, the sequence of steps involved in such a lipid pathway entry has not yet been elucidated. Here, we test the hypothesis that the endogenous cannabinoid sn-2-arachidonoylglycerol (2-AG) attains access to the CB2 receptor via the lipid bilayer. To this end, we have employed microsecond time scale all-atom molecular dynamics (MD) simulations of the interaction of 2-AG with CB2 via a palmitoyl-oleoyl-phosphatidylcholine lipid bilayer. Results suggest the following: 1) 2-AG first partitions out of bulk lipid at the transmembrane α-helix (TMH) 6/7 interface; 2) 2-AG then enters the CB2 receptor binding pocket by passing between TMH6 and TMH7; 3) the entrance of the 2-AG headgroup into the CB2 binding pocket is sufficient to trigger breaking of the intracellular TMH3/6 ionic lock and the movement of the TMH6 intracellular end away from TMH3; and 4) subsequent to protonation at D3.49/D6.30, further 2-AG entry into the ligand binding pocket results in both a W6.48 toggle switch change and a large influx of water. To our knowledge, this is the first demonstration via unbiased molecular dynamics that a ligand can access the binding pocket of a class A G protein-coupled receptor via the lipid bilayer and the first demonstration via molecular dynamics of G protein-coupled receptor activation triggered by a ligand binding event. PMID:20220143
Neural contractions in colonic strips from patients with diverticular disease: role of endocannabinoids and substance P.

PubMed

Guagnini, F; Valenti, M; Mukenge, S; Matias, I; Bianchetti, A; Di Palo, S; Ferla, G; Di Marzo, V; Croci, T

2006-07-01

Diverticulosis is a common disease of not completely defined pathogenesis. Motor abnormalities of the intestinal wall have been frequently described but very little is known about their mechanisms. We investigated in vitro the neural response of colonic longitudinal muscle strips from patients undergoing surgery for complicated diverticular disease (diverticulitis). The neural contractile response to electrical field stimulation of longitudinal muscle strips from the colon of patients undergoing surgery for colonic cancer or diverticulitis was challenged by different receptor agonists and antagonists. Contractions of colonic strips from healthy controls and diverticulitis specimens were abolished by atropine. The beta adrenergic agonist (-) isoprenaline and the tachykinin NK1 receptor antagonist SR140333 had similar potency in reducing the electrical twitch response in controls and diseased tissues, while the cannabinoid receptor agonist (+)WIN 55,212-2 was 100 times more potent in inhibiting contractions in controls (IC50 42 nmol/l) than in diverticulitis strips. SR141716, a selective antagonist of the cannabinoid CB1 receptor, had no intrinsic activity in control preparations but potentiated the neural twitch in diseased tissues by up to 196% in a concentration dependent manner. SR141716 inhibited (+)WIN 55,212-2 induced relaxation in control strips but had no efficacy on (+)WIN 55,212-2 responses in strips from diverticular disease patients. Colonic levels of the endogenous ligand of cannabinoid and vanilloid TRPV1 receptors anandamide were more than twice those of control tissues (54 v 27 pmol/g tissue). The axonal conduction blocker tetrodotoxin had opposite effects in the two preparations, completely inhibiting the contractions of control strips but potentiating those in diverticular preparations, an effect selectively inhibited by SR140333. Neural control of colon motility is profoundly altered in patients with diverticulitis. Their raised levels of anandamide, apparent desensitisation of the presynaptic neural cannabinoid CB1 receptor, and the SR141716 induced intrinsic response, suggest that endocannabinoids may be involved in the pathophysiology of complications of colonic diverticular disease.
Endocannabinoid System: A Multi-Facet Therapeutic Target.

PubMed

Kaur, Rimplejeet; Ambwani, Sneha R; Singh, Surjit

2016-01-01

Cannabis sativa is also popularly known as marijuana. It has been cultivated and used by man for recreational and medicinal purposes since many centuries. Study of cannabinoids was at bay for very long time and its therapeutic value could not be adequately harnessed due to its legal status as proscribed drug in most of the countries. The research of drugs acting on endocannabinoid system has seen many ups and downs in the recent past. Presently, it is known that endocannabinoids has role in pathology of many disorders and they also serve "protective role" in many medical conditions. Several diseases like emesis, pain, inflammation, multiple sclerosis, anorexia, epilepsy, glaucoma, schizophrenia, cardiovascular disorders, cancer, obesity, metabolic syndrome related diseases, Parkinson's disease, Huntington's disease, Alzheimer's disease and Tourette's syndrome could possibly be treated by drugs modulating endocannabinoid system. Presently, cannabinoid receptor agonists like nabilone and dronabinol are used for reducing the chemotherapy induced vomiting. Sativex (cannabidiol and THC combination) is approved in the UK, Spain and New Zealand to treat spasticity due to multiple sclerosis. In US it is under investigation for cancer pain, another drug Epidiolex (cannabidiol) is also under investigation in US for childhood seizures. Rimonabant, CB1 receptor antagonist appeared as a promising anti-obesity drug during clinical trials but it also exhibited remarkable psychiatric side effect profile. Due to which the US Food and Drug Administration did not approve Rimonabant in US. It sale was also suspended across the EU in 2008. Recent discontinuation of clinical trial related to FAAH inhibitor due to occurrence of serious adverse events in the participating subjects could be discouraging for the research fraternity. Despite some mishaps in clinical trials related to drugs acting on endocannabinoid system, still lot of research is being carried out to explore and establish the therapeutic targets for both cannabinoid receptor agonists and antagonists. One challenge is to develop drugs that target only cannabinoid receptors in a particular tissue and another is to invent drugs that act selectively on cannabinoid receptors located outside the blood brain barrier. Besides this, development of the suitable dosage forms with maximum efficacy and minimum adverse effects is also warranted. Another angle to be introspected for therapeutic abilities of this group of drugs is non-CB1 and non-CB2 receptor targets for cannabinoids. In order to successfully exploit the therapeutic potential of endocannabinoid system, it is imperative to further characterize the endocannabinoid system in terms of identification of the exact cellular location of cannabinoid receptors and their role as "protective" and "disease inducing substance", time-dependent changes in the expression of cannabinoid receptors.
Can cannabinoids be a potential therapeutic tool in amyotrophic lateral sclerosis?

PubMed

Giacoppo, Sabrina; Mazzon, Emanuela

2016-12-01

Amyotrophic lateral sclerosis (ALS) is the most common degenerative disease of the motor neuron system. Over the last years, a growing interest was aimed to discovery new innovative and safer therapeutic approaches in the ALS treatment. In this context, the bioactive compounds of Cannabis sativa have shown antioxidant, anti-inflammatory and neuroprotective effects in preclinical models of central nervous system disease. However, most of the studies proving the ability of cannabinoids in delay disease progression and prolong survival in ALS were performed in animal model, whereas the few clinical trials that investigated cannabinoids-based medicines were focused only on the alleviation of ALS-related symptoms, not on the control of disease progression. The aim of this report was to provide a short but important overview of evidences that are useful to better characterize the efficacy as well as the molecular pathways modulated by cannabinoids.
CB2 Cannabinoid Receptor Knockout in Mice Impairs Contextual Long-Term Memory and Enhances Spatial Working Memory

PubMed Central

Li, Yong; Kim, Jimok

2016-01-01

Neurocognitive effects of cannabinoids have been extensively studied with a focus on CB1 cannabinoid receptors because CB1 receptors have been considered the major cannabinoid receptor in the nervous system. However, recent discoveries of CB2 cannabinoid receptors in the brain demand accurate determination of whether and how CB2 receptors are involved in the cognitive effects of cannabinoids. CB2 cannabinoid receptors are primarily involved in immune functions, but also implicated in psychiatric disorders such as schizophrenia and depression. Here, we examined the effects of CB2 receptor knockout in mice on memory to determine the roles of CB2 receptors in modulating cognitive function. Behavioral assays revealed that hippocampus-dependent, long-term contextual fear memory was impaired whereas hippocampus-independent, cued fear memory was normal in CB2 receptor knockout mice. These mice also displayed enhanced spatial working memory when tested in a Y-maze. Motor activity and anxiety of CB2 receptor knockout mice were intact when assessed in an open field arena and an elevated zero maze. In contrast to the knockout of CB2 receptors, acute blockade of CB2 receptors by AM603 in C57BL/6J mice had no effect on memory, motor activity, or anxiety. Our results suggest that CB2 cannabinoid receptors play diverse roles in regulating memory depending on memory types and/or brain areas. PMID:26819779
Small Molecules from Nature Targeting G-Protein Coupled Cannabinoid Receptors: Potential Leads for Drug Discovery and Development

PubMed Central

Sharma, Charu; Sadek, Bassem; Goyal, Sameer N.; Sinha, Satyesh; Ojha, Shreesh

2015-01-01

The cannabinoid molecules are derived from Cannabis sativa plant which acts on the cannabinoid receptors types 1 and 2 (CB1 and CB2) which have been explored as potential therapeutic targets for drug discovery and development. Currently, there are numerous cannabinoid based synthetic drugs used in clinical practice like the popular ones such as nabilone, dronabinol, and Δ9-tetrahydrocannabinol mediates its action through CB1/CB2 receptors. However, these synthetic based Cannabis derived compounds are known to exert adverse psychiatric effect and have also been exploited for drug abuse. This encourages us to find out an alternative and safe drug with the least psychiatric adverse effects. In recent years, many phytocannabinoids have been isolated from plants other than Cannabis. Several studies have shown that these phytocannabinoids show affinity, potency, selectivity, and efficacy towards cannabinoid receptors and inhibit endocannabinoid metabolizing enzymes, thus reducing hyperactivity of endocannabinoid systems. Also, these naturally derived molecules possess the least adverse effects opposed to the synthetically derived cannabinoids. Therefore, the plant based cannabinoid molecules proved to be promising and emerging therapeutic alternative. The present review provides an overview of therapeutic potential of ligands and plants modulating cannabinoid receptors that may be of interest to pharmaceutical industry in search of new and safer drug discovery and development for future therapeutics. PMID:26664449
Ultra-low dose naltrexone enhances cannabinoid-induced antinociception.

PubMed

Paquette, Jay; Olmstead, Mary C; Olmstead, Mary

2005-12-01

Both opioids and cannabinoids have inhibitory effects at micromolar doses, which are mediated by activated receptors coupling to Gi/o-proteins. Surprisingly, the analgesic effects of opioids are enhanced by ultra-low doses (nanomolar to picomolar) of the opioid antagonist, naltrexone. As opioid and cannabinoid systems interact, this study investigated whether ultra-low dose naltrexone also influences cannabinoid-induced antinociception. Separate groups of Long-Evans rats were tested for antinociception following an injection of vehicle, a sub-maximal dose of the cannabinoid agonist WIN 55 212-2, naltrexone (an ultra-low or a high dose) or a combination of WIN 55 212-2 and naltrexone doses. Tail-flick latencies were recorded for 3 h, at 10-min intervals for the first hour, and at 15-min intervals thereafter. Ultra-low dose naltrexone elevated WIN 55 212-2-induced tail flick thresholds without extending its duration of action. This enhancement was replicated in animals receiving intraperitoneal or intravenous injections. A high dose of naltrexone had no effect on WIN 55 212-2-induced tail flick latencies, but a high dose of the cannabinoid 1 receptor antagonist SR 141716 blocked the elevated tail-flick thresholds produced by WIN 55 212-2+ultra-low dose naltrexone. These data suggest a mechanism of cannabinoid-opioid interaction whereby activated opioid receptors that couple to Gs-proteins may attenuate cannabinoid-induced antinociception and/or motor functioning.
The Therapeutic Potential of Cannabinoids for Movement Disorders

PubMed Central

Kluger, Benzi; Triolo, Piera; Jones, Wallace; Jankovic, Joseph

2014-01-01

Background There is growing interest in the therapeutic potential of marijuana (cannabis) and cannabinoid-based chemicals within the medical community and particularly for neurologic conditions. This interest is driven both by changes in the legal status of cannabis in many areas and increasing research into the roles of endocannabinoids within the central nervous system and their potential as symptomatic and/or neuroprotective therapies. We review basic science, preclinical and clinical studies on the therapeutic potential of cannabinoids specifically as it relates to movement disorders. Results The pharmacology of cannabis is complex with over 60 neuroactive chemicals identified to date. The endocannabinoid system modulates neurotransmission involved in motor function, particularly within the basal ganglia. Preclinical research in animal models of several movement disorders have shown variable evidence for symptomatic benefits but more consistently suggest potential neuroprotective effects in several animal models of Parkinson’s (PD) and Huntington’s disease (HD). Clinical observations and clinical trials of cannabinoid-based therapies suggests a possible benefit of cannabinoids for tics and probably no benefit for tremor in multiple sclerosis or dyskinesias or motor symptoms in PD. Data are insufficient to draw conclusions regarding HD, dystonia or ataxia and nonexistent for myoclonus or restless legs syndrome. Conclusions Despite the widespread publicity about the medical benefits of cannabinoids, further preclinical and clinical research is needed to better characterize the pharmacological, physiological and therapeutic effects of this class of drugs in movement disorders. PMID:25649017
Activation of cannabinoid system in anterior cingulate cortex and orbitofrontal cortex modulates cost-benefit decision making.

PubMed

Khani, Abbas; Kermani, Mojtaba; Hesam, Soghra; Haghparast, Abbas; Argandoña, Enrike G; Rainer, Gregor

2015-06-01

Despite the evidence for altered decision making in cannabis abusers, the role of the cannabinoid system in decision-making circuits has not been studied. Here, we examined the effects of cannabinoid modulation during cost-benefit decision making in the anterior cingulate cortex (ACC) and orbitofrontal cortex (OFC), key brain areas involved in decision making. We trained different groups of rats in a delay-based and an effort-based form of cost-benefit T-maze decision-making task. During test days, the rats received local injections of either vehicle or ACEA, a cannabinoid type-1 receptor (CB1R) agonist in the ACC or OFC. We measured spontaneous locomotor activity following the same treatments and characterized CB1Rs localization on different neuronal populations within these regions using immunohistochemistry. We showed that CB1R activation in the ACC impaired decision making such that rats were less willing to invest physical effort to gain high reward. Similarly, CB1R activation in the OFC induced impulsive pattern of choice such that rats preferred small immediate rewards to large delayed rewards. Control tasks ensured that the effects were specific for differential cost-benefit tasks. Furthermore, we characterized widespread colocalizations of CB1Rs on GABAergic axonal ends but few colocalizations on glutamatergic, dopaminergic, and serotonergic neuronal ends. These results provide first direct evidence that the cannabinoid system plays a critical role in regulating cost-benefit decision making in the ACC and OFC and implicate cannabinoid modulation of synaptic ends of predominantly interneurons and to a lesser degree other neuronal populations in these two frontal regions.
Targeting the endocannabinoid system to treat anxiety-related disorders.

PubMed

Korem, Nachshon; Zer-Aviv, Tomer Mizrachi; Ganon-Elazar, Eti; Abush, Hila; Akirav, Irit

2016-05-01

The endocannabinoid system plays an important role in the control of emotions, and its dysregulation has been implicated in several psychiatric disorders. The most common self-reported reason for using cannabis is rooted in its ability to reduce feelings of stress, tension, and anxiety. Nevertheless, there are only few studies in controlled clinical settings that confirm that administration of cannabinoids can benefit patients with a post-traumatic stress disorder (PTSD). There are considerable encouraging preclinical data to suggest that endocannabinoid-targeted therapeutics for anxiety disorders should continue. In this review, we will describe data supporting a role for the endocannabinoid system in preventing and treating anxiety-like behavior in animal models and PTSD patients. Cannabinoids have shown beneficial outcomes in rat and mouse models of anxiety and PTSD, but they also may have untoward effects that discourage their chronic usage, including anxiogenic effects. Hence, clinical and preclinical research on the endocannabinoid system should further study the effects of cannabinoids on anxiety and help determine whether the benefits of using exogenous cannabinoids outweigh the risks. In general, this review suggests that targeting the endocannabinoid system represents an attractive and novel approach to the treatment of anxiety-related disorders and, in particular, PTSD.
Attenuating Nicotine Reinforcement and Relapse by Enhancing Endogenous Brain Levels of Kynurenic Acid in Rats and Squirrel Monkeys.

PubMed

Secci, Maria E; Auber, Alessia; Panlilio, Leigh V; Redhi, Godfrey H; Thorndike, Eric B; Schindler, Charles W; Schwarcz, Robert; Goldberg, Steven R; Justinova, Zuzana

2017-07-01

The currently available antismoking medications have limited efficacy and often fail to prevent relapse. Thus, there is a pressing need for newer, more effective treatment strategies. Recently, we demonstrated that enhancing endogenous levels of kynurenic acid (KYNA, a neuroinhibitory product of tryptophan metabolism) counteracts the rewarding effects of cannabinoids by acting as a negative allosteric modulator of α7 nicotinic receptors (α7nAChRs). As the effects of KYNA on cannabinoid reward involve nicotinic receptors, in the present study we used rat and squirrel monkey models of reward and relapse to examine the possibility that enhancing KYNA can counteract the effects of nicotine. To assess specificity, we also examined models of cocaine reward and relapse in monkeys. KYNA levels were enhanced by administering the kynurenine 3-monooxygenase (KMO) inhibitor, Ro 61-8048. Treatment with Ro 61-8048 decreased nicotine self-administration in rats and monkeys, but did not affect cocaine self-administration. In rats, Ro 61-8048 reduced the ability of nicotine to induce dopamine release in the nucleus accumbens shell, a brain area believed to underlie nicotine reward. Perhaps most importantly, Ro 61-8048 prevented relapse-like behavior when abstinent rats or monkeys were reexposed to nicotine and/or cues that had previously been associated with nicotine. Ro 61-8048 was also effective in monkey models of cocaine relapse. All of these effects of Ro 61-8048 in monkeys, but not in rats, were reversed by pretreatment with a positive allosteric modulator of α7nAChRs. These findings suggest that KMO inhibition may be a promising new approach for the treatment of nicotine addiction.
Endocannabinoids as mediators in the heart: a potential target for therapy of remodelling after myocardial infarction?

PubMed Central

Hiley, C Robin; Ford, William R

2003-01-01

Endocannabinoid production by platelets and macrophages is increased in circulatory shock. This may be protective of the cardiovascular system as blockade of CB1 cannabinoid receptors exacerbates endothelial dysfunction in haemorrhagic and endotoxin shock and reduces survival. Now evidence suggests that blockade of CB1 receptors starting 24 h after myocardial infarction in rats has a deleterious effect on cardiac performance, while use of a nonselective cannabinoid receptor agonist prevents hypotension and reduces endothelial dysfunction, although left ventricular end diastolic pressure is elevated. Cannabinoids and endocannabinoid systems may therefore present useful targets for therapy following myocardial infarction. PMID:12711614
Alcohol Versus Cannabinoids: A Review of Their Opposite Neuro-Immunomodulatory Effects and Future Therapeutic Potentials

PubMed Central

Nair, Madhavan P.; Figueroa, Gloria; Casteleiro, Gianna; Muñoz, Karla; Agudelo, Marisela

2015-01-01

Due to the legalization of marijuana and the increased demand for cannabis and alcohol consumption, research efforts highlighting the biomedical consequences of the use of alcohol and cannabinoids are not only relevant to the substance abuse scientific field, but are also of public health interest. Moreover, an overview of the recent literature about alcohol and cannabinoids neuro-immunomodulatory effects highlighting their future therapeutic potentials will provide a significant contribution to science and medicine. Therefore, in the current review, we will first discuss briefly the prevalence of alcohol and marijuana abuse, followed by a discussion on the individual effects of alcohol and cannabinoids on the immune system; then, we will focus on the role of endocannabinoids on the alcohol-induced inflammatory effects. In addition, the review also incorporates cytokine array data obtained from human monocyte-derived dendritic cells, providing a different perspective on the alcohol and cannabinoid abuse divergent effects on cytokine production. The final section will highlight the therapeutic potential of cannabinoid receptors and the novel strategies to treat alcohol dependence as determined by in vitro, in vivo and clinical studies. PMID:26478902
Cannabinoids: Medical implications.

PubMed

Schrot, Richard J; Hubbard, John R

2016-01-01

Herbal cannabis has been used for thousands of years for medical purposes. With elucidation of the chemical structures of tetrahydrocannabinol (THC) and cannabidiol (CBD) and with discovery of the human endocannabinoid system, the medical usefulness of cannabinoids has been more intensively explored. While more randomized clinical trials are needed for some medical conditions, other medical disorders, like chronic cancer and neuropathic pain and certain symptoms of multiple sclerosis, have substantial evidence supporting cannabinoid efficacy. While herbal cannabis has not met rigorous FDA standards for medical approval, specific well-characterized cannabinoids have met those standards. Where medical cannabis is legal, patients typically see a physician who "certifies" that a benefit may result. Physicians must consider important patient selection criteria such as failure of standard medical treatment for a debilitating medical disorder. Medical cannabis patients must be informed about potential adverse effects, such as acute impairment of memory, coordination and judgment, and possible chronic effects, such as cannabis use disorder, cognitive impairment, and chronic bronchitis. In addition, social dysfunction may result at work/school, and there is increased possibility of motor vehicle accidents. Novel ways to manipulate the endocannbinoid system are being explored to maximize benefits of cannabinoid therapy and lessen possible harmful effects.
Activation of spinal cannabinoid CB2 receptors inhibits neuropathic pain in streptozotocin-induced diabetic mice.

PubMed

Ikeda, H; Ikegami, M; Kai, M; Ohsawa, M; Kamei, J

2013-10-10

The role of spinal cannabinoid systems in neuropathic pain of streptozotocin (STZ)-induced diabetic mice was studied. In normal mice, injection of the cannabinoid receptor agonist WIN-55,212-2 (1 and 3μg, i.t.) dose-dependently prolonged the tail-flick latency, whereas there were no changes with the injection of either cannabinoid CB1 (AM 251, 1 μg, i.t.) or CB2 (AM 630, 4 μg, i.t.) receptor antagonists. AM 251 (1 μg, i.t.), but not AM 630 (4 μg, i.t.), significantly inhibited the prolongation of the tail-flick latency induced by WIN-55,212-2 (3 μg, i.t.). In STZ-induced diabetic mice, the tail-flick latency was significantly shorter than that in normal mice. A low dose of WIN-55,212-2 (1 μg, i.t.) significantly recovered the tail-flick latency in STZ-induced diabetic mice. The effect of WIN-55,212-2 (1 μg, i.t.) in STZ-induced diabetic mice was significantly inhibited by AM 630 (4 μg, i.t.), but not AM 251 (1 μg). The selective cannabinoid CB2 receptor agonist L-759,656 (19 and 38 μg, i.t.) also dose-dependently recovered the tail-flick latency in STZ-induced diabetic mice, and this recovery was inhibited by AM 630 (4 μg, i.t.). The protein levels of cannabinoid CB1 receptors, CB2 receptors and diacylglycerol lipase α (DGL-α), the enzyme that synthesizes endocannabinoid 2-arachidonoylglycerol, in the spinal cord were examined using Western blotting. The protein levels of both cannabinoid CB1 and CB2 receptors were increased in STZ-induced diabetic mice, whereas the protein level of DGL-α was significantly decreased. These results indicate that spinal cannabinoid systems are changed in diabetic mice and suggest that cannabinoid CB2 receptor agonists might have an ability to recover diabetic neuropathic pain. Copyright © 2013 IBRO. Published by Elsevier Ltd. All rights reserved.
Chemoenzymatic synthesis and cannabinoid activity of a new diazabicyclic amide of phenylacetylricinoleic acid.

PubMed

López-Ortíz, Manuel; Herrera-Solís, Andrea; Luviano-Jardón, Axel; Reyes-Prieto, Nidia; Castillo, Ivan; Monsalvo, Ivan; Demare, Patricia; Méndez-Díaz, Mónica; Regla, Ignacio; Prospéro-García, Oscar

2010-06-01

Endocannabinoids (eCBs) are endogenous neuromodulators of synaptic transmission. Their dysfunction may cause debilitating disorders of diverse clinical manifestation. For example, drug addiction, lack of sex desire, eating disorders, such as anorexia or bulimia and dyssomnias. eCBs also participate in the regulation of core temperature and pain perception. In this context, it is important to recognize the utility of cannabinoid receptor 1 (CB1R) agonists, natural as Delta(9)-tetrahydrocannabinol (THC) or synthetic as Nabilone as useful drugs to alleviate this kind of patients' suffering. Therefore, we have developed a new drug, (R,Z)-18-((1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)-18-oxooctadec-9-en-7-yl phenylacetate (PhAR-DBH-Me), that appears to bind and activate the CB1R. This diazabicyclic amide was synthesized from phenylacetylricinoleic acid and (1S,4S)-2,5-diazabicyclo[2.2.1]heptane. To test its cannabinergic properties we evaluated its effects on core temperature, pain perception, and the sleep-waking cycle of rats. Results indicate that 20 and 40mg/kg of PhAR-DBH-Me readily reduced core temperature and increased pain perception threshold. In addition, 20mg/kg increased REM sleep in otherwise normal rats. All these effects were prevented or attenuated by AM251, a CB1R antagonist. Place preference conditioning studies indicated that this molecule does not produce rewarding effects. These results strongly support that PhAR-DBH-Me possesses cannabinoid activity without the reinforcement effects. Copyright 2010 Elsevier Ltd. All rights reserved.

Novelty-induced emotional arousal modulates cannabinoid effects on recognition memory and adrenocortical activity.

PubMed

Campolongo, Patrizia; Morena, Maria; Scaccianoce, Sergio; Trezza, Viviana; Chiarotti, Flavia; Schelling, Gustav; Cuomo, Vincenzo; Roozendaal, Benno

2013-06-01

Although it is well established that cannabinoid drugs can influence cognitive performance, the findings-describing both enhancing and impairing effects-have been ambiguous. Here, we investigated the effects of posttraining systemic administration of the synthetic cannabinoid agonist WIN55,212-2 (0.1, 0.3, or 1.0 mg/kg) on short- and long-term retention of object recognition memory under two conditions that differed in their training-associated arousal level. In male Sprague-Dawley rats that were not previously habituated to the experimental context, WIN55,212-2 administered immediately after a 3-min training trial, biphasically impaired retention performance at a 1-h interval. In contrast, WIN55,212-2 enhanced 1-h retention of rats that had received extensive prior habituation to the experimental context. Interestingly, immediate posttraining administration of WIN55,212-2 to non-habituated rats, in doses that impaired 1-h retention, enhanced object recognition performance at a 24-h interval. Posttraining WIN55,212-2 administration to habituated rats did not significantly affect 24-h retention. In light of intimate interactions between cannabinoids and the hypothalamic-pituitary-adrenal axis, we further investigated whether cannabinoid administration might differently influence training-induced glucocorticoid activity in rats in these two habituation conditions. WIN55,212-2 administered after object recognition training elevated plasma corticosterone levels in non-habituated rats whereas it decreased corticosterone levels in habituated rats. Most importantly, following pretreatment with the corticosterone-synthesis inhibitor metyrapone, WIN55,212-2 effects on 1- and 24-h retention of non-habituated rats became similar to those seen in the low-aroused habituated animals, indicating that cannabinoid-induced regulation of adrenocortical activity contributes to the environmentally sensitive effects of systemically administered cannabinoids on short- and long-term retention of object recognition memory.
Novelty-Induced Emotional Arousal Modulates Cannabinoid Effects on Recognition Memory and Adrenocortical Activity

PubMed Central

Campolongo, Patrizia; Morena, Maria; Scaccianoce, Sergio; Trezza, Viviana; Chiarotti, Flavia; Schelling, Gustav; Cuomo, Vincenzo; Roozendaal, Benno

2013-01-01

Although it is well established that cannabinoid drugs can influence cognitive performance, the findings—describing both enhancing and impairing effects—have been ambiguous. Here, we investigated the effects of posttraining systemic administration of the synthetic cannabinoid agonist WIN55,212-2 (0.1, 0.3, or 1.0 mg/kg) on short- and long-term retention of object recognition memory under two conditions that differed in their training-associated arousal level. In male Sprague-Dawley rats that were not previously habituated to the experimental context, WIN55,212-2 administered immediately after a 3-min training trial, biphasically impaired retention performance at a 1-h interval. In contrast, WIN55,212-2 enhanced 1-h retention of rats that had received extensive prior habituation to the experimental context. Interestingly, immediate posttraining administration of WIN55,212-2 to non-habituated rats, in doses that impaired 1-h retention, enhanced object recognition performance at a 24-h interval. Posttraining WIN55,212-2 administration to habituated rats did not significantly affect 24-h retention. In light of intimate interactions between cannabinoids and the hypothalamic–pituitary–adrenal axis, we further investigated whether cannabinoid administration might differently influence training-induced glucocorticoid activity in rats in these two habituation conditions. WIN55,212-2 administered after object recognition training elevated plasma corticosterone levels in non-habituated rats whereas it decreased corticosterone levels in habituated rats. Most importantly, following pretreatment with the corticosterone-synthesis inhibitor metyrapone, WIN55,212-2 effects on 1- and 24-h retention of non-habituated rats became similar to those seen in the low-aroused habituated animals, indicating that cannabinoid-induced regulation of adrenocortical activity contributes to the environmentally sensitive effects of systemically administered cannabinoids on short- and long-term retention of object recognition memory. PMID:23340520
Endocannabinoid modulation of homeostatic and non-homeostatic feeding circuits.

PubMed

Lau, Benjamin K; Cota, Daniela; Cristino, Luigia; Borgland, Stephanie L

2017-09-15

The endocannabinoid system has emerged as a key player in the control of eating. Endocannabinoids, including 2-arachidonoylglycerol (2-AG) and anandamide (AEA), modulate neuronal activity via cannabinoid 1 receptors (CB1Rs) in multiple nuclei of the hypothalamus to induce or inhibit food intake depending on nutritional and hormonal status, suggesting that endocannabinoids may act in the hypothalamus to integrate different types of signals informing about the animal's energy needs. In the mesocorticolimbic system, (endo)cannabinoids modulate synaptic transmission to promote dopamine release in response to palatable food. In addition, (endo)cannabinoids act within the nucleus accumbens to increase food's hedonic impact; although this effect depends on activation of CB1Rs at excitatory, but not inhibitory inputs in the nucleus accumbens. While hyperactivation of the endocannabinoid system is typically associated with overeating and obesity, much evidence has emerged in recent years suggesting a more complicated system than first thought - endocannabinoids promote or suppress feeding depending on cell and input type, or modulation by various neuronal or hormonal signals. This review presents our latest knowledge of the endocannabinoid system in non-homeostatic and homeostatic feeding circuits. In particular, we discuss the functional role and cellular mechanism of action by endocannabinoids within the hypothalamus and mesocorticolimbic system, and how these are modulated by neuropeptide signals related to feeding. In light of recent advances and complexity in the field, we review cannabinoid-based therapeutic strategies for the treatment of obesity and how peripheral restriction of CB1R antagonists may provide a different mechanism of weight loss without the central adverse effects. This article is part of the Special Issue entitled "A New Dawn in Cannabinoid Neurobiology". Copyright © 2017 Elsevier Ltd. All rights reserved.
The therapeutic potential of cannabinoids for movement disorders.

PubMed

Kluger, Benzi; Triolo, Piera; Jones, Wallace; Jankovic, Joseph

2015-03-01

There is growing interest in the therapeutic potential of marijuana (cannabis) and cannabinoid-based chemicals within the medical community and, particularly, for neurological conditions. This interest is driven both by changes in the legal status of cannabis in many areas and increasing research into the roles of endocannabinoids within the central nervous system and their potential as symptomatic and/or neuroprotective therapies. We review basic science as well as preclinical and clinical studies on the therapeutic potential of cannabinoids specifically as it relates to movement disorders. The pharmacology of cannabis is complex, with over 60 neuroactive chemicals identified to date. The endocannabinoid system modulates neurotransmission involved in motor function, particularly within the basal ganglia. Preclinical research in animal models of several movement disorders have shown variable evidence for symptomatic benefits, but more consistently suggest potential neuroprotective effects in several animal models of Parkinson's (PD) and Huntington's disease (HD). Clinical observations and clinical trials of cannabinoid-based therapies suggests a possible benefit of cannabinoids for tics and probably no benefit for tremor in multiple sclerosis or dyskinesias or motor symptoms in PD. Data are insufficient to draw conclusions regarding HD, dystonia, or ataxia and nonexistent for myoclonus or RLS. Despite the widespread publicity about the medical benefits of cannabinoids, further preclinical and clinical research is needed to better characterize the pharmacological, physiological, and therapeutic effects of this class of drugs in movement disorders. © 2015 International Parkinson and Movement Disorder Society.
Selective activation of cannabinoid receptor-2 reduces neuroinflammation after traumatic brain injury via alternative macrophage polarization.

PubMed

Braun, Molly; Khan, Zenab T; Khan, Mohammad B; Kumar, Manish; Ward, Ayobami; Achyut, Bhagelu R; Arbab, Ali S; Hess, David C; Hoda, Md Nasrul; Baban, Babak; Dhandapani, Krishnan M; Vaibhav, Kumar

2018-02-01

Inflammation is an important mediator of secondary neurological injury after traumatic brain injury (TBI). Endocannabinoids, endogenously produced arachidonate based lipids, have recently emerged as powerful anti-inflammatory compounds, yet the molecular and cellular mechanisms underlying these effects are poorly defined. Endocannabinoids are physiological ligands for two known cannabinoid receptors, CB1R and CB2R. In the present study, we hypothesized that selective activation of CB2R attenuates neuroinflammation and reduces neurovascular injury after TBI. Using a murine controlled cortical impact (CCI) model of TBI, we observed a dramatic upregulation of CB2R within infiltrating myeloid cells beginning at 72 h. Administration of the selective CB2R agonist, GP1a (1-5 mg/kg), attenuated pro-inflammatory M1 macrophage polarization, increased anti-inflammatory M2 polarization, reduced edema development, enhanced cerebral blood flow, and improved neurobehavioral outcomes after TBI. In contrast, the CB2R antagonist, AM630, worsened outcomes. Taken together, our findings support the development of selective CB2R agonists as a therapeutic strategy to improve TBI outcomes while avoiding the psychoactive effects of CB1R activation. Published by Elsevier Inc.
Endocannabinoids and the Endocrine System in Health and Disease.

PubMed

Hillard, Cecilia J

2015-01-01

Some of the earliest reports of the effects of cannabis consumption on humans were related to endocrine system changes. In this review, the effects of cannabinoids and the role of the CB1 cannabinoid receptor in the regulation of the following endocrine systems are discussed: the hypothalamic-pituitary-gonadal axis, prolactin and oxytocin, thyroid hormone and growth hormone, and the hypothalamic-pituitary-adrenal axis. Preclinical and human study results are presented.
CB1 cannabinoid receptor-mediated anandamide signaling mechanisms of the inferior colliculus modulate the haloperidol-induced catalepsy.

PubMed

Medeiros, P; de Freitas, R L; Silva, M O; Coimbra, N C; Melo-Thomas, L

2016-11-19

The inferior colliculus (IC), a midbrain structure that processes acoustic information of aversive nature, is distinguished from other auditory nuclei in the brainstem by its connections with structures of the motor system. Previous evidence relating the IC to motor behavior shows that glutamatergic and GABAergic mechanisms in the IC exert influence on systemic haloperidol-induced catalepsy. There is substantial evidence supporting a role played by the endocannabinoid system as a modulator of the glutamatergic neurotransmission, as well as the dopaminergic activity in the basal nuclei and therefore it may be considered as a potential pharmacological target for the treatment of movement disorders. The present study evaluated if the endocannabinoid system in the IC plays a role in the elaboration of systemic haloperidol-induced catalepsy. Male Wistar rats received intracollicular microinjection of either the endogenous cannabinoid anandamide (AEA) at different concentrations (5, 50 or 100pmol/0.2μl), the CB 1 cannabinoid receptor antagonist AM251 at 50, 100 or 200pmol/0.2μl or vehicle, followed by intraperitoneal (IP) administration of either haloperidol at 0.5 or 1mg/kg or physiological saline. Systemic injection of haloperidol at both doses (0.5 or 1mg/kg, IP) produced a cataleptic state, compared to vehicle/physiological saline-treated group, lasting 30 and 50min after systemic administration of the dopaminergic receptors non-selective antagonist. The midbrain microinjection of AEA at 50pmol/0.2μl increased the latency for stepping down from the horizontal bar after systemic administration of haloperidol. Moreover, the intracollicular administration of AEA at 50pmol/0.2μl was able to increase the duration of catalepsy as compared to AEA at 100pmol/0.2-μl-treated group. Intracollicular pretreatment with AM251 at the intermediate concentration (100pmol/0.2μl) was able to decrease the duration of catalepsy after systemic administration of haloperidol. However, neither the intracollicular microinjection of AM251 at the lowest (50pmol/0.2μl) nor at the highest (200pmol/0.2μl) concentration was able to block the systemic haloperidol-induced catalepsy. Furthermore, the intracollicular administration of AM251 at 100pmol/0.2μl was able to decrease the duration of catalepsy as compared to AM251 at 50pmol/0.2μl- and AM251 at 200pmol/0.2-μl-treated group. The latency for stepping down from the horizontal bar - induced by haloperidol administration - was decreased when microinjection of AEA at 50pmol/0.2μl was preceded with blockade of CB1 receptor with AM251 (100pmol/0.2μl). Our results strengthen the involvement of CB1-signaled endocannabinoid mechanisms of the IC in the neuromodulation of catalepsy induced by systemic administration of the dopaminergic receptors non-selective antagonist haloperidol. Copyright © 2016 IBRO. Published by Elsevier Ltd. All rights reserved.
The roles of cannabinoid and dopamine receptor systems in neural emotional learning circuits: implications for schizophrenia and addiction.

PubMed

Laviolette, S R; Grace, A A

2006-07-01

Cannabinoids represent one of the most widely used hallucinogenic drugs and induce profound alterations in sensory perception and emotional processing. Similarly, the dopamine (DA) neurotransmitter system is critical for the central processing of emotion and motivation. Functional disturbances in either of these neurotransmitter systems are well-established correlates of the psychopathological symptoms and behavioral manifestations observed in addiction and schizophrenia. Increasing evidence from the anatomical, pharmacological and behavioral neuroscience fields points to complex functional interactions between these receptor systems at the anatomical, pharmacological and neural systems levels. An important question relates to whether these systems act in an orchestrated manner to produce the emotional processing and sensory perception deficits underlying addiction and schizophrenia. This review describes evidence for functional neural interactions between cannabinoid and DA receptor systems and how disturbances in this neural circuitry may underlie the aberrant emotional learning and processing observed in disorders such as addiction and schizophrenia.
Cannabinoid receptor activation inhibits cell cycle progression by modulating 14-3-3β.

PubMed

Jung, Hye-Won; Park, Inae; Ghil, Sungho

2014-09-01

Cannabinoids display various pharmacological activities, including tumor regression, anti-inflammatory and neuroprotective effects. To investigate the molecular mechanisms underlying the pharmacological effects of cannabinoids, we used a yeast two-hybrid system to screen a mouse brain cDNA library for proteins interacting with type 1 cannabinoid receptor (CB1R). Using the intracellular loop 3 of CB1R as bait, we identified 14-3-3β as an interacting partner of CB1R and confirmed their interaction using affinity-binding assays. 14-3-3β has been reported to induce a cell cycle delay at the G2/M phase. We tested the effects of cannabinoids on cell cycle progression in HeLa cells synchronized using a double-thymidine block-and-release protocol and found an increase in the population of G2/M phase cells. We further found that CB1R activation augmented the interaction of 14-3-3β with Wee1 and Cdc25B, and promoted phosphorylation of Cdc2 at Tyr-15. These results suggest that cannabinoids induce cell cycle delay at the G2/M phase by activating 14-3-3β.
Male-female differences in the effects of cannabinoids on sexual behavior and gonadal hormone function.

PubMed

Gorzalka, Boris B; Hill, Matthew N; Chang, Sabrina C H

2010-06-01

The putative role of the endocannabinoid system and the effects of cannabis use in male and female sexual functioning are summarized. The influence of cannabis intake on sexual behavior and arousability appear to be dose-dependent in both men and women, although women are far more consistent in reporting facilitatory effects. Furthermore, evidence from nonhuman species indicate somewhat more beneficial than debilitating effects of cannabinoids on female sexual proceptivity and receptivity while suggesting predominantly detrimental effects on male sexual motivation and erectile functioning. Data from human and nonhuman species converge on the ephemeral nature of THC-induced testosterone decline. However, it is clear that cannabinoid-induced inhibition of male sexual behavior is independent of concurrent declines in testosterone levels. Investigations also reveal a suppression of gonadotropin release by cannabinoids across various species. Historical milestones and promising future directions in the area of cannabinoid and sexuality research are also outlined in this review. Copyright 2009 Elsevier Inc. All rights reserved.
[Medical cannabis: the opportunity versus the temptation].

PubMed

Naftali, Timna

2011-12-01

The cannabis plant has been known to humanity for centuries as a remedy for pain, diarrhea, and inflammation. Current research has shown cannabis to be a useful remedy for many diseases, including multiple sclerosis, dystonia, and chronic pain. Cannabinoids are used to improve food intake in anorexia of AIDS patients and to prevent vomiting due to cancer chemotherapy. In inflammatory conditions cannabinoids improve pain in rheumatoid arthritis and pain and diarrhea in Crohn's disease. Cannabinoids reduce the size of brain infarct and cardiac reperfusion injury. However, cannabinoid treatment is not free of side effects including euphoria, psychosis, anxiety, paranoia, dependence and abuse. Since the cannabinoid system is involved in many physiological and pathological processes, the therapeutic potential is great. We must not be blind to the opportunity offered to us by medical cannabis just because it is an illicit drug, nor should we be temped by the quick response of patients to the central effect of cannabis. More research is warranted to explore the full potential of cannabis as medicine.
Medical cannabis vs. synthetic cannabinoids: What does the future hold?

PubMed

Bolognini, D; Ross, R A

2015-06-01

The medical use of cannabis has an intricate therapeutic history that finds its roots in ancient China (∼2700 BC). The main psychoactive component of cannabis, Δ(9) -tetrahydrocannabinol (Δ(9) -THC), was discovered in 1964. This was a significant breakthrough, as it allowed the generation of synthetic analogs of Δ(9) -THC, the discovery of cannabinoid receptors, and the generation of synthetic small molecules. Despite this, today there is still a paucity of drugs that target the cannabinoid system. © 2015 American Society for Clinical Pharmacology and Therapeutics.
Synthetic cannabinoid and marijuana exposures reported to poison centers.

PubMed

Forrester, M B; Kleinschmidt, K; Schwarz, E; Young, A

2012-10-01

Synthetic cannabinoids have recently gained popularity as a recreational drug because they are believed to result in a marijuana-like high. This investigation compared synthetic cannabinoids and marijuana exposures reported to a large statewide poison center system. Synthetic cannabinoid and marijuana exposures reported to Texas poison centers during 2010 were identified. The distribution of exposures to the two agents with respect to various demographic and clinical factors were compared by calculating the rate ratio (RR) of the synthetic cannabinoid and marijuana percentages for each subgroup and 95% confidence interval (CI). The proportion of synthetic cannabinoid and marijuana exposures, respectively, were 87.3% and 46.5% via inhalation (RR 1.88, 95% CI 1.38-2.61), 74.9% and 65.7% in male (RR 1.14, 95% CI 0.87-1.51), 40.2% and 56.6% age ≤ 19 years (RR 0.71, 95% CI 0.52-0.98), 79.2% and 58.6% occurring at a residence (RR 1.35, 95% CI 1.02-1.82), 8.4% and 16.2% managed on-site (RR 0.52. 95% CI 0.28-1.00), and 59.3% and 41.4% with serious medical outcomes (RR 1.43, 95% CI 1.03-2.05). Compared to marijuana, synthetic cannabinoid exposures were more likely to be used through inhalation, to involve adults, to be used at a residence, and to result in serious outcomes.
Cannabinoids & Stress: impact of HU-210 on behavioral tests of anxiety in acutely stressed mice.

PubMed

Kinden, Renee; Zhang, Xia

2015-05-01

Anxiety disorders are one of the most prevalent classes of mental disorders affecting the general population, but current treatment strategies are restricted by their limited efficacy and side effect profiles. Although the cannabinoid system is speculated to be a key player in the modulation of stress responses and emotionality, the vast majority of current research initiatives had not incorporated stress exposure into their experimental designs. This study was the first to investigate the impact of exogenous cannabinoid administration in an acutely stressed mouse model, where CD1 mice were pre-treated with HU-210, a potent CB1R agonist, prior to acute stress exposure and subsequent behavioral testing. Exogenous cannabinoid administration induced distinct behavioral phenotypes in stressed and unstressed mice. While low doses of HU-210 were anxiolytic in unstressed subjects, this effect was abolished when mice were exposed to an acute stressor. The administration of higher HU-210 doses in combination with acute stress exposure led to severe locomotor deficits that were not previously observed at the same dose in unstressed subjects. These findings suggest that exogenous cannabinoids and acute stress act synergistically in an anxiogenic manner. This study underlies the importance of including stress exposure into future anxiety-cannabinoid research due to the differential impact of cannabinoid administration on stressed and unstressed subjects. Copyright © 2015 Elsevier B.V. All rights reserved.
Endocannabinoids: Effectors of glucocorticoid signaling.

PubMed

Balsevich, Georgia; Petrie, Gavin N; Hill, Matthew N

2017-10-01

For decades, there has been speculation regarding the interaction of cannabinoids with glucocorticoid systems. Given the functional redundancy between many of the physiological effects of glucocorticoids and cannabinoids, it was originally speculated that the biological mechanisms of cannabinoids were mediated by direct interactions with glucocorticoid systems. With the discovery of the endocannabinoid system, additional research demonstrated that it was actually the opposite; glucocorticoids recruit endocannabinoid signaling, and that the engagement of endocannabinoid signaling mediated many of the neurobiological and physiological effects of glucocorticoids. With the development of advances in pharmacology and genetics, significant advances in this area have been made, and it is now clear that functional interactions between these systems are critical for a wide array of physiological processes. The current review acts a comprehensive summary of the contemporary state of knowledge regarding the biological interactions between glucocorticoids and endocannabinoids, and their potential role in health and disease. Copyright © 2017 Elsevier Inc. All rights reserved.
Modulation of cannabinoid signaling by hippocampal 5-HT4 serotonergic system in fear conditioning.

PubMed

Nasehi, Mohammad; Farrahizadeh, Maryam; Ebrahimi-Ghiri, Mohaddeseh; Zarrindast, Mohammad-Reza

2016-09-01

Behavioral studies have suggested a key role for the cannabinoid system in the modulation of conditioned fear memory. Likewise, much of the literature has revealed that the serotonergic system affects Pavlovian fear conditioning and extinction. A high level of functional overlap between the serotonin and cannabinoid systems has also been reported. To clarify the interaction between the hippocampal serotonin (5-HT4) receptor and the cannabinoid CB1 receptor in the acquisition of fear memory, the effects of 5-HT4 agents, arachidonylcyclopropylamide (ACPA; CB1 receptor agonist), and the combined use of these drugs on fear learning were studied in a fear conditioning task in adult male NMRI mice. Pre-training intraperitoneal administration of ACPA (0.1 mg/kg) decreased the percentage of freezing time in both context- and tone-dependent fear conditions, suggesting impairment of the acquisition of fear memory. Pre-training, intra-hippocampal (CA1) microinjection of RS67333, a 5-HT4 receptor agonist, at doses of 0.1 and 0.2 or 0.2 µg/mouse impaired contextual and tone fear memory, respectively. A subthreshold dose of RS67333 (0.005 µg/mouse) did not alter the ACPA response in either condition. Moreover, intra-CA1 microinjection of RS23597 as a 5-HT4 receptor antagonist did not alter context-dependent fear memory acquisition, but it did impair tone-dependent fear memory acquisition. However, a subthreshold dose of the RS23597 (0.01 µg/mouse) potentiated ACPA-induced fear memory impairment in both conditions. Therefore, we suggest that the blockade of hippocampal 5-HT4 serotonergic system modulates cannabinoid signaling induced by the activation of CB1 receptors in conditioned fear. © The Author(s) 2016.
Advances Towards The Discovery of GPR55 Ligands.

PubMed

Morales, Paula; Jagerovic, Nadine

2016-01-01

The G-protein-coupled receptor 55 (GPR55) was identified in 1999. It was proposed as a novel member of the endocannabinoid system due to the fact that some endogenous, plant-derived and synthetic cannabinoid ligands act on GPR55. However, the complexity of the cellular downstream signaling pathways related to GPR55 activation delayed the discovery of selective GPR55 ligands. It was only a few years ago that the high throughput screening of libraries of pharmaceutical companies and governmental organizations allowed to identify selective GPR55 agonists and antagonists. Since then, several GPR55 modulator scaffolds have been reported. The relevance of GPR55 has been explored in diverse physiological and pathological processes revealing its role in inflammation, neuropathic pain, bone physiology, diabetes and cancer. Considering GPR55 as a new promising therapeutic target, there is a clear need for new selective and potent GPR55 modulators. This review will address a current structural update of GPR55 ligands.
Studies of the brain cannabinoid system using positron emission tomography

DOE Office of Scientific and Technical Information (OSTI.GOV)

Gatley, S.J.; Volkow, N.D.

Studies using radiolabeled psychoactive drugs in conjunction with positron emission tomography (PET) have permitted the imaging of binding sites in the human brain. Similar studies of marijuana have been hampered by the unsuitability of radiolabeled THC for PET studies, and the current unavailability of other in vivo imaging agents for cannabinoid receptors. Recent developments in medicinal chemistry suggest that a PET radiotracer for cannabinoid receptors will soon become available. This chapter briefly reviews these developments, together with the results of PET studies of the effects of marijuana and other abused drugs on brain metabolism. It also reviews PET studies ofmore » cocaine binding sites, to demonstrate the kind of investigations that will be possible when a cannabinoid receptor PET radioligand becomes available.« less
Cannabinoids Reverse the Effects of Early Stress on Neurocognitive Performance in Adulthood

ERIC Educational Resources Information Center

Alteba, Shirley; Korem, Nachshon; Akirav, Irit

2016-01-01

Early life stress (ES) significantly increases predisposition to psychopathologies. Cannabinoids may cause cognitive deficits and exacerbate the effects of ES. Nevertheless, the endocannabinoid system has been suggested as a therapeutic target for the treatment of stress- and anxiety-related disorders. Here we examined whether cannabinoids…
Cannabinoid hyperemesis syndrome: potential mechanisms for the benefit of capsaicin and hot water hydrotherapy in treatment.

PubMed

Richards, John R; Lapoint, Jeff M; Burillo-Putze, Guillermo

2018-01-01

Cannabinoid hyperemesis syndrome is a clinical disorder that has become more prevalent with increasing use of cannabis and synthetic cannabinoids, and which is difficult to treat. Standard antiemetics commonly fail to alleviate the severe nausea and vomiting characteristic of the syndrome. Curiously, cannabinoid hyperemesis syndrome patients often report dramatic relief of symptoms with hot showers and baths, and topical capsaicin. In this review, we detail the pharmacokinetics and pharmacodynamics of capsaicin and explore possible mechanisms for its beneficial effect, including activation of transient receptor potential vanilloid 1 and neurohumoral regulation. Putative mechanisms responsible for the benefit of hot water hydrotherapy are also investigated. An extensive search of PubMed, OpenGrey, and Google Scholar from inception to April 2017 was performed to identify known and theoretical thermoregulatory mechanisms associated with the endocannabinoid system. The searches resulted in 2417 articles. These articles were screened for relevant mechanisms behind capsaicin and heat activation having potential antiemetic effects. References from the selected articles were also hand-searched. A total of 137 articles were considered relevant and included. Capsaicin: Topical capsaicin is primarily used for treatment of neuropathic pain, but it has also been used successfully in some 20 cases of cannabinoid hyperemesis syndrome. The pharmacokinetics and pharmacodynamics of capsaicin as a transient receptor potential vanilloid 1 agonist may explain this effect. Topical capsaicin has a longer half-life than oral administration, thus its potential duration of benefit is longer. Capsaicin and transient receptor potential vanilloid 1: Topical capsaicin binds and activates the transient receptor potential vanilloid 1 receptor, triggering influx of calcium and sodium, as well as release of inflammatory neuropeptides leading to transient burning, stinging, and itching. This elicits a novel type of desensitization analgesia. Transient receptor potential vanilloid 1 receptors also respond to noxious stimuli, such as heat (>43 °C), acids (pH <6), pain, change in osmolarity, and endovanilloids. The action of topical capsaicin may mimic the effect of heat-activation of transient receptor potential vanilloid 1. Endocannabinoid system and transient receptor potential vanilloid 1: Cannabinoid hyperemesis syndrome may result from a derangement in the endocannabinoid system secondary to chronic exogenous stimulation. The relief of cannabinoid hyperemesis syndrome symptoms from heat and use of transient receptor potential vanilloid 1 agonists suggests a complex interrelation between the endocannabinoid system and transient receptor potential vanilloid 1. Temperature regulation: Hot water hydrotherapy is a mainstay of self-treatment for cannabinoid hyperemesis syndrome patients. This may be explained by heat-induced transient receptor potential vanilloid 1 activation. "Sensocrine" antiemetic effects: Transient receptor potential vanilloid 1 activation by heat or capsaicin results in modulation of tachykinins, somatostatin, pituitary adenylate-cyclase activating polypeptide, and calcitonin gene-related peptide as well as histaminergic, cholinergic, and serotonergic transmission. These downstream effects represent further possible explanations for transient receptor potential vanilloid 1-associated antiemesis. These complex interactions between the endocannabinoid systems and transient receptor potential vanilloid 1, in the setting of cannabinoid receptor desensitization, may yield important clues into the pathophysiology and treatment of cannabinoid hyperemesis syndrome. This knowledge can provide clinicians caring for these patients with additional treatment options that may reduce length of stay, avoid unnecessary imaging and laboratory testing, and decrease the use of potentially harmful medications such as opioids.

N-Arachidonoyl Dopamine Modulates Acute Systemic Inflammation via Nonhematopoietic TRPV1

PubMed Central

Lawton, Samira K.; Xu, Fengyun; Tran, Alphonso; Wong, Erika; Schumacher, Mark; Wilhelmsen, Kevin

2017-01-01

N-Arachidonoyl dopamine (NADA) is an endogenous lipid that potently activates the transient receptor potential vanilloid 1 (TRPV1), which mediates pain and thermosensation. NADA is also an agonist of cannabinoid receptors 1 and 2. We have reported that NADA reduces the activation of cultured human endothelial cells by LPS and TNF-α. Thus far, in vivo studies using NADA have focused on its neurologic and behavioral roles. In this article, we show that NADA potently decreases in vivo systemic inflammatory responses and levels of the coagulation intermediary plasminogen activator inhibitor 1 in three mouse models of inflammation: LPS, bacterial lipopeptide, and polymicrobial intra-abdominal sepsis. We also found that the administration of NADA increases survival in endotoxemic mice. Additionally, NADA reduces blood levels of the neuropeptide calcitonin gene-related peptide but increases the neuropeptide substance P in LPS-treated mice. We demonstrate that the anti-inflammatory effects of NADA are mediated by TRPV1 expressed by nonhematopoietic cells and provide data suggesting that neuronal TRPV1 may mediate NADA’s anti-inflammatory effects. These results indicate that NADA has novel TRPV1-dependent anti-inflammatory properties and suggest that the endovanilloid system might be targeted therapeutically in acute inflammation. PMID:28701511
The endocannabinoid system in anxiety, fear memory and habituation

PubMed Central

Ruehle, S; Rey, A Aparisi; Remmers, F

2012-01-01

Evidence for the involvement of the endocannabinoid system (ECS) in anxiety and fear has been accumulated, providing leads for novel therapeutic approaches. In anxiety, a bidirectional influence of the ECS has been reported, whereby anxiolytic and anxiogenic responses have been obtained after both increases and decreases of the endocannabinoid tone. The recently developed genetic tools have revealed different but complementary roles for the cannabinoid type 1 (CB1) receptor on GABAergic and glutamatergic neuronal populations. This dual functionality, together with the plasticity of CB1 receptor expression, particularly on GABAergic neurons, as induced by stressful and rewarding experiences, gives the ECS a unique regulatory capacity for maintaining emotional homeostasis. However, the promiscuity of the endogenous ligands of the CB1 receptor complicates the interpretation of experimental data concerning ECS and anxiety. In fear memory paradigms, the ECS is mostly involved in the two opposing processes of reconsolidation and extinction of the fear memory. Whereas ECS activation deteriorates reconsolidation, proper extinction depends on intact CB1 receptor signalling. Thus, both for anxiety and fear memory processing, endocannabinoid signalling may ensure an appropriate reaction to stressful events. Therefore, the ECS can be considered as a regulatory buffer system for emotional responses. PMID:21768162
Medical Marijuana: Just the Beginning of a Long, Strange Trip?

PubMed

Ciccone, Charles D

2017-02-01

Medical marijuana continues to gain acceptance and become legalized in many states. Various species of the marijuana plant have been cultivated, and this plant can contain up to 100 active compounds known as cannabinoids. Two cannabinoids seem the most clinically relevant: Δ9-tetrahydrocannabinol (THC), which tends to produce the psychotropic effects commonly associated with marijuana, and cannabidiol (CBD), which may produce therapeutic effects without appreciable psychoactive properties. Smoking marijuana, or ingesting extracts from the whole plant orally (in baked goods, teas, and so forth), introduces variable amounts of THC, CBD, and other minor cannabinoids into the systemic circulation, where they ultimately reach the central and peripheral nervous systems. Alternatively, products containing THC, CBD, or a combination of both compounds, can be ingested as oral tablets or via sprays applied to the oral mucosal membranes. These products may provide a more predictable method for delivering a known amount of specific cannabinoids into the body. Although there is still a need for randomized controlled trials, preliminary studies have suggested that medical marijuana and related cannabinoids may be beneficial in treating people with chronic pain, inflammation, spasticity, and other conditions seen commonly in physical therapist practice. Physical therapists, therefore, should be aware of the options that are available for patients considering medical marijuana and should be ready to provide information for these patients. Clinicians also should be aware that marijuana can produce untoward effects on cognition, coordination, balance, and cardiovascular and pulmonary function and should be vigilant for any problems that may arise if patients are using cannabinoids during physical rehabilitation. © 2017 American Physical Therapy Association.
Cannabis for inflammatory bowel disease.

PubMed

Naftali, Timna; Mechulam, Raphael; Lev, Lihi Bar; Konikoff, Fred M

2014-01-01

The marijuana plant Cannabis sativa has been used for centuries as a treatment for a variety of ailments. It contains over 60 different cannabinoid compounds. Studies have revealed that the endocannabinoid system is involved in almost all major immune events. Cannabinoids may, therefore, be beneficial in inflammatory disorders. In murine colitis, cannabinoids decrease histologic and microscopic inflammation. In humans, cannabis has been used to treat a plethora of gastrointestinal problems, including anorexia, emesis, abdominal pain, diarrhea, and diabetic gastroparesis. Despite anecdotal reports on medical cannabis in inflammatory bowel disease (IBD), there are few controlled studies. In an observational study in 30 patients with Crohn's disease (CD), we found that medical cannabis was associated with improvement in disease activity and reduction in the use of other medications. In a more recent placebo-controlled study in 21 chronic CD patients, we showed a decrease in the CD activity index >100 in 10 of 11 subjects on cannabis compared to 4 of 10 on placebo. Complete remission was achieved in 5 of 11 subjects in the cannabis group and 1 of 10 in the placebo group. Yet, in an additional study, low-dose cannabidiol did not have an effect on CD activity. In summary, evidence is gathering that manipulating the endocannabinoid system can have beneficial effects in IBD, but further research is required to declare cannabinoids a medicine. We need to establish the specific cannabinoids, as well as appropriate medical conditions, optimal dose, and mode of administration, to maximize the beneficial effects while avoiding any potential harmful effects of cannabinoid use. © 2014 S. Karger AG, Basel.
Actions of the dual FAAH/MAGL inhibitor JZL195 in a murine neuropathic pain model

PubMed Central

Adamson Barnes, Nicholas S.; Mitchell, Vanessa A.; Kazantzis, Nicholas P.

2015-01-01

Background and Purpose While cannabinoids have been proposed as a potential treatment for neuropathic pain, they have limitations. Cannabinoid receptor agonists have good efficacy in animal models of neuropathic pain; they have a poor therapeutic window. Conversely, selective fatty acid amide hydrolase (FAAH) inhibitors that enhance the endocannabinoid system have a better therapeutic window, but lesser efficacy. We examined whether JZL195, a dual inhibitor of FAAH and monacylglycerol lipase (MAGL), could overcome these limitations. Experimental Approach C57BL/6 mice underwent the chronic constriction injury (CCI) model of neuropathic pain. Mechanical and cold allodynia, plus cannabinoid side effects, were assessed in response to systemic drug application. Key Results JZL195 and the cannabinoid receptor agonist WIN55212 produced dose‐dependent reductions in CCI‐induced mechanical and cold allodynia, plus side effects including motor incoordination, catalepsy and sedation. JZL195 reduced allodynia with an ED50 at least four times less than that at which it produced side effects. By contrast, WIN55212 reduced allodynia and produce side effects with similar ED50s. The maximal anti‐allodynic effect of JZL195 was greater than that produced by selective FAAH, or MAGL inhibitors. The JZL195‐induced anti‐allodynia was maintained during repeated treatment. Conclusions and Implications These findings suggest that JZL195 has greater anti‐allodynic efficacy than selective FAAH, or MAGL inhibitors, plus a greater therapeutic window than a cannabinoid receptor agonist. Thus, dual FAAH/MAGL inhibition may have greater potential in alleviating neuropathic pain, compared with selective FAAH and MAGL inhibitors, or cannabinoid receptor agonists. PMID:26398331
Endogenous fatty acid ethanolamides suppress nicotine-induced activation of mesolimbic dopamine neurons through nuclear receptors.

PubMed

Melis, Miriam; Pillolla, Giuliano; Luchicchi, Antonio; Muntoni, Anna Lisa; Yasar, Sevil; Goldberg, Steven R; Pistis, Marco

2008-12-17

Nicotine stimulates the activity of mesolimbic dopamine neurons, which is believed to mediate the rewarding and addictive properties of tobacco use. Accumulating evidence suggests that the endocannabinoid system might play a major role in neuronal mechanisms underlying the rewarding properties of drugs of abuse, including nicotine. Here, we investigated the modulation of nicotine effects by the endocannabinoid system on dopamine neurons in the ventral tegmental area with electrophysiological techniques in vivo and in vitro. We discovered that pharmacological inhibition of fatty acid amide hydrolase (FAAH), the enzyme that catabolizes fatty acid ethanolamides, among which the endocannabinoid anandamide (AEA) is the best known, suppressed nicotine-induced excitation of dopamine cells. Importantly, this effect was mimicked by the administration of the FAAH substrates oleoylethanolamide (OEA) and palmitoylethanolamide (PEA), but not methanandamide, the hydrolysis resistant analog of AEA. OEA and PEA are naturally occurring lipid signaling molecules structurally related to AEA, but devoid of affinity for cannabinoid receptors. They blocked the effects of nicotine by activation of the peroxisome proliferator-activated receptor-alpha (PPAR-alpha), a nuclear receptor transcription factor involved in several aspects of lipid metabolism and energy balance. Activation of PPAR-alpha triggered a nongenomic stimulation of tyrosine kinases, which might lead to phosphorylation and negative regulation of neuronal nicotinic acetylcholine receptors. These data indicate for the first time that the anorexic lipids OEA and PEA possess neuromodulatory properties as endogenous ligands of PPAR-alpha in the brain and provide a potential new target for the treatment of nicotine addiction.
Evaluation of fatty acid amides in the carrageenan-induced paw edema model.

PubMed

Wise, Laura E; Cannavacciulo, Roberta; Cravatt, Benjamin F; Martin, Billy F; Lichtman, Aron H

2008-01-01

While it has long been recognized that Delta(9)-tetrahydrocannabinol (THC), the primary psychoactive constituent of cannabis, and other cannabinoid receptor agonists possess anti-inflammatory properties, their well known CNS effects have dampened enthusiasm for therapeutic development. On the other hand, genetic deletion of fatty acid amide hydrolase (FAAH), the enzyme responsible for degradation of fatty acid amides, including endogenous cannabinoid N-arachidonoyl ethanolamine (anandamide; AEA), N-palmitoyl ethanolamine (PEA), N-oleoyl ethanolamine (OEA), and oleamide, also elicits anti-edema, but does not produce any apparent cannabinoid effects. The purpose of the present study was to investigate whether exogenous administration of FAAs would augment the anti-inflammatory phenotype of FAAH (-/-) mice in the carrageenan model. Thus, we evaluated the effects of the FAAs AEA, PEA, OEA, and oleamide in wild-type and FAAH (-/-) mice. For comparison, we evaluated the anti-edema effects of THC, dexamethasone (DEX), a synthetic glucocorticoid, diclofenac (DIC), a nonselective cyclooxygenase (COX) inhibitor, in both genotypes. A final study determined if tolerance to the anti-edema effects of PEA occurs after repeated dosing. PEA, THC, DEX, DIC elicited significant decreases in carrageenan-induced paw edema in wild-type mice. In contrast OEA produced a less reliable anti-edema effect than these other drugs, and AEA and oleamide failed to produce any significant decreases in paw edema. Moreover, none of the agents evaluated augmented the anti-edema phenotype of FAAH (-/-) mice, suggesting that maximal anti-edema effects had already been established. PEA was the most effective FAA in preventing paw edema and its effects did not undergo tolerance. While the present findings do not support a role for AEA in preventing carrageenan-induced edema, PEA administration and FAAH blockade elicited anti-edema effects of an equivalent magnitude as produced by THC, DEX, and DIC in this assay.
Developmental pattern of diacylglycerol lipase-α (DAGLα) immunoreactivity in brain regions important for song learning and control in the zebra finch (Taeniopygia guttata).

PubMed

Soderstrom, Ken; Wilson, Ashley R

2013-11-01

Zebra finch song is a learned behavior dependent upon successful progress through a sensitive period of late-postnatal development. This learning is associated with maturation of distinct brain nuclei and the fiber tract interconnections between them. We have previously found remarkably distinct and dense CB1 cannabinoid receptor expression within many of these song control brain regions, implying a normal role for endocannabinoid signaling in vocal learning. Activation of CB1 receptors via daily treatments with exogenous agonist during sensorimotor stages of song learning (but not in adulthood) results in persistent alteration of song patterns. Now we are working to understand physiological changes responsible for this cannabinoid-altered vocal learning. We have found that song-altering developmental treatments are associated with changes in expression of endocannabinoid signaling elements, including CB1 receptors and the principal CNS endogenous agonist, 2-AG. Within CNS, 2-AG is produced largely through activity of the α isoform of the enzyme diacylglycerol lipase (DAGLα). To better appreciate the role of 2-AG production in normal vocal development we have determined the spatial distribution of DAGLα expression within zebra finch CNS during vocal development. Early during vocal development at 25 days, DAGLα staining is typically light and of fibroid processes. Staining peaks late in the sensorimotor stage of song learning at 75 days and is characterized by fiber, neuropil and some staining of both small and large cell somata. Results provide insight to the normal role for endocannabinoid signaling in the maturation of brain regions responsible for song learning and vocal-motor output, and suggest mechanisms by which exogenous cannabinoid exposure alters acquisition of this form of vocal communication. Copyright © 2013 Elsevier B.V. All rights reserved.
Chronic ethanol exposure decreases CB1 receptor function at GABAergic synapses in the rat central amygdala

PubMed Central

Varodayan, Florence P.; Soni, Neeraj; Bajo, Michal; Luu, George; Madamba, Samuel G.; Schweitzer, Paul; Parsons, Loren H.; Roberto, Marisa

2015-01-01

The endogenous cannabinoids (eCBs) influence the acute response to ethanol and the development of tolerance, dependence and relapse. Chronic alcohol exposure alters eCB levels and type 1 cannabinoid receptor (CB1) expression and function in brain regions associated with addiction. CB1 inhibits GABA release, and GABAergic dysregulation in the central nucleus of the amygdala (CeA) is critical in the transition to alcohol dependence. We investigated possible disruptions in CB1 signaling of rat CeA GABAergic transmission following intermittent ethanol exposure. In the CeA of alcohol-naïve rats, CB1 agonist WIN 55,212-2 (WIN) decreased the frequency of spontaneous and miniature GABAA receptor-mediated inhibitory postsynaptic currents (s/mIPSCs). This effect was prevented by CB1 antagonism, but not type 2 cannabinoid receptor (CB2) antagonism. After 2–3 weeks of intermittent ethanol exposure, these WIN inhibitory effects were attenuated, suggesting ethanol-induced impairments in CB1 function. The CB1 antagonist AM251 revealed a tonic eCB/CB1 control of GABAergic transmission in the alcohol-naïve CeA that was occluded by calcium chelation in the postsynaptic cell. Chronic ethanol exposure abolished this tonic CB1 influence on mIPSC, but not sIPSC, frequency. Finally, acute ethanol increased CeA GABA release in both naïve and ethanol exposed rats. Although CB1 activation prevented this effect, the AM251- and ethanol-induced GABA release were additive, ruling out a direct participation of CB1 signaling in the ethanol effect. Collectively, these observations demonstrate an important CB1 influence on CeA GABAergic transmission and indicate that the CeA is particularly sensitive to alcohol-induced disruptions of CB1 signaling. PMID:25940135
Interactions between environmental aversiveness and the anxiolytic effects of enhanced cannabinoid signaling by FAAH inhibition in rats.

PubMed

Haller, J; Barna, I; Barsvari, B; Gyimesi Pelczer, K; Yasar, S; Panlilio, L V; Goldberg, S

2009-07-01

Since the discovery of endogenous cannabinoid signaling, the number of studies exploring its role in health and disease has increased exponentially. Fatty acid amide hydrolase (FAAH), the enzyme responsible for degradation of the endocannabinoid anandamide, has emerged as a promising target for anxiety-related disorders. FAAH inhibitors (e.g., URB597) increase brain levels of anandamide and induce anxiolytic-like effects in rodents. Recent findings, however, questioned the efficacy of URB597 as an anxiolytic. We tested here the hypothesis that conflicting findings are due to variations in the stressfulness of experimental conditions employed in various studies. We found that URB597 (0.1-0.3 mg/kg) did not produce anxiolytic effects when the aversiveness of testing procedures was minimized by handling rats daily before experimentation, by habituating them to the experimental room, or by employing low illumination during testing. In contrast, URB597 had robust anxiolytic effects when the aversiveness of the testing environment was increased by eliminating habituation to the experimental room or by employing bright lighting conditions. Unlike URB597, the benzodiazepine chlordiazepoxide (5 mg/kg) had anxiolytic effects under all testing conditions. The anxiolytic effects of URB597 were abolished by the cannabinoid CB1-receptor antagonist AM251, showing that they were mediated by CB1 receptors. Close inspection of experimental conditions employed in earlier reports suggests that conflicting findings with URB597 can be explained by different testing conditions, such as those manipulated in the present study. Our findings show that FAAH inhibition does not affect anxiety under mildly stressful circumstances but protects against the anxiogenic effects of aversive stimuli.
Adding Spice to the Porridge: The development of a synthetic cannabinoid market in an English prison.

PubMed

Ralphs, Rob; Williams, Lisa; Askew, Rebecca; Norton, Anna

2017-02-01

In 2014, the annual report of the Her Majesty's Chief Inspector of Prisons (HMIP) for England and Wales raised concerns regarding New Psychoactive Substance (NPS) use in custody, specifically the consumption of synthetic cannabinoids. To date, however, the use of these substances in prison populations, and the markets that have emerged to facilitate it, have been under-researched. Our research was conducted in an English adult male prison using multi-method techniques. These included: in-depth interviews and focus groups with prison staff and prisoners; observations of prisoner-led focus groups, workshops and restorative justice circles involving discussion of synthetic cannabinoid use and markets; and analysis of routinely collected prison data measuring drug seizures, incidents of violence and incidents of self-harm. The findings highlight: (1) the scale and nature of synthetic cannabinoid markets in a custodial setting and the motivations for establishing them; (2) the nature and motivations for synthetic cannabinoids use in prison; and (3) the impact synthetic cannabinoid markets in this setting have upon prisoners, the prison system and the wider criminal justice system. The policy implications of the stated motivations for use and reported problems are discussed in relation to both prison and community settings, and the recently implemented Psychoactive Substance Act (2016). The paper concludes that the rise in synthetic cannabinoid use in custody and the size of the drug market are posing significant challenges to the management of offenders; including healthcare, appropriate detection techniques, license recall and sanctions for both use and supply. We argue that the primary motivation for consumption in this setting is the avoidance of drug use detection, and that this is likely to supersede other motivations for consumption in the future. We propose a revision of the use of mandatory drug tests (MDTs) both in prisons and in the management of offenders in the community. Copyright © 2016 The Authors. Published by Elsevier B.V. All rights reserved.
Cannabidiol and (−)Δ9-tetrahydrocannabinol are neuroprotective antioxidants

PubMed Central

Hampson, A. J.; Grimaldi, M.; Axelrod, J.; Wink, D.

1998-01-01

The neuroprotective actions of cannabidiol and other cannabinoids were examined in rat cortical neuron cultures exposed to toxic levels of the excitatory neurotransmitter glutamate. Glutamate toxicity was reduced by both cannabidiol, a nonpsychoactive constituent of marijuana, and the psychotropic cannabinoid (−)Δ9-tetrahydrocannabinol (THC). Cannabinoids protected equally well against neurotoxicity mediated by N-methyl-d-aspartate receptors, 2-amino-3-(4-butyl-3-hydroxyisoxazol-5-yl)propionic acid receptors, or kainate receptors. N-methyl-d-aspartate receptor-induced toxicity has been shown to be calcium dependent; this study demonstrates that 2-amino-3-(4-butyl-3-hydroxyisoxazol-5-yl)propionic acid/kainate receptor-type neurotoxicity is also calcium-dependent, partly mediated by voltage sensitive calcium channels. The neuroprotection observed with cannabidiol and THC was unaffected by cannabinoid receptor antagonist, indicating it to be cannabinoid receptor independent. Previous studies have shown that glutamate toxicity may be prevented by antioxidants. Cannabidiol, THC and several synthetic cannabinoids all were demonstrated to be antioxidants by cyclic voltametry. Cannabidiol and THC also were shown to prevent hydroperoxide-induced oxidative damage as well as or better than other antioxidants in a chemical (Fenton reaction) system and neuronal cultures. Cannabidiol was more protective against glutamate neurotoxicity than either ascorbate or α-tocopherol, indicating it to be a potent antioxidant. These data also suggest that the naturally occurring, nonpsychotropic cannabinoid, cannabidiol, may be a potentially useful therapeutic agent for the treatment of oxidative neurological disorders such as cerebral ischemia. PMID:9653176
Cannabinoids - a new weapon against cancer?

PubMed

Pokrywka, Małgorzata; Góralska, Joanna; Solnica, Bogdan

2016-12-29

Cannabis has been cultivated by man since Neolithic times. It was used, among others for fiber and rope production, recreational purposes and as an excellent therapeutic agent. The isolation and characterization of the structure of one of the main active ingredients of cannabis - Δ9 - tetrahydrocannabinol as well the discovery of its cannabinoid binding receptors CB1 and CB2, has been a milestone in the study of the possibilities of the uses of Cannabis sativa and related products in modern medicine. Many scientific studies indicate the potential use of cannabinoids in the fight against cancer. Experiments carried out on cell lines in vitro and on animal models in vivo have shown that phytocannabinoids, endocannabinoids, synthetic cannabinoids and their analogues can lead to inhibition of the growth of many tumor types, exerting cytostatic and cytotoxic neoplastic effect on cells thereby negatively influencing neo-angiogenesis and the ability of cells to metastasize. The main molecular mechanism leading to inhibition of proliferation of cancer cells by cannabinoids is apoptosis. Studies have shown, however, that the process of apoptosis in cells, treated with recannabinoids, is a consequence of induction of endoplasmic reticulum stress and autophagy. On the other hand, in the cellular context and dosage dependence, cannabinoids may enhance the proliferation of tumor cells by suppressing the immune system or by activating mitogenic factors. Leading from this there is a an obvious need to further explore cannabinoid associated molecular pathways making it possible to develop safe therapeutic drug agents for patients in the future.
Cannabinoid Poisoning by Hemp Seed Oil in a Child.

PubMed

Chinello, Matteo; Scommegna, Salvatore; Shardlow, Alison; Mazzoli, Francesca; De Giovanni, Nadia; Fucci, Nadia; Borgiani, Paola; Ciccacci, Cinzia; Locasciulli, Anna; Calvani, Mauro

2017-05-01

We report a case of mild cannabinoid poisoning in a preschool child, after 3-week ingestion of hemp seed oil prescribed by his pediatrician to strengthen his immune system. The patient presented neurological symptoms that disappeared after intravenous hydration. A possible mild withdrawal syndrome was reported after discharge. The main metabolite of Δ-tetrahydrocannabinol was detected in urine, and very low concentration of Δ-tetrahydrocannabinol was detected in the ingested product. This is, as far as we know, the first report of cannabinoid poisoning after medical prescription of hemp seed oil in a preschool child.
Involvement of Cannabinoid Signaling in Vincristine-Induced Gastrointestinal Dysmotility in the Rat.

PubMed

Vera, Gema; López-Pérez, Ana E; Uranga, José A; Girón, Rocío; Martín-Fontelles, Ma Isabel; Abalo, Raquel

2017-01-01

Background: In different models of paralytic ileus, cannabinoid receptors are overexpressed and endogenous cannabinoids are massively released, contributing to gastrointestinal dysmotility. The antitumoral drug vincristine depresses gastrointestinal motility and a similar mechanism could participate in this effect. Therefore, our aim was to determine, using CB 1 and CB 2 antagonists, whether an increased endocannabinoid tone is involved in vincristine-induced gastrointestinal ileus. Methods: First, we confirmed the effects of vincristine on the gut mucosa, by conventional histological techniques, and characterized its effects on motility, by radiographic means. Conscious male Wistar rats received an intraperitoneal injection of vincristine (0.1-0.5 mg/kg), and barium sulfate (2.5 ml; 2 g/ml) was intragastrically administered 0, 24, or 48 h later. Serial X-rays were obtained at different time-points (0-8 h) after contrast. X-rays were used to build motility curves for each gastrointestinal region and determine the size of stomach and caecum. Tissue samples were taken for histology 48 h after saline or vincristine (0.5 mg/kg). Second, AM251 (a CB 1 receptor antagonist) and AM630 (a CB 2 receptor antagonist) were used to determine if CB 1 and/or CB 2 receptors are involved in vincristine-induced gastrointestinal dysmotility. Key results: Vincristine induced damage to the mucosa of ileum and colon and reduced gastrointestinal motor function at 0.5 mg/kg. The effect on motor function was particularly evident when the study started 24 h after administration. AM251, but not AM630, significantly prevented vincristine effect, particularly in the small intestine, when administered thrice. AM251 alone did not significantly alter gastrointestinal motility. Conclusions: The fact that AM251, but not AM630, is capable of reducing the effect of vincristine suggests that, like in other experimental models of paralytic ileus, an increased cannabinoid tone develops and is at least partially responsible for the alterations induced by the antitumoral drug on gastrointestinal motor function. Thus, CB 1 antagonists might be useful to prevent/treat ileus induced by vincristine.
Involvement of Cannabinoid Signaling in Vincristine-Induced Gastrointestinal Dysmotility in the Rat

PubMed Central

Vera, Gema; López-Pérez, Ana E.; Uranga, José A.; Girón, Rocío; Martín-Fontelles, Ma Isabel; Abalo, Raquel

2017-01-01

Background: In different models of paralytic ileus, cannabinoid receptors are overexpressed and endogenous cannabinoids are massively released, contributing to gastrointestinal dysmotility. The antitumoral drug vincristine depresses gastrointestinal motility and a similar mechanism could participate in this effect. Therefore, our aim was to determine, using CB1 and CB2 antagonists, whether an increased endocannabinoid tone is involved in vincristine-induced gastrointestinal ileus. Methods: First, we confirmed the effects of vincristine on the gut mucosa, by conventional histological techniques, and characterized its effects on motility, by radiographic means. Conscious male Wistar rats received an intraperitoneal injection of vincristine (0.1–0.5 mg/kg), and barium sulfate (2.5 ml; 2 g/ml) was intragastrically administered 0, 24, or 48 h later. Serial X-rays were obtained at different time-points (0–8 h) after contrast. X-rays were used to build motility curves for each gastrointestinal region and determine the size of stomach and caecum. Tissue samples were taken for histology 48 h after saline or vincristine (0.5 mg/kg). Second, AM251 (a CB1 receptor antagonist) and AM630 (a CB2 receptor antagonist) were used to determine if CB1 and/or CB2 receptors are involved in vincristine-induced gastrointestinal dysmotility. Key results: Vincristine induced damage to the mucosa of ileum and colon and reduced gastrointestinal motor function at 0.5 mg/kg. The effect on motor function was particularly evident when the study started 24 h after administration. AM251, but not AM630, significantly prevented vincristine effect, particularly in the small intestine, when administered thrice. AM251 alone did not significantly alter gastrointestinal motility. Conclusions: The fact that AM251, but not AM630, is capable of reducing the effect of vincristine suggests that, like in other experimental models of paralytic ileus, an increased cannabinoid tone develops and is at least partially responsible for the alterations induced by the antitumoral drug on gastrointestinal motor function. Thus, CB1 antagonists might be useful to prevent/treat ileus induced by vincristine. PMID:28220074
Compartmentalization of endocannabinoids into lipid rafts in a microglial cell line devoid of caveorrlin-1

PubMed Central

Rimmerman, Neta; Bradshaw, Heather B; Kozela, Ewa; Levy, Rivka; Juknat, Ana; Vogel, Zvi

2012-01-01

BACKGROUND AND PURPOSE N-acyl ethanolamines (NAEs) and 2-arachidonoyl glycerol (2-AG) are endogenous cannabinoids and along with related lipids are synthesized on demand from membrane phospholipids. Here, we have studied the compartmentalization of NAEs and 2-AG into lipid raft fractions isolated from the caveolin-1-lacking microglial cell line BV-2, following vehicle or cannabidiol (CBD) treatment. Results were compared with those from the caveolin-1-positive F-11 cell line. EXPERIMENTAL APPROACH BV-2 cells were incubated with CBD or vehicle. Cells were fractionated using a detergent-free continuous OptiPrep density gradient. Lipids in fractions were quantified using HPLC/MS/MS. Proteins were measured using Western blot. KEY RESULTS BV-2 cells were devoid of caveolin-1. Lipid rafts were isolated from BV-2 cells as confirmed by co-localization with flotillin-1 and sphingomyelin. Small amounts of cannabinoid CB1 receptors were found in lipid raft fractions. After incubation with CBD, levels and distribution in lipid rafts of 2-AG, N-arachidonoyl ethanolamine (AEA), and N-oleoyl ethanolamine (OEA) were not changed. Conversely, the levels of the saturated N-stearoyl ethanolamine (SEA) and N-palmitoyl ethanolamine (PEA) were elevated in lipid raft fractions. In whole cells with growth medium, CBD treatment increased AEA and OEA time-dependently, while levels of 2-AG, PEA and SEA did not change. CONCLUSIONS AND IMPLICATIONS Whereas levels of 2-AG were not affected by CBD treatment, the distribution and levels of NAEs showed significant changes. Among the NAEs, the degree of acyl chain saturation predicted the compartmentalization after CBD treatment suggesting a shift in cell signalling activity. LINKED ARTICLES This article is part of a themed section on Cannabinoids in Biology and Medicine. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2012.165.issue-8. To view Part I of Cannabinoids in Biology and Medicine visit http://dx.doi.org/10.1111/bph.2011.163.issue-7 PMID:21449981
Molecular model of cannabis sensitivity in developing neuronal circuits

PubMed Central

Keimpema, Erik; Mackie, Ken; Harkany, Tibor

2011-01-01

Prenatal cannabis exposure can complicate in utero development of the nervous system. Cannabis impacts the formation and functions of neuronal circuitries by targeting cannabinoid receptors. Endocannabinoid signaling emerges as a signaling cassette to orchestrate neuronal differentiation programs through the precisely timed interaction of endocannabinoid ligands with their cognate cannabinoid receptors. By indiscriminately prolonging the ‘switched-on’ period of cannabinoid receptors, cannabis can hijack endocannabinoid signals to evoke molecular rearrangements, leading to the erroneous wiring of neuronal networks. Here, we formulate a hierarchical network design necessary and sufficient to describe molecular underpinnings of cannabis-induced neural growth defects. We integrate signalosome components deduced from genome- and proteome-wide arrays and candidate analyses to propose a mechanistic hypothesis on how cannabis-induced ectopic cannabinoid receptor activity overrides physiological neurodevelopmental endocannabinoid signals, affecting the timely formation of synapses. PMID:21757242
[Passive inhalation of cannabis smoke--is it detectable?].

PubMed

Westin, Andreas Austgulen; Slørdal, Lars

2009-01-15

It is frequently questioned whether cannabinoids are detectable in urine from individuals having been passively exposed to hashish or marihuana smoke. Literature was reviewed to shed light on an issue that is often debated in the health services, judicial system and in sports. A Medline search with the index terms "cannabis", "hashish", "marihuana" was conducted in September 2007. Summaries, abstracts and reference lists of selected articles were screened for relevancy. Seven experimental studies with humans were identified. Cannabinoids were detected in urine in two studies where the subjects had been exposed to high smoke levels. In studies conducted under less extreme conditions no urine samples were positive for more than a few hours after exposure and the measured cannabinoid levels were low. When cannabinoids are detected in urine with conventional methods and limits of quantification the results are commensurate with active smoking.
The Synthetic Cannabinoids Phenomenon.

PubMed

Karila, Laurent; Benyamina, Amine; Blecha, Lisa; Cottencin, Olivier; Billieux, Joël

2016-01-01

« Spice » is generally used to describe the diverse types of herbal blends that encompass synthetic cannabinoids on the market. The emergence of smokable herbal products containing synthetic cannabinoids, which mimic the effects of cannabis, appears to become increasingly popular, in the new psychoactive substances landscape. In 2014, the existence of 134 different types of synthetic cannabinoids were reported by the European Union Early Warning System. These drugs are mainly sold online as an alternative to controlled and regulated psychoactive substances. They appear to have a life cycle of about 1-2 years before being replaced by a next wave of products. Legislation controlling these designer drugs has been introduced in many countries with the objective to limit the spread of existing drugs and control potential new analogs. The majority of the synthetic cannabinoids are full agonists at the CB1 receptor and do not contain tobacco or cannabis. They are becoming increasingly popular in adolescents, students and clubbers as an abused substance. Relatively high incidence of adverse effects associated with synthetic cannabinoids use has been documented in the literature. Numerous fatalities linked with their use and abuse have been reported. In this paper, we will review the available data regarding the use and effects of synthetic cannabinoids in humans in order to highlight their impact on public health. To reach this objective, a literature search was performed on two representative databases (Pubmed, Google Scholar), the Erowid Center website (a US non-profit educational organization that provides information about psychoactive plants and chemicals), and various governmental websites. The terms used for the database search were: "synthetic cannabinoids", "spice", "new psychoactive substances", and/or "substance use disorder", and/or "adverse effects", and/or "fatalities". The search was limited to years 2005 to 2016 due to emerging scientific literature at this period Health professionals should take into account that limited scientific evidence is available regarding the effect of synthetic cannabinoids use in humans. It thus urges to launch more systematic epidemiological studies, to develop and validate screening procedures, and to investigate the neurobiological and psychological correlates and risk factors associated to synthetic cannabinoids use and misuse. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Polypharmacology Shakes Hands with Complex Aetiopathology.

PubMed

Brodie, James S; Di Marzo, Vincenzo; Guy, Geoffrey W

2015-12-01

Chronic diseases are due to deviations of fundamental physiological systems, with different pathologies being characterised by similar malfunctioning biological networks. The ensuing compensatory mechanisms may weaken the body's dynamic ability to respond to further insults and reduce the efficacy of conventional single target treatments. The multitarget, systemic, and prohomeostatic actions emerging for plant cannabinoids exemplify what might be needed for future medicines. Indeed, two combined cannabis extracts were approved as a single medicine (Sativex(®)), while pure cannabidiol, a multitarget cannabinoid, is emerging as a treatment for paediatric drug-resistant epilepsy. Using emerging cannabinoid medicines as an example, we revisit the concept of polypharmacology and describe a new empirical model, the 'therapeutic handshake', to predict efficacy/safety of compound combinations of either natural or synthetic origin. Copyright © 2015 Elsevier Ltd. All rights reserved.
Epigenetic Regulation of Immunological Alterations Following Prenatal Exposure to Marijuana Cannabinoids and its Long Term Consequences in Offspring

PubMed Central

Zumbrun, Elizabeth E.; Sido, Jessica M.; Nagarkatti, Prakash S.

2015-01-01

Use of marijuana during pregnancy is fairly commonplace and can be expected increase in frequency as more states legalize its recreational use. The cannabinoids present in marijuana have been shown to be immunosuppressive, yet the effect of prenatal exposure to cannabinoids on the immune system of the developing fetus, its long term consequences during adult stage of life, and transgenerational effects have not been well characterized. Confounding factors such as coexisting drug use make the impact of cannabis use on progeny inherently difficult to study in a human population. Data from various animal models suggests that in utero exposure to cannabinoids results in profound T cell dysfunction and a greatly reduced immune response to viral antigens. Furthermore, evidence from animal studies indicates that the immunosuppressive effects of cannabinoids can be mediated through epigenetic mechanisms such as altered microRNA, DNA methylation and histone modification profiles. Such studies support the hypothesis that that parental or prenatal exposure to cannabis can trigger epigenetic changes that could have significant immunological consequences for offspring as well as long term transgenerational effects. PMID:25618446
Cannabinoids and traumatic stress modulation of contextual fear extinction and GR expression in the amygdala-hippocampal-prefrontal circuit.

PubMed

Ganon-Elazar, Eti; Akirav, Irit

2013-09-01

Considerable evidence suggests that cannabinoids modulate the behavioral and physiological response to stressful events. We have recently shown that activating the cannabinoid system using the CB1/CB2 receptor agonist WIN55,212-2 (WIN) in proximity to exposure to single-prolonged stress (SPS), a rat model of emotional trauma, prevented the stress-induced enhancement of acoustic startle response, the impairment in avoidance extinction and the enhanced negative feedback on the hypothalamic-pituitary-adrenal (HPA) axis (Ganon-Elazar and Akirav, 2012). Some of the effects were found to be mediated by CB1 receptors in the basolateral amygdala (BLA). Here we examined whether cannabinoid receptor activation in a putative brain circuit that includes the BLA, hippocampus and prefrontal cortex (PFC), could prevent the effects of traumatic stress on contextual fear extinction and alterations in glucocorticoid receptor (GR) protein levels. We found that: (i) SPS impaired contextual fear extinction tested one week after trauma exposure and that WIN prevented the stress-induced impairment of extinction when microinjected immediately after trauma exposure into the BLA or hippocampus (5 μg), but not when microinjected into the PFC, (ii) the ameliorating effects of WIN on contextual extinction were prevented by blocking GRs in the BLA and hippocampus, and (iii) SPS up regulated GRs in the BLA, PFC and hippocampus and systemic WIN administration (0.5 mg/kg) after trauma exposure normalized GR levels in the BLA and hippocampus, but not in the PFC. Cannabinoid receptor activation in the aftermath of trauma exposure may regulate the emotional response to the trauma and prevent stress-induced impairment of extinction and GR up regulation through the mediation of CB1 receptors in the BLA and hippocampus. Taken together, the findings suggest that the interaction between the cannabinoid and glucocorticoid systems is crucial in the modulation of emotional trauma. Copyright © 2013 Elsevier Ltd. All rights reserved.
Epigenetic Interactions between Alcohol and Cannabinergic Effects: Focus on Histone Modification and DNA Methylation

PubMed Central

Parira, Tiyash; Laverde, Alejandra; Agudelo, Marisela

2017-01-01

Epigenetic studies have led to a more profound understanding of the mechanisms involved in chronic conditions. In the case of alcohol addiction, according to the National Institute on Alcohol Abuse and Alcoholism, 16 million adults suffer from Alcohol Use Disorders (AUDs). Even though therapeutic interventions like behavioral therapy and medications to prevent relapse are currently available, no robust cure exists, which stems from the lack of understanding the mechanisms of action of alcohol and the lack of development of precision medicine approaches to treat AUDs. Another common group of addictive substance, cannabinoids, have been studied extensively to reveal they work through cannabinoid receptors. Therapeutic applications have been found for the cannabinoids and a deeper understanding of the endocannabinoid system has been gained over the years. Recent reports of cannabinergic mechanisms in AUDs has opened an exciting realm of research that seeks to elucidate the molecular mechanisms of alcohol-induced end organ diseases and hopefully provide insight into new therapeutic strategies for the treatment of AUDs. To date, several epigenetic mechanisms have been associated with alcohol and cannabinoids independently. Therefore, the scope of this review is to compile the most recent literature regarding alcohol and cannabinoids in terms of a possible epigenetic connection between the endocannabinoid system and alcohol effects. First, we will provide an overview of epigenetics, followed by an overview of alcohol and epigenetic mechanisms with an emphasis on histone modifications and DNA methylations. Then, we will provide an overview of cannabinoids and epigenetic mechanisms. Lastly, we will discuss evidence of interactions between alcohol and cannabinergic pathways and possible insights into the novel epigenetic mechanisms underlying alcohol-cannabinergic pathway activity. Finalizing the review will be a discussion of future directions and therapeutic applications. PMID:28730160
Synthetic Cannabinoids and Their Effects on the Cardiovascular System.

PubMed

Von Der Haar, Jonathan; Talebi, Soheila; Ghobadi, Farzaneh; Singh, Shailinder; Chirurgi, Roger; Rajeswari, Pingle; Kalantari, Hossein; Hassen, Getaw Worku

2016-02-01

In the past couple of years, there has been an outbreak of synthetic cannabinoid (SC) use in major cities in the United States. Patients can present with various symptoms affecting the central nervous and cardiovascular systems. The effects of endocannabinoid on contractility and Ca(2+) signaling have been shown through both cannabinoid receptors and a direct effect on ion channels. These effects result in abnormalities in ionotropy, chronotropy, and conduction. Here we report on two cases of SC abuse and abnormalities in the cardiovascular system. These cases raise concerns about the adverse effects of SCs and the possibility of QTc prolongation and subsequent complications when using antipsychotic medication in the presence of SC abuse. WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS?: Given the rise in SC use and the potential effect on the cardiovascular system, physicians need to be mindful of potential cardiac complications, such as QTc prolongation and torsade de pointe, especially when administering medications that have the potential to cause QTc prolongation. Copyright © 2016 Elsevier Inc. All rights reserved.
Effects of fatty acid amide hydrolase (FAAH) inhibitors on working memory in rats.

PubMed

Panlilio, Leigh V; Thorndike, Eric B; Nikas, Spyros P; Alapafuja, Shakiru O; Bandiera, Tiziano; Cravatt, Benjamin F; Makriyannis, Alexandros; Piomelli, Daniele; Goldberg, Steven R; Justinova, Zuzana

2016-05-01

Manipulations of the endocannabinoid system could potentially produce therapeutic effects with minimal risk of adverse cannabis-like side effects. Inhibitors of fatty acid amide hydrolase (FAAH) increase endogenous levels of the cannabinoid-receptor agonist, anandamide, and show promise for treating a wide range of disorders. However, their effects on learning and memory have not been fully characterized. We determined the effects of five structurally different FAAH inhibitors in an animal model of working memory known to be sensitive to impairment by delta-9 tetrahydrocannabinol (THC). A delayed nonmatching-to-position procedure was used in rats. Illuminated nosepoke holes were used to provide sample cues (left versus right) and record responses (correct versus incorrect) after delays ranging from 0 to 28 s. Various test drugs were given acutely up to two times per week before daily sessions. One FAAH inhibitor, AM3506 (3 mg/kg), decreased accuracy in the memory task. Four other FAAH inhibitors (URB597, URB694, PF-04457845, and ARN14633) and a monoacylglycerol lipase inhibitor (JZL184, which blocks the degradation of the endocannabinoid 2-arachidonoylglycerol) had no effect. Testing of AM3506 in combination with antagonists for receptors known to be affected by anandamide and other fatty acid amides indicated that the impairment induced by AM3506 was mediated by cannabinoid CB1 receptors, and not by alpha-type peroxisome proliferator-activated receptors (PPAR-alpha) or vanilloid transient receptor potential cation channels (TRPV1). FAAH inhibitors differ with respect to their potential for memory impairment, abuse liability, and probably other cannabis-like effects, and they should be evaluated individually for specific therapeutic and adverse effects.
Effects of fatty acid amide hydrolase (FAAH) inhibitors on working memory in rats

PubMed Central

Panlilio, Leigh V.; Thorndike, Eric B.; Nikas, Spyros P.; Alapafuja, Shakiru O.; Bandiera, Tiziano; Cravatt, Benjamin F.; Makriyannis, Alexandros; Piomelli, Daniele; Goldberg, Steven R.; Justinova, Zuzana

2015-01-01

Rationale Manipulations of the endocannabinoid system could potentially produce therapeutic effects with minimal risk of adverse cannabis-like side effects. Inhibitors of fatty acid amide hydrolase (FAAH) increase endogenous levels of the cannabinoid-receptor agonist, anandamide, and show promise for treating a wide range of disorders. However, their effects on learning and memory have not been fully characterized. Objectives We determined the effects of five structurally different FAAH inhibitors in an animal model of working memory known to be sensitive to impairment by delta-9 tetrahydrocannabinol (THC). Methods A delayed nonmatching-to-position procedure was used in rats. Illuminated nosepoke holes were used to provide sample cues (left versus right) and record responses (correct versus incorrect) after delays ranging from 0-28 seconds. Various test drugs were given acutely up to two times per week before daily sessions. Results One FAAH inhibitor, AM3506 (3 mg/kg), decreased accuracy in the memory task. Four other FAAH inhibitors (URB597, URB694, PF-04457845, and ARN14633) and a monoacylglycerol lipase inhibitor (JZL184, which blocks the degradation of the endocannabinoid 2-arachidonoylglycerol) had no effect. Testing of AM3506 in combination with antagonists for receptors known to be affected by anandamide and other fatty-acid amides indicated that the impairment induced by AM3506 was mediated by cannabinoid CB1 receptors, and not by alpha-type peroxisome proliferator-activated receptors (PPAR-alpha) or vanilloid transient receptor potential cation channels (TRPV1). Conclusions FAAH inhibitors differ with respect to their potential for memory impairment, abuse liability, and probably other cannabis-like effects, and they should be evaluated individually for specific therapeutic and adverse effects. PMID:26558620
The cannabinoid receptor CB1 modulates the signaling properties of the lysophosphatidylinositol receptor GPR55.

PubMed

Kargl, Julia; Balenga, Nariman; Parzmair, Gerald P; Brown, Andrew J; Heinemann, Akos; Waldhoer, Maria

2012-12-28

The G protein-coupled receptor (GPCR) 55 (GPR55) and the cannabinoid receptor 1 (CB1R) are co-expressed in many tissues, predominantly in the central nervous system. Seven transmembrane spanning (7TM) receptors/GPCRs can form homo- and heteromers and initiate distinct signaling pathways. Recently, several synthetic CB1 receptor inverse agonists/antagonists, such as SR141716A, AM251, and AM281, were reported to activate GPR55. Of these, SR141716A was marketed as a promising anti-obesity drug, but was withdrawn from the market because of severe side effects. Here, we tested whether GPR55 and CB1 receptors are capable of (i) forming heteromers and (ii) whether such heteromers could exhibit novel signaling patterns. We show that GPR55 and CB1 receptors alter each others signaling properties in human embryonic kidney (HEK293) cells. We demonstrate that the co-expression of FLAG-CB1 receptors in cells stably expressing HA-GPR55 specifically inhibits GPR55-mediated transcription factor activation, such as nuclear factor of activated T-cells and serum response element, as well as extracellular signal-regulated kinases (ERK1/2) activation. GPR55 and CB1 receptors can form heteromers, but the internalization of both receptors is not affected. In addition, we observe that the presence of GPR55 enhances CB1R-mediated ERK1/2 and nuclear factor of activated T-cell activation. Our data provide the first evidence that GPR55 can form heteromers with another 7TM/GPCR and that this interaction with the CB1 receptor has functional consequences in vitro. The GPR55-CB1R heteromer may play an important physiological and/or pathophysiological role in tissues endogenously co-expressing both receptors.
The Cannabinoid Receptor CB1 Modulates the Signaling Properties of the Lysophosphatidylinositol Receptor GPR55*

PubMed Central

Kargl, Julia; Balenga, Nariman; Parzmair, Gerald P.; Brown, Andrew J.; Heinemann, Akos; Waldhoer, Maria

2012-01-01

The G protein-coupled receptor (GPCR) 55 (GPR55) and the cannabinoid receptor 1 (CB1R) are co-expressed in many tissues, predominantly in the central nervous system. Seven transmembrane spanning (7TM) receptors/GPCRs can form homo- and heteromers and initiate distinct signaling pathways. Recently, several synthetic CB1 receptor inverse agonists/antagonists, such as SR141716A, AM251, and AM281, were reported to activate GPR55. Of these, SR141716A was marketed as a promising anti-obesity drug, but was withdrawn from the market because of severe side effects. Here, we tested whether GPR55 and CB1 receptors are capable of (i) forming heteromers and (ii) whether such heteromers could exhibit novel signaling patterns. We show that GPR55 and CB1 receptors alter each others signaling properties in human embryonic kidney (HEK293) cells. We demonstrate that the co-expression of FLAG-CB1 receptors in cells stably expressing HA-GPR55 specifically inhibits GPR55-mediated transcription factor activation, such as nuclear factor of activated T-cells and serum response element, as well as extracellular signal-regulated kinases (ERK1/2) activation. GPR55 and CB1 receptors can form heteromers, but the internalization of both receptors is not affected. In addition, we observe that the presence of GPR55 enhances CB1R-mediated ERK1/2 and nuclear factor of activated T-cell activation. Our data provide the first evidence that GPR55 can form heteromers with another 7TM/GPCR and that this interaction with the CB1 receptor has functional consequences in vitro. The GPR55-CB1R heteromer may play an important physiological and/or pathophysiological role in tissues endogenously co-expressing both receptors. PMID:23161546
Anandamide enhances extracellular levels of adenosine and induces sleep: an in vivo microdialysis study.

PubMed

Murillo-Rodriguez, Eric; Blanco-Centurion, Carlos; Sanchez, Cristina; Piomelli, Daniele; Shiromani, Priyattam J

2003-12-15

The principal component of marijuana, delta-9-tetrahydrocannabinol increases sleep in humans. Endogenous cannabinoids, such as N-arachidonoylethanolamine (anandamide), also increase sleep. However, the mechanism by which these molecules promote sleep is not known but might involve a sleep-inducing molecule such as adenosine. Microdialysis samples were collected from the basal forebrain in order to detect levels of adenosine before and after injection of anandamide. Rats were implanted for sleep studies, and a cannula was placed in the basal forebrain to collect microdialysis samples. Samples were analyzed using high-performance liquid chromatography. Basic neuroscience research laboratory. Three-month-old male F344 rats. At the start of the lights-on period, animals received systemic injections of dimethyl sulfoxide (vehicle), anandamide, SR141716A (cannabinoid receptor 1 [CB1] antagonist), or SR141716A and anandamide. One hour after injections, microdialysis samples were collected (5 microL) from the basal forebrain every hour over a 20-minute period for 5 hours. The samples were immediately analyzed via high-performance liquid chromatography for adenosine levels. Sleep was also recorded continuously over the same period. Anandamide increased adenosine levels compared to vehicle controls with the peak levels being reached during the third hour after drug injection. There was a significant increase in slow-wave sleep during the third hour. The induction in sleep and the rise in adenosine were blocked by the CB1-receptor antagonist, SR141716A. Anandamide increased adenosine levels in the basal forebrain and also increased sleep. The soporific effects of anandamide were mediated by the CB1 receptor, since the effects were blocked by the CB1-receptor antagonist. These findings identify a potential therapeutic use of endocannabinoids to induce sleep in conditions where sleep may be severely attenuated.
Activation of spinal and supraspinal cannabinoid-1 receptors lead to antinociception in a rat model of neuropathic spinal cord injury pain

PubMed Central

Hama, Aldric; Sagen, Jacqueline

2011-01-01

Activation of CNS cannabinoid subtype-1 (CB1) receptors has been shown to mediate the antinociceptive and other effects of systemically administered CB receptor agonists. The endogenous peptide CB receptor ligand hemopressin (HE) has previously demonstrated an antinociceptive effect in rats with a hind paw inflammation, without exhibiting characteristic CB1 receptor-mediated side-effects. The current study evaluated the effect of intrathecal (i.t.) and intracerebroventricular (i.c.v.) injection of HE in a rat model of neuropathic spinal cord injury (SCI) pain. The non-subtype selective CB receptor agonist WIN 55,212-2 was also centrally administered in SCI rats as a comparator. Four weeks following an acute compression of the mid-thoracic spinal cord, rats displayed markedly decreased hind paw withdrawal thresholds, indicative of below-level neuropathic pain. Central administration of WIN 55,212-2 significantly increased withdrawal thresholds, whereas HE did not. Hemopressin has been reported to block CB1 receptors in vitro, similar to the CB1 receptor antagonist rimonabant. Pretreatment with rimonabant completely blocked the antinociceptive effect of centrally administered WIN 55,212-2, but pretreatment with HE did not. While the data confirm that activation of either supraspinal or spinal CB1 receptors leads to significant antinociception in SCI rats, the current data do not support an antinociceptive effect from an acute blockade of central CB1 receptors, HE’s putative antinociceptive mechanism, in neuropathic SCI rats. Although such a mechanism could be useful in other models of pain with a significant inflammatory component, the current data indicate that activation of CB1 receptors is needed to ameliorate neuropathic SCI pain. PMID:21813113
Functional Redundancy Between Canonical Endocannabinoid Signaling Systems in the Modulation of Anxiety.

PubMed

Bedse, Gaurav; Hartley, Nolan D; Neale, Emily; Gaulden, Andrew D; Patrick, Toni A; Kingsley, Philip J; Uddin, Md Jashim; Plath, Niels; Marnett, Lawrence J; Patel, Sachin

2017-10-01

Increasing the available repertoire of effective treatments for mood and anxiety disorders represents a critical unmet need. Pharmacological augmentation of endogenous cannabinoid (eCB) signaling has been suggested to represent a novel approach to the treatment of anxiety disorders; however, the functional interactions between two canonical eCB pathways mediated via anandamide (N-arachidonylethanolamine [AEA]) and 2-arachidonoylglycerol (2-AG) in the regulation of anxiety are not well understood. We utilized pharmacological augmentation and depletion combined with behavioral and electrophysiological approaches to probe the role of 2-AG signaling in the modulation of stress-induced anxiety and the functional redundancy between AEA and 2-AG signaling in the modulation of anxiety-like behaviors in mice. Selective 2-AG augmentation reduced anxiety in the light/dark box assay and prevented stress-induced increases in anxiety associated with limbic AEA deficiency. In contrast, acute 2-AG depletion increased anxiety-like behaviors, which was normalized by selective pharmacological augmentation of AEA signaling and via direct cannabinoid receptor 1 stimulation with Δ 9 -tetrahydrocannabinol. Electrophysiological studies revealed 2-AG modulation of amygdala glutamatergic transmission as a key synaptic correlate of the anxiolytic effects of 2-AG augmentation. Although AEA and 2-AG likely subserve distinct physiological roles, a pharmacological and functional redundancy between these canonical eCB signaling pathways exists in the modulation of anxiety-like behaviors. These data support development of eCB-based treatment approaches for mood and anxiety disorders and suggest a potentially wider therapeutic overlap between AEA and 2-AG augmentation approaches than was previously appreciated. Copyright © 2017 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.
Molecular model of cannabis sensitivity in developing neuronal circuits.

PubMed

Keimpema, Erik; Mackie, Ken; Harkany, Tibor

2011-09-01

Prenatal cannabis exposure can complicate in utero development of the nervous system. Cannabis impacts the formation and functions of neuronal circuitries by targeting cannabinoid receptors. Endocannabinoid signaling emerges as a signaling cassette that orchestrates neuronal differentiation programs through the precisely timed interaction of endocannabinoid ligands with their cognate cannabinoid receptors. By indiscriminately prolonging the 'switched-on' period of cannabinoid receptors, cannabis can hijack endocannabinoid signals to evoke molecular rearrangements, leading to the erroneous wiring of neuronal networks. Here, we formulate a hierarchical network design necessary and sufficient to describe the molecular underpinnings of cannabis-induced neural growth defects. We integrate signalosome components, deduced from genome- and proteome-wide arrays and candidate analyses, to propose a mechanistic hypothesis of how cannabis-induced ectopic cannabinoid receptor activity overrides physiological neurodevelopmental endocannabinoid signals, affecting the timely formation of synapses. Copyright © 2011 Elsevier Ltd. All rights reserved.
Cannabidiol as an Emergent Therapeutic Strategy for Lessening the Impact of Inflammation on Oxidative Stress

PubMed Central

Booz, George W.

2011-01-01

Oxidative stress with reactive oxygen species generation is a key weapon in the arsenal of the immune system for fighting invading pathogens and to initiate tissue repair. If excessive or unresolved, however, immune-related oxidative stress can initiate further increasing levels of oxidative stress that cause organ damage and dysfunction. Targeting oxidative stress in these various diseases therapeutically has proven more problematic than first anticipated given the complexities and perversity of both the underlying disease and the immune response. However, growing evidence suggests that the endocannabinoid system, which includes the CB1 and CB2 G protein-coupled receptors and their endogenous lipid ligands, may be an area that is ripe for therapeutic exploitation. In this context, the related nonpsychotropic cannabinoid cannabidiol, which may interact with the endocannabinoid system, but has actions that are distinct, offers promise as a prototype for anti-inflammatory drug development. This review discusses recent studies suggesting that cannabidiol may have utility in treating a number of human diseases and disorders now known to involve activation of the immune system and associated oxidative stress, as a contributor to their etiology and progression. These include rheumatoid arthritis, types I and II diabetes, atherosclerosis, Alzheimer’s disease, hypertension, the metabolic syndrome, ischemia-reperfusion injury, depression, and neuropathic pain. PMID:21238581
Monoglyceride lipase as a drug target: At the crossroads of arachidonic acid metabolism and endocannabinoid signaling.

PubMed

Grabner, Gernot F; Zimmermann, Robert; Schicho, Rudolf; Taschler, Ulrike

2017-07-01

Monoglyerides (MGs) are short-lived, intermediary lipids deriving from the degradation of phospho- and neutral lipids, and monoglyceride lipase (MGL), also designated as monoacylglycerol lipase (MAGL), is the major enzyme catalyzing the hydrolysis of MGs into glycerol and fatty acids. This distinct function enables MGL to regulate a number of physiological and pathophysiological processes since both MGs and fatty acids can act as signaling lipids or precursors thereof. The most prominent MG species acting as signaling lipid is 2-arachidonoyl glycerol (2-AG) which is the most abundant endogenous agonist of cannabinoid receptors in the body. Importantly, recent observations demonstrate that 2-AG represents a quantitatively important source for arachidonic acid, the precursor of prostaglandins and other inflammatory mediators. Accordingly, MGL-mediated 2-AG degradation affects lipid signaling by cannabinoid receptor-dependent and independent mechanisms. Recent genetic and pharmacological studies gave important insights into MGL's role in (patho-)physiological processes, and the enzyme is now considered as a promising drug target for a number of disorders including cancer, neurodegenerative and inflammatory diseases. This review summarizes the basics of MG (2-AG) metabolism and provides an overview on the therapeutic potential of MGL. Copyright © 2017 Elsevier Inc. All rights reserved.
THC and endocannabinoids differentially regulate neuronal activity in the prefrontal cortex and hippocampus in the subchronic PCP model of schizophrenia.

PubMed

Aguilar, David D; Giuffrida, Andrea; Lodge, Daniel J

2016-02-01

Cannabis use has been associated with an increased risk to develop schizophrenia as well as symptom exacerbation in patients. In contrast, clinical studies have revealed an inverse relationship between the cerebrospinal fluid levels of the endocannabinoid anandamide and symptom severity, suggesting a therapeutic potential for endocannabinoid-enhancing drugs. Indeed, preclinical studies have shown that these drugs can reverse distinct behavioral deficits in a rodent model of schizophrenia. The mechanisms underlying the differences between exogenous and endogenous cannabinoid administration are currently unknown. Using the phencyclidine (PCP) rat model of schizophrenia, we compared the effects on neuronal activity of systematic administration of delta-9-tetrahydrocannabinol (THC) with the fatty acid amide hydrolase inhibitor URB597. Specifically, we found that the inhibitory response in the prefrontal cortex to THC administration was absent in PCP-treated rats. In contrast, an augmented response to endocannabinoid upregulation was observed in the prefrontal cortex of PCP-treated rats. Interestingly, differential effects were also observed at the neuronal population level, as endocannabinoid upregulation induced opposite effects on coordinated activity when compared with THC. Such information is important for understanding why marijuana and synthetic cannabinoid use may be contraindicated in schizophrenia patients while endocannabinoid enhancement may provide a novel therapeutic approach. © The Author(s) 2015.
THC and endocannabinoids differentially regulate neuronal activity in the prefrontal cortex and hippocampus in the sub-chronic PCP model of schizophrenia

PubMed Central

Aguilar, David D; Giuffrida, Andrea; Lodge, Daniel J

2017-01-01

Cannabis use has been associated with an increased risk to develop schizophrenia as well as symptom exacerbation in patients. In contrast, clinical studies have revealed an inverse relationship between the CSF levels of the endocannabinoid anandamide and symptom severity, suggesting a therapeutic potential for endocannabinoid enhancing drugs. Indeed, preclinical studies have shown that these drugs can reverse distinct behavioral deficits in a rodent model of schizophrenia. The mechanisms underlying the differences between exogenous and endogenous cannabinoid administration are currently unknown. Using the phencyclidine (PCP) rat model of schizophrenia, we compared the effects on neuronal activity of systematic administration of delta-9-tetrahydrocannabinol (THC) with the fatty acid amide hydrolase inhibitor URB597. Specifically, we found that the inhibitory response in the prefrontal cortex to THC administration was absent in PCP-treated rats. In contrast, an augmented response to endocannabinoid upregulation was observed in the prefrontal cortex of PCP-treated rats. Interestingly, differential effects were also observed at the neuronal population level, as endocannabinoid upregulation induced opposite effects on coordinated activity when compared to THC. Such information is important for understanding why marijuana and synthetic cannabinoid use may be contraindicated in schizophrenia patients while endocannabinoid enhancement may provide a novel therapeutic approach. PMID:26510449
The selective reversible FAAH inhibitor, SSR411298, restores the development of maladaptive behaviors to acute and chronic stress in rodents.

PubMed

Griebel, Guy; Stemmelin, Jeanne; Lopez-Grancha, Mati; Fauchey, Valérie; Slowinski, Franck; Pichat, Philippe; Dargazanli, Gihad; Abouabdellah, Ahmed; Cohen, Caroline; Bergis, Olivier E

2018-02-05

Enhancing endogenous cannabinoid (eCB) signaling has been considered as a potential strategy for the treatment of stress-related conditions. Fatty acid amide hydrolase (FAAH) represents the primary degradation enzyme of the eCB anandamide (AEA), oleoylethanolamide (OEA) and palmitoylethanolamide (PEA). This study describes a potent reversible FAAH inhibitor, SSR411298. The drug acts as a selective inhibitor of FAAH, which potently increases hippocampal levels of AEA, OEA and PEA in mice. Despite elevating eCB levels, SSR411298 did not mimic the interoceptive state or produce the behavioral side-effects (memory deficit and motor impairment) evoked by direct-acting cannabinoids. When SSR411298 was tested in models of anxiety, it only exerted clear anxiolytic-like effects under highly aversive conditions following exposure to a traumatic event, such as in the mouse defense test battery and social defeat procedure. Results from experiments in models of depression showed that SSR411298 produced robust antidepressant-like activity in the rat forced-swimming test and in the mouse chronic mild stress model, restoring notably the development of inadequate coping responses to chronic stress. This preclinical profile positions SSR411298 as a promising drug candidate to treat diseases such as post-traumatic stress disorder, which involves the development of maladaptive behaviors.
Cannabinoids impair the formation of cholesteryl ester in cultured human cells.

PubMed

Cornicelli, J A; Gilman, S R; Krom, B A; Kottke, B A

1981-01-01

The ability of cultured human fibroblasts to form cholesteryl esters from 14C-oleate is impaired by delta'-tetrahydrocannabinol, cannabidiol, and cannabinol, a group of natural products isolated from Cannabis sativa. This inhibition is compound and dose-related; 30 microM cannabidiol reduced esterification to less than 20% of the control values. The esterification of endogenous and exogenous cholesterol was affected, since inhibition was seen with either low density lipoproteins (200 micrograms/ml) or 25-hydroxycholesterol (5 micrograms/ml) as esterification stimuli. Cells treated with these compounds at doses of from 1 to 30 microM showed no impairment of protein synthesis, triglyceride or phospholipid formation, or ability to metabolize 125I-low density lipoproteins. An inhibition of cholesterol esterification was seen in human aortic medial cells. With increasing doses of these compounds, low density lipoproteins (25 micrograms/ml) became progressively less effective in suppressing HMG-CoA reductase in cultured human fibroblasts; with 30 microM cannabidiol the enzyme suppression was only 24% of that found in cells incubated with low density lipoproteins in the absence of drugs. Based on these data, we conclude that the cannabinoids "compartmentalize" cholesterol and, thus, make is unavailable for regulating cellular cholesterol metabolism. This may occur as a result of enhanced sterol efflux.
The contractile effect of anandamide in the guinea-pig small intestine is mediated by prostanoids but not TRPV1 receptors or capsaicin-sensitive nerves.

PubMed

Dékány, András; Benko, Rita; Szombati, Veronika; Bartho, Lorand

2013-05-01

Although exogenous and endogenous cannabinoid receptor agonists have well-documented inhibitory effects on gastrointestinal motility, a TRPV1 receptor-mediated excitatory action of anandamide (arachidonoyl ethanolamide, AEA) in the guinea-pig ileum strip has also been described. We used in vitro capsaicin desensitization for assessing the possible participation of sensory neurons in the contractile effect of anandamide on the guinea-pig whole ileum, as well as autonomic drugs and a cyclooxygenase inhibitor for characterizing this response. Isolated organ experiments were used with isotonic recording. Contractions induced by anandamide (1 or 10 μM) were strongly inhibited by tetrodotoxin, indomethacin or atropine plus a tachykinin NK(1) receptor antagonist, but weakly to moderately reduced by atropine alone and partly diminished by the fatty acid amide hydrolase inhibitor URB 597. Neither capsaicin pre-treatment nor the TRPV1 receptor antagonist BCTC, the ganglionic blocking drug hexamethonium or cannabinoid (CB1 or CB2 ) receptor antagonists, influenced the effect of anandamide. It is concluded that the capsaicin-insensitive, neuronal excitatory effect of anandamide in the intestine is most probably mediated by cyclooxygenase products. Such a mechanism may also play a role at other sites in the mammalian body. © 2012 Nordic Pharmacological Society. Published by Blackwell Publishing Ltd.

Fatal overdose from synthetic cannabinoids and cathinones in Japan: demographics and autopsy findings.

PubMed

Ezaki, Jiro; Ro, Ayako; Hasegawa, Masayuki; Kibayashi, Kazuhiko

2016-09-01

Sixty-one autopsy cases involving cathinones and/or cannabinoids (synthetic cathinones/cannabinoids) use have been reported. However, little is known about the demographics and autopsy findings in fatal synthetic cathinones/cannabinoids users. To elucidate demographic and autopsy findings (i.e. major organ pathology and causes of death) in synthetic cathinones/cannabinoids cases. We reviewed forensic autopsy reports in Department of Legal Medicine of Tokyo Women's Medical University (Tokyo, Japan) between 2011 and 2015 (a total of 359). We compared demographic and autopsy findings between synthetic cathinones/cannabinoids and methamphetamine cases (as control subjects). There were 12 synthetic cathinones/cannabinoids cases and 10 methamphetamine cases. Synthetic cathinones/cannabinoids users were significantly younger than methamphetamine users (p < 0.01), and there were no cases that used both synthetic cathinones/cannabinoids and methamphetamine. Acute intoxication and cardiac ischemia were the two most prominent causes of death in both synthetic cathinones/cannabinoids users and methamphetamine users. Excited delirium syndrome and pulmonary aspiration were found only in synthetic cathinones/cannabinoids cases. The populations of synthetic cathinones/cannabinoids and methamphetamine users who died of an overdose are different in Japan. Acute intoxication, cardiac ischemia, excited delirium syndrome, pulmonary aspiration, and drowning are the major autopsy findings in synthetic cathinones/cannabinoids-related death. Clinicians shuld be aware of these potentially fatal complications in the medical management of synthetic cathinones/cannabinoids users.
Monoacylglycerol lipase inhibition by organophosphorus compounds leads to elevation of brain 2-arachidonoylglycerol and the associated hypomotility in mice

DOE Office of Scientific and Technical Information (OSTI.GOV)

Quistad, Gary B.; Klintenberg, Rebecka; Caboni, Pierluigi

2006-02-15

Three components of the cannabinoid system are sensitive to selected organophosphorus (OP) compounds: monoacylglycerol (MAG) lipase that hydrolyzes the major endogenous agonist 2-arachidonoylglycerol (2-AG); fatty acid amide hydrolase (FAAH) that cleaves the agonist anandamide present in smaller amounts; the CB1 receptor itself. This investigation considers which component of the cannabinoid system is the most likely contributor to OP-induced hypomotility in mice. Structure-activity studies by our laboratory and others rule against major involvement of a direct toxicant-CB1 receptor interaction for selected OPs. Attention was therefore focused on the OP sensitivities of MAG lipase and FAAH, assaying 19 structurally diverse OP chemicalsmore » (pesticides, their metabolites and designer compounds) for in vitro inhibition of both enzymes. Remarkably high potency and low selectivity is observed with three O-alkyl (C{sub 1}, C{sub 2}, C{sub 3}) alkylphosphonofluoridates (C{sub 8}, C{sub 12}) (IC50 0.60-3.0 nM), five S-alkyl (C{sub 5}, C{sub 7}, C{sub 9}) and alkyl (C{sub 1}, C{sub 12}) benzodioxaphosphorin oxides (IC50 0.15-5.7 nM) and one OP insecticide metabolite (chlorpyrifos oxon, IC50 34-40 nM). In ip-treated mice, the OPs at 1-30 mg/kg more potently inhibit brain FAAH than MAG lipase, but FAAH inhibition is not correlated with hypomotility. However, the alkylphosphonofluoridate-treated mice show dose-dependent increases in severity of hypomotility, inhibition of MAG lipase activity and elevation of 2-AG. Moderate to severe hypomotility is accompanied by 64 to 86% MAG lipase inhibition and about 6-fold elevation of brain 2-AG level. It therefore appears that OP-induced MAG lipase inhibition leads to elevated 2-AG and the associated hypomotility.« less
Analysis of natural product regulation of cannabinoid receptors in the treatment of human disease.

PubMed

Badal, S; Smith, K N; Rajnarayanan, R

2017-12-01

The organized, tightly regulated signaling relays engaged by the cannabinoid receptors (CBs) and their ligands, G proteins and other effectors, together constitute the endocannabinoid system (ECS). This system governs many biological functions including cell proliferation, regulation of ion transport and neuronal messaging. This review will firstly examine the physiology of the ECS, briefly discussing some anomalies in the relay of the ECS signaling as these are consequently linked to maladies of global concern including neurological disorders, cardiovascular disease and cancer. While endogenous ligands are crucial for dispatching messages through the ECS, there are also commonalities in binding affinities with copious exogenous ligands, both natural and synthetic. Therefore, this review provides a comparative analysis of both types of exogenous ligands with emphasis on natural products given their putative safer efficacy and the role of Δ9-tetrahydrocannabinol (Δ9-THC) in uncovering the ECS. Efficacy is congruent to both types of compounds but noteworthy is the effect of a combination therapy to achieve efficacy without unideal side-effects. An example is Sativex that displayed promise in treating Huntington's disease (HD) in preclinical models allowing for its transition to current clinical investigation. Despite the in vitro and preclinical efficacy of Δ9-THC to treat neurodegenerative ailments, its psychotropic effects limit its clinical applicability to treating feeding disorders. We therefore propose further investigation of other compounds and their combinations such as the triterpene, α,β-amyrin that exhibited greater binding affinity to CB 1 than CB 2 and was more potent than Δ9-THC and the N-alkylamides that exhibited CB 2 selective affinity; the latter can be explored towards peripherally exclusive ECS modulation. The synthetic CB 1 antagonist, Rimonabant was pulled from commercial markets for the treatment of diabetes, however its analogue SR144528 maybe an ideal lead molecule towards this end and HU-210 and Org27569 are also promising synthetic small molecules. Copyright © 2017 Elsevier Inc. All rights reserved.
Cannabis use amongst patients with inflammatory bowel disease.

PubMed

Lal, Simon; Prasad, Neeraj; Ryan, Manijeh; Tangri, Sabrena; Silverberg, Mark S; Gordon, Allan; Steinhart, Hillary

2011-10-01

Experimental evidence suggests the endogenous cannabinoid system may protect against colonic inflammation, leading to the possibility that activation of this system may have a therapeutic role in inflammatory bowel disease (IBD). Medicinal use of cannabis for chronic pain and other symptoms has been reported in a number of medical conditions. We aimed to evaluate cannabis use in patients with IBD. One hundred patients with ulcerative colitis (UC) and 191 patients with Crohn's disease (CD) attending a tertiary-care outpatient clinic completed a questionnaire regarding current and previous cannabis use, socioeconomic factors, disease history and medication use, including complimentary alternative medicines. Quality of life was assessed using the short-inflammatory bowel disease questionnaire. A comparable proportion of UC and CD patients reported lifetime [48/95 (51%) UC vs. 91/189 (48%) CD] or current [11/95 (12%) UC vs. 30/189 (16%) CD] cannabis use. Of lifetime users, 14/43 (33%) UC and 40/80 (50%) CD patients have used it to relieve IBD-related symptoms, including abdominal pain, diarrhoea and reduced appetite. Patients were more likely to use cannabis for symptom relief if they had a history of abdominal surgery [29/48 (60%) vs. 24/74 (32%); P=0.002], chronic analgesic use [29/41 (71%) vs. 25/81 (31%); P<0.001], complimentary alternative medicine use [36/66 (55%) vs. 18/56 (32%); P=0.01] and a lower short inflammatory bowel disease questionnaire score (45.1±2.1 vs. 50.3±1.5; P=0.03). Patients who had used cannabis [60/139 (43%)] were more likely than nonusers [13/133 (10%); P<0.001 vs. users] to express an interest in participating in a hypothetical therapeutic trial of cannabis for IBD. Cannabis use is common amongst patients with IBD for symptom relief, particularly amongst those with a history of abdominal surgery, chronic abdominal pain and/or a low quality of life index. The therapeutic benefits of cannabinoid derivatives in IBD may warrant further exploration.
[Cannabinoids in pain medicine].

PubMed

Karst, M

2018-06-07

The endocannabinoid system (ECS) controls a large number of vital functions. Suboptimal tone of the ECS in certain regions of the nervous system may be associated with disorders that are also associated with pain. Pain and inflammation processes can be modulated by the exogenous supply of cannabinoids. Low-to-moderate pain-relieving effects and in individual cases large pain-relieving effects were observed in randomized, controlled studies of various types of chronic pain. People with chronic neuropathic pain and stress symptoms seem to particularly benefit. The therapeutic range of cannabinoids is small; often small doses are sufficient for clinically significant effects. The "Cannabis-als-Medizin-Gesetz" (cannabis as medicine law) allows the prescription of cannabis preparations under certain conditions. Available data indicate good long-term efficacy and tolerability. However, there is little systematic long-term experience from clinical studies.
Engineering yeasts as platform organisms for cannabinoid biosynthesis.

PubMed

Zirpel, Bastian; Degenhardt, Friederike; Martin, Chantale; Kayser, Oliver; Stehle, Felix

2017-10-10

Δ 9 -tetrahydrocannabinolic acid (THCA) is a plant derived secondary natural product from the plant Cannabis satival. The discovery of the human endocannabinoid system in the late 1980s resulted in a growing number of known physiological functions of both synthetic and plant derived cannabinoids. Thus, manifold therapeutic indications of cannabinoids currently comprise a significant area of research. Here we reconstituted the final biosynthetic cannabinoid pathway in yeasts. The use of the soluble prenyltransferase NphB from Streptomyces sp. strain CL190 enables the replacement of the native transmembrane prenyltransferase cannabigerolic acid synthase from C. sativa. In addition to the desired product cannabigerolic acid, NphB catalyzes an O-prenylation leading to 2-O-geranyl olivetolic acid. We show for the first time that the bacterial prenyltransferase and the final enzyme of the cannabinoid pathway tetrahydrocannabinolic acid synthase can both be actively expressed in the yeasts Saccharomyces cerevisiae and Komagataella phaffii simultaneously. While enzyme activities in S. cerevisiae were insufficient to produce THCA from olivetolic acid and geranyl diphosphate, genomic multi-copy integrations of the enzyme's coding sequences in K. phaffii resulted in successful synthesis of THCA from olivetolic acid and geranyl diphosphate. This study is an important step toward total biosynthesis of valuable cannabinoids and derivatives and demonstrates the potential for developing a sustainable and secure yeast bio-manufacturing platform. Copyright © 2017 Elsevier B.V. All rights reserved.
Cannabinoid modulation of prefrontal-limbic activation during fear extinction learning and recall in humans

PubMed Central

Rabinak, Christine A.; Angstadt, Mike; Lyons, Maryssa; Mori, Shoko; Milad, Mohammed R.; Liberzon, Israel; Phan, K. Luan

2013-01-01

Pre-extinction administration of ∆9-tetrahydrocannibinol (THC) facilitates recall of extinction in healthy humans, and evidence from animal studies suggest that this likely involves via enhancement of the cannabinoid system within the ventromedial prefrontal cortex (vmPFC) and hippocampus (HIPP), brain structures critical to fear extinction. However, the effect of cannabinoids on the underlying neural circuitry of extinction memory recall in humans has not been demonstrated. We conducted a functional magnetic resonance imaging (fMRI) study using a randomized, double-blind, placebo-controlled, between-subjects design (N=14/group) coupled with a standard Pavlovian fear extinction paradigm and an acute pharmacological challenge with oral dronabinol (synthetic THC) in healthy adult volunteers. We examined the effects of THC on vmPFC and HIPP activation when tested for recall of extinction learning 24 hours after extinction learning. Compared to subjects who received placebo, participants who received THC showed increased vmPFC and HIPP activation to a previously extinguished conditioned stimulus (CS+E) during extinction memory recall. This study provides the first evidence that pre-extinction administration of THC modulates prefrontal-limbic circuits during fear extinction in humans and prompts future investigation to test if cannabinoid agonists can rescue or correct the impaired behavioral and neural function during extinction recall in patients with PTSD. Ultimately, the cannabinoid system may serve as a promising target for innovative intervention strategies (e.g. pharmacological enhancement of exposure-based therapy) in PTSD and other fear learning-related disorders. PMID:24055595
Effects of Intra-Amygdala Infusion of CB1 Receptor Agonists on the Reconsolidation of Fear-Potentiated Startle

ERIC Educational Resources Information Center

Lin, Hui-Ching; Mao, Sheng-Chun; Gean, Po-Wu

2006-01-01

The cannabinoid CB1 receptor has been shown to be critically involved in the extinction of fear memory. Systemic injection of a CB1 receptor antagonist prior to extinction training blocked extinction. Conversely, administration of the cannabinoid uptake inhibitor AM404 facilitated extinction in a dose-dependent manner. Here we show that bilateral…
Cannabinoid and Cholinergic Systems Interact during Performance of a Short-Term Memory Task in the Rat

ERIC Educational Resources Information Center

Goonawardena, Anushka V.; Robinson, Lianne; Hampson, Robert E.; Riedel, Gernot

2010-01-01

It is now well established that cannabinoid agonists such as [delta][superscript 9]-tetrahydrocannabinol (THC), anandamide, and WIN 55,212-2 (WIN-2) produce potent and specific deficits in working memory (WM)/short-term memory (STM) tasks in rodents. Although mediated through activation of CB1 receptors located in memory-related brain regions such…
Can We Selectively Reduce Appetite for Energy-Dense Foods? An Overview of Pharmacological Strategies for Modification of Food Preference Behavior.

PubMed

Bojanowska, Ewa; Ciosek, Joanna

2016-01-01

Excessive intake of food, especially palatable and energy-dense carbohydrates and fats, is largely responsible for the growing incidence of obesity worldwide. Although there are a number of candidate antiobesity drugs, only a few of them have been proven able to inhibit appetite for palatable foods without the concurrent reduction in regular food consumption. In this review, we discuss the interrelationships between homeostatic and hedonic food intake control mechanisms in promoting overeating with palatable foods and assess the potential usefulness of systemically administered pharmaceuticals that impinge on the endogenous cannabinoid, opioid, aminergic, cholinergic, and peptidergic systems in the modification of food preference behavior. Also, certain dietary supplements with the potency to reduce specifically palatable food intake are presented. Based on human and animal studies, we indicate the most promising therapies and agents that influence the effectiveness of appetite-modifying drugs. It should be stressed, however, that most of the data included in our review come from preclinical studies; therefore, further investigations aimed at confirming the effectiveness and safety of the aforementioned medications in the treatment of obese humans are necessary.
Can We Selectively Reduce Appetite for Energy-Dense Foods? An Overview of Pharmacological Strategies for Modification of Food Preference Behavior

PubMed Central

Bojanowska, Ewa; Ciosek, Joanna

2016-01-01

Excessive intake of food, especially palatable and energy-dense carbohydrates and fats, is largely responsible for the growing incidence of obesity worldwide. Although there are a number of candidate antiobesity drugs, only a few of them have been proven able to inhibit appetite for palatable foods without the concurrent reduction in regular food consumption. In this review, we discuss the interrelationships between homeostatic and hedonic food intake control mechanisms in promoting overeating with palatable foods and assess the potential usefulness of systemically administered pharmaceuticals that impinge on the endogenous cannabinoid, opioid, aminergic, cholinergic, and peptidergic systems in the modification of food preference behavior. Also, certain dietary supplements with the potency to reduce specifically palatable food intake are presented. Based on human and animal studies, we indicate the most promising therapies and agents that influence the effectiveness of appetite-modifying drugs. It should be stressed, however, that most of the data included in our review come from preclinical studies; therefore, further investigations aimed at confirming the effectiveness and safety of the aforementioned medications in the treatment of obese humans are necessary. PMID:26549651
Poly-ε-caprolactone microspheres as a drug delivery system for cannabinoid administration: development, characterization and in vitro evaluation of their antitumoral efficacy.

PubMed

Hernán Pérez de la Ossa, D; Ligresti, A; Gil-Alegre, M E; Aberturas, M R; Molpeceres, J; Di Marzo, V; Torres Suárez, A I

2012-08-10

Cannabinoids show promise for the treatment of various medical conditions such as emesis, anorexia, pain, cancer, multiple sclerosis, Parkinson's disease and glaucoma. However, their high lipohilicity and instability complicate their handling and dosing, and restrict their use as pharmaceuticals. The objective of the present work was to assess the feasibility of developing cannabinoid loaded poly-ε-caprolactone (PCL) microparticles prepared by the oil-in-water emulsion-solvent evaporation technique as a suitable dosage form for their administration. Spherical microparticles with a size range of 20-50 μm, and high entrapment efficiency (around 100%) were obtained. Cannabidiol (CBD) dissolved in the polymeric matrix of the microspheres was slowly released in vitro within 10 days. In vitro cell viability studies demonstrated the antitumoral activity of CBD released from microparticles. After 4 and 7 days of incubation, CBD in microspheres significantly inhibited the growth of MDA-MB-231 cells by 60% as compared to the 50% attained with free drug. The results suggest that PCL microparticles could be an alternative delivery system for long-term cannabinoid administration, showing potential therapeutic advantages over free drug. Copyright © 2012 Elsevier B.V. All rights reserved.
Molecularly imprinted polymer based quartz crystal microbalance sensor system for sensitive and label-free detection of synthetic cannabinoids in urine.

PubMed

Battal, Dilek; Akgönüllü, Semra; Yalcin, M Serkan; Yavuz, Handan; Denizli, Adil

2018-07-15

Herein, we prepared a novel quartz crystal microbalance (QCM) sensor for synthetic cannabinoids (JWH-073, JWH-073 butanoic acid, JWH-018 and JWH-018 pentanoic acid,) detection. Firstly, the synthetic cannabinoid (SCs) imprinted (MIP) and non-imprinted (NIP) nanoparticles were synthesized by mini-emulsion polymerization system. The SCs-imprinted nanoparticles were first characterized by SEM, TEM, zeta-size and FTIR-ATR analysis and then were dropped onto the gold QCM surface. The SCs-imprinted QCM sensor was characterized by an ellipsometer, contact angle, and AFM. The limit of detection was found as 0.3, 0.45, 0.4, 0.2 pg/mL JWH-018, JWH-073, JWH-018 pentanoic acid and JWH-073 butanoic acid, respectively. The selectivity of the SCs-imprinted QCM sensor was shown by using JWH-018, JWH-018 pentanoic acid, JWH-073 and JWH-073 butanoic acid. According to the results, the SCs-imprinted QCM sensors show highly selective and sensitive in a broad range of synthetic cannabinoid concentrations (0.0005-1.0 ng/mL) in both aqueous and synthetic urine solutions. Copyright © 2018 Elsevier B.V. All rights reserved.
Regulation of brain reward by the endocannabinoid system: a critical review of behavioral studies in animals.

PubMed

Vlachou, S; Panagis, G

2014-01-01

The endocannabinoid system has been implicated in the regulation of a variety of physiological processes, including a crucial involvement in brain reward systems and the regulation of motivational processes. Behavioral studies have shown that cannabinoid reward may involve the same brain circuits and similar brain mechanisms with other drugs of abuse, such as nicotine, cocaine, alcohol and heroin, as well as natural rewards, such as food, water and sucrose, although the conditions under which cannabinoids exert their rewarding effects may be more limited. The purpose of the present review is to briefly describe and evaluate the behavioral and pharmacological research concerning the major components of the endocannabinoid system and reward processes. Special emphasis is placed on data received from four procedures used to test the effects of the endocannabinoid system on brain reward in animals; namely, the intracranial self-stimulation paradigm, the self-administration procedure, the conditioned place preference procedure and the drug-discrimination procedure. The effects of cannabinoid 1 (CB1) and cannabinoid 2 (CB2) receptor agonists, antagonists and endocannabinoid modulators in these procedures are examined. Further, the involvement of CB1 and CB2 receptors, as well the fatty acid amid hydrolase (FAAH) enzyme in reward processes is investigated through presentation of respective genetic ablation studies in mice. We suggest that the endocannabinoid system plays a major role in modulating motivation and reward processes. Further research will provide us with a better understanding of these processes and, thus, could lead to the development of potential therapeutic compounds for the treatment of reward-related disorders.
Prospects for Creation of Cardioprotective Drugs Based on Cannabinoid Receptor Agonists.

PubMed

Maslov, Leonid N; Khaliulin, Igor; Zhang, Yi; Krylatov, Andrey V; Naryzhnaya, Natalia V; Mechoulam, Raphael; De Petrocellis, Luciano; Downey, James M

2016-05-01

Cannabinoids can mimic the infarct-reducing effect of early ischemic preconditioning, delayed ischemic preconditioning, and ischemic postconditioning against myocardial ischemia/reperfusion. They do this primarily through both CB1 and CB2 receptors. Cannabinoids are also involved in remote preconditioning of the heart. The cannabinoid receptor ligands also exhibit an antiapoptotic effect during ischemia/reperfusion of the heart. The acute cardioprotective effect of cannabinoids is mediated by activation of protein kinase C, extracellular signal-regulated kinase, and p38 kinase. The delayed cardioprotective effect of cannabinoid anandamide is mediated via stimulation of phosphatidylinositol-3-kinase-Akt signaling pathway and enhancement of heat shock protein 72 expression. The delayed cardioprotective effect of another cannabinoid, Δ9-tetrahydrocannabinol, is associated with augmentation of nitric oxide (NO) synthase expression, but data on the involvement of NO synthase in the acute cardioprotective effect of cannabinoids are contradictory. The adenosine triphosphate-sensitive K(+)channel is involved in the synthetic cannabinoid HU-210-induced cardiac resistance to ischemia/reperfusion injury. Cannabinoids inhibit Na(+)/Ca(2+)exchange via peripheral cannabinoid receptor (CB2) activation that may also be related to the antiapoptotic and cardioprotective effects of cannabinoids. The cannabinoid receptor agonists should be considered as prospective group of compounds for creation of drugs that are able to protect the heart against ischemia-reperfusion injury in the clinical setting. © The Author(s) 2015.
The therapeutic potential of the cannabinoids in neuroprotection.

PubMed

Grundy, Robert I

2002-10-01

After thousands of years of interest the last few decades have seen a huge increase in our knowledge of the cannabinoids and their mode of action. Their potential as medical therapeutics has long been known. However, very real concerns over their safety and efficacy have lead to caution and suspicion when applying the legislature of modern medicine to these compounds. The ability of this diverse family of compounds to modulate neurotransmission and act as anti-inflammatory and antioxidative agents has prompted researchers to investigate their potential as neuroprotective agents. Indeed, various cannabinoids rescue dying neurones in experimental forms of acute neuronal injury, such as cerebral ischaemia and traumatic brain injury. Cannabinoids also provide symptomatic relief in experimental models of chronic neurodegenerative diseases, such as multiple sclerosis and Huntington's disease. This preclinical evidence has provided the impetus for the launch of a number of clinical trials in various conditions of neurodegeneration and neuronal injury using compounds derived from the cannabis plant. Our understanding of cannabinoid neurobiology, however, must improve if we are to effectively exploit this system and take advantage of the numerous characteristics that make this group of compounds potential neuroprotective agents.
LiCABEDS II. Modeling of ligand selectivity for G-protein-coupled cannabinoid receptors.

PubMed

Ma, Chao; Wang, Lirong; Yang, Peng; Myint, Kyaw Z; Xie, Xiang-Qun

2013-01-28

The cannabinoid receptor subtype 2 (CB2) is a promising therapeutic target for blood cancer, pain relief, osteoporosis, and immune system disease. The recent withdrawal of Rimonabant, which targets another closely related cannabinoid receptor (CB1), accentuates the importance of selectivity for the development of CB2 ligands in order to minimize their effects on the CB1 receptor. In our previous study, LiCABEDS (Ligand Classifier of Adaptively Boosting Ensemble Decision Stumps) was reported as a generic ligand classification algorithm for the prediction of categorical molecular properties. Here, we report extension of the application of LiCABEDS to the modeling of cannabinoid ligand selectivity with molecular fingerprints as descriptors. The performance of LiCABEDS was systematically compared with another popular classification algorithm, support vector machine (SVM), according to prediction precision and recall rate. In addition, the examination of LiCABEDS models revealed the difference in structure diversity of CB1 and CB2 selective ligands. The structure determination from data mining could be useful for the design of novel cannabinoid lead compounds. More importantly, the potential of LiCABEDS was demonstrated through successful identification of newly synthesized CB2 selective compounds.
Cannabinoids in the management of difficult to treat pain.

PubMed

Russo, Ethan B

2008-02-01

This article reviews recent research on cannabinoid analgesia via the endocannabinoid system and non-receptor mechanisms, as well as randomized clinical trials employing cannabinoids in pain treatment. Tetrahydrocannabinol (THC, Marinol((R))) and nabilone (Cesamet((R))) are currently approved in the United States and other countries, but not for pain indications. Other synthetic cannabinoids, such as ajulemic acid, are in development. Crude herbal cannabis remains illegal in most jurisdictions but is also under investigation. Sativex((R)), a cannabis derived oromucosal spray containing equal proportions of THC (partial CB(1) receptor agonist ) and cannabidiol (CBD, a non-euphoriant, anti-inflammatory analgesic with CB(1) receptor antagonist and endocannabinoid modulating effects) was approved in Canada in 2005 for treatment of central neuropathic pain in multiple sclerosis, and in 2007 for intractable cancer pain. Numerous randomized clinical trials have demonstrated safety and efficacy for Sativex in central and peripheral neuropathic pain, rheumatoid arthritis and cancer pain. An Investigational New Drug application to conduct advanced clinical trials for cancer pain was approved by the US FDA in January 2006. Cannabinoid analgesics have generally been well tolerated in clinical trials with acceptable adverse event profiles. Their adjunctive addition to the pharmacological armamentarium for treatment of pain shows great promise.
Cannabinoids: new promising agents in the treatment of neurological diseases.

PubMed

Giacoppo, Sabrina; Mandolino, Giuseppe; Galuppo, Maria; Bramanti, Placido; Mazzon, Emanuela

2014-11-17

Nowadays, Cannabis sativa is considered the most extensively used narcotic. Nevertheless, this fame obscures its traditional employ in native medicine of South Africa, South America, Turkey, Egypt and in many regions of Asia as a therapeutic drug. In fact, the use of compounds containing Cannabis and their introduction in clinical practice is still controversial and strongly limited by unavoidable psychotropic effects. So, overcoming these adverse effects represents the main open question on the utilization of cannabinoids as new drugs for treatment of several pathologies. To date, therapeutic use of cannabinoid extracts is prescribed in patients with glaucoma, in the control of chemotherapy-related vomiting and nausea, for appetite stimulation in patients with anorexia-cachexia syndrome by HIV, and for the treatment of multiple sclerosis symptoms. Recently, researcher efforts are aimed to employ the therapeutic potentials of Cannabis sativa in the modulation of cannabinoid receptor activity within the central nervous system, particularly for the treatment of neurodegenerative diseases, as well as psychiatric and non-psychiatric disorders. This review evaluates the most recent available data on cannabinoids utilization in experimental and clinical studies, and highlights their beneficial effects in the prevention of the main neurological diseases and for the clinical treatment of symptoms with them correlated.
Comparison of outcome expectancies for synthetic cannabinoids and botanical marijuana.

PubMed

Lauritsen, Kirstin J; Rosenberg, Harold

2016-07-01

Although initially developed for medical purposes, synthetic cannabinoids have also been consumed for recreational purposes. To evaluate whether agreement with positive and negative outcome expectancies differed for synthetic cannabinoids versus botanical marijuana, and assess reported reasons for using synthetic cannabinoids. Using a web-based recruitment and data collection procedure, 186 adults who had used both synthetic cannabinoids and botanical marijuana and 181 adults who had used botanical marijuana but not synthetic cannabinoids, completed measures of outcome expectancies and other relevant questionnaires. A significant interaction revealed that participants who had used both synthetic cannabinoids and botanical marijuana indicated lower agreement with positive expectancies for synthetic cannabinoids, and higher agreement with positive expectancies for botanical marijuana, than did those participants who used only botanical marijuana. There was no interaction between type of drug and use history on agreement with negative expectancies, and participants agreed more strongly with negative outcome expectancies for synthetic cannabinoids than for botanical marijuana whether they had used one or both types of these drugs. The most frequently provided reasons for using synthetic cannabinoids included availability, perceived legality, cost, curiosity, and social interaction. Given growing public acceptance of recreational and medical marijuana, coupled with negative perceptions and increasing regulation of synthetic cannabinoid compounds, botanical marijuana is likely to remain more available and more popular than synthetic cannabinoids.

Cytotoxicity of synthetic cannabinoids on primary neuronal cells of the forebrain: the involvement of cannabinoid CB{sub 1} receptors and apoptotic cell death

DOE Office of Scientific and Technical Information (OSTI.GOV)

Tomiyama, Ken-ichi; Funada, Masahiko, E-mail: mfunada@ncnp.go.jp

2014-01-01

The abuse of herbal products containing synthetic cannabinoids has become an issue of public concern. The purpose of this paper was to evaluate the acute cytotoxicity of synthetic cannabinoids on mouse brain neuronal cells. Cytotoxicity induced by synthetic cannabinoid (CP-55,940, CP-47,497, CP-47,497-C8, HU-210, JWH-018, JWH-210, AM-2201, and MAM-2201) was examined using forebrain neuronal cultures. These synthetic cannabinoids induced cytotoxicity in the forebrain cultures in a concentration-dependent manner. The cytotoxicity was suppressed by preincubation with the selective CB{sub 1} receptor antagonist AM251, but not with the selective CB{sub 2} receptor antagonist AM630. Furthermore, annexin-V-positive cells were found among the treated forebrainmore » cells. Synthetic cannabinoid treatment induced the activation of caspase-3, and preincubation with a caspase-3 inhibitor significantly suppressed the cytotoxicity. These synthetic cannabinoids induced apoptosis through a caspase-3-dependent mechanism in the forebrain cultures. Our results indicate that the cytotoxicity of synthetic cannabinoids towards primary neuronal cells is mediated by the CB{sub 1} receptor, but not by the CB{sub 2} receptor, and further suggest that caspase cascades may play an important role in the apoptosis induced by these synthetic cannabinoids. In conclusion, excessive synthetic cannabinoid abuse may present a serious acute health concern due to neuronal damage or deficits in the brain. - Highlights: • Synthetic cannabinoids (classical cannabinoids, non-classical cannabinoids, and aminoalkylindole derivatives) induce cytotoxicity in mouse forebrain cultures. • Synthetic cannabinoid-induced cytotoxicity towards forebrain cultures is mediated by the CB{sub 1} receptor, but not by the CB{sub 2} receptor, and involves caspase-dependent apoptosis. • A high concentration of synthetic cannabinoids may be toxic to neuronal cells that express CB{sub 1} receptors.« less
CB1 Cannabinoid Receptor Activation Dose-Dependently Modulates Neuronal Activity within Caudal but not Rostral Song Control Regions of Adult Zebra Finch Telencephalon

PubMed Central

Soderstrom, Ken; Tian, Qiyu

2008-01-01

CB1 cannabinoid receptors are distinctly expressed at high density within several regions of zebra finch telencephalon including those known to be involved in song learning (lMAN and Area X) and production (HVC and RA). Because: (1) exposure to cannabinoid agonists during developmental periods of auditory and sensory-motor song learning alters song patterns produced later in adulthood and; (2) densities of song region expression of CB1 waxes-and-wanes during song learning, it is becoming clear that CB1 receptor-mediated signaling is important to normal processes of vocal development. To better understand mechanisms involved in cannabinoid modulation of vocal behavior we have investigated the dose-response relationship between systemic cannabinoid exposure and changes in neuronal activity (as indicated by expression of the transcription factor, c-Fos) within telencephalic brain regions with established involvement in song learning and/or control. In adults we have found that low doses (0.1 mg/kg) of the cannabinoid agonist WIN-55212-2 decrease neuronal activity (as indicated by densities of c-fos-expressing nuclei) within vocal motor regions of caudal telencephalon (HVC and RA) while higher doses (3 mg/kg) stimulate activity. Both effects were reversed by pretreatment with the CB1-selective antagonist rimonabant. Interestingly, no effects of cannabinoid treatment were observed within the rostral song regions lMAN and Area X, despite distinct and dense CB1 receptor expression within these areas. Overall, our results demonstrate that, depending on dosage, CB1 agonism can both inhibit and stimulate neuronal activity within brain regions controlling adult vocal motor output, implicating involvement of multiple CB1-sensitive neuronal circuits. PMID:18509622
The endocannabinoid/endovanilloid N-arachidonoyl dopamine (NADA) and synthetic cannabinoid WIN55,212-2 abate the inflammatory activation of human endothelial cells.

PubMed

Wilhelmsen, Kevin; Khakpour, Samira; Tran, Alphonso; Sheehan, Kayla; Schumacher, Mark; Xu, Fengyun; Hellman, Judith

2014-05-09

Although cannabinoids, such as Δ(9)-tetrahydrocannabinol, have been studied extensively for their psychoactive effects, it has become apparent that certain cannabinoids possess immunomodulatory activity. Endothelial cells (ECs) are centrally involved in the pathogenesis of organ injury in acute inflammatory disorders, such as sepsis, because they express cytokines and chemokines, which facilitate the trafficking of leukocytes to organs, and they modulate vascular barrier function. In this study, we find that primary human ECs from multiple organs express the cannabinoid receptors CB1R, GPR18, and GPR55, as well as the ion channel transient receptor potential cation channel vanilloid type 1. In contrast to leukocytes, CB2R is only minimally expressed in some EC populations. Furthermore, we show that ECs express all of the known endocannabinoid (eCB) metabolic enzymes. Examining a panel of cannabinoids, we demonstrate that the synthetic cannabinoid WIN55,212-2 and the eCB N-arachidonoyl dopamine (NADA), but neither anandamide nor 2-arachidonoylglycerol, reduce EC inflammatory responses induced by bacterial lipopeptide, LPS, and TNFα. We find that endothelial CB1R/CB2R are necessary for the effects of NADA, but not those of WIN55,212-2. Furthermore, transient receptor potential cation channel vanilloid type 1 appears to counter the anti-inflammatory properties of WIN55,212-2 and NADA, but conversely, in the absence of these cannabinoids, its inhibition exacerbates the inflammatory response in ECs activated with LPS. These data indicate that the eCB system can modulate inflammatory activation of the endothelium and may have important implications for a variety of acute inflammatory disorders that are characterized by EC activation.
The Endocannabinoid/Endovanilloid N-Arachidonoyl Dopamine (NADA) and Synthetic Cannabinoid WIN55,212-2 Abate the Inflammatory Activation of Human Endothelial Cells*

PubMed Central

Wilhelmsen, Kevin; Khakpour, Samira; Tran, Alphonso; Sheehan, Kayla; Schumacher, Mark; Xu, Fengyun; Hellman, Judith

2014-01-01

Although cannabinoids, such as Δ9-tetrahydrocannabinol, have been studied extensively for their psychoactive effects, it has become apparent that certain cannabinoids possess immunomodulatory activity. Endothelial cells (ECs) are centrally involved in the pathogenesis of organ injury in acute inflammatory disorders, such as sepsis, because they express cytokines and chemokines, which facilitate the trafficking of leukocytes to organs, and they modulate vascular barrier function. In this study, we find that primary human ECs from multiple organs express the cannabinoid receptors CB1R, GPR18, and GPR55, as well as the ion channel transient receptor potential cation channel vanilloid type 1. In contrast to leukocytes, CB2R is only minimally expressed in some EC populations. Furthermore, we show that ECs express all of the known endocannabinoid (eCB) metabolic enzymes. Examining a panel of cannabinoids, we demonstrate that the synthetic cannabinoid WIN55,212-2 and the eCB N-arachidonoyl dopamine (NADA), but neither anandamide nor 2-arachidonoylglycerol, reduce EC inflammatory responses induced by bacterial lipopeptide, LPS, and TNFα. We find that endothelial CB1R/CB2R are necessary for the effects of NADA, but not those of WIN55,212-2. Furthermore, transient receptor potential cation channel vanilloid type 1 appears to counter the anti-inflammatory properties of WIN55,212-2 and NADA, but conversely, in the absence of these cannabinoids, its inhibition exacerbates the inflammatory response in ECs activated with LPS. These data indicate that the eCB system can modulate inflammatory activation of the endothelium and may have important implications for a variety of acute inflammatory disorders that are characterized by EC activation. PMID:24644287
Fatty acid amide hydrolase (FAAH) inhibition enhances memory acquisition through activation of PPAR-α nuclear receptors

PubMed Central

Mazzola, Carmen; Medalie, Julie; Scherma, Maria; Panlilio, Leigh V.; Solinas, Marcello; Tanda, Gianluigi; Drago, Filippo; Cadet, Jean Lud; Goldberg, Steven R.; Yasar, Sevil

2009-01-01

Inhibitors of fatty acid amide hydrolase (FAAH) increase endogenous levels of anandamide (a cannabinoid CB1-receptor ligand) and oleoylethanolamide and palmitoylethanolamide (OEA and PEA, ligands for α-type peroxisome proliferator-activated nuclear receptors, PPAR-α) when and where they are naturally released in the brain. Using a passive-avoidance task in rats, we found that memory acquisition was enhanced by the FAAH inhibitor URB597 or by the PPAR-α agonist WY14643, and these enhancements were blocked by the PPAR-α antagonist MK886. These findings demonstrate novel mechanisms for memory enhancement by activation of PPAR-α, either directly by administering a PPAR-α agonist or indirectly by administering a FAAH inhibitor. PMID:19403796
Molecular Mechanisms of Cannabis Signaling in the Brain.

PubMed

Ronan, Patrick J; Wongngamnit, Narin; Beresford, Thomas P

2016-01-01

Cannabis has been cultivated and used by humans for thousands of years. Research for decades was focused on understanding the mechanisms of an illegal/addictive drug. This led to the discovery of the vast endocannabinoid system. Research has now shifted to understanding fundamental biological questions related to one of the most widespread signaling systems in both the brain and the body. Our understanding of cannabinoid signaling has advanced significantly in the last two decades. In this review, we discuss the state of knowledge on mechanisms of Cannabis signaling in the brain and the modulation of key brain neurotransmitter systems involved in both brain reward/addiction and psychiatric disorders. It is highly probable that various cannabinoids will be found to be efficacious in the treatment of a number of psychiatric disorders. However, while there is clearly much potential, marijuana has not been properly vetted by the medical-scientific evaluation process and there are clearly a range of potentially adverse side-effects-including addiction. We are at crossroads for research on endocannabinoid function and therapeutics (including the use of exogenous treatments such as Cannabis). With over 100 cannabinoid constituents, the majority of which have not been studied, there is much Cannabis research yet to be done. With more states legalizing both the medicinal and recreational use of marijuana the rigorous scientific investigation into cannabinoid signaling is imperative. Copyright © 2016. Published by Elsevier Inc.
Training-Associated Emotional Arousal Shapes Endocannabinoid Modulation of Spatial Memory Retrieval in Rats.

PubMed

Morena, Maria; De Castro, Valentina; Gray, J Megan; Palmery, Maura; Trezza, Viviana; Roozendaal, Benno; Hill, Matthew N; Campolongo, Patrizia

2015-10-14

Variations in environmental aversiveness influence emotional memory processes in rats. We have previously shown that cannabinoid effects on memory are dependent on the stress level at the time of training as well as on the aversiveness of the environmental context. Here, we investigated whether the hippocampal endocannabinoid system modulates memory retrieval depending on the training-associated arousal level. Male adult Sprague Dawley rats were trained on a water maze spatial task at two different water temperatures (19°C and 25°C) to elicit either higher or lower stress levels, respectively. Rats trained under the higher stress condition had better memory and higher corticosterone concentrations than rats trained at the lower stress condition. The cannabinoid receptor agonist WIN55212-2 (10-30 ng/side), the 2-arachidonoyl glycerol (2-AG) hydrolysis inhibitor JZL184 (0.1-1 μg/side), and the anandamide (AEA) hydrolysis inhibitor URB597 (10-30 ng/side) were administered bilaterally into the hippocampus 60 min before probe-trial retention testing. WIN55212-2 or JZL184, but not URB597, impaired probe-trial performances only of rats trained at the higher stressful condition. Furthermore, rats trained under higher stress levels displayed an increase in hippocampal 2-AG, but not AEA, levels at the time of retention testing and a decreased affinity of the main 2-AG-degrading enzyme for its substrate. The present findings indicate that the endocannabinoid 2-AG in the hippocampus plays a key role in the selective regulation of spatial memory retrieval of stressful experience, shedding light on the neurobiological mechanisms involved in the impact of stress effects on memory processing. Endogenous cannabinoids play a central role in the modulation of memory for emotional events. Here we demonstrate that the endocannabinoid 2-arachidonoylglycerol in the hippocampus, a brain region crucially involved in the regulation of memory processes, selectively modulates spatial memory recall of stressful experiences. Thus, our findings provide evidence that the endocannabinoid 2-arachidonoylglycerol is a key player in mediating the impact of stress on memory retrieval. These findings can pave the way to new potential therapeutic intervention for the treatment of neuropsychiatric disorders, such as post-traumatic stress disorder, where a previous exposure to traumatic events could alter the response to traumatic memory recall leading to mental illness. Copyright © 2015 the authors 0270-6474/15/3513963-13$15.00/0.
The Cannabinoid System in the Retrosplenial Cortex Modulates Fear Memory Consolidation, Reconsolidation, and Extinction

ERIC Educational Resources Information Center

Sachser, Ricardo Marcelo; Crestani, Ana Paula; Quillfeldt, Jorge Alberto; e Souza, Tadeu Mello; de Oliveira Alvares, Lucas

2015-01-01

Despite the fact that the cannabinoid receptor type 1 (CB1R) plays a pivotal role in emotional memory processing in different regions of the brain, its function in the retrosplenial cortex (RSC) remains unknown. Here, using contextual fear conditioning in rats, we showed that a post-training intra-RSC infusion of the CB1R antagonist AM251…
Cannabinoid CB2 receptors in the gastrointestinal tract: a regulatory system in states of inflammation

PubMed Central

Wright, K L; Duncan, M; Sharkey, K A

2007-01-01

The emerging potential for the cannabinoid (CB) system in modulating gastrointestinal inflammation has gained momentum over the last few years. Traditional and anecdotal use of marijuana for gastrointestinal disorders, such as diarrhoea and abdominal cramps is recognized, but the therapeutic benefit of cannabinoids in the 21st century is overshadowed by the psychoactive problems associated with CB1 receptor activation. However, the presence and function of the CB2 receptor in the GI tract, whilst not yet well characterized, holds great promise due to its immunomodulatory roles in inflammatory systems and its lack of psychotropic effects. This review of our current knowledge of CB2 receptors in the gastrointestinal tract highlights its role in regulating abnormal motility, modulating intestinal inflammation and limiting visceral sensitivity and pain. CB2 receptors represent a braking system and a pathophysiological mechanism for the resolution of inflammation and many of its symptoms. CB2 receptor activation therefore represents a very promising therapeutic target in gastrointestinal inflammatory states where there is immune activation and motility dysfunction. PMID:17906675
The skeletal endocannabinoid system: clinical and experimental insights.

PubMed

Raphael, Bitya; Gabet, Yankel

2016-05-01

Recently, there has been a rapidly growing interest in the role of cannabinoids in the regulation of skeletal remodeling and bone mass, addressed in basic, translational and clinical research. Since the first publications in 2005, there are more than 1000 publications addressing the skeletal endocannabinoid system. This review focuses on the roles of the endocannabinoid system in skeletal biology via the cannabinoid receptors CB1, CB2 and others. Endocannabinoids play important roles in bone formation, bone resorption and skeletal growth, and are sometimes age, gender, species and strain dependent. Controversies in the literature and potential therapeutic approaches targeting the endocannabinoid system in skeletal disorders are also discussed.
A cannabinoid link between mitochondria and memory.

PubMed

Hebert-Chatelain, Etienne; Desprez, Tifany; Serrat, Román; Bellocchio, Luigi; Soria-Gomez, Edgar; Busquets-Garcia, Arnau; Pagano Zottola, Antonio Christian; Delamarre, Anna; Cannich, Astrid; Vincent, Peggy; Varilh, Marjorie; Robin, Laurie M; Terral, Geoffrey; García-Fernández, M Dolores; Colavita, Michelangelo; Mazier, Wilfrid; Drago, Filippo; Puente, Nagore; Reguero, Leire; Elezgarai, Izaskun; Dupuy, Jean-William; Cota, Daniela; Lopez-Rodriguez, Maria-Luz; Barreda-Gómez, Gabriel; Massa, Federico; Grandes, Pedro; Bénard, Giovanni; Marsicano, Giovanni

2016-11-24

Cellular activity in the brain depends on the high energetic support provided by mitochondria, the cell organelles which use energy sources to generate ATP. Acute cannabinoid intoxication induces amnesia in humans and animals, and the activation of type-1 cannabinoid receptors present at brain mitochondria membranes (mtCB 1 ) can directly alter mitochondrial energetic activity. Although the pathological impact of chronic mitochondrial dysfunctions in the brain is well established, the involvement of acute modulation of mitochondrial activity in high brain functions, including learning and memory, is unknown. Here, we show that acute cannabinoid-induced memory impairment in mice requires activation of hippocampal mtCB 1 receptors. Genetic exclusion of CB 1 receptors from hippocampal mitochondria prevents cannabinoid-induced reduction of mitochondrial mobility, synaptic transmission and memory formation. mtCB 1 receptors signal through intra-mitochondrial Gα i protein activation and consequent inhibition of soluble-adenylyl cyclase (sAC). The resulting inhibition of protein kinase A (PKA)-dependent phosphorylation of specific subunits of the mitochondrial electron transport system eventually leads to decreased cellular respiration. Hippocampal inhibition of sAC activity or manipulation of intra-mitochondrial PKA signalling or phosphorylation of the Complex I subunit NDUFS2 inhibit bioenergetic and amnesic effects of cannabinoids. Thus, the G protein-coupled mtCB 1 receptors regulate memory processes via modulation of mitochondrial energy metabolism. By directly linking mitochondrial activity to memory formation, these data reveal that bioenergetic processes are primary acute regulators of cognitive functions.
Pro-drugs for indirect cannabinoids as therapeutic agents.

PubMed

Ashton, John

2008-10-01

Medicinal cannabis, cannabis extracts, and other cannabinoids are currently in use or under clinical trial investigation for the control of nausea, emesis and wasting in patients undergoing chemotherapy, the control of neuropathic pain and arthritic pain, and the control of the symptoms of multiple sclerosis. The further development of medicinal cannabinoids has been challenged with problems. These include the psychoactivity of cannabinoid CB1 receptor agonists and the lack of availability of highly selective cannabinoid receptor full agonists (for the CB1 or CB2 receptor), as well as problems of pharmacokinetics. Global activation of cannabinoid receptors is usually undesirable, and so enhancement of local endocannabinoid receptor activity with indirect cannabimimetics is an attractive strategy for therapeutic modulation of the endocannabinoid system. However, existing drugs of this type tend to be metabolized by the same enzymes as their target endocannabinoids and are not yet available in a form that is clinically useful. A potential solution to these problems may now have been suggested by the discovery that paracetamol (acetaminophen) exerts its analgesic (and probably anti-pyretic) effects by its degradation into an anandamide (an endocannabinoid) reuptake inhibitor (AM404) within the body, thus classifying it as pro-drug for an indirect cannabimimetic. Given the proven efficacy and safety of paracetamol, the challenge now is to develop related drugs, or entirely different substrates, into pro-drug indirect cannabimimetics with a similar safety profile to paracetamol but at high effective dose titrations.
State-dependent, bidirectional modulation of neural network activity by endocannabinoids.

PubMed

Piet, Richard; Garenne, André; Farrugia, Fanny; Le Masson, Gwendal; Marsicano, Giovanni; Chavis, Pascale; Manzoni, Olivier J

2011-11-16

The endocannabinoid (eCB) system and the cannabinoid CB1 receptor (CB1R) play key roles in the modulation of brain functions. Although actions of eCBs and CB1Rs are well described at the synaptic level, little is known of their modulation of neural activity at the network level. Using microelectrode arrays, we have examined the role of CB1R activation in the modulation of the electrical activity of rat and mice cortical neural networks in vitro. We find that exogenous activation of CB1Rs expressed on glutamatergic neurons decreases the spontaneous activity of cortical neural networks. Moreover, we observe that the net effect of the CB1R antagonist AM251 inversely correlates with the initial level of activity in the network: blocking CB1Rs increases network activity when basal network activity is low, whereas it depresses spontaneous activity when its initial level is high. Our results reveal a complex role of CB1Rs in shaping spontaneous network activity, and suggest that the outcome of endogenous neuromodulation on network function might be state dependent.
The alpha subunit of Go interacts with promyelocytic leukemia zinc finger protein and modulates its functions.

PubMed

Won, Jung Hee; Park, Jung Sik; Ju, Hyun Hee; Kim, Soyeon; Suh-Kim, Haeyoung; Ghil, Sung Ho

2008-05-01

Heterotrimeric GTP-binding proteins (G proteins) mediate signal transduction generated by neurotransmitters and hormones. Go, a member of the Go/Gi family, is the most abundant heterotrimeric G protein in the brain. Most mechanistic analyses on Go activation demonstrate that its action is mediated by the Gbetagamma dimer; downstream effectors for its alpha subunit (Goalpha) have not been clearly defined. Here, we employ the yeast two-hybrid system to screen for Goalpha-interacting partners in a cDNA library from human fetal brain. The transcription factor promyelocytic leukemia zinc finger protein (PLZF) specifically bound to Goalpha. Interactions between PLZF and Goalpha were confirmed using in vitro and in vivo affinity binding assays. Activated Goalpha interacted directly with PLZF, and enhanced its function as a transcriptional and cell growth suppressor. Notably, PLZF activity was additionally promoted by the Go/ialpha-coupled cannabinoid receptor (CB) in HL60 cells endogenously expressing CB and PLZF. These results collectively suggest that Goalpha modulates the function of PLZF via direct interactions. Our novel findings provide insights into the diverse cellular roles of Goalpha and its coupled receptor.
Cannabinoids for pediatric epilepsy? Up in smoke or real science?

PubMed Central

2015-01-01

Public interest in the use of “medical marijuana” for the treatment of childhood epilepsy has burgeoned in the last few years. This has occurred in parallel with a growing interest in “medical marijuana” in general. Physicians and pediatricians must balance their patients’ desire for immediate access to these products with the tenets of evidence-based medicine. This review discusses the biochemistry of cannabis products (the phytocannabinoids) setting this in the context of the endogenous endocannabinoid system. The differing and potentially modulating effects of delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD) are reviewed. The evidence-base supporting or not the use of cannabis products for the treatment of neurological disease and specifically epilepsy is explored. The potential for adverse effects and particularly of neurotoxicity is addressed. Finally, public health and sociocultural implications are touched upon. Specific recommendations for interested physicians are provided including advocacy for patients and for a change in the “scheduling” of cannabis in order to better foster much-needed high-quality scientific research in this important area. PMID:26835389
Bivalent ligands that target μ opioid (MOP) and cannabinoid1 (CB1) receptors are potent analgesics devoid of tolerance.

PubMed

Le Naour, Morgan; Akgün, Eyup; Yekkirala, Ajay; Lunzer, Mary M; Powers, Mike D; Kalyuzhny, Alexander E; Portoghese, Philip S

2013-07-11

Given that μ opioid (MOP) and canabinoid (CB1) receptors are colocalized in various regions of the central nervous system and have been reported to associate as heteromer (MOP-CB1) in cultured cells, the possibility of functional, endogenous MOP-CB1 in nociception and other pharmacologic effects has been raised. As a first step in investigating this possibility, we have synthesized a series of bivalent ligands 1-5 that contain both μ agonist and CB1 antagonist pharmacophores for use as tools to study the functional interaction between MOP and CB1 receptors in vivo. Immunofluorescent studies on HEK293 cells coexpressing both receptors suggested 5 (20-atom spacer) to be the only member of the series that bridges the protomers of the heteromer. Antinociceptive testing in mice revealed 5 to be the most potent member of the series. As neither a mixture of monovalent ligands 9 + 10 nor bivalents 2-5 produced tolerance in mice, MOR-CB1 apparently is not an important target for reducing tolerance.
Blockade of THC-seeking behavior and relapse in monkeys by the cannabinoid CB(1)-receptor antagonist rimonabant.

PubMed

Justinova, Zuzana; Munzar, Patrik; Panlilio, Leigh V; Yasar, Sevil; Redhi, Godfrey H; Tanda, Gianluigi; Goldberg, Steven R

2008-11-01

Accumulating evidence suggests the endocannabinoid system modulates environmental cues' ability to induce seeking of drugs, including nicotine and alcohol. However, little attention has been directed toward extending these advances to the growing problem of cannabis use disorders. Therefore, we studied intravenous self-administration of Delta(9)-tetrahydrocannabinol (THC), the main psychoactive constituent of marijuana, using a second-order schedule of drug seeking. Squirrel monkeys' lever responses produced only a brief cue light until the end of the session, when the final response delivered THC along with the cue. When a reinstatement procedure was used to model relapse following a period of abstinence, THC-seeking behavior was robustly reinstated by the cue or by pre-session administration of THC, other cannabinoid agonists, or morphine, but not cocaine. The cannabinoid antagonist rimonabant blocked cue-induced drug seeking, THC-induced drug seeking, and the direct reinforcing effects of THC. Thus, rimonabant and related medications might be effective as treatments for cannabinoid dependence.
Cannabis and joints: scientific evidence for the alleviation of osteoarthritis pain by cannabinoids.

PubMed

O'Brien, Melissa; McDougall, Jason J

2018-04-07

Cannabis has been used for millennia to treat a multitude of medical conditions including chronic pain. Osteoarthritis (OA) pain is one of the most common types of pain and patients often turn to medical cannabis to manage their symptoms. While the majority of these reports are anecdotal, there is a growing body of scientific evidence which supports the analgesic potential of cannabinoids to treat OA pain. OA pain manifests as a combination of inflammatory, nociceptive, and neuropathic pain, each requiring modality-specific analgesics. The body's innate endocannabinoid system (ECS) has been shown to ameliorate all of these pain subtypes. This review summarizes the components of the ECS and details the latest research pertaining to plant-based and man-made cannabinoids for the treatment of OA pain. Recent pre-clinical evidence supporting a role for the ECS to control OA pain is described as well as current clinical evidence of the efficacy of cannabinoids for treating OA pain in mixed patient populations. Copyright © 2018 Elsevier Ltd. All rights reserved.
The multidrug transporter ABCG2 (BCRP) is inhibited by plant-derived cannabinoids.

PubMed

Holland, M L; Lau, D T T; Allen, J D; Arnold, J C

2007-11-01

Cannabinoids are used therapeutically for the palliation of the adverse side effects associated with cancer chemotherapy. However, cannabinoids also inhibit both the activity and expression of the multidrug transporter, P-glycoprotein in vitro. Here we address the interaction of cannabinol (CBN), cannabidiol (CBD) and delta 9-tetrahydrocannabinol (THC) with the related multidrug transporter, ABCG2. Cannabinoid inhibition of Abcg2/ABCG2 was assessed using flow cytometric analysis of substrate accumulation and ATPase activity assays. The cytotoxicity and chemosensitization by cannabinoids was determined with cell viability assays. Expression of cannabinoid and vanilloid receptors was assessed using reverse transcriptase polymerase chain reaction, and cannabinoid modulation of ABCG2 expression was examined using immunoblotting. CBN, CBD and THC increased the intracellular accumulation of the Abcg2/ABCG2 substrate, mitoxantrone, in an over-expressing cell line. The THC metabolite, (-)-11-nor-9-carboxy-delta 9-THC was much less potent. The plant cannabinoids inhibited both basal and substrate stimulated ATPase activity of human ABCG2. Cannabinoid cytotoxicity occurred in the absence of known cannabinoid cell surface receptors, and only at concentrations higher than those required for Abcg2/ABCG2 inhibition. Sub-toxic concentrations of the cannabinoids resensitized the overexpressing cell line to the cytotoxic effect of Abcg2/ABCG2 substrates, mitoxantrone and topotecan. This occurred in the absence of any effect on ABCG2 expression. Cannabinoids are novel Abcg2/ABCG2 inhibitors, reversing the Abcg2-mediated multidrug-resistant phenotype in vitro. This finding may have implications for the co-administration of cannabinoids with pharmaceuticals that are ABCG2 substrates.
MDMA & cannabis: a mini-review of cognitive, behavioral, and neurobiological effects of co-consumption.

PubMed

Schulz, Sybille

2011-06-01

Although the prevalence of co-use of cannabis and 3,4 methylenedioxymethamphetamine (MDMA) is very common among polydrug users in western societies, few studies have tested the consequences on behavior, cognition or neurobiology. This review examines 23 articles published between 2002 and 2010 with an explicit focus on the combination, or administration, of MDMA and cannabis or cannabinoid agents. The aim was to provide a short overview on the latest human research concerning cognitive effects of co-consumption of MDMA and cannabis, and a more elaborate picture of the state of knowledge about the interaction of cannabinoid agents and MDMA from animal studies. It was found that recent retrospective studies on cognitive functions in long-term drug abusers point to an additive negative effect on different types of memory, as well as a cannabis-independent decrease in learning and decision-making in MDMA users. Behavioral experiments in rodents and in vitro studies investigating the combined effect of MDMA and cannabinoid agents demonstrate modulator effects of acute co-administration on measures like body temperature, conditioned reinforcement, and presumed neurotoxicity. As neural mechanism underlying these changes, an interaction between the cannabinoid system, especially cannabinoid receptor 1, and the serotonergic and dopaminergic system in the prefrontal cortex, nucleus accumbens, and hippocampus is suggested. In conclusion, there are few and somewhat contradictory studies examining the effects of co-use of these drugs on cognitive measures like impulsivity, memory and executive functions or underlying neurobiological alterations, and a shortage of animal studies examining long-term effects of chronic co-administration.

Effects of cannabinoid drugs on the deficit of prepulse inhibition of startle in an animal model of schizophrenia: the SHR strain.

PubMed

Levin, Raquel; Peres, Fernanda F; Almeida, Valéria; Calzavara, Mariana B; Zuardi, Antonio W; Hallak, Jaime E C; Crippa, José Alexandre S; Abílio, Vanessa C

2014-01-01

Clinical and neurobiological findings suggest that the cannabinoids and the endocannabinoid system may be implicated in the pathophysiology and treatment of schizophrenia. We described that the spontaneously hypertensive rats (SHR) strain presents a schizophrenia behavioral phenotype that is specifically attenuated by antipsychotic drugs, and potentiated by proschizophrenia manipulations. Based on these findings, we have suggested this strain as an animal model of schizophrenia. The aim of this study was to evaluate the effects of cannabinoid drugs on the deficit of prepulse inhibition (PPI) of startle, the main paradigm used to study sensorimotor gating impairment related to schizophrenia, presented by the SHR strain. The following drugs were used: (1) WIN55212,2 (cannabinoid agonist), (2) rimonabant (CB1 antagonist), (3) AM404 (anandamide uptake inhibitor), and (4) cannabidiol (CBD; indirect CB1/CB2 receptor antagonist, among other effects). Wistar rats (WRs) and SHRs were treated with vehicle (VEH) or different doses of WIN55212 (0.3, 1, or 3 mg/kg), rimonabant (0.75, 1.5, or 3 mg/kg), AM404 (1, 5, or 10 mg/kg), or CBD (15, 30, or 60 mg/kg). VEH-treated SHRs showed a decreased PPI when compared to WRs. This PPI deficit was reversed by 1 mg/kg WIN and 30 mg/kg CBD. Conversely, 0.75 mg/kg rimonabant decreased PPI in SHR strain, whereas AM404 did not modify it. Our results reinforce the role of the endocannabinoid system in the sensorimotor gating impairment related to schizophrenia, and point to cannabinoid drugs as potential therapeutic strategies.
New insights into antimetastatic and antiangiogenic effects of cannabinoids.

PubMed

Ramer, Robert; Hinz, Burkhard

2015-01-01

Cannabinoids exert antitumorigenic effects via multiple mechanisms. Of these, antimetastatic and antiangiogenic actions have attracted considerable interest in the past years. Regarding the underlying antimetastatic mechanism, several studies revealed cannabinoids to alter the gene expression of cancer cells toward a less-aggressive phenotype and to modulate their secretomic profile. Cannabinoids likewise modulate the release of factors from tumor cells that subsequently suppress the chemoattraction of vessel cells thereby conferring antiangiogenesis. Among the diverse mediators of cannabinoids' antitumorigenic action, the tissue inhibitor of matrix metalloproteinases-1, which is released from cancer cells upon cannabinoid treatment, has been implicated as a pivotal factor conferring both anti-invasive properties of cancer cells as well as antiangiogenic capacities of endothelial cells. In addition, cannabinoids have been shown to inhibit angiogenic capacities of endothelial cells directly via suppressing their proliferation, tube formation, and migration. This chapter reviews the cell- and substance-specific antitumorigenic mechanisms of cannabinoids with particular consideration of their antimetastatic/anti-invasive and antiangiogenic actions. In addition, beneficial interactions of cannabinoids with currently used chemotherapeutics as well as the influence of cannabinoids on tumor-immune surveillance are addressed. Collectively, the currently available data suggest cannabinoids as a potential tool in modern cancer pharmacotherapy. Copyright © 2015 Elsevier Inc. All rights reserved.
Comprehensive Review of Medicinal Marijuana, Cannabinoids, and Therapeutic Implications in Medicine and Headache: What a Long Strange Trip It's Been ….

PubMed

Baron, Eric P

2015-06-01

The use of cannabis, or marijuana, for medicinal purposes is deeply rooted though history, dating back to ancient times. It once held a prominent position in the history of medicine, recommended by many eminent physicians for numerous diseases, particularly headache and migraine. Through the decades, this plant has taken a fascinating journey from a legal and frequently prescribed status to illegal, driven by political and social factors rather than by science. However, with an abundance of growing support for its multitude of medicinal uses, the misguided stigma of cannabis is fading, and there has been a dramatic push for legalizing medicinal cannabis and research. Almost half of the United States has now legalized medicinal cannabis, several states have legalized recreational use, and others have legalized cannabidiol-only use, which is one of many therapeutic cannabinoids extracted from cannabis. Physicians need to be educated on the history, pharmacology, clinical indications, and proper clinical use of cannabis, as patients will inevitably inquire about it for many diseases, including chronic pain and headache disorders for which there is some intriguing supportive evidence. To review the history of medicinal cannabis use, discuss the pharmacology and physiology of the endocannabinoid system and cannabis-derived cannabinoids, perform a comprehensive literature review of the clinical uses of medicinal cannabis and cannabinoids with a focus on migraine and other headache disorders, and outline general clinical practice guidelines. The literature suggests that the medicinal use of cannabis may have a therapeutic role for a multitude of diseases, particularly chronic pain disorders including headache. Supporting literature suggests a role for medicinal cannabis and cannabinoids in several types of headache disorders including migraine and cluster headache, although it is primarily limited to case based, anecdotal, or laboratory-based scientific research. Cannabis contains an extensive number of pharmacological and biochemical compounds, of which only a minority are understood, so many potential therapeutic uses likely remain undiscovered. Cannabinoids appear to modulate and interact at many pathways inherent to migraine, triptan mechanisms ofaction, and opiate pathways, suggesting potential synergistic or similar benefits. Modulation of the endocannabinoid system through agonism or antagonism of its receptors, targeting its metabolic pathways, or combining cannabinoids with other analgesics for synergistic effects, may provide the foundation for many new classes of medications. Despite the limited evidence and research suggesting a role for cannabis and cannabinoids in some headache disorders, randomized clinical trials are lacking and necessary for confirmation and further evaluation. © 2015 American Headache Society.
Spicing thing up: Synthetic cannabinoids

PubMed Central

Spaderna, Max; Addy, Peter H; D’Souza, Deepak Cyril

2013-01-01

Rationale Recently, products containing synthetic cannabinoids, collectively referred to as Spice, are increasingly being used recreationally. Objectives The availability, acute subjective effects—including self-reports posted on Erowid—laboratory detection, addictive potential, and regulatory challenges of the Spice phenomenon are reviewed. Results Spice is sold under the guise of potpourri or incense. Unlike THC, the synthetic cannabinoids present in Spice are high-potency, high-efficacy, cannabinoid-receptor full agonists. Since standard urine toxicology does not test for the synthetic cannabinoids in Spice, it is often used by those who want to avoid detection of drug use. These compounds have not yet been subjected to rigorous testing in humans. Acute psychoactive effects include changes in mood, anxiety, perception, thinking, memory, and attention. Adverse effects include anxiety, agitation, panic, dysphoria, psychosis, and bizarre behavior. Psychosis outcomes associated with Spice provide additional data linking cannabinoids and psychosis. Adverse events necessitating intervention by Poison Control Centers, law enforcement, emergency responders, and hospitals are increasing. Despite statutes prohibiting the manufacture, distribution, and sale of Spice products, manufacturers are replacing banned compounds with newer synthetic cannabinoids that are not banned. Conclusions There is an urgent need for better research on the effects of synthetic cannabinoids to help clinicians manage adverse events and to better understand cannabinoid pharmacology in humans. The reported psychosis outcomes associated with synthetic cannabinoids contribute to the ongoing debate on the association between cannabinoids and psychosis. Finally, drug-detection tests for synthetic cannabinoids need to become clinically available. PMID:23836028
Novel endogenous N-acyl amides activate TRPV1-4 receptors, BV-2 microglia, and are regulated in brain in an acute model of inflammation

PubMed Central

Raboune, Siham; Stuart, Jordyn M.; Leishman, Emma; Takacs, Sara M.; Rhodes, Brandon; Basnet, Arjun; Jameyfield, Evan; McHugh, Douglas; Widlanski, Theodore; Bradshaw, Heather B.

2014-01-01

A family of endogenous lipids, structurally analogous to the endogenous cannabinoid, N-arachidonoyl ethanolamine (Anandamide), and called N-acyl amides have emerged as a family of biologically active compounds at TRP receptors. N-acyl amides are constructed from an acyl group and an amine via an amide bond. This same structure can be modified by changing either the fatty acid or the amide to form potentially hundreds of lipids. More than 70 N-acyl amides have been identified in nature. We have ongoing studies aimed at isolating and characterizing additional members of the family of N-acyl amides in both central and peripheral tissues in mammalian systems. Here, using a unique in-house library of over 70 N-acyl amides we tested the following three hypotheses: (1) Additional N-acyl amides will have activity at TRPV1-4, (2) Acute peripheral injury will drive changes in CNS levels of N-acyl amides, and (3) N-acyl amides will regulate calcium in CNS-derived microglia. Through these studies, we have identified 20 novel N-acyl amides that collectively activate (stimulating or inhibiting) TRPV1-4. Using lipid extraction and HPLC coupled to tandem mass spectrometry we showed that levels of at least 10 of these N-acyl amides that activate TRPVs are regulated in brain after intraplantar carrageenan injection. We then screened the BV2 microglial cell line for activity with this N-acyl amide library and found overlap with TRPV receptor activity as well as additional activators of calcium mobilization from these lipids. Together these data provide new insight into the family of N-acyl amides and their roles as signaling molecules at ion channels, in microglia, and in the brain in the context of inflammation. PMID:25136293
The Endocannabinoid System as a Target for Treatment of Breast Cancer

DTIC Science & Technology

2010-08-01

psychoactive constituent of marijuana (Gaoni and Mechoulam, 1964), as well as other naturally occurring and synthetically derived cannabinoids bind to and...the primary psychoactive constituent present in marijuana , and WIN55,212-2, a highly potent, full CB1 receptor agonist. Female mice implanted with...potent and highly efficacious synthetic cannabinoid receptor agonist originally developed as a nonsteroidal anti-inflammatory drug (Ward et al., 1991
Local administration of a cannabinoid agonist alters norepinephrine efflux in the rat frontal cortex.

PubMed

Page, M E; Oropeza, V C; Van Bockstaele, E J

2008-01-24

Delta(9)-tetrahydrocannabinol, the main psychoactive ingredient in marijuana, activates specific cannabinoid (CB) receptors to exert complex actions on modulatory neurotransmitters involved in attention and cognition. Previous research has demonstrated that systemic administration of the synthetic cannabinoid agonist, WIN 55,212-2, increases norepinephrine efflux in the frontal cortex. The distribution of CB1 receptors on noradrenergic fibers in the frontal cortex suggests this may be one potential site for the regulation of norepinephrine release. In the present study, we first examined the ability of a CB1 antagonist, applied locally in the frontal cortex of adult male Sprague-Dawley rats, to block the actions of systemic WIN 55,212-2. Pretreatment with SR 141716A (300 microM) significantly attenuated the excitatory effects of WIN 55,212-2 (15 mg/kg, i.p.). Next, the impact of direct perfusion of WIN 55,212-2 into the frontal cortex on extracellular norepinephrine efflux was measured. Direct application of WIN 55,212-2 (100 microM) into the frontal cortex elicited a significant increase in extracellular norepinephrine efflux suggesting that activation of cortical cannabinoid receptors contributes to alterations in norepinephrine levels in this brain region. Finally, local administration of SR 141716A followed by local administration of WIN 55,212-2 revealed a paradoxical inhibition of norepinephrine efflux.
State of the evidence: Cannabinoids and cancer pain-A systematic review.

PubMed

Tateo, Sydney

2017-02-01

Cannabinoids are widely used to alleviate intractable symptoms such as pain, nausea, and muscle spasticity. The purpose of this review was to ascertain the current state of the science regarding use of cannabinoids for cancer pain. Four electronic databases were searched for randomized control trials of cannabinoids and cancer pain. Studies included examined the analgesic effects of cannabinoids for cancer pain. Methodological quality was assessed using the Jadad scale. Eight randomized control trials met the inclusion criteria for review. Most trials found analgesic effects from cannabinoids when compared to placebo, although not all associations reached statistical significance. The analgesic effects of cannabinoids were also limited by dose-dependent side effects. Side effects most commonly reported were changes in cognition, sedation, and dizziness. There is evidence that cannabinoids are effective adjuvants for cancer pain not completely relieved by opioid therapy, but there is a dearth of high-quality studies to support a stronger conclusion. Cannabinoids appear to be safe in low and medium doses. Methodological limitations of the trials limited the ability to make sound conclusions. Further research is warranted before efficacy, safety, and utility of cannabinoids for cancer pain can be determined. ©2016 American Association of Nurse Practitioners.
The multidrug transporter ABCG2 (BCRP) is inhibited by plant-derived cannabinoids

PubMed Central

Holland, M L; Lau, D T T; Allen, J D; Arnold, J C

2007-01-01

Background and purpose: Cannabinoids are used therapeutically for the palliation of the adverse side effects associated with cancer chemotherapy. However, cannabinoids also inhibit both the activity and expression of the multidrug transporter, P-glycoprotein in vitro. Here we address the interaction of cannabinol (CBN), cannabidiol (CBD) and Δ9-tetrahydrocannabinol (THC) with the related multidrug transporter, ABCG2. Experimental approach: Cannabinoid inhibition of Abcg2/ABCG2 was assessed using flow cytometric analysis of substrate accumulation and ATPase activity assays. The cytotoxicity and chemosensitization by cannabinoids was determined with cell viability assays. Expression of cannabinoid and vanilloid receptors was assessed using reverse transcriptase polymerase chain reaction, and cannabinoid modulation of ABCG2 expression was examined using immunoblotting. Key results: CBN, CBD and THC increased the intracellular accumulation of the Abcg2/ABCG2 substrate, mitoxantrone, in an over-expressing cell line. The THC metabolite, (−)-11-nor-9-carboxy-Δ9-THC was much less potent. The plant cannabinoids inhibited both basal and substrate stimulated ATPase activity of human ABCG2. Cannabinoid cytotoxicity occurred in the absence of known cannabinoid cell surface receptors, and only at concentrations higher than those required for Abcg2/ABCG2 inhibition. Sub-toxic concentrations of the cannabinoids resensitized the overexpressing cell line to the cytotoxic effect of Abcg2/ABCG2 substrates, mitoxantrone and topotecan. This occurred in the absence of any effect on ABCG2 expression. Conclusions and implications: Cannabinoids are novel Abcg2/ABCG2 inhibitors, reversing the Abcg2-mediated multidrug-resistant phenotype in vitro. This finding may have implications for the co-administration of cannabinoids with pharmaceuticals that are ABCG2 substrates. PMID:17906686
Cannabinoids inhibit neurodegeneration in models of multiple sclerosis.

PubMed

Pryce, Gareth; Ahmed, Zubair; Hankey, Deborah J R; Jackson, Samuel J; Croxford, J Ludovic; Pocock, Jennifer M; Ledent, Catherine; Petzold, Axel; Thompson, Alan J; Giovannoni, Gavin; Cuzner, M Louise; Baker, David

2003-10-01

Multiple sclerosis is increasingly being recognized as a neurodegenerative disease that is triggered by inflammatory attack of the CNS. As yet there is no satisfactory treatment. Using experimental allergic encephalo myelitis (EAE), an animal model of multiple sclerosis, we demonstrate that the cannabinoid system is neuroprotective during EAE. Mice deficient in the cannabinoid receptor CB1 tolerate inflammatory and excitotoxic insults poorly and develop substantial neurodegeneration following immune attack in EAE. In addition, exogenous CB1 agonists can provide significant neuroprotection from the consequences of inflammatory CNS disease in an experimental allergic uveitis model. Therefore, in addition to symptom management, cannabis may also slow the neurodegenerative processes that ultimately lead to chronic disability in multiple sclerosis and probably other diseases.
Cross-Reactivity of Pantoprazole with Three Commercial Cannabinoids Immunoassays in Urine.

PubMed

Gomila, Isabel; Barceló, Bernardino; Rosell, Antonio; Avella, Sonia; Sahuquillo, Laura; Dastis, Macarena

2017-11-01

Pantoprazole is a frequently prescribed proton pump inhibitor (PPI) commonly utilized in the management of gastrointestinal symptoms. Few substances have proved to cause a false-positive cannabinoid urine screen. However, a case of false-positive urine cannabinoid screen in a patient who received a pantoprazole dose has been recently published. The purpose of this study was to determine the potential cross-reactivity of pantoprazole in the cannabinoid immunoassays: Alere Triage® TOX Drug Screen, KIMS® Cannabinoids II and DRI® Cannabinoids Assay. Drug-free urine to which pantoprazole was added up to 12,000 μg/mL produced negative results in the DRI® Cannabinoids and KIMS® Cannabinoids II. Alere Triage® TOX Drug Screen assay gave positive results at pantoprazole concentrations higher than 1,000 μg/mL. Urine samples from 8 pediatric patients were collected at the beginning of their pantoprazole treatment. Alere Triage® TOX Drug Screen assay produced positive test results in all patient samples and KIMS® Cannabinoids II immunoassay produced positive test results in one patient sample. None patient sample gave a false-positive result when analyzed by the DRI® Cannabinoids Assay. Our findings demonstrate that some cannabinoids immunoassays are susceptible to cross-reaction errors resulting from the presence in urine of pantoprazole and the resulting metabolism of the parent drug. Clinicians should be aware of the possibility of false-positive results for cannabinoids after a pantoprazole treatment. © The Author 2017. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.
Rheumatologists lack confidence in their knowledge of cannabinoids pertaining to the management of rheumatic complaints.

PubMed

Fitzcharles, Mary-Ann; Ste-Marie, Peter A; Clauw, Daniel J; Jamal, Shahin; Karsh, Jacob; LeClercq, Sharon; McDougall, Jason J; Shir, Yoram; Shojania, Kam; Walsh, Zach

2014-07-30

Arthritis pain is reported as one of the most common reasons for persons using medical herbal cannabis in North America. "Severe arthritis" is the condition justifying legal use of cannabis in over half of all authorizations in Canada, where cannabis remains a controlled substance. As champions for the care of persons with arthritis, rheumatologists must be knowledgeable of treatment modalities both traditional and non-traditional, used by their patients. As study of cannabinoid molecules in medicine is recent, we have examined the confidence in the knowledge of cannabinoids expressed by Canadian rheumatologists. The confidence of rheumatologists in their knowledge of cannabinoid molecules and mechanisms relevant to rheumatology, and their ability to advise patients about cannabinoid treatments was recorded by an online questionnaire circulated via email to the entire Canadian Rheumatology Association membership. Over three quarters of the 128 respondents lacked confidence in their knowledge of cannabinoid molecules. While 45% of respondents believed there was no current role for cannabinoids in rheumatology patient care, only 25% supported any use of herbal cannabis. With 70% never having previously prescribed or recommended any cannabinoid treatment, uncertainty regarding good prescribing practices was prevalent. Concerns about risks of cannabis use were in line with the current literature. Rheumatologists lacked confidence in their knowledge of cannabinoid molecules in general and in their competence to prescribe any cannabinoid for rheumatic complaints. In line with this uncertainty, there is reticence to prescribe cannabinoid preparations for rheumatology patients. Guidance is required to inform rheumatologists on the evidence regarding cannabinoids.
Evaluation of fatty acid amides in the carrageenan-induced paw edema model

PubMed Central

Wise, Laura E.; Cannavacciulo, Roberta; Cravatt, Benjamin F.; Martin, Billy F.; Lichtman, Aron H.

2008-01-01

While it has long been recognized that Δ9-tetrahydrocannabinol (THC), the primary psychoactive constituent of cannabis, and other cannabinoid receptor agonists possess anti-inflammatory properties, their well known CNS effects have dampened enthusiasm for therapeutic development. On the other hand, genetic deletion of fatty acid amide hydrolase (FAAH), the enzyme responsible for degradation of fatty acid amides, including endogenous cannabinoid N-arachidonoyl ethanolamine (anandamide; AEA), N-palmitoyl ethanolamine (PEA), N-oleoyl ethanolamine (OEA), and oleamide, also elicits anti-edema, but does not produce any apparent cannabinoid effects. The purpose of the present study was to investigate whether exogenous administration of FAAs would augment the anti-inflammatory phenotype of FAAH (-/-) mice in the carrageenan model. Thus, we evaluated the effects of the FAAs AEA, PEA, OEA, and oleamide in wild-type and FAAH (-/-) mice. For comparison, we evaluated the anti-edema effects of THC, dexamethasone (DEX), a synthetic glucocorticoid, diclofenac (DIC), a nonselective cyclooxygenase (COX) inhibitor, in both genotypes. A final study determined if tolerance to the anti-edema effects of PEA occurs after repeated dosing. PEA, THC, DEX, DIC elicited significant decreases in carrageenan-induced paw edema in wild type mice. In contrast OEA produced a less reliable anti-edema effect than these other drugs, and AEA and oleamide failed to produce any significant decreases in paw edema. Moreover, none of the agents evaluated augmented the anti-edema phenotype of FAAH (-/-) mice, suggesting that maximal anti-edema effects had already been established. PEA was the most effective FAA in preventing paw edema and its effects did not undergo tolerance. While the present findings do not support a role for AEA in preventing carrageenan-induced edema, PEA administration and FAAH blockade elicited anti-edema effects of an equivalent magnitude as produced by THC, DEX, and DIC in this assay. PMID:17675189
Behavioral Characterization of the Effects of Cannabis Smoke and Anandamide in Rats

PubMed Central

Bruijnzeel, Adriaan W.; Qi, Xiaoli; Guzhva, Lidia V.; Wall, Shannon; Deng, Jie V.; Gold, Mark S.; Febo, Marcelo; Setlow, Barry

2016-01-01

Cannabis is the most widely used illicit drug in the world. Delta-9-tetrahydrocannabinol (Δ9-THC) is the main psychoactive component of cannabis and its effects have been well-studied. However, cannabis contains many other cannabinoids that affect brain function. Therefore, these studies investigated the effect of cannabis smoke exposure on locomotor activity, rearing, anxiety-like behavior, and the development of dependence in rats. It was also investigated if cannabis smoke exposure leads to tolerance to the locomotor-suppressant effects of the endogenous cannabinoid anandamide. Cannabis smoke was generated by burning 5.7% Δ9-THC cannabis cigarettes in a smoking machine. The effect of cannabis smoke on the behavior of rats in a small and large open field and an elevated plus maze was evaluated. Cannabis smoke exposure induced a brief increase in locomotor activity followed by a prolonged decrease in locomotor activity and rearing in the 30-min small open field test. The cannabinoid receptor type 1 (CB1) receptor antagonist rimonabant increased locomotor activity and prevented the smoke-induced decrease in rearing. Smoke exposure also increased locomotor activity in the 5-min large open field test and the elevated plus maze test. The smoke exposed rats spent more time in the center zone of the large open field, which is indicative of a decrease in anxiety-like behavior. A high dose of anandamide decreased locomotor activity and rearing in the small open field and this was not prevented by rimonabant or pre-exposure to cannabis smoke. Serum Δ9-THC levels were 225 ng/ml after smoke exposure, which is similar to levels in humans after smoking cannabis. Exposure to cannabis smoke led to dependence as indicated by more rimonabant-precipitated somatic withdrawal signs in the cannabis smoke exposed rats than in the air-control rats. In conclusion, chronic cannabis smoke exposure in rats leads to clinically relevant Δ9-THC levels, dependence, and has a biphasic effect on locomotor activity. PMID:27065006
Behavioral Characterization of the Effects of Cannabis Smoke and Anandamide in Rats.

PubMed

Bruijnzeel, Adriaan W; Qi, Xiaoli; Guzhva, Lidia V; Wall, Shannon; Deng, Jie V; Gold, Mark S; Febo, Marcelo; Setlow, Barry

2016-01-01

Cannabis is the most widely used illicit drug in the world. Delta-9-tetrahydrocannabinol (Δ9-THC) is the main psychoactive component of cannabis and its effects have been well-studied. However, cannabis contains many other cannabinoids that affect brain function. Therefore, these studies investigated the effect of cannabis smoke exposure on locomotor activity, rearing, anxiety-like behavior, and the development of dependence in rats. It was also investigated if cannabis smoke exposure leads to tolerance to the locomotor-suppressant effects of the endogenous cannabinoid anandamide. Cannabis smoke was generated by burning 5.7% Δ9-THC cannabis cigarettes in a smoking machine. The effect of cannabis smoke on the behavior of rats in a small and large open field and an elevated plus maze was evaluated. Cannabis smoke exposure induced a brief increase in locomotor activity followed by a prolonged decrease in locomotor activity and rearing in the 30-min small open field test. The cannabinoid receptor type 1 (CB1) receptor antagonist rimonabant increased locomotor activity and prevented the smoke-induced decrease in rearing. Smoke exposure also increased locomotor activity in the 5-min large open field test and the elevated plus maze test. The smoke exposed rats spent more time in the center zone of the large open field, which is indicative of a decrease in anxiety-like behavior. A high dose of anandamide decreased locomotor activity and rearing in the small open field and this was not prevented by rimonabant or pre-exposure to cannabis smoke. Serum Δ9-THC levels were 225 ng/ml after smoke exposure, which is similar to levels in humans after smoking cannabis. Exposure to cannabis smoke led to dependence as indicated by more rimonabant-precipitated somatic withdrawal signs in the cannabis smoke exposed rats than in the air-control rats. In conclusion, chronic cannabis smoke exposure in rats leads to clinically relevant Δ9-THC levels, dependence, and has a biphasic effect on locomotor activity.
Blockade of Endocannabinoid Hydrolytic Enzymes Attenuates Precipitated Opioid Withdrawal Symptoms in MiceS⃞

PubMed Central

Ramesh, Divya; Ross, Gracious R.; Schlosburg, Joel E.; Owens, Robert A.; Abdullah, Rehab A.; Kinsey, Steven G.; Long, Jonathan Z.; Nomura, Daniel K.; Sim-Selley, Laura J.; Cravatt, Benjamin F.; Akbarali, Hamid I.

2011-01-01

Δ9-Tetrahydrocannbinol (THC), the primary active constituent of Cannabis sativa, has long been known to reduce opioid withdrawal symptoms. Although THC produces most of its pharmacological actions through the activation of CB1 and CB2 cannabinoid receptors, the role these receptors play in reducing the variety of opioid withdrawal symptoms remains unknown. The endogenous cannabinoids, N-arachidonoylethanolamine (anandamide; AEA) and 2-arachidonylglycerol (2-AG), activate both cannabinoid receptors but are rapidly metabolized by fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL), respectively. The objective of this study was to test whether increasing AEA or 2-AG, via inhibition of their respective hydrolytic enzymes, reduces naloxone-precipitated morphine withdrawal symptoms in in vivo and in vitro models of opioid dependence. Morphine-dependent mice challenged with naloxone reliably displayed a profound withdrawal syndrome, consisting of jumping, paw tremors, diarrhea, and weight loss. THC and the MAGL inhibitor 4-nitrophenyl 4-(dibenzo[d][1,3]dioxol-5-yl(hydroxy)methyl)piperidine-1-carboxylate (JZL184) dose dependently reduced the intensity of most measures through the activation of CB1 receptors. JZL184 also attenuated spontaneous withdrawal signs in morphine-dependent mice. The FAAH inhibitor N-(pyridin-3-yl)-4-(3-(5-(trifluoromethyl)pyridin-2-yloxy)benzyl)-piperdine-1-carboxamide (PF-3845) reduced the intensity of naloxone-precipitated jumps and paw flutters through the activation of CB1 receptors but did not ameliorate incidence of diarrhea or weight loss. In the final series of experiments, we investigated whether JZL184 or PF-3845 would attenuate naloxone-precipitated contractions in morphine-dependent ilea. Both enzyme inhibitors attenuated the intensity of naloxone-induced contractions, although this model does not account mechanistically for the autonomic withdrawal responses (i.e., diarrhea) observed in vivo. These results indicate that endocannabinoid catabolic enzymes are promising targets to treat opioid dependence. PMID:21719468
Cannabinergic pain medicine: a concise clinical primer and survey of randomized-controlled trial results.

PubMed

Aggarwal, Sunil K

2013-02-01

This article attempts to cover pragmatic clinical considerations involved in the use of cannabinergic medicines in pain practice, including geographical and historical considerations, pharmacokinetics, pharmacodynamics, adverse effects, drug interactions, indications, and contraindications. Topics include molecular considerations such as the 10-fold greater abundance of cannabinoid type 1 receptors compared to µ-opioid receptors in the central nervous system and anatomic distributions of cannabinoid receptors in pain circuits. The article uses a narrative review methodology drawing from authoritative textbooks and journals of cannabinoid medicine, Food and Drug Administration-approved cannabinoid drug labels, and current and historical pain medicine literature to address core clinical considerations. To survey the current evidence base for pain management with cannabinergic medicines, a targeted PubMed search was performed to survey the percentage of positive and negative published randomized-controlled trial (RCT) results with this class of pain medicines, using appropriate search limit parameters and the keyword search string "cannabinoid OR cannabis-based AND pain." Of the 56 hits generated, 38 published RCTs met the survey criteria. Of these, 71% (27) concluded that cannabinoids had empirically demonstrable and statistically significant pain-relieving effects, whereas 29% (11) did not. Cannabis and other cannabinergic medicines' efficacies for relieving pain have been studied in RCTs, most of which have demonstrated a beneficial effect for this indication, although most trials are short-term. Adverse effects are generally nonserious and well tolerated. Incorporating cannabinergic medicine topics into pain medicine education seems warranted and continuing clinical research and empiric treatment trials are appropriate.
Cannabinoids and post-traumatic stress disorder: clinical and preclinical evidence for treatment and prevention.

PubMed

Mizrachi Zer-Aviv, Tomer; Segev, Amir; Akirav, Irit

2016-10-01

There is substantial evidence from studies in humans and animal models for a role of the endocannabinoid system in the control of emotional states. Several studies have shown an association between exposure to trauma and substance use. Specifically, it has been shown that there is increased prevalence of cannabis use in post-traumatic stress disorder (PTSD) patients and vice versa. Clinical studies suggest that PTSD patients may cope with their symptoms by using cannabis. This treatment-seeking strategy may explain the high prevalence of cannabis use among individuals with PTSD. Preliminary studies in humans also suggest that treatment with cannabinoids may decrease PTSD symptoms including sleep quality, frequency of nightmares, and hyperarousal. However, there are no large-scale, randomized, controlled studies investigating this specifically. Studies in animal models have shown that cannabinoids can prevent the effects of stress on emotional function and memory processes, facilitate fear extinction, and have an anti-anxiety-like effect in a variety of tasks. Moreover, cannabinoids administered shortly after exposure to a traumatic event were found to prevent the development of PTSD-like phenotype. In this article, we review the existing literature on the use of cannabinoids for treating and preventing PTSD in humans and animal models. There is a need for large-scale clinical trials examining the potential decrease in PTSD symptomatology with the use of cannabis. In animal models, there is a need for a better understanding of the mechanism of action and efficacy of cannabis. Nevertheless, the end result of the current clinical and preclinical data is that cannabinoid agents may offer therapeutic benefits for PTSD.
Marijuana and other cannabinoids as a treatment for posttraumatic stress disorder: A literature review.

PubMed

Steenkamp, Maria M; Blessing, Esther M; Galatzer-Levy, Isaac R; Hollahan, Laura C; Anderson, William T

2017-03-01

Posttraumatic stress disorder (PTSD) is common in the general population, yet there are limitations to the effectiveness, tolerability, and acceptability of available first-line interventions. We review the extant knowledge on the effects of marijuana and other cannabinoids on PTSD. Potential therapeutic effects of these agents may largely derive from actions on the endocannabinoid system and we review major animal and human findings in this area. Preclinical and clinical studies generally support the biological plausibility for cannabinoids' potential therapeutic effects, but underscore heterogeneity in outcomes depending on dose, chemotype, and individual variation. Treatment outcome studies of whole plant marijuana and related cannabinoids on PTSD are limited and not methodologically rigorous, precluding conclusions about their potential therapeutic effects. Reported benefits for nightmares and sleep (particularly with synthetic cannabinoid nabilone) substantiate larger controlled trials to determine effectiveness and tolerability. Of concern, marijuana use has been linked to adverse psychiatric outcomes, including conditions commonly comorbid with PTSD such as depression, anxiety, psychosis, and substance misuse. Available evidence is stronger for marijuana's harmful effects on the development of psychosis and substance misuse than for the development of depression and anxiety. Marijuana use is also associated with worse treatment outcomes in naturalistic studies, and with maladaptive coping styles that may maintain PTSD symptoms. Known risks of marijuana thus currently outweigh unknown benefits for PTSD. Although controlled research on marijuana and other cannabinoids' effects on PTSD remains limited, rapid shifts in the legal landscape may now enable such studies, potentially opening new avenues in PTSD treatment research. © 2017 Wiley Periodicals, Inc.
The endocannabinoid system as a target for the treatment of neurodegenerative disease.

PubMed

Scotter, Emma L; Abood, Mary E; Glass, Michelle

2010-06-01

The Cannabis sativa plant has been exploited for medicinal, agricultural and spiritual purposes in diverse cultures over thousands of years. Cannabis has been used recreationally for its psychotropic properties, while effects such as stimulation of appetite, analgesia and anti-emesis have lead to the medicinal application of cannabis. Indeed, reports of medicinal efficacy of cannabis can been traced back as far as 2700 BC, and even at that time reports also suggested a neuroprotective effect of the cultivar. The discovery of the psychoactive component of cannabis resin, Delta(9)-tetrahydrocannabinol (Delta(9)-THC) occurred long before the serendipitous identification of a G-protein coupled receptor at which Delta(9)-THC is active in the brain. The subsequent finding of endogenous cannabinoid compounds, the synthesis of which is directed by neuronal excitability and which in turn served to regulate that excitability, further widened the range of potential drug targets through which the endocannabinoid system can be manipulated. As a result of this, alterations in the endocannabinoid system have been extensively investigated in a range of neurodegenerative disorders. In this review we examine the evidence implicating the endocannabinoid system in the cause, symptomatology or treatment of neurodegenerative disease. We examine data from human patients and compare and contrast this with evidence from animal models of these diseases. On the basis of this evidence we discuss the likely efficacy of endocannabinoid-based therapies in each disease context.

Postnatal development of neurotransmitter systems and their relevance to extinction of conditioned fear.

PubMed

Kim, Jee Hyun; Perry, Christina J; Ganella, Despina E; Madsen, Heather B

2017-02-01

Remembering and forgetting are fundamental features of an organism. Extinction is a type of forgetting where there is a decrease in the significance and/or the meaning of an associative memory when elements of that memory no longer predict one another. The neural mechanisms underlying extinction of fear memories have been extensively studied in the laboratory because extinction processes are clinically relevant to exposure therapies that treat anxiety disorders. However, only in the last decade have we begun to unveil the similarities and differences in plasticity underlying extinction across development. So far it is clear that extinction is a developmentally dissociated process in behavior and in pharmacology, however there are many large gaps in the literature in understanding how the developmental trajectory of different neurotransmitters contribute to changes in the nature of extinction across development. We attempt to address these gaps in the present review. Major neurotransmitter systems including the glutamatergic and GABAergic systems, the monoamines, the endogenous opioid and cannabinoid systems, acetylcholines, and neuropeptides such as oxytocin have all been identified to play some role in extinction of fear memories and have been covered in this review. We hope to facilitate more research into mechanisms of extinction at different stages of life, especially noting that mental disorders are increasingly classified as neurodevelopmental disorders. Copyright © 2016 Elsevier Inc. All rights reserved.
Interplay Between n-3 and n-6 Long-Chain Polyunsaturated Fatty Acids and the Endocannabinoid System in Brain Protection and Repair.

PubMed

Dyall, Simon C

2017-11-01

The brain is enriched in arachidonic acid (ARA) and docosahexaenoic acid (DHA), long-chain polyunsaturated fatty acids (LCPUFAs) of the n-6 and n-3 series, respectively. Both are essential for optimal brain development and function. Dietary enrichment with DHA and other long-chain n-3 PUFA, such as eicosapentaenoic acid (EPA), has shown beneficial effects on learning and memory, neuroinflammatory processes, and synaptic plasticity and neurogenesis. ARA, DHA and EPA are precursors to a diverse repertoire of bioactive lipid mediators, including endocannabinoids. The endocannabinoid system comprises cannabinoid receptors, their endogenous ligands, the endocannabinoids, and their biosynthetic and degradation enzymes. Anandamide (AEA) and 2-arachidonoylglycerol (2-AG) are the most widely studied endocannabinoids and are both derived from phospholipid-bound ARA. The endocannabinoid system also has well-established roles in neuroinflammation, synaptic plasticity and neurogenesis, suggesting an overlap in the neuroprotective effects observed with these different classes of lipids. Indeed, growing evidence suggests a complex interplay between n-3 and n-6 LCPUFA and the endocannabinoid system. For example, long-term DHA and EPA supplementation reduces AEA and 2-AG levels, with reciprocal increases in levels of the analogous endocannabinoid-like DHA and EPA-derived molecules. This review summarises current evidence of this interplay and discusses the therapeutic potential for brain protection and repair.
Modulation of Astrocyte Activity by Cannabidiol, a Nonpsychoactive Cannabinoid

PubMed Central

Kozela, Ewa; Juknat, Ana; Vogel, Zvi

2017-01-01

The astrocytes have gained in recent decades an enormous interest as a potential target for neurotherapies, due to their essential and pleiotropic roles in brain physiology and pathology. Their precise regulation is still far from understood, although several candidate molecules/systems arise as promising targets for astrocyte-mediated neuroregulation and/or neuroprotection. The cannabinoid system and its ligands have been shown to interact and affect activities of astrocytes. Cannabidiol (CBD) is the main non-psychotomimetic cannabinoid derived from Cannabis. CBD is devoid of direct CB1 and CB2 receptor activity, but exerts a number of important effects in the brain. Here, we attempt to sum up the current findings on the effects of CBD on astrocyte activity, and in this way on central nervous system (CNS) functions, across various tested models and neuropathologies. The collected data shows that increased astrocyte activity is suppressed in the presence of CBD in models of ischemia, Alzheimer-like and Multiple-Sclerosis-like neurodegenerations, sciatic nerve injury, epilepsy, and schizophrenia. Moreover, CBD has been shown to decrease proinflammatory functions and signaling in astrocytes. PMID:28788104
Modulation of Astrocyte Activity by Cannabidiol, a Nonpsychoactive Cannabinoid.

PubMed

Kozela, Ewa; Juknat, Ana; Vogel, Zvi

2017-07-31

The astrocytes have gained in recent decades an enormous interest as a potential target for neurotherapies, due to their essential and pleiotropic roles in brain physiology and pathology. Their precise regulation is still far from understood, although several candidate molecules/systems arise as promising targets for astrocyte-mediated neuroregulation and/or neuroprotection. The cannabinoid system and its ligands have been shown to interact and affect activities of astrocytes. Cannabidiol (CBD) is the main non-psychotomimetic cannabinoid derived from Cannabis . CBD is devoid of direct CB1 and CB2 receptor activity, but exerts a number of important effects in the brain. Here, we attempt to sum up the current findings on the effects of CBD on astrocyte activity, and in this way on central nervous system (CNS) functions, across various tested models and neuropathologies. The collected data shows that increased astrocyte activity is suppressed in the presence of CBD in models of ischemia, Alzheimer-like and Multiple-Sclerosis-like neurodegenerations, sciatic nerve injury, epilepsy, and schizophrenia. Moreover, CBD has been shown to decrease proinflammatory functions and signaling in astrocytes.
The medicinal use of cannabis and cannabinoids--an international cross-sectional survey on administration forms.

PubMed

Hazekamp, Arno; Ware, Mark A; Muller-Vahl, Kirsten R; Abrams, Donald; Grotenhermen, Franjo

2013-01-01

Cannabinoids, including tetrahydrocannabinol and cannabidiol, are the most important active constituents of the cannabis plant. Over recent years, cannabinoid-based medicines (CBMs) have become increasingly available to patients in many countries, both as pharmaceutical products and as herbal cannabis (marijuana). While there seems to be a demand for multiple cannabinoid-based therapeutic products, specifically for symptomatic amelioration in chronic diseases, therapeutic effects of different CBMs have only been directly compared in a few clinical studies. The survey presented here was performed by the International Association for Cannabinoid Medicines (IACM), and is meant to contribute to the understanding of cannabinoid-based medicine by asking patients who used cannabis or cannabinoids detailed questions about their experiences with different methods of intake. The survey was completed by 953 participants from 31 countries, making this the largest international survey on a wide variety of users of cannabinoid-based medicine performed so far. In general, herbal non-pharmaceutical CBMs received higher appreciation scores by participants than pharmaceutical products containing cannabinoids. However, the number of patients who reported experience with pharmaceutical products was low, limiting conclusions on preferences. Nevertheless, the reported data may be useful for further development of safe and effective medications based on cannabis and single cannabinoids.
Activation of the cannabinoid system in the nucleus accumbens affects effort-based decision making.

PubMed

Fatahi, Zahra; Haghparast, Abbas

2018-02-01

Effort-based decision making addresses how we make an action choice based on an integration of action and goal values. The nucleus accumbens (NAc) is implicated in allowing an animal to overcome effort constraints to obtain greater benefits, and it has been previously shown that cannabis derivatives may affect such processes. Therefore, in this study, we intend to evaluate the involvement of the cannabinoid system in the entire NAc on effort-based decision making. Rats were trained in a T-maze cost-benefit decision making the task in which they could choose either to climb a barrier to obtain a large reward in one arm or run into the other arm without a barrier to obtaining a small reward. Following training, the animals were bilaterally implanted with guide cannulae in the NAc. On test day, rats received cannabinoid agonist (Win 55,212-2; 2, 10 and 50μM) and/or antagonist (AM251; 45μM), afterward percentage of large reward choice and latency of reward attainment were investigated. Results revealed that the administration of cannabinoid agonist led to decrease of large reward choice percentage such that the animals preferred to receive a small reward with low effort instead of receiving a large reward with high effort. The administration of antagonist solely did not affect effort-based decision making, but did attenuate the Win 55,212-2-induced impairments in effort allocation. In agonist-treated animals, the latency of reward collection increased. Moreover, when the effort was equated on both arms, the animals returned to choosing large reward showing that obtained results were not caused by spatial memory impairment. Our finding suggested that activation of the cannabinoid system in the NAc impaired effort-based decision making and led to rats were less willing to invest the physical effort to gain large reward. Copyright © 2017 Elsevier Inc. All rights reserved.
The in vitro GcMAF effects on endocannabinoid system transcriptionomics, receptor formation, and cell activity of autism-derived macrophages.

PubMed

Siniscalco, Dario; Bradstreet, James Jeffrey; Cirillo, Alessandra; Antonucci, Nicola

2014-04-17

Immune system dysregulation is well-recognized in autism and thought to be part of the etiology of this disorder. The endocannabinoid system is a key regulator of the immune system via the cannabinoid receptor type 2 (CB2R) which is highly expressed on macrophages and microglial cells. We have previously published significant differences in peripheral blood mononuclear cell CB2R gene expression in the autism population. The use of the Gc protein-derived Macrophage Activating Factor (GcMAF), an endogenous glycosylated vitamin D binding protein responsible for macrophage cell activation has demonstrated positive effects in the treatment of autistic children. In this current study, we investigated the in vitro effects of GcMAF treatment on the endocannabinoid system gene expression, as well as cellular activation in blood monocyte-derived macrophages (BMDMs) from autistic patients compared to age-matched healthy developing controls. To achieve these goals, we used biomolecular, biochemical and immunocytochemical methods. GcMAF treatment was able to normalize the observed differences in dysregulated gene expression of the endocannabinoid system of the autism group. GcMAF also down-regulated the over-activation of BMDMs from autistic children. This study presents the first observations of GcMAF effects on the transcriptionomics of the endocannabinoid system and expression of CB2R protein. These data point to a potential nexus between endocannabinoids, vitamin D and its transporter proteins, and the immune dysregulations observed with autism.
The in vitro GcMAF effects on endocannabinoid system transcriptionomics, receptor formation, and cell activity of autism-derived macrophages

PubMed Central

2014-01-01

Background Immune system dysregulation is well-recognized in autism and thought to be part of the etiology of this disorder. The endocannabinoid system is a key regulator of the immune system via the cannabinoid receptor type 2 (CB2R) which is highly expressed on macrophages and microglial cells. We have previously published significant differences in peripheral blood mononuclear cell CB2R gene expression in the autism population. The use of the Gc protein-derived Macrophage Activating Factor (GcMAF), an endogenous glycosylated vitamin D binding protein responsible for macrophage cell activation has demonstrated positive effects in the treatment of autistic children. In this current study, we investigated the in vitro effects of GcMAF treatment on the endocannabinoid system gene expression, as well as cellular activation in blood monocyte-derived macrophages (BMDMs) from autistic patients compared to age-matched healthy developing controls. Methods To achieve these goals, we used biomolecular, biochemical and immunocytochemical methods. Results GcMAF treatment was able to normalize the observed differences in dysregulated gene expression of the endocannabinoid system of the autism group. GcMAF also down-regulated the over-activation of BMDMs from autistic children. Conclusions This study presents the first observations of GcMAF effects on the transcriptionomics of the endocannabinoid system and expression of CB2R protein. These data point to a potential nexus between endocannabinoids, vitamin D and its transporter proteins, and the immune dysregulations observed with autism. PMID:24739187
Cannabinoids for Symptom Management and Cancer Therapy: The Evidence.

PubMed

Davis, Mellar P

2016-07-01

Cannabinoids bind not only to classical receptors (CB1 and CB2) but also to certain orphan receptors (GPR55 and GPR119), ion channels (transient receptor potential vanilloid), and peroxisome proliferator-activated receptors. Cannabinoids are known to modulate a multitude of monoamine receptors. Structurally, there are 3 groups of cannabinoids. Multiple studies, most of which are of moderate to low quality, demonstrate that tetrahydrocannabinol (THC) and oromucosal cannabinoid combinations of THC and cannabidiol (CBD) modestly reduce cancer pain. Dronabinol and nabilone are better antiemetics for chemotherapy-induced nausea and vomiting (CINV) than certain neuroleptics, but are not better than serotonin receptor antagonists in reducing delayed emesis, and cannabinoids have largely been superseded by neurokinin-1 receptor antagonists and olanzapine; both cannabinoids have been recommended for breakthrough nausea and vomiting among other antiemetics. Dronabinol is ineffective in ameliorating cancer anorexia but does improve associated cancer-related dysgeusia. Multiple cancers express cannabinoid receptors directly related to the degree of anaplasia and grade of tumor. Preclinical in vitro and in vivo studies suggest that cannabinoids may have anticancer activity. Paradoxically, cannabinoid receptor antagonists also have antitumor activity. There are few randomized smoked or vaporized cannabis trials in cancer on which to judge the benefits of these forms of cannabinoids on symptoms and the clinical course of cancer. Smoked cannabis has been found to contain Aspergillosis. Immunosuppressed patients should be advised of the risks of using "medical marijuana" in this regard. Copyright © 2016 by the National Comprehensive Cancer Network.
Cannabinoids induce apathetic and impulsive patterns of choice through CB1 receptors and TRPV1 channels.

PubMed

Fatahi, Zahra; Reisi, Zahra; Rainer, Gregor; Haghparast, Abbas; Khani, Abbas

2018-05-01

Despite evidence from psychiatry and psychology clinics pointing to altered cognition and decision making following the consumption of cannabis, the effects of cannabis derivatives are still under dispute and the mechanisms of cannabinoid effects on cognition are not known. In this study, we used effort-based and delay-based decision tasks and showed that ACEA, a potent cannabinoid agonist induced apathetic and impulsive patterns of choice in rats in a dose-dependent manner when locally injected into the anterior cingulate cortex (ACC) and orbitofrontal cortex (OFC), respectively. Pre-treatment with AM251, a selective cannabinoid type 1 (CB1) receptor antagonist, reversed ACEA-induced impulsive and apathetic patterns of choice in doses higher than a minimally effective dose. Unlike CB1 receptor antagonist, pretreatment with capsazepine, a transient receptor potential vanilloid type 1 (TRPV1) channel antagonist, was effective only at an intermediary dose. Furthermore, capsazepine per se induced impulsivity and apathy at a high dose suggesting a basal tonic activation of TRPV1 channels that exist in the ACC and OFC to support cost-benefit decision making and to help avoid apathetic and impulsive patterns of decision making. Taken together, unlike previous reports supporting opposing roles for the CB1 receptors and TRPV1 channels in anxiety and panic behavior, our findings demonstrate a different sort of interaction between endocannabinoid and endovanilloid systems and suggest that both systems contribute to the cognitive disrupting effects of cannabinoids. Given prevalent occurrence of apathy and particularly impulsivity in psychiatric disorders, these results have significant implications for pharmacotherapy research targeting these receptors. Copyright © 2018 Elsevier Ltd. All rights reserved.
Dietary fats and pharmaceutical lipid excipients increase systemic exposure to orally administered cannabis and cannabis-based medicines

PubMed Central

Zgair, Atheer; Wong, Jonathan CM; Lee, Jong Bong; Mistry, Jatin; Sivak, Olena; Wasan, Kishor M; Hennig, Ivo M; Barrett, David A; Constantinescu, Cris S; Fischer, Peter M; Gershkovich, Pavel

2016-01-01

There has been an escalating interest in the medicinal use of Cannabis sativa in recent years. Cannabis is often administered orally with fat-containing foods, or in lipid-based pharmaceutical preparations. However, the impact of lipids on the exposure of patients to cannabis components has not been explored. Therefore, the aim of this study is to elucidate the effect of oral co-administration of lipids on the exposure to two main active cannabinoids, Δ9-tetrahydrocannabinol (THC) and cannabidiol (CBD). In this study, oral co-administration of lipids enhanced the systemic exposure of rats to THC and CBD by 2.5-fold and 3-fold, respectively, compared to lipid-free formulations. In vitro lipolysis was conducted to explore the effect of lipids on the intestinal solubilisation of cannabinoids. More than 30% of THC and CBD were distributed into micellar fraction following lipolysis, suggesting that at least one-third of the administered dose will be available for absorption following co-administration with lipids. Both cannabinoids showed very high affinity for artificial CM-like particles, as well as for rat and human CM, suggesting high potential for intestinal lymphatic transport. Moreover, comparable affinity of cannabinoids for rat and human CM suggests that similar increased exposure effects may be expected in humans. In conclusion, co-administration of dietary lipids or pharmaceutical lipid excipients has the potential to substantially increase the exposure to orally administered cannabis and cannabis-based medicines. The increase in patient exposure to cannabinoids is of high clinical importance as it could affect the therapeutic effect, but also toxicity, of orally administered cannabis or cannabis-based medicines. PMID:27648135
Pro-psychotic effects of synthetic cannabinoids: interactions with central dopamine, serotonin, and glutamate systems.

PubMed

Fantegrossi, William E; Wilson, Catheryn D; Berquist, Michael D

2018-02-01

An association between marijuana use and schizophrenia has been noted for decades, and the recent emergence of high-efficacy synthetic cannabinoids (SCBs) as drugs of abuse has lead to a growing number of clinical reports of persistent psychotic effects in users of these substances. The mechanisms underlying SCB-elicited pro-psychotic effects is unknown, but given the ubiquitous neuromodulatory functions of the endocannabinoid system, it seems likely that agonist actions at cannabinoid type-1 receptors (CB1Rs) might modulate the functions of other neurotransmitter systems known to be involved in schizophrenia. The present review surveys what is currently known about the interactions of CB1Rs with dopamine, serotonin, and glutamate systems, because all three of those neurotransmitters are well-established in the pathophysiology of schizophrenia and psychosis. Identification of molecular mechanisms underlying the pro-psychotic effects of SCB drugs of abuse may establish certain classes of these substances as particularly dangerous, guiding regulations to control availability of these drugs. Likewise, an understanding of the pharmacological interactions which lead to schizophrenia and psychosis subsequent to SCB exposure might guide the development of novel therapies to treat afflicted users.
Fatty acid amide hydrolase-morphine interaction influences ventilatory response to hypercapnia and postoperative opioid outcomes in children.

PubMed

Chidambaran, Vidya; Pilipenko, Valentina; Spruance, Kristie; Venkatasubramanian, Raja; Niu, Jing; Fukuda, Tsuyoshi; Mizuno, Tomoyuki; Zhang, Kejian; Kaufman, Kenneth; Vinks, Alexander A; Martin, Lisa J; Sadhasivam, Senthilkumar

2017-01-01

Fatty acid amide hydrolase (FAAH) degrades anandamide, an endogenous cannabinoid. We hypothesized that FAAH variants will predict risk of morphine-related adverse outcomes due to opioid-endocannabinoid interactions. In 101 postsurgical adolescents receiving morphine analgesia, we prospectively studied ventilatory response to 5% CO 2 (HCVR), respiratory depression (RD) and vomiting. Blood was collected for genotyping and morphine pharmacokinetics. We found significant FAAH-morphine interaction for missense (rs324420) and several regulatory variants, with HCVR (p < 0.0001) and vomiting (p = 0.0339). HCVR was more depressed in patients who developed RD compared with those who did not (p = 0.0034), thus FAAH-HCVR association predicts risk of impending RD from morphine use. FAAH genotypes predict risk for morphine-related adverse outcomes.
Pain and beyond: fatty acid amides and fatty acid amide hydrolase inhibitors in cardiovascular and metabolic diseases.

PubMed

Pillarisetti, Sivaram; Alexander, Christopher W; Khanna, Ish

2009-12-01

Fatty acid amide hydrolase (FAAH) is responsible for the hydrolysis of several important endogenous fatty acid amides (FAAs), including anandamide, oleoylethanolamide and palmitoylethanolamide. Because specific FAAs interact with cannabinoid and vanilloid receptors, they are often referred to as 'endocannabinoids' or 'endovanilloids'. Initial interest in this area, therefore, has focused on developing FAAH inhibitors to augment the actions of FAAs and reduce pain. However, recent literature has shown that these FAAs - through interactions with unique receptors (extracellular and intracellular) - can induce a diverse array of effects that include appetite suppression, modulation of lipid and glucose metabolism, vasodilation, cardiac function and inflammation. This review gives an overview of FAAs and diverse FAAH inhibitors and their potential therapeutic utility in pain and non-pain indications.
The Pharmacologic and Clinical Effects of Illicit Synthetic Cannabinoids.

PubMed

White, C Michael

2017-03-01

This article presents information on illicitly used synthetic cannabinoids. Synthetic cannabinoids are structurally heterogeneous and commonly used drugs of abuse that act as full agonists of the cannabinoid type-1 receptor but have a variety of additional pharmacologic effects. There are numerous cases of patient harm and death in the United States, Europe, and Australia with many psychological, neurological, cardiovascular, pulmonary, and renal adverse events. Although most users prefer using cannabis, there are convenience, legal, and cost reasons driving the utilization of synthetic cannabinoids. Clinicians should be aware of pharmacologic and clinical similarities and differences between synthetic cannabinoid and cannabis use, the limited ability to detect synthetic cannabinoids in the urine or serum, and guidance to treat adverse events. © 2016, The American College of Clinical Pharmacology.
Endocannabinoids in Multiple Sclerosis and Amyotrophic Lateral Sclerosis.

PubMed

Pryce, Gareth; Baker, David

2015-01-01

There are numerous reports that people with multiple sclerosis (MS) have for many years been self-medicating with illegal street cannabis or more recently medicinal cannabis to alleviate the symptoms associated with MS and also amyotrophic lateral sclerosis (ALS). These anecdotal reports have been confirmed by data from animal models and more recently clinical trials on the ability of cannabinoids to alleviate limb spasticity, a common feature of progressive MS (and also ALS) and neurodegeneration. Experimental studies into the biology of the endocannabinoid system have revealed that cannabinoids have efficacy, not only in symptom relief but also as neuroprotective agents which may slow disease progression and thus delay the onset of symptoms. This review discusses what we now know about the endocannabinoid system as it relates to MS and ALS and also the therapeutic potential of cannabinoid therapeutics as disease-modifying or symptom control agents, as well as future therapeutic strategies including the potential for slowing disease progression in MS and ALS.
Spicing Up Pharmacology: A Review of Synthetic Cannabinoids From Structure to Adverse Events.

PubMed

Davidson, Colin; Opacka-Juffry, Jolanta; Arevalo-Martin, Angel; Garcia-Ovejero, Daniel; Molina-Holgado, Eduardo; Molina-Holgado, Francisco

2017-01-01

Recreational use of synthetic cannabinoids (SCB), a class of novel psychoactive substances is an increasing public health problem specifically in Western societies, with teenagers, young adults, and the prison population being the most affected. Some of these SCB are analogs of tetrahydrocannabinol, aminoalkylindoles, and other phytocannabinoid analogs have been detected in herbal preparations generically called "Spice." Spice, "K2" or "fake cannabis" is a general term used for variable herbal mixtures of unknown ingredients or chemical composition. SCB are highly potent CB 1 cannabinoid receptor agonists falsely marketed and sold as safe and legal drugs. Here, we present an overview of the endocannabinoid system, CB, and SCB chemical structures and activity at CB receptors. Finally, we highlight the psychological effects of SCB, particularly on learning and memory, and adverse clinical effects including on the cardiovascular system, kidneys, and CNS, including psychosis. Taken together, it is clear that many SCB are extremely dangerous and a major public health problem. © 2017 Elsevier Inc. All rights reserved.
Quantitative urine confirmatory testing for synthetic cannabinoids in randomly collected urine specimens

PubMed Central

Castaneto, Marisol S.; Scheidweiler, Karl B.; Gandhi, Adarsh; Wohlfarth, Ariane; Klette, Kevin L.; Martin, Thomas M.; Huestis, Marilyn A.

2014-01-01

Synthetic cannabinoid intake is an ongoing health issue worldwide, with new compounds continually emerging, making drug testing complex. Parent synthetic cannabinoids are rarely detected in urine, the most common matrix employed in workplace drug testing. Optimal identification of synthetic cannabinoid markers in authentic urine specimens and correlation of metabolite concentrations and toxicities would improve synthetic cannabinoid result interpretation. We screened 20,017 randomly collected US military urine specimens between July 2011 and June 2012 with a synthetic cannabinoid immunoassay yielding 1,432 presumptive positive specimens. We analyzed all presumptive positive and 1,069 negative specimens with our qualitative synthetic cannabinoid LC-MS/MS method, which confirmed 290 positive specimens. All 290 positive and 487 randomly-selected negative specimens were quantified with the most comprehensive urine quantitative LC-MS/MS method published to date. 290 specimens confirmed positive for 22 metabolites from 11 parent synthetic cannabinoids. The five most predominant metabolites were JWH-018 pentanoic acid (93%), JWH-018 N-hydroxypentyl (84%), AM2201 N-hydroxypentyl (69%), JWH-073 butanoic acid (69%), and JWH-122 N-hydroxypentyl (45%) with 11.1 (0.1–2434), 5.1 (0.1–1239), 2.0 (0.1–321), 1.1 (0.1–48.6), and 1.1 (0.1–250) μg/L median (range) concentrations, respectively. Alkyl hydroxy and carboxy metabolites provided suitable biomarkers for 11 parent synthetic cannabinoids; although, hydroxyindoles also were observed. This is by far the largest data set of synthetic cannabinoid metabolites urine concentrations from randomly collected workplace drug testing specimens rather than acute intoxications or driving under the influence of drugs. These data improve the interpretation of synthetic cannabinoid urine test results and suggest suitable urine markers of synthetic cannabinoid intake. PMID:25231213
Effects of cannabinoids and cannabinoid-enriched Cannabis extracts on TRP channels and endocannabinoid metabolic enzymes

PubMed Central

De Petrocellis, Luciano; Ligresti, Alessia; Moriello, Aniello Schiano; Allarà, Marco; Bisogno, Tiziana; Petrosino, Stefania; Stott, Colin G; Di Marzo, Vincenzo

2011-01-01

BACKGROUND AND PURPOSE Cannabidiol (CBD) and Δ9-tetrahydrocannabinol (THC) interact with transient receptor potential (TRP) channels and enzymes of the endocannabinoid system. EXPERIMENTAL APPROACH The effects of 11 pure cannabinoids and botanical extracts [botanical drug substance (BDS)] from Cannabis varieties selected to contain a more abundant cannabinoid, on TRPV1, TRPV2, TRPM8, TRPA1, human recombinant diacylglycerol lipase α (DAGLα), rat brain fatty acid amide hydrolase (FAAH), COS cell monoacylglycerol lipase (MAGL), human recombinant N-acylethanolamine acid amide hydrolase (NAAA) and anandamide cellular uptake (ACU) by RBL-2H3 cells, were studied using fluorescence-based calcium assays in transfected cells and radiolabelled substrate-based enzymatic assays. Cannabinol (CBN), cannabichromene (CBC), the acids (CBDA, CBGA, THCA) and propyl homologues (CBDV, CBGV, THCV) of CBD, cannabigerol (CBG) and THC, and tetrahydrocannabivarin acid (THCVA) were also tested. KEY RESULTS CBD, CBG, CBGV and THCV stimulated and desensitized human TRPV1. CBC, CBD and CBN were potent rat TRPA1 agonists and desensitizers, but THCV-BDS was the most potent compound at this target. CBG-BDS and THCV-BDS were the most potent rat TRPM8 antagonists. All non-acid cannabinoids, except CBC and CBN, potently activated and desensitized rat TRPV2. CBDV and all the acids inhibited DAGLα. Some BDS, but not the pure compounds, inhibited MAGL. CBD was the only compound to inhibit FAAH, whereas the BDS of CBC > CBG > CBGV inhibited NAAA. CBC = CBG > CBD inhibited ACU, as did the BDS of THCVA, CBGV, CBDA and THCA, but the latter extracts were more potent inhibitors. CONCLUSIONS AND IMPLICATIONS These results are relevant to the analgesic, anti-inflammatory and anti-cancer effects of cannabinoids and Cannabis extracts. LINKED ARTICLES This article is part of a themed issue on Cannabinoids in Biology and Medicine. To view the other articles in this issue visit http://dx.doi.org/10.1111/bph.2011.163.issue-7 PMID:21175579
Social isolation and chronic handling alter endocannabinoid signaling and behavioral reactivity to context in adult rats

PubMed Central

Sciolino, Natale R.; Bortolato, Marco; Eisenstein, Sarah A.; Fu, Jin; Oveisi, Fariba; Hohmann, Andrea G.; Piomelli, Daniele

2010-01-01

Social deprivation in early life disrupts emotionality and attentional processes in humans. Rearing rats in isolation reproduces some of these abnormalities, which are attenuated by daily handling. However, the neurochemical mechanisms underlying these responses remain poorly understood. We hypothesized that post-weaning social isolation alters the endocannabinoid system, a neuromodulatory system that controls emotional responding. We characterized behavioral consequences of social isolation and evaluated whether handling would reverse social isolation-induced alterations in behavioral reactivity to context and the endocannabinoid system. At weaning, pups were single or group housed and concomitantly handled or not handled daily until adulthood. Rats were tested in emotionality- and attentional-sensitive behavioral assays (open field, elevated plus maze, startle and prepulse inhibition). Cannabinoid receptor densities and endocannabinoid levels were quantified in a separate group of rats. Social isolation negatively altered behavioral responding. Socially-isolated rats that were handled showed less deficits in the open field, elevated plus maze, and prepulse inhibition tests. Social isolation produced site-specific alterations (supraoptic nucleus, ventrolateral thalamus, rostral striatum) in cannabinoid receptor densities compared to group rearing. Handling altered the endocannabinoid system in neural circuitry controlling emotional expression. Handling altered endocannabinoid content (prefrontal and piriform cortices, nucleus accumbens) and cannabinoid receptor densities (lateral globus pallidus, cingulate and piriform cortices, hippocampus) in a region-specific manner. Some effects of social isolation on the endocannabinoid system were moderated by handling. Isolates were unresponsive to handling-induced increases in cannabinoid receptor densities (caudal striatum, anterior thalamus), but were sensitive to handling-induced increases in endocannabinoid content (piriform cortex), compared to group-reared rats. Our findings suggest alterations in the endocannabinoid system may contribute to the abnormal isolate phenotype. Handling modifies the endocannabinoid system and behavioral reactivity to context, but surmounts only some effects of social isolation. These data implicate a pivotal role for the endocannabinoid system in stress adaptation and emotionality-related disturbances. PMID:20394803

Dominant negative DISC1 mutant mice display specific social behaviour deficits and aberration in BDNF and cannabinoid receptor expression.

PubMed

Kaminitz, Ayelet; Barzilay, Ran; Segal, Hadar; Taler, Michal; Offen, Daniel; Gil-Ad, Irit; Mechoulam, Raphael; Weizman, Abraham

2014-01-01

OBJECTIVES. Disrupted in schizophrenia 1 (DISC1) is considered the most prominent candidate gene for schizophrenia. In this study, we aimed to characterize behavioural and brain biochemical traits in a mouse expressing a dominant negative DISC1mutant (DN-DISC1). DN-DISC1 mice underwent behavioural tests to evaluate object recognition, social preference and social novelty seeking. ELISA was conducted on brain tissue to evaluate BDNF levels. Western blot was employed to measure BDNF receptor (TrkB) and cannabinoid receptor CB1. The mutant DISC1 mice displayed deficits in preference to social novelty while both social preference and object recognition were intact. Biochemical analysis of prefrontal cortex and hippocampus revealed a modest reduction in cortical TrkB protein levels of male mice while no differences in BDNF levels were observed. We found sex dependent differences in the expression of cannabinoid-1 receptors. We describe novel behavioural and biochemical abnormalities in the DN-DISC1 mouse model of schizophrenia. The data shows for the first time a possible link between DISC1 mutation and the cannabinoid system.
Enhancing the activity of cannabidiol and other cannabinoids in vitro through modifications to drug combinations and treatment schedules.

PubMed

Scott, Katherine Ann; Shah, Sini; Dalgleish, Angus George; Liu, Wai Man

2013-10-01

Cannabinoids are the bioactive components of the Cannabis plant that display a diverse range of therapeutic qualities. We explored the activity of six cannabinoids, used both alone and in combination in leukaemic cells. Cannabinoids were cytostatic and caused a simultaneous arrest at all phases of the cell cycle. Re-culturing pre-treated cells in drug-free medium resulted in dramatic reductions in cell viability. Furthermore, combining cannabinoids was not antagonistic. We suggest that the activities of some cannabinoids are influenced by treatment schedules; therefore, it is important to carefully select the most appropriate strategy in order to maximise their efficacy.
Speckle-tracking strain assessment of left ventricular dysfunction in synthetic cannabinoid and heroin users.

PubMed

Demirkıran, Aykut; Albayrak, Neslihan; Albayrak, Yakup; Zorkun, Cafer Sadık

2018-06-01

There is growing evidence regarding the numerous adverse effects of synthetic cannabinoids (SCBs) on the cardiovascular system; however, no studies have shown the cardiovascular effects of opioids using strain echocardiography. This study examines the cardiac structure and function using echocardiographic strain imaging in heroin and synthetic cannabinoid users. This double-blind study included patients who were admitted or referred to a rehabilitation center for heroin (n=31) and synthetic cannabinoid users (n=30). Heroin users and synthetic cannabinoid users were compared with healthy volunteers (n=32) using two-dimensional (2D) speckle-tracking (ST) echocardiography. No differences were found in the baseline characteristics and 2D echocardiography values. The mean global longitudinal strain value was -20.5%±2.4% for SCB users, -22.3%±2.4% for opioid users, and -22.5%±2.2% for healthy volunteers (p=0.024). The mean apical 2-chamber (AP2C) L-strain values were -20.1%±3.1%, -22.4%±3.0%, and -22.3%±2.8% for SCB users, opioid users, and healthy volunteers, respectively (p=0.032). The mean apical 4-chamber (AP4C) L-strain values were -20.7%±2.5% for SCB users, -23.2%±3.2% for opioid users, and -23.8%±3.1% for healthy volunteers (p<0.001). SCBs are potential causes of subclinical left ventricular dysfunction.
Analysis of Parent Synthetic Cannabinoids in Blood and Urinary Metabolites by Liquid Chromatography Tandem Mass Spectrometry

PubMed Central

Knittel, Jessica L.; Holler, Justin M.; Chmiel, Jeffrey D.; Vorce, Shawn P.; Magluilo, Joseph; Levine, Barry; Ramos, Gerardo; Bosy, Thomas Z.

2016-01-01

Synthetic cannabinoids emerged on the designer drug market in recent years due to their ability to produce cannabis-like effects without the risk of detection by traditional drug testing techniques such as immunoassay and gas chromatography–mass spectrometry. As government agencies work to schedule existing synthetic cannabinoids, new, unregulated and structurally diverse compounds continue to be developed and sold. Synthetic cannabinoids undergo extensive metabolic conversion. Consequently, both blood and urine specimens may play an important role in the forensic analysis of synthetic cannabinoids. It has been observed that structurally similar synthetic cannabinoids follow common metabolic pathways, which often produce metabolites with similar metabolic transformations. Presented are two validated quantitative methods for extracting and identifying 15 parent synthetic cannabinoids in blood, 17 synthetic cannabinoid metabolites in urine and the qualitative identification of 2 additional parent compounds. The linear range for most synthetic cannabinoid compounds monitored was 0.1–10 ng/mL with the limit of detection between 0.01 and 0.5 ng/mL. Selectivity, specificity, accuracy, precision, recovery and matrix effect were also examined and determined to be acceptable for each compound. The validated methods were used to analyze a compilation of synthetic cannabinoid investigative cases where both blood and urine specimens were submitted. The study suggests a strong correlation between the metabolites detected in urine and the parent compounds found in blood. PMID:26792810
Chronic cannabinoid receptor 2 activation reverses paclitaxel neuropathy without tolerance or cannabinoid receptor 1-dependent withdrawal.

PubMed

Deng, Liting; Guindon, Josée; Cornett, Benjamin L; Makriyannis, Alexandros; Mackie, Ken; Hohmann, Andrea G

2015-03-01

Mixed cannabinoid receptor 1 and 2 (CB1 and CB2) agonists such as Δ(9)-tetrahydrocannabinol (Δ(9)-THC) can produce tolerance, physical withdrawal, and unwanted CB1-mediated central nervous system side effects. Whether repeated systemic administration of a CB2-preferring agonist engages CB1 receptors or produces CB1-mediated side effects is unknown. We evaluated antiallodynic efficacy, possible tolerance, and cannabimimetic side effects of repeated dosing with a CB2-preferring agonist AM1710 in a model of chemotherapy-induced neuropathy produced by paclitaxel using CB1 knockout (CB1KO), CB2 knockout (CB2KO), and wild-type (WT) mice. Comparisons were made with the prototypic classic cannabinoid Δ(9)-THC. We also explored the site and possible mechanism of action of AM1710. Paclitaxel-induced mechanical and cold allodynia developed to an equivalent degree in CB1KO, CB2KO, and WT mice. Both AM1710 and Δ(9)-THC suppressed established paclitaxel-induced allodynia in WT mice. In contrast to Δ(9)-THC, chronic administration of AM1710 did not engage CB1 activity or produce antinociceptive tolerance, CB1-mediated cannabinoid withdrawal, hypothermia, or motor dysfunction. Antiallodynic efficacy of systemic administration of AM1710 was absent in CB2KO mice and WT mice receiving the CB2 antagonist AM630, administered either systemically or intrathecally. Intrathecal administration of AM1710 also attenuated paclitaxel-induced allodynia in WT mice, but not CB2KO mice, implicating a possible role for spinal CB2 receptors in AM1710 antiallodynic efficacy. Finally, both acute and chronic administration of AM1710 decreased messenger RNA levels of tumor necrosis factor-α and monocyte chemoattractant protein 1 in lumbar spinal cord of paclitaxel-treated WT mice. Our results highlight the potential of prolonged use of CB2 agonists for managing chemotherapy-induced allodynia with a favorable therapeutic ratio marked by sustained efficacy and absence of tolerance, physical withdrawal, or CB1-mediated side effects. Copyright © 2015 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.
Association of herbal cannabis use with negative psychosocial parameters in patients with fibromyalgia.

PubMed

Ste-Marie, Peter A; Fitzcharles, Mary-Ann; Gamsa, Ann; Ware, Mark A; Shir, Yoram

2012-08-01

Patients with chronic pain, including fibromyalgia (FM), may seek treatments outside of mainstream medicine. Medicinal cannabinoids are popularly advocated for pain relief but with limited evidence for efficacy in FM. The extent of use of cannabinoids in FM is unknown. We have documented the self-reported prevalence of cannabinoid use in 457 patients with the diagnosis of FM and referred to a tertiary care pain center. We validated the diagnosis of FM and examined the associations of cannabinoid use in these patients. Cannabinoids were being used by 13% of all patients, of whom 80% used herbal cannabis (marijuana), 24% used prescription cannabinoids, and 3% used both herbal cannabis and prescription cannabinoids. One-third of all men used cannabinoids. Current unstable mental illness (36% versus 23%; P = 0.002), opioid drug-seeking behavior (17% versus 4%; P = 0.002), and male sex (26% versus 7%; P = 0.0002) were all associated with herbal cannabis use. There was a trend for cannabinoid users to be unemployed and receiving disability payments. The diagnosis of FM was validated in 302 patients, with 155 assigned another primary diagnosis. When the FM group was analyzed separately, significant associations were lost, but trends remained. Cannabinoids were used by 13% of patients referred with a diagnosis of FM. The association of herbal cannabis use with negative psychosocial parameters raises questions regarding the motive for this self-medication practice. Although cannabinoids may offer some therapeutic effect, caution regarding any recommendation should be exercised pending clarification of general health and psychosocial problems, especially for those self-medicating. Copyright © 2012 by the American College of Rheumatology.
76 FR 2287 - Schedules of Controlled Substances: Temporary Placement of Five Synthetic Cannabinoids Into...

Federal Register 2010, 2011, 2012, 2013, 2014

2011-01-13

...] Schedules of Controlled Substances: Temporary Placement of Five Synthetic Cannabinoids Into Schedule I... Notice of Intent announcing its intention to temporarily place five synthetic cannabinoids into Schedule... announced its intention to temporarily place five synthetic cannabinoids into schedule I of the Controlled...
The l-α-Lysophosphatidylinositol/GPR55 System and Its Potential Role in Human Obesity

PubMed Central

Moreno-Navarrete, José María; Catalán, Victoria; Whyte, Lauren; Díaz-Arteaga, Adenis; Vázquez-Martínez, Rafael; Rotellar, Fernando; Guzmán, Rocío; Gómez-Ambrosi, Javier; Pulido, Marina R.; Russell, Wendy R.; Imbernón, Mónica; Ross, Ruth A.; Malagón, María M.; Dieguez, Carlos; Fernández-Real, José Manuel; Frühbeck, Gema; Nogueiras, Ruben

2012-01-01

GPR55 is a putative cannabinoid receptor, and l-α-lysophosphatidylinositol (LPI) is its only known endogenous ligand. We investigated 1) whether GPR55 is expressed in fat and liver; 2) the correlation of both GPR55 and LPI with several metabolic parameters; and 3) the actions of LPI on human adipocytes. We analyzed CB1, CB2, and GPR55 gene expression and circulating LPI levels in two independent cohorts of obese and lean subjects, with both normal or impaired glucose tolerance and type 2 diabetes. Ex vivo experiments were used to measure intracellular calcium and lipid accumulation. GPR55 levels were augmented in the adipose tissue of obese subjects and further so in obese patients with type 2 diabetes when compared with nonobese subjects. Visceral adipose tissue GPR55 correlated positively with weight, BMI, and percent fat mass, particularly in women. Hepatic GPR55 gene expression was similar in obese and type 2 diabetic subjects. Circulating LPI levels were increased in obese patients and correlated with fat percentage and BMI in women. LPI increased the expression of lipogenic genes in visceral adipose tissue explants and intracellular calcium in differentiated visceral adipocytes. These findings indicate that the LPI/GPR55 system is positively associated with obesity in humans. PMID:22179809
The emerging role of the endocannabinoid system in cardiovascular disease

PubMed Central

2009-01-01

Endocannabinoids are endogenous bioactive lipid mediators present both in the brain and various peripheral tissues, which exert their biological effects via interaction with specific G-protein-coupled cannabinoid receptors, the CB1 and CB2. Pathological overactivation of the endocannabinoid system (ECS) in various forms of shock and heart failure may contribute to the underlying pathology and cardiodepressive state by the activation of the cardiovascular CB1 receptors. Furthermore, tonic activation of CB1 receptors by endocannabinoids has also been implicated in the development of various cardiovascular risk factors in obesity/metabolic syndrome and diabetes, such as plasma lipid alterations, abdominal obesity, hepatic steatosis, inflammation, and insulin and leptin resistance. In contrast, activation of CB2 receptors in immune cells exerts various immunomodulatory effects, and the CB2 receptors in endothelial and inflammatory cells appear to limit the endothelial inflammatory response, chemotaxis, and inflammatory cell adhesion and activation in atherosclerosis and reperfusion injury. Here, we will overview the cardiovascular actions of endocannabinoids and the growing body of evidence implicating the dysregulation of the ECS in a variety of cardiovascular diseases. We will also discuss the therapeutic potential of the modulation of the ECS by selective agonists/antagonists in various cardiovascular disorders associated with inflammation and tissue injury, ranging from myocardial infarction and heart failure to atherosclerosis and cardiometabolic disorders. PMID:19357846
Effects of 2-AG on the reinforcing properties of wheel activity in obese and lean Zucker rats.

PubMed

Smith, Shilo L; Rasmussen, Erin B

2010-07-01

The endocannabinoid system plays a role in obesity, primarily by its role in food reward. Activity, also involved in obesity, seems to be at least partially controlled by the endocannabinoid system, but the relevant behavioral and neurochemical mechanisms have not been well established. This study represents an attempt to begin elucidating these mechanisms by examining the effects of an endogenous cannabinoid ligand, 2-arachidonoylglycerol (2-AG), on the reinforcing properties of exercise reinforcement in lean and obese Zucker rats. Ten obese and 10 lean Zucker rats pressed a locked door under a progressive ratio schedule of reinforcement that, when unlocked, provided access to a running wheel for 2-min periods. After baseline breakpoints were established, doses of 2-AG (0.3-3 mg/kg) were administered before experimental sessions. Obese rats exhibited lower breakpoints for wheel activity, lower response rates, and fewer revolutions compared with lean rats. 2-AG decreased breakpoints, response rates, and revolutions for obese rats, and revolutions only for lean rats. These data suggest that 2-AG may reduce the reinforcing properties of activity, and that obese Zuckers may show a greater sensitivity to 2-AG. The data also suggest that endocannabinoids may play a role in the reinforcing properties of exercise.
The Endocannabinoid Signaling System in the CNS: A Primer.

PubMed

Hillard, Cecilia J

2015-01-01

The purpose of this chapter is to provide an introduction to the mechanisms for the regulation of endocannabinoid signaling through CB1 cannabinoid receptors in the central nervous system. The processes involved in the synthesis and degradation of the two most well-studied endocannabinoids, 2-arachidonoylglycerol and N-arachidonylethanolamine are outlined along with information regarding the regulation of the proteins involved. Signaling mechanisms and pharmacology of the CB1 cannabinoid receptor are outlined, as is the paradigm of endocannabinoid/CB1 receptor regulation of neurotransmitter release. The reader is encouraged to appreciate the importance of the endocannabinoid/CB1 receptor signaling system in the regulation of synaptic activity in the brain. © 2015 Elsevier Inc. All rights reserved.
An outbreak of acute delirium from exposure to the synthetic cannabinoid AB-CHMINACA.

PubMed

Tyndall, Joseph A; Gerona, Roy; De Portu, Giuliano; Trecki, Jordan; Elie, Marie-Carmelle; Lucas, Judith; Slish, John; Rand, Kenneth; Bazydlo, Lindsay; Holder, Martina; Ryan, Matthew F; Myers, Paul; Iovine, Nicole; Plourde, Michelle; Weeks, Emily; Hanley, James R; Endres, Greg; St Germaine, Danielle; Dobrowolski, Paul J; Schwartz, Michael

2015-01-01

Synthetic cannabinoid containing products are a public health threat as reflected by a number of outbreaks of serious adverse health effects over the past 4 years. The designer drug epidemic is characterized by the rapid turnover of synthetic cannabinoid compounds on the market which creates a challenge in identifying the particular etiology of an outbreak, confirming exposure in cases, and providing current information to law enforcement. Between 28 May 2014 and 8 June 2014, 35 patients were evaluated and treated at the University of Florida Health Medical Center in Gainesville following reported exposure to a synthetic cannabinoid containing product obtained from a common source. Patients demonstrated acute delirium (24) and seizures (14), and five required ventilator support and ICU-level care; none died. The presence of N-[(1S)-1-(aminocarbonyl)-2-methylpropyl]-1-(cyclohexylmethyl)-1H-indazole-3-carboxamide (AB-CHMINACA), or one of its predicted metabolites was confirmed in 15 of 21 cases. A rapid public health response and aggressive public messaging prevented further morbidity, identified the source, and led to law enforcement seizure of the implicated product. The significance of this outbreak lies as much in the rapid occurrence of unpredictable, life-threatening adverse health effects from a newly identified synthetic cannabinoid compound as it does in the multidisciplinary investigation and novel partnership between local public health, the laboratory, and the chemical industry, resulting in termination of the outbreak. A coordinated response and collaboration between law enforcement, the local public health, emergency medical services and Health Center staff, were all key interventions in preventing a more substantial public health outbreak resulting from use of a novel synthetic cannabinoid compound. Real time collaborations between toxicology laboratories, suppliers of analytical standards and the public health system may be useful in the face of future novel chemical exposures.
Activation of GPR55 increases neural stem cell proliferation and promotes early adult hippocampal neurogenesis.

PubMed

Hill, Jeremy D; Zuluaga-Ramirez, Viviana; Gajghate, Sachin; Winfield, Malika; Persidsky, Yuri

2018-06-11

The cannabinoid system exerts functional regulation of neural stem cell (NSC) proliferation and adult neurogenesis, yet not all effects of cannabinoid-like compounds seen can be attributed to the cannabinoid 1 receptor (CB 1 R) or cannabinoid 2 receptor (CB 2 R). The recently de-orphaned GPR55 has been shown to be activated by numerous cannabinoid ligands suggesting that GPR55 is a third cannabinoid receptor. Here we examined the role of GPR55 activation in NSC proliferation and early adult neurogenesis. The effects of GPR55 agonists (LPI, O-1602, ML184) on human NSC proliferation in vitro were assessed by flow cytometry. hNSC differentiation was determined by flow cytometry, qPCR, and immunohistochemistry. Immature neuron formation in the hippocampus of C57BL/6 and GPR55 -/- mice was evaluated by immunohistochemistry. Activation of GPR55 significantly increased proliferation rates of hNSCs in vitro. These effects were attenuated by ML193, a selective GPR55 antagonist. ML184 significantly promoted neuronal differentiation in vitro while ML193 reduced differentiation rates as compared to vehicle treatment. Continuous administration into the hippocampus of O-1602 via cannula connected to osmotic pump resulted in increased Ki67+ cells within the dentate gyrus. O-1602 increased immature neuron generation as assessed by DCX+ and BrdU+ cells as compared to vehicle treated animals. GPR55 -/- animals displayed reduced rates of proliferation and neurogenesis within the hippocampus while O-1602 had no effect as compared to vehicle controls. Together, these findings suggest GPR55 activation as a novel target and strategy to regulate NSC proliferation and adult neurogenesis. This article is protected by copyright. All rights reserved.
A review of oral cannabinoids and medical marijuana for the treatment of chemotherapy-induced nausea and vomiting: a focus on pharmacokinetic variability and pharmacodynamics.

PubMed

Badowski, Melissa E

2017-09-01

Oral cannabinoids (i.e., dronabinol, nabilone) containing the active component of marijuana, delta(Δ)9-tetrahydrocannabinol (THC), are available for the treatment of chemotherapy-induced nausea and vomiting (CINV) in patients with cancer who have failed to adequately respond to conventional antiemetic therapy. The aim of this article is to provide an overview of the efficacy, pharmacokinetics (PK), pharmacodynamics (PD), and safety of oral cannabinoids for patients with CINV. A PubMed search of the English-language literature available through 4 January 2017 was conducted to identify relevant articles for inclusion in the review. Oral cannabinoids have been shown to have similar or improved efficacy compared with conventional antiemetics for the resolution of nausea and/or vomiting in patients with cancer. However, oral THC has high PK variability, with variability in oral dronabinol peak plasma concentrations (C max ) estimated between 150 and 200%. A new oral dronabinol solution has decreased intraindividual variability (area under the curve) vs oral dronabinol capsules. Further, oral THC has a slower time to C max compared with THC administered intravenously (IV) or by smoking, and a lower systemic availability than IV or smoked THC. The PD profile (e.g., "high") of oral THC differs from that of IV or smoked THC in healthy individuals. Oral cannabinoids are associated with greater incidence of adverse effects compared with conventional antiemetic therapy or placebo (e.g., dizziness, hypotension, and dysphoria or depression). A new formulation of oral cannabinoids (i.e., dronabinol oral solution) minimized the PK/PD variability currently observed with capsule formulations.
Cannabinoid Regulation of Brain Reward Processing with an Emphasis on the Role of CB1 Receptors: A Step Back into the Future.

PubMed

Panagis, George; Mackey, Brian; Vlachou, Styliani

2014-01-01

Over the last decades, the endocannabinoid system has been implicated in a large variety of functions, including a crucial modulation of brain-reward circuits and the regulation of motivational processes. Importantly, behavioral studies have shown that cannabinoid compounds activate brain reward mechanisms and circuits in a similar manner to other drugs of abuse, such as nicotine, alcohol, cocaine, and heroin, although the conditions under which cannabinoids exert their rewarding effects may be more limited. Furthermore, there is evidence on the involvement of the endocannabinoid system in the regulation of cue- and drug-induced relapsing phenomena in animal models. The aim of this review is to briefly present the available data obtained using diverse behavioral experimental approaches in experimental animals, namely, the intracranial self-stimulation paradigm, the self-administration procedure, the conditioned place preference procedure, and the reinstatement of drug-seeking behavior procedure, to provide a comprehensive picture of the current status of what is known about the endocannabinoid system mechanisms that underlie modification of brain-reward processes. Emphasis is placed on the effects of cannabinoid 1 (CB1) receptor agonists, antagonists, and endocannabinoid modulators. Further, the role of CB1 receptors in reward processes is investigated through presentation of respective genetic ablation studies in mice. The vast majority of studies in the existing literature suggest that the endocannabinoid system plays a major role in modulating motivation and reward processes. However, much remains to be done before we fully understand these interactions. Further research in the future will shed more light on these processes and, thus, could lead to the development of potential pharmacotherapies designed to treat reward-dysfunction-related disorders.
[Efficacy, tolerability and safety of cannabinoids for chronic neuropathic pain: A systematic review of randomized controlled studies].

PubMed

Petzke, F; Enax-Krumova, E K; Häuser, W

2016-02-01

Recently published systematic reviews came to different conclusions with respect to the efficacy, tolerability and safety of cannabinoids for treatment of chronic neuropathic pain. A systematic search of the literature was carried out in MEDLINE, the Cochrane central register of controlled trials (CENTRAL) and clinicaltrials.gov up until November 2015. We included double-blind randomized placebo-controlled studies (RCT) of at least 2 weeks duration and with at least 9 patients per treatment arm comparing medicinal cannabis, plant-based or synthetic cannabinoids with placebo or any other active drug treatment in patients with chronic neuropathic pain. Clinical endpoints of the analyses were efficacy (more than 30 % or 50 % reduction of pain, average pain intensity, global improvement and health-related quality of life), tolerability (drop-out rate due to side effects, central nervous system and psychiatric side effects) and safety (severe side effects). Using a random effects model absolute risk differences (RD) were calculated for categorical data and standardized mean differences (SMD) for continuous variables. The methodological quality of RCTs was rated by the Cochrane risk of bias tool. We included 15 RCTs with 1619 participants. Study duration ranged between 2 and 15 weeks. Of the studies 10 used a plant-derived oromucosal spray with tetrahydrocannabinol/cannabidiol, 3 studies used a synthetic cannabinoid (2 with nabilone and 1 with dronabinol) and 2 studies used medicinal cannabis. The 13 studies with parallel or cross-over design yielded the following results with 95 % confidence intervals (CI): cannabinoids were superior to placebo in the reduction of mean pain intensity with SMD - 0.10 (95 % CI - 0.20- - 0.00, p = 0.05, 13 studies with 1565 participants), in the frequency of at least a 30 % reduction in pain with an RD of 0.10 [95 % CI 0.03-0.16, p = 0.004, 9 studies with 1346 participants, number needed to treat for additional benefit (NNTB) 14, 95 % CI 8-45] and in the frequency of a large or very large global improvement with an RD of 0.09 (95 % CI 0.01-0.17, p = 0.009, 7 studies with 1092 participants). There were no statistically significant differences between cannabinoids and placebo in the frequency of at least a 50 % reduction in pain, in improvement of health-related quality of life and in the frequency of serious adverse events. Patients treated with cannabinoids dropped out more frequently due to adverse events with an RD of 0.04 [95 % CI 0.01-0.07, p = 0.009, 11 studies with 1572 participants, number needed to treat for additional harm (NNTH) 19, 95 % CI 13-37], reported central nervous system side effects more frequently with an RD of 0.38 (95 % CI 0.18-0.58, p = 0.0003, 9 studies with 1304 participants, NNTH 3, 95 % CI 2-4) and psychiatric side effects with an RD of 0.11 (95 % CI 0.06-0.16, p < 0.0001, 9 studies with 1304 participants, NNTH 8, 95 % CI 7-12). Cannabinoids were marginally superior to placebo in terms of efficacy and inferior in terms of tolerability. Cannabinoids and placebo did not differ in terms of safety during the study period. Short-term and intermediate-term therapy with cannabinoids can be considered in selected patients with chronic neuropathic pain after failure of first-line and second-line therapies.
The Use of Cannabis and Cannabinoids in Treating Symptoms of Multiple Sclerosis: a Systematic Review of Reviews.

PubMed

Nielsen, Suzanne; Germanos, Rada; Weier, Megan; Pollard, John; Degenhardt, Louisa; Hall, Wayne; Buckley, Nicholas; Farrell, Michael

2018-02-13

Pharmaceutical cannabinoids such as nabiximols, nabilone and dronabinol, and plant-based cannabinoids have been investigated for their therapeutic potential in treating multiple sclerosis (MS) symptoms. This review of reviews aimed to synthesise findings from high quality systematic reviews that examined the safety and effectiveness of cannabinoids in multiple sclerosis. We examined the outcomes of disability and disability progression, pain, spasticity, bladder function, tremor/ataxia, quality of life and adverse effects. We identified 11 eligible systematic reviews providing data from 32 studies, including 10 moderate to high quality RCTs. Five reviews concluded that there was sufficient evidence that cannabinoids may be effective for symptoms of pain and/or spasticity in MS. Few reviews reported conclusions for other symptoms. Recent high quality reviews find cannabinoids may have modest effects in MS for pain or spasticity. Future research should include studies with non-cannabinoid comparators; this is an important gap in the evidence.
An update on PPAR activation by cannabinoids

PubMed Central

2016-01-01

Some cannabinoids activate the different isoforms of PPARs (α, β and γ), as shown through the use of reporter gene assays, binding studies, selective antagonists and knockout studies. Activation of all isoforms, but primarily PPARα and γ, mediates some (but not all) of the analgesic, neuroprotective, neuronal function modulation, anti‐inflammatory, metabolic, anti‐tumour, gastrointestinal and cardiovascular effects of some cannabinoids, often in conjunction with activation of the more traditional target sites of action such as the cannabinoid CB1 and CB2 receptors and the TRPV1 ion channel. PPARs also mediate some of the effects of inhibitors of endocannabinoid degradation or transport. Cannabinoids may be chaperoned to the PPARs by fatty acid binding proteins. The aims of this review are to update the evidence supporting PPAR activation by cannabinoids and to review the physiological responses to cannabinoids that are mediated, and not mediated, by PPAR activation. PMID:27077495
An update on PPAR activation by cannabinoids.

PubMed

O'Sullivan, Saoirse Elizabeth

2016-06-01

Some cannabinoids activate the different isoforms of PPARs (α, β and γ), as shown through the use of reporter gene assays, binding studies, selective antagonists and knockout studies. Activation of all isoforms, but primarily PPARα and γ, mediates some (but not all) of the analgesic, neuroprotective, neuronal function modulation, anti-inflammatory, metabolic, anti-tumour, gastrointestinal and cardiovascular effects of some cannabinoids, often in conjunction with activation of the more traditional target sites of action such as the cannabinoid CB1 and CB2 receptors and the TRPV1 ion channel. PPARs also mediate some of the effects of inhibitors of endocannabinoid degradation or transport. Cannabinoids may be chaperoned to the PPARs by fatty acid binding proteins. The aims of this review are to update the evidence supporting PPAR activation by cannabinoids and to review the physiological responses to cannabinoids that are mediated, and not mediated, by PPAR activation. © 2016 The British Pharmacological Society.
The Structure–Function Relationships of Classical Cannabinoids: CB1/CB2 Modulation

PubMed Central

Bow, Eric W.; Rimoldi, John M.

2016-01-01

The cannabinoids are members of a deceptively simple class of terpenophenolic secondary metabolites isolated from Cannabis sativa highlighted by (−)-Δ9-tetrahydrocannabinol (THC), eliciting distinct pharmacological effects mediated largely by cannabinoid receptor (CB1 or CB2) signaling. Since the initial discovery of THC and related cannabinoids, synthetic and semisynthetic classical cannabinoid analogs have been evaluated to help define receptor binding modes and structure–CB1/CB2 functional activity relationships. This perspective will examine the classical cannabinoids, with particular emphasis on the structure–activity relationship of five regions: C3 side chain, phenolic hydroxyl, aromatic A-ring, pyran B-ring, and cyclohexenyl C-ring. Cumulative structure–activity relationship studies to date have helped define the critical structural elements required for potency and selectivity toward CB1 and CB2 and, more importantly, ushered the discovery and development of contemporary nonclassical cannabinoid modulators with enhanced physicochemical and pharmacological profiles. PMID:27398024

Interacting Cannabinoid and Opioid Receptors in the Nucleus Accumbens Core Control Adolescent Social Play

PubMed Central

Manduca, Antonia; Lassalle, Olivier; Sepers, Marja; Campolongo, Patrizia; Cuomo, Vincenzo; Marsicano, Giovanni; Kieffer, Brigitte; Vanderschuren, Louk J. M. J; Trezza, Viviana; Manzoni, Olivier J. J.

2016-01-01

Social play behavior is a highly rewarding, developmentally important form of social interaction in young mammals. However, its neurobiological underpinnings remain incompletely understood. Previous work has suggested that opioid and endocannabinoid neurotransmission interact in the modulation of social play. Therefore, we combined behavioral, pharmacological, electrophysiological, and genetic approaches to elucidate the role of the endocannabinoid 2-arachidonoylglycerol (2-AG) in social play, and how cannabinoid and opioid neurotransmission interact to control social behavior in adolescent rodents. Systemic administration of the 2-AG hydrolysis inhibitor JZL184 or the opioid receptor agonist morphine increased social play behavior in adolescent rats. These effects were blocked by systemic pretreatment with either CB1 cannabinoid receptor (CB1R) or mu-opioid receptor (MOR) antagonists. The social play-enhancing effects of systemic morphine or JZL184 treatment were also prevented by direct infusion of the CB1R antagonist SR141716 and the MOR antagonist naloxone into the nucleus accumbens core (NAcC). Searching for synaptic correlates of these effects in adolescent NAcC excitatory synapses, we observed that CB1R antagonism blocked the effect of the MOR agonist DAMGO and, conversely, that naloxone reduced the effect of a cannabinoid agonist. These results were recapitulated in mice, and completely abolished in CB1R and MOR knockout mice, suggesting that the functional interaction between CB1R and MOR in the NAcC in the modulation of social behavior is widespread in rodents. The data shed new light on the mechanism by which endocannabinoid lipids and opioid peptides interact to orchestrate rodent socioemotional behaviors. PMID:27899885
The effects of synthetic cannabinoids on executive function.

PubMed

Cohen, K; Kapitány-Fövény, M; Mama, Y; Arieli, M; Rosca, P; Demetrovics, Z; Weinstein, A

2017-04-01

There is a growing use of novel psychoactive substances (NPSs) including synthetic cannabinoids. Synthetic cannabinoid products have effects similar to those of natural cannabis but the new synthetic cannabinoids are more potent and dangerous and their use has resulted in various adverse effects. The purpose of the study was to assess whether persistent use of synthetic cannabinoids is associating with impairments of executive function in chronic users. A total of 38 synthetic cannabinoids users, 43 recreational cannabis users, and 41 non-user subjects were studied in two centers in Hungary and Israel. Computerized cognitive function tests, the classical Stroop word-color task, n-back task, and a free-recall memory task were used. Synthetic cannabinoid users performed significantly worse than both recreational and non-cannabis users on the n-back task (less accuracy), the Stroop task (overall slow responses and less accuracy), and the long-term memory task (less word recall). Additionally, they have also shown higher ratings of depression and anxiety compared with both recreational and non-users groups. This study showed impairment of executive function in synthetic cannabinoid users compared with recreational users of cannabis and non-users. This may have major implications for our understanding of the long-term consequences of synthetic cannabinoid based drugs.
Analysis of Parent Synthetic Cannabinoids in Blood and Urinary Metabolites by Liquid Chromatography Tandem Mass Spectrometry.

PubMed

Knittel, Jessica L; Holler, Justin M; Chmiel, Jeffrey D; Vorce, Shawn P; Magluilo, Joseph; Levine, Barry; Ramos, Gerardo; Bosy, Thomas Z

2016-04-01

Synthetic cannabinoids emerged on the designer drug market in recent years due to their ability to produce cannabis-like effects without the risk of detection by traditional drug testing techniques such as immunoassay and gas chromatography-mass spectrometry. As government agencies work to schedule existing synthetic cannabinoids, new, unregulated and structurally diverse compounds continue to be developed and sold. Synthetic cannabinoids undergo extensive metabolic conversion. Consequently, both blood and urine specimens may play an important role in the forensic analysis of synthetic cannabinoids. It has been observed that structurally similar synthetic cannabinoids follow common metabolic pathways, which often produce metabolites with similar metabolic transformations. Presented are two validated quantitative methods for extracting and identifying 15 parent synthetic cannabinoids in blood, 17 synthetic cannabinoid metabolites in urine and the qualitative identification of 2 additional parent compounds. The linear range for most synthetic cannabinoid compounds monitored was 0.1-10 ng/mL with the limit of detection between 0.01 and 0.5 ng/mL. Selectivity, specificity, accuracy, precision, recovery and matrix effect were also examined and determined to be acceptable for each compound. The validated methods were used to analyze a compilation of synthetic cannabinoid investigative cases where both blood and urine specimens were submitted. The study suggests a strong correlation between the metabolites detected in urine and the parent compounds found in blood. © The Author 2016. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.
Assessment of types of synthetic cannabinoids in narcotic cases assessed by the Council of Forensic Medicine between 2011-2015, Ankara, Turkey.

PubMed

Göl, Ersin; Çok, İsmet

2017-11-01

Synthetic cannabinoids mimic the effects of cannabis and are the largest and fastest growing class of newly appearing designer drugs. Reports have revealed that various types of synthetic cannabinoids are mixed with herbal substances. The present study investigated the herbal substance cases involving synthetic cannabinoids in Ankara and nearby cities in Turkey. Data were collected from the reports of synthetic cannabinoids that were analyzed between January 01, 2011 and December 31, 2015 in the Ankara Narcotic Department of the Council of Forensic Medicine at the request of the judicial authorities. In all, 4610 narcotic reports were obtained and reviewed. Among these narcotic reports during the period, 370 reports (8%) were related to synthetic cannabinoids. 28 synthetic cannabinoid compounds could be identified in herbals: 5-F-AB-PINACA, 5-F-AKB-48, 5-F-NNEI, 5-F-PB-22, AB-CHMINACA, AB-FUBINACA, AB-PINACA, ADB-CHMINACA, ADB-FUBINACA, AKB-48, AM-2201, EAM-2201, JWH-018, JWH-022, JWH-031, JWH-122, JWH-201, JWH-210, JWH-250, JWH-251, JWH-307, MAM-2201, NM-2201, PB-22, RCS-4, THJ-2201, UR-144, XLR-11. The amount of herbals was 30.72g, 329.22g, 665.89g, 4844.7g, and 5684.3g in 2011, 2012, 2013, 2014, and 2015, respectively. Generally, herbals contained more than one synthetic cannabinoids. ADB-FUBINACA was the most common synthetic cannabinoid among the herbals determined in this study, which was 3132.43g, excepting multi-synthetic cannabinoid herbals. The amount and diversity of synthetic cannabinoid compounds have increased dramatically between 2011 and 2015. Copyright © 2017 Elsevier B.V. All rights reserved.
Pharmacologic interaction between cannabinoid and either clonidine or neostigmine in the rat formalin test.

PubMed

Yoon, Myung Ha; Choi, Jeong Il

2003-09-01

Although spinal cannabinoid receptor agonist (WIN 55,212-2) has been shown to encounter various models of pain, the role of two subtypes of cannabinoid receptor for the antinociceptive effect of cannabinoids has not been investigated at the spinal level. Spinal alpha 2 receptor agonist (clonidine) and cholinesterase inhibitor (neostigmine) are also active in the modulation of nociception. The authors examined the properties of drug interaction after coadministration of WIN 55,212-2-clonidine, and intrathecal WIN 55,212-2-neostigmine, and further clarified the role of cannabinoid 1 and 2 receptors in cannabinoid-induced antinociception at the spinal level. Catheters were inserted into the intrathecal space of male Sprague-Dawley rats, and 50 microl of 5% formalin solution was injected into the hind paw to evoke the pain. Isobolographic analysis was used for evaluation of pharmacologic interaction. Intrathecal 55,212-2, clonidine, and neostigmine dose-dependently suppressed the flinching observed during phase 1 and 2 in the formalin test. Isobolographic analysis revealed a synergistic interaction after intrathecal delivery of WIN 55,212-2-clonidine or WIN 55,212-2-neostigmine mixture in both phases. The antinociceptive effect of WIN 55,212-2 was antagonized by cannabinoid 1 receptor antagonist (AM 251) but not by cannabinoid 2 receptor antagonist (AM 630). No antinociceptive effect was seen after intrathecal administration of cannabinoid 2 receptor agonist (JWH 133). Intrathecal 55,212-2, clonidine, and neostigmine attenuate the facilitated state and acute pain. WIN 55,212-2 interacts synergistically with either clonidine or neostigmine. The antinociception of WIN 55,212-2 is mediated through the cannabinoid 1 receptor, but not the cannabinoid 2 receptor, at the spinal level.
The acute effects of cannabinoids on memory in humans: a review.

PubMed

Ranganathan, Mohini; D'Souza, Deepak Cyril

2006-11-01

Cannabis is one of the most frequently used substances. Cannabis and its constituent cannabinoids are known to impair several aspects of cognitive function, with the most robust effects on short-term episodic and working memory in humans. A large body of the work in this area occurred in the 1970s before the discovery of cannabinoid receptors. Recent advances in the knowledge of cannabinoid receptors' function have rekindled interest in examining effects of exogenous cannabinoids on memory and in understanding the mechanism of these effects. The literature about the acute effects of cannabinoids on memory tasks in humans is reviewed. The limitations of the human literature including issues of dose, route of administration, small sample sizes, sample selection, effects of other drug use, tolerance and dependence to cannabinoids, and the timing and sensitivity of psychological tests are discussed. Finally, the human literature is discussed against the backdrop of preclinical findings. Acute administration of Delta-9-THC transiently impairs immediate and delayed free recall of information presented after, but not before, drug administration in a dose- and delay-dependent manner. In particular, cannabinoids increase intrusion errors. These effects are more robust with the inhaled and intravenous route and correspond to peak drug levels. This profile of effects suggests that cannabinoids impair all stages of memory including encoding, consolidation, and retrieval. Several mechanisms, including effects on long-term potentiation and long-term depression and the inhibition of neurotransmitter (GABA, glutamate, acetyl choline, dopamine) release, have been implicated in the amnestic effects of cannabinoids. Future research in humans is necessary to characterize the neuroanatomical and neurochemical basis of the memory impairing effects of cannabinoids, to dissect out their effects on the various stages of memory and to bridge the expanding gap between the humans and preclinical literature.
Quantitative urine confirmatory testing for synthetic cannabinoids in randomly collected urine specimens.

PubMed

Castaneto, Marisol S; Scheidweiler, Karl B; Gandhi, Adarsh; Wohlfarth, Ariane; Klette, Kevin L; Martin, Thomas M; Huestis, Marilyn A

2015-06-01

Synthetic cannabinoid intake is an ongoing health issue worldwide, with new compounds continually emerging, making drug testing complex. Parent synthetic cannabinoids are rarely detected in urine, the most common matrix employed in workplace drug testing. Optimal identification of synthetic cannabinoid markers in authentic urine specimens and correlation of metabolite concentrations and toxicities would improve synthetic cannabinoid result interpretation. We screened 20 017 randomly collected US military urine specimens between July 2011 and June 2012 with a synthetic cannabinoid immunoassay yielding 1432 presumptive positive specimens. We analyzed all presumptive positive and 1069 negative specimens with our qualitative synthetic cannabinoid liquid chromatography-tandem mass spectrometry (LC-MS/MS) method, which confirmed 290 positive specimens. All 290 positive and 487 randomly selected negative specimens were quantified with the most comprehensive urine quantitative LC-MS/MS method published to date; 290 specimens confirmed positive for 22 metabolites from 11 parent synthetic cannabinoids. The five most predominant metabolites were JWH-018 pentanoic acid (93%), JWH-N-hydroxypentyl (84%), AM2201 N-hydroxypentyl (69%), JWH-073 butanoic acid (69%), and JWH-122 N-hydroxypentyl (45%) with 11.1 (0.1-2,434), 5.1 (0.1-1,239), 2.0 (0.1-321), 1.1 (0.1-48.6), and 1.1 (0.1-250) µg/L median (range) concentrations, respectively. Alkyl hydroxy and carboxy metabolites provided suitable biomarkers for 11 parent synthetic cannabinoids; although hydroxyindoles were also observed. This is by far the largest data set of synthetic cannabinoid metabolites urine concentrations from randomly collected workplace drug testing specimens rather than acute intoxications or driving under the influence of drugs. These data improve the interpretation of synthetic cannabinoid urine test results and suggest suitable urine markers of synthetic cannabinoid intake. This article is a U.S. Government work and is in the public domain in the USA.
Differential physiological and behavioral cues observed in individuals smoking botanical marijuana versus synthetic cannabinoid drugs.

PubMed

Chase, Peter B; Hawkins, Jeff; Mosier, Jarrod; Jimenez, Ernest; Boesen, Keith; Logan, Barry K; Walter, Frank G

2016-01-01

Synthetic cannabinoid use has increased in many states, and medicinal and/or recreational marijuana use has been legalized in some states. These changes present challenges to law enforcement drug recognition experts (DREs) who determine whether drivers are impaired by synthetic cannabinoids or marijuana, as well as to clinical toxicologists who care for patients with complications from synthetic cannabinoids and marijuana. Our goal was to compare what effects synthetic cannabinoids and marijuana had on performance and behavior, including driving impairment, by reviewing records generated by law enforcement DREs who evaluated motorists arrested for impaired driving. Data were from a retrospective, convenience sample of de-identified arrest reports from impaired drivers suspected of using synthetic cannabinoids (n = 100) or marijuana (n = 33). Inclusion criteria were arrested drivers who admitted to using either synthetic cannabinoids or marijuana, or who possessed either synthetic cannabinoids or marijuana; who also had a DRE evaluation at the scene; and whose blood screens were negative for alcohol and other drugs. Exclusion criteria were impaired drivers arrested with other intoxicants found in their drug or alcohol blood screens. Blood samples were analyzed for 20 popular synthetic cannabinoids by using liquid chromatography-tandem mass spectrometry. Delta-9-tetrahydrocannabinol (THC) and THC-COOH were quantified by gas chromatography-mass spectrometry. Statistical significance was determined by using Fisher's exact test or Student's t-test, where appropriate, to compare the frequency of characteristics of those in the synthetic cannabinoid group versus those in the marijuana group. 16 synthetic cannabinoid and 25 marijuana records met selection criteria; the drivers of these records were arrested for moving violations. Median age for the synthetic cannabinoid group (n = 16, 15 males) was 20 years (IQR 19-23 years). Median age for the marijuana group (n = 25, 21 males) was 20 years (IQR 19-24 years) (p = 0.46). In the synthetic cannabinoid group, 94% (15/16) admitted to using synthetic cannabinoids. In the marijuana group, 96% (24/25) admitted to using marijuana. Blood was available for testing in 96% (24/25) of the marijuana group; 21 of these 24 had quantitative levels of THC (mean + SD = 10.7 + 5 ng/mL) and THC-COOH (mean + SD = 57.8 + 3 ng/mL). Blood was available for testing in 63% (10/16) of the synthetic cannabinoid group, with 80% (8/10) of these positive for synthetic cannabinoids. Those in the synthetic cannabinoid group were more frequently confused (7/16 [44%] vs. 0/25 [0%], p ≤ 0.003) and disoriented (5/16 [31%] vs. 0/25 [0%], p ≤ 0.003), and more frequently had incoherent, slurred speech (10/16 [63%] vs. 3/25 [12%], p = 0.0014) and horizontal gaze nystagmus (8/16 [50%] vs. 3/25 [12%], p = 0.01) than those in the marijuana group. Drivers under the influence of synthetic cannabinoids were more frequently impaired with confusion, disorientation, and incoherent, slurred speech than drivers under the influence of marijuana in this population evaluated by DREs.
Safety and Toxicology of Cannabinoids.

PubMed

Sachs, Jane; McGlade, Erin; Yurgelun-Todd, Deborah

2015-10-01

There is extensive research on the safety, toxicology, potency, and therapeutic potential of cannabis. However, uncertainty remains facilitating continued debate on medical and recreational cannabis policies at the state and federal levels. This review will include a brief description of cannabinoids and the endocannabinoid system; a summary of the acute and long-term effects of cannabis; and a discussion of the therapeutic potential of cannabis. The conclusions about safety and efficacy will then be compared with the current social and political climate to suggest future policy directions and general guidelines.
Paranoid Schizophrenia is Characterized by Increased CB1 Receptor Binding in the Dorsolateral Prefrontal Cortex

PubMed Central

Dalton, Victoria S; Long, Leonora E; Weickert, Cyndi Shannon; Zavitsanou, Katerina

2011-01-01

A number of studies suggest a dysregulation of the endogenous cannabinoid system in schizophrenia (SCZ). In the present study, we examined cannabinoid CB1 receptor (CB1R) binding and mRNA expression in the dorsolateral prefrontal cortex (DLPFC) (Brodmann's area 46) of SCZ patients and controls, post-mortem. Receptor density was investigated using autoradiography with the CB1R ligand [3H] CP 55 940 and CB1R mRNA expression was measured using quantitative RT-PCR in a cohort of 16 patients with paranoid SCZ, 21 patients with non-paranoid SCZ and 37 controls matched for age, post-mortem interval and pH. All cases were obtained from the University of Sydney Tissue Resource Centre. Results were analyzed using one-way analysis of variance (ANOVA) and post hoc Bonferroni tests and with analysis of covariance (ANCOVA) to control for demographic factors that would potentially influence CB1R expression. There was a main effect of diagnosis on [3H] CP 55 940 binding quantified across all layers of the DLPFC (F(2,71)=3.740, p=0.029). Post hoc tests indicated that this main effect was due to patients with paranoid SCZ having 22% higher levels of CB1R binding compared with the control group. When ANCOVA was employed, this effect was strengthened (F(2,67)=6.048, p=0.004) with paranoid SCZ patients differing significantly from the control (p=0.004) and from the non-paranoid group (p=0.016). In contrast, no significant differences were observed in mRNA expression between the different disease subtypes and the control group. Our findings confirm the existence of a CB1R dysregulation in SCZ and underline the need for further investigation of the role of this receptor particularly in those diagnosed with paranoid SCZ. PMID:21471953
Paranoid schizophrenia is characterized by increased CB1 receptor binding in the dorsolateral prefrontal cortex.

PubMed

Dalton, Victoria S; Long, Leonora E; Weickert, Cyndi Shannon; Zavitsanou, Katerina

2011-07-01

A number of studies suggest a dysregulation of the endogenous cannabinoid system in schizophrenia (SCZ). In the present study, we examined cannabinoid CB(1) receptor (CB(1)R) binding and mRNA expression in the dorsolateral prefrontal cortex (DLPFC) (Brodmann's area 46) of SCZ patients and controls, post-mortem. Receptor density was investigated using autoradiography with the CB(1)R ligand [(3)H] CP 55,940 and CB(1)R mRNA expression was measured using quantitative RT-PCR in a cohort of 16 patients with paranoid SCZ, 21 patients with non-paranoid SCZ and 37 controls matched for age, post-mortem interval and pH. All cases were obtained from the University of Sydney Tissue Resource Centre. Results were analyzed using one-way analysis of variance (ANOVA) and post hoc Bonferroni tests and with analysis of covariance (ANCOVA) to control for demographic factors that would potentially influence CB(1)R expression. There was a main effect of diagnosis on [(3)H] CP 55,940 binding quantified across all layers of the DLPFC (F(2,71) = 3.740, p = 0.029). Post hoc tests indicated that this main effect was due to patients with paranoid SCZ having 22% higher levels of CB(1)R binding compared with the control group. When ANCOVA was employed, this effect was strengthened (F(2,67) = 6.048, p = 0.004) with paranoid SCZ patients differing significantly from the control (p = 0.004) and from the non-paranoid group (p = 0.016). In contrast, no significant differences were observed in mRNA expression between the different disease subtypes and the control group. Our findings confirm the existence of a CB(1)R dysregulation in SCZ and underline the need for further investigation of the role of this receptor particularly in those diagnosed with paranoid SCZ.
The multiplicity of spinal AA-5-HT anti-nociceptive action in a rat model of neuropathic pain.

PubMed

Malek, Natalia; Kostrzewa, Magdalena; Makuch, Wioletta; Pajak, Agnieszka; Kucharczyk, Mateusz; Piscitelli, Fabiana; Przewlocka, Barbara; Di Marzo, Vincenzo; Starowicz, Katarzyna

2016-09-01

There is considerable evidence to support the role of anandamide (AEA), an endogenous ligand of cannabinoid receptors, in neuropathic pain modulation. AEA also produces effects mediated by other biological targets, of which the transient receptor potential vanilloid type 1 (TRPV1) has been the most investigated. Both, inhibition of AEA breakdown by fatty acid amide hydrolase (FAAH) and blockage of TRPV1 have been shown to produce anti-nociceptive effects. Recent research suggests the usefulness of dual-action compounds, which may afford greater anti-allodynic efficacy. Therefore, in the present study, we examined the effect of N-arachidonoyl-serotonin (AA-5-HT), a blocker of FAAH and TRPV1, in a rat model of neuropathic pain after intrathecal administration. We found that treatment with AA-5-HT increased the pain threshold to mechanical and thermal stimuli, with highest effect at the dose of 500nM, which was most strongly attenuated by AM-630, CB2 antagonist, administration. The single action blockers PF-3845 (1000nM, for FAAH) and I-RTX (1nM, for TRPV1) showed lower efficacy than AA-5-HT. Moreover AA-5-HT (500nM) elevated AEA and palmitoylethanolamide (PEA) levels. Among the possible targets of these mediators, only the mRNA levels of CB2, GPR18 and GPR55, which are believed to be novel cannabinoid receptors, were upregulated in the spinal cord and/or DRG of CCI rats. It was previously reported that AA-5-HT acts in CB1 and TRPV1-dependent manner after systemic administration, but here for the first time we show that AA-5-HT action at the spinal level involves CB2, with potential contributions from GRP18 and/or GPR55 receptors. Copyright © 2016 Elsevier Ltd. All rights reserved.
Peripheral endocannabinoid system dysregulation in first-episode psychosis.

PubMed

Bioque, Miquel; García-Bueno, Borja; Macdowell, Karina S; Meseguer, Ana; Saiz, Pilar A; Parellada, Mara; Gonzalez-Pinto, Ana; Rodriguez-Jimenez, Roberto; Lobo, Antonio; Leza, Juan C; Bernardo, Miguel

2013-12-01

Several hypotheses involving alterations of the immune system have been proposed among etiological explanations for psychotic disorders. The endocannabinoid system (ECS) has a homeostatic role as an endogenous neuroprotective and anti-inflammatory system. Alterations of this system have been associated with psychosis. Cannabis use is a robust risk factor for these disorders that could alter the ECS signalling. In this study, 95 patients with a first episode of psychosis (FEP) and 90 healthy controls were recruited. Protein expression of cannabinoid receptor 2 (CB2), the protein levels of the main endocannabinoid synthesizing enzymes N-acyl phosphatidylethanolamine phospholipase (NAPE) and diacylglycerol lipase (DAGL), and of degradation enzymes fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL) were determined by western blot analysis in peripheral blood mononuclear cells (PBMCs). Patients with a FEP showed a decreased expression of CB2 and of both endocannabinoids synthesizing enzymes (NAPE and DAGL) in comparison to healthy controls. After controlling for age, gender, body mass index, and cannabis use, NAPE and DAGL expression remained significantly decreased, whereas FAAH and MAGL expression were increased. On the other hand, FEP subjects with history of severe cannabis use showed a larger ECS dysregulation compared with healthy controls. These results indicate an ECS dysregulation in PBMC of FEP patients. The alteration of the ECS presented at the initial phases of psychosis could be contributing to the pathophysiology of the disease and constitutes a possible biomarker of psychotic disorders and an interesting pharmacological target to take into account for therapeutic purposes.
Medical cannabis: Another piece in the mosaic of autoimmunity?

PubMed

Katz, D; Katz, I; Porat-Katz, B S; Shoenfeld, Y

2017-02-01

Legalization of cannabis' medicinal use is rapidly increasing worldwide, raising the need to evaluate medical implications of cannabis. Currently, evidence supports cannabis and its active ingredients as immune-modulating agents, affecting T-cells, B-cells, monocytes, and microglia cells, causing an overall reduction in pro-inflammatory cytokine expression and an increase in anti-inflammatory cytokines. Due to the supporting evidence of cannabinoids as an immune-modulating agent, research focusing on cannabinoids and autoimmunity has emerged. Several clinical trials in multiple sclerosis, inflammatory bowel disease, and fibromyalgia suggest cannabis' effectiveness as an immune-modulator. However, contradicting results and lack of large-scale clinical trials obscure these results. Although lacking clinical research, in vitro and in vivo experiments in rheumatoid arthritis, diabetes type 1, and systemic sclerosis demonstrate a correlation between disease activity and cannabinoids. © 2016 American Society for Clinical Pharmacology and Therapeutics.
[Cannabis and cannabinoids. Possibilities of their therapeutic use].

PubMed

Heim, M E

1982-03-04

Newer aspects of therapeutic potentials of cannabis and cannabinoids are reviewed. The major active constituent of cannabis sativa, delta-9-tetrahydrocannabinol and synthetic cannabinoids are evaluated in several clinical trials on their antiemetic efficacy in cancer chemotherapy induced vomiting. 80% of patients refractory to standard antiemetic treatment could be improved with the synthetic cannabinoid levonantradol. Other therapeutic effects, which are presently investigated in clinical trials are analgesia, antispasticity, anticonvulsion and the reduction of intraocular pressure in glaucoma. The future goal of cannabinoid research is the separation between specific pharmacologic activities and undesirable psychotropic effects.
The Cannabinoids Δ8THC, CBD, and HU-308 Act via Distinct Receptors to Reduce Corneal Pain and Inflammation.

PubMed

Thapa, Dinesh; Cairns, Elizabeth A; Szczesniak, Anna-Maria; Toguri, James T; Caldwell, Meggie D; Kelly, Melanie E M

2018-01-01

Background and Purpose: Corneal injury can result in dysfunction of corneal nociceptive signaling and corneal sensitization. Activation of the endocannabinoid system has been reported to be analgesic and anti-inflammatory. The purpose of this research was to investigate the antinociceptive and anti-inflammatory effects of cannabinoids with reported actions at cannabinoid 1 (CB 1 R) and cannabinoid 2 (CB 2 R) receptors and/or noncannabinoid receptors in an experimental model of corneal hyperalgesia. Methods: Corneal hyperalgesia (increased pain response) was generated using chemical cauterization of the corneal epithelium in wild-type (WT) and CB 2 R knockout (CB 2 R -/- ) mice. Cauterized eyes were treated topically with the phytocannabinoids Δ 8 -tetrahydrocannabinol (Δ 8 THC) or cannabidiol (CBD), or the CBD derivative HU-308, in the presence or absence of the CB 1 R antagonist AM251 (2.0 mg/kg i.p.), or the 5-HT 1A receptor antagonist WAY100635 (1 mg/kg i.p.). Behavioral pain responses to a topical capsaicin challenge at 6 h postinjury were quantified from video recordings. Mice were euthanized at 6 and 12 h postcorneal injury for immunohistochemical analysis to quantify corneal neutrophil infiltration. Results: Corneal cauterization resulted in hyperalgesia to capsaicin at 6 h postinjury compared to sham control eyes. Neutrophil infiltration, indicative of inflammation, was apparent at 6 and 12 h postinjury in WT mice. Application of Δ 8 THC, CBD, and HU-308 reduced the pain score and neutrophil infiltration in WT mice. The antinociceptive and anti-inflammatory actions of Δ 8 THC, but not CBD, were blocked by the CB 1 R antagonist AM251, but were still apparent, for both cannabinoids, in CB 2 R -/- mice. However, the antinociceptive and anti-inflammatory actions of HU-308 were absent in the CB 2 R -/- mice. The antinociceptive and anti-inflammatory effects of CBD were blocked by the 5-HT 1A antagonist WAY100635. Conclusion: Topical cannabinoids reduce corneal hyperalgesia and inflammation. The antinociceptive and anti-inflammatory effects of Δ 8 THC are mediated primarily via CB 1 R, whereas that of the cannabinoids CBD and HU-308, involve activation of 5-HT 1A receptors and CB 2 Rs, respectively. Cannabinoids could be a novel clinical therapy for corneal pain and inflammation resulting from ocular surface injury.
Cannabis and endocannabinoid modulators: Therapeutic promises and challenges

PubMed Central

Grant, Igor; Cahn, B. Rael

2008-01-01

The discovery that botanical cannabinoids such as delta-9 tetrahydrocannabinol exert some of their effect through binding specific cannabinoid receptor sites has led to the discovery of an endocannabinoid signaling system, which in turn has spurred research into the mechanisms of action and addiction potential of cannabis on the one hand, while opening the possibility of developing novel therapeutic agents on the other. This paper reviews current understanding of CB1, CB2, and other possible cannabinoid receptors, their arachidonic acid derived ligands (e.g. anandamide; 2 arachidonoyl glycerol), and their possible physiological roles. CB1 is heavily represented in the central nervous system, but is found in other tissues as well; CB2 tends to be localized to immune cells. Activation of the endocannabinoid system can result in enhanced or dampened activity in various neural circuits depending on their own state of activation. This suggests that one function of the endocannabinoid system may be to maintain steady state. The therapeutic action of botanical cannabis or of synthetic molecules that are agonists, antagonists, or which may otherwise modify endocannabinoid metabolism and activity indicates they may have promise as neuroprotectants, and may be of value in the treatment of certain types of pain, epilepsy, spasticity, eating disorders, inflammation, and possibly blood pressure control. PMID:18806886
Autophagy activation by novel inducers prevents BECN2-mediated drug tolerance to cannabinoids

PubMed Central

Kuramoto, Kenta; Wang, Nan; Fan, Yuying; Zhang, Weiran; Schoenen, Frank J.; Frankowski, Kevin J.; Marugan, Juan; Zhou, Yifa; Huang, Sui; He, Congcong

2016-01-01

ABSTRACT Cannabinoids and related drugs generate profound behavioral effects (such as analgesic effects) through activating CNR1 (cannabinoid receptor 1 [brain]). However, repeated cannabinoid administration triggers lysosomal degradation of the receptor and rapid development of drug tolerance, limiting the medical use of marijuana in chronic diseases. The pathogenic mechanisms of cannabinoid tolerance are not fully understood, and little is known about its prevention. Here we show that a protein involved in macroautophagy/autophagy (a conserved lysosomal degradation pathway), BECN2 (beclin 2), mediates cannabinoid tolerance by preventing CNR1 recycling and resensitization after prolonged agonist exposure, and deletion of Becn2 rescues CNR1 activity in mouse brain and conveys resistance to analgesic tolerance to chronic cannabinoids. To target BECN2 therapeutically, we established a competitive recruitment model of BECN2 and identified novel synthetic, natural or physiological stimuli of autophagy that sequester BECN2 from its binding with GPRASP1, a receptor protein for CNR1 degradation. Co-administration of these autophagy inducers effectively restores the level and signaling of brain CNR1 and protects mice from developing tolerance to repeated cannabinoid usage. Overall, our findings demonstrate the functional link among autophagy, receptor signaling and animal behavior regulated by psychoactive drugs, and develop a new strategy to prevent tolerance and improve medical efficacy of cannabinoids by modulating the BECN2 interactome and autophagy activity. PMID:27305347
Immunomodulatory properties of kappa opioids and synthetic cannabinoids in HIV-1 neuropathogenesis.

PubMed

Hu, Shuxian; Sheng, Wen S; Rock, Robert Bryan

2011-12-01

Anti-retroviral therapy (ART) has had a tremendous impact on the clinical outcomes of HIV-1 infected individuals. While ART has produced many tangible benefits, chronic, long-term consequences of HIV infection have grown in importance. HIV-1-associated neurocognitive disorder (HAND) represents a collection of neurological syndromes that have a wide range of functional cognitive impairments. HAND remains a serious threat to AIDS patients, and there currently remains no specific therapy for the neurological manifestations of HIV-1. Based upon work in other models of neuroinflammation, kappa opioid receptors (KOR) and synthetic cannabinoids have emerged as having neuroprotective properties and the ability to dampen pro-inflammatory responses of glial cells; properties that may have a positive influence in HIV-1 neuropathogenesis. The ability of KOR ligands to inhibit HIV-1 production in human microglial cells and CD4 T lymphocytes, demonstrate neuroprotection, and dampen chemokine production in astrocytes provides encouraging data to suggest that KOR ligands may emerge as potential therapeutic agents in HIV neuropathogenesis. Based upon findings that synthetic cannabinoids inhibit HIV-1 expression in human microglia and suppress production of inflammatory mediators such as nitric oxide (NO) in human astrocytes, as well as a substantial literature demonstrating neuroprotective properties of cannabinoids in other systems, synthetic cannabinoids have also emerged as potential therapeutic agents in HIV neuropathogenesis. This review focuses on these two classes of compounds and describes the immunomodulatory and neuroprotective properties attributed to each in the context of HIV neuropathogenesis.
Vaping Synthetic Cannabinoids: A Novel Preclinical Model of E-Cigarette Use in Mice

PubMed Central

Lefever, Timothy W; Marusich, Julie A; Thomas, Brian F; Barrus, Daniel G; Peiper, Nicholas C; Kevin, Richard C; Wiley, Jenny L

2017-01-01

Smoking is the most common route of administration for cannabis; however, vaping cannabis extracts and synthetic cannabinoids (“fake marijuana”) in electronic cigarette devices has become increasingly popular. Yet, most animal models used to investigate biological mechanisms underlying cannabis use employ injection as the route of administration. This study evaluated a novel e-cigarette device that delivers aerosolized cannabinoids to mice. The effects of aerosolized and injected synthetic cannabinoids (CP 55,940, AB-CHMINACA, XLR-11, and JWH-018) in mice were compared in a battery of bioassays in which psychoactive cannabinoids produce characteristic effects. The most potent cannabinoids (CP 55,940 and AB-CHMINACA) produced the full cannabinoid profile (ie, hypothermia, hypolocomotion, and analgesia), regardless of the route of administration. In contrast, aerosolized JWH-018 and XLR-11 did not produce the full profile of cannabimimetic effects. Results of time course analysis for hypothermia showed that aerosol exposure to CP 55,940 and AB-CHMINACA produced faster onset of effects and shorter duration of action than injection. The ability to administer cannabinoids to rodents using the most common route of administration among humans provides a method for collecting preclinical data with enhanced translational relevance. PMID:28469427

Vaping Synthetic Cannabinoids: A Novel Preclinical Model of E-Cigarette Use in Mice.

PubMed

Lefever, Timothy W; Marusich, Julie A; Thomas, Brian F; Barrus, Daniel G; Peiper, Nicholas C; Kevin, Richard C; Wiley, Jenny L

2017-01-01

Smoking is the most common route of administration for cannabis; however, vaping cannabis extracts and synthetic cannabinoids ("fake marijuana") in electronic cigarette devices has become increasingly popular. Yet, most animal models used to investigate biological mechanisms underlying cannabis use employ injection as the route of administration. This study evaluated a novel e-cigarette device that delivers aerosolized cannabinoids to mice. The effects of aerosolized and injected synthetic cannabinoids (CP 55,940, AB-CHMINACA, XLR-11, and JWH-018) in mice were compared in a battery of bioassays in which psychoactive cannabinoids produce characteristic effects. The most potent cannabinoids (CP 55,940 and AB-CHMINACA) produced the full cannabinoid profile (ie, hypothermia, hypolocomotion, and analgesia), regardless of the route of administration. In contrast, aerosolized JWH-018 and XLR-11 did not produce the full profile of cannabimimetic effects. Results of time course analysis for hypothermia showed that aerosol exposure to CP 55,940 and AB-CHMINACA produced faster onset of effects and shorter duration of action than injection. The ability to administer cannabinoids to rodents using the most common route of administration among humans provides a method for collecting preclinical data with enhanced translational relevance.
Individual differences and vulnerability to drug addiction: a focus on the endocannabinoid system.

PubMed

Sagheddu, Claudia; Melis, Miriam

2015-01-01

Vulnerability to drug addiction depends upon the interactions between the biological makeup of the individual, the environment, and age. These interactions are complex and difficult to tease apart. Since dopamine is involved in the rewarding effects of drugs of abuse, it is postulated that innate differences in mesocorticolimbic pathway can influence the response to drug exposure. In particular, higher and lower expression of dopamine D2 receptors in the ventral striatum (i.e. a marker of dopamine function) has been considered a putative protective and a risk factor, respectively, that can influence one's susceptibility to continued drug abuse as well as the transition to addiction. This phenomenon, which is phylogenetically preserved, appears to be a compensatory change to increased impulse activity of midbrain dopamine neurons. Hence, dopamine neuronal excitability plays a fundamental role in the diverse stages of the drug addiction cycle. In this review, a framework for the evidence that modulation of dopamine neuronal activity plays in the context of vulnerability to drug addiction will be presented. Furthermore, since endogenous cannabinoids serve as retrograde messengers to shape afferent neuronal activity in a short- and long-lasting fashion, their role in individual differences and vulnerability to drug addiction will be discussed.
Synthetic Cathinone and Cannabinoid Designer Drugs Pose a Major Risk for Public Health

PubMed Central

Weinstein, Aviv M.; Rosca, Paola; Fattore, Liana; London, Edythe D.

2017-01-01

As part of an increasing worldwide use of designer drugs, recent use of compounds containing cathinones and synthetic cannabinoids is especially prevalent. Here, we reviewed current literature on the prevalence, epidemiology, bio-behavioral effects, and detection of these compounds. Gender differences and clinical effects will also be examined. Chronic use of synthetic cathinone compounds can have major effects on the central nervous system and can induce acute psychosis, hypomania, paranoid ideation, and delusions, similar to the effects of other better-known amphetamine-type stimulants. Synthetic cannabinoid products have effects that are somewhat similar to those of natural cannabis but more potent and long-lasting than THC. Some of these compounds are potent and dangerous, having been linked to psychosis, mania, and suicidal ideation. Novel compounds are developed rapidly and new screening techniques are needed to detect them as well as a rigorous regulation and legislation reinforcement to prevent their distribution and use. Given the rapid increase in the use of synthetic cathinones and cannabinoid designer drugs, their potential for dependence and abuse, and harmful medical and psychiatric effects, there is a need for research and education in the areas of prevention and treatment. PMID:28878698
Endocannabinoids as positive or negative factors in hematopoietic cell migration and differentiation.

PubMed

Patinkin, Deborah; Milman, Garry; Breuer, Aviva; Fride, Ester; Mechoulam, Raphael

2008-10-24

The ethanolamides of arachidonic, myristic and linoleic acids reduce bone marrow cell migration, while the 2-glyceryl esters of these acids enhance migration. Thus the 2 major endocannabinoids, anandamide (arachidonoyl ethanolamide) and 2-AG (2-arachidonoyl glycerol), whose structural difference lies in the nature of the end-group alone, work in opposite directions. The endocannabinoid arachidonoyl serine, a vasodilator, also reduces migration. The effect of 2-AG is mediated, in part at least, through the cannabinoid receptors, while the effect of anandamide, as well as the rest of the compounds assayed, are not mediated through them. Almost all cannabinoids tested, including anandamide and 2-AG, lead to approximate doubling of CFU-GEMM (colony-forming unit: granulocyte, erythrocyte, macrophage, megakaryocyte) colonies. The effect of anandamide is considerably more potent than that of 2-AG. A surprising dose-response increase of erythroid cells is noted in cultures with the ester cannabinoids (in the absence of the cytokine erythropoietin), while a considerable dose-response augmentation of megakaryocytes is noted in cultures with the ethanolamide cannabinoids (in the presence of erythropoietin). This is suggestive of some cross-talk between two different regulatory systems, one governed by glycoprotein ligands and the other by endocannabinoids.
Synthetic cannabinoids: the hidden side of Spice drugs.

PubMed

Pintori, Nicholas; Loi, Barbara; Mereu, Maddalena

2017-09-01

Spice drugs are herbal mixtures sprayed with synthetic cannabinoids designed to mimic the psychoactive ingredient in marijuana [Δ-tetrahydrocannabinol (Δ-THC)] and synthesized by introducing modifications to the chemical structure of parental compounds aiming to circumvent legal regulations. Synthetic cannabinoid use/abuse can be devastating as toxicological effects and adverse reactions cannot be entirely predicted and may vary with the dose, route of administration, individual vulnerability and concomitant intake with other drugs. The absence of validated testing procedures in the clinical field makes difficult the adoption of a therapeutic approach effective in coping with the synthetic cannabinoid phenomenon, posing a significant challenge for prevention, treatment and public health in general. The aim of this review is to gain insights into the epidemiological, pharmacological and toxicological properties of synthetic cannabinoids, aiming to provide a reliable background needed for the management of synthetic cannabinoid-related adverse effects. Consumers, competent authorities and medical care professionals should be aware of the risks associated with synthetic cannabinoid use.
The neuroprotective properties of palmitoylethanolamine against oxidative stress in a neuronal cell line

PubMed Central

2009-01-01

Background N-acylethanolamines (NAEs) are lipids upregulated in response to cell and tissue injury and are involved in cytoprotection. Arachidonylethanolamide (AEA) is a well characterized NAE that is an endogenous ligand at cannabinoid and vanilloid receptors, but it exists in small quantities relative to other NAE types. The abundance of other NAE species, such as palmitoylethanolamine (PEA), together with their largely unknown function and receptors, has prompted us to examine the neuroprotective properties and mechanism of action of PEA. We hypothesized that PEA protects HT22 cells from oxidative stress and activates neuroprotective kinase signaling pathways. Results Indeed PEA protected HT22 cells from oxidative stress in part by mediating an increase in phosphorylated Akt (pAkt) and ERK1/2 immunoreactivity as well as pAkt nuclear translocation. These changes take place within a time frame consistent with neuroprotection. Furthermore, we determined that changes in pAkt immunoreactivity elicited by PEA were not mediated by activation of cannabinoid receptor type 2 (CB2), thus indicating a novel mechanism of action. These results establish a role for PEA as a neuroprotectant against oxidative stress, which occurs in a variety of neurodegenerative diseases. Conclusions The results from this study reveal that PEA protects HT22 cells from oxidative stress and alters the localization and expression levels of kinases known to be involved in neuroprotection by a novel mechanism. Overall, these results identify PEA as a neuroprotectant with potential as a possible therapeutic agent in neurodegenerative diseases involving oxidative stress. PMID:20003317
Pregnenolone blocks cannabinoid-induced acute psychotic-like states in mice

PubMed Central

Busquets-Garcia, Arnau; Soria-Gómez, Edgar; Redon, Bastien; Mackenbach, Yarmo; Chaouloff, Francis; Varilh, Marjorie; Ferreira, Guillaume; Piazza, Pier-Vincenzo; Marsicano, Giovanni

2017-01-01

Cannabis-induced acute psychotic-like states (CIAPS) represent a growing health issue, but their underlying neurobiological mechanisms are poorly understood. The use of antipsychotics and benzodiazepines against CIAPS is limited by side-effects and/or by their ability to tackle only certain aspects of psychosis. Thus, safer wide-spectrum treatments are currently needed. Although the blockade of cannabinoid type-1 receptor (CB1) had been suggested as a therapeutical means against CIAPS, the use of orthosteric CB1 receptor full antagonists is strongly limited by undesired side effects and low efficacy. The neurosteroid pregnenolone has been recently shown to act as a potent endogenous allosteric signal-specific inhibitor of CB1 receptors. Thus, we tested in mice the potential therapeutic use of pregnenolone against acute psychotic-like effects of Δ9-tetrahydrocannabinol (THC), the main psychoactive component of cannabis. We found that pregnenolone blocks a wide spectrum of THC-induced endophenotypes typically associated with psychotic-like states, including impairments in cognitive functions, somatosensory gating and social interaction. In order to capture THC-induced positive psychotic-like symptoms (e.g. perceptual delusions), we adapted a behavioral paradigm based on associations between different sensory modalities and selective devaluation, allowing the measurement of mental sensory representations in mice. Acting at hippocampal CB1 receptors, THC impaired the correct processing of mental sensory representations (reality testing) in an antipsychotic- and pregnenolone-sensitive manner. Overall, this work reveals that signal-specific inhibitors mimicking pregnenolone effects can be considered as promising new therapeutic tools to treat CIAPS. PMID:28220044
Centrally mediated antinociceptive effects of cannabinoid receptor ligands in rat models of nociception

PubMed Central

Hama, Aldric; Sagen, Jacqueline

2011-01-01

The endogenous nonapeptide hemopressin (HE) demonstrates potent block of the cannabinoid subtype-1 (CB1) receptor in vitro and robust antinociception in vivo. The current study evaluated the effects of centrally administered HE in mechanistically distinct pre-clinical rat models of pain—the hot plate test and the hind paw formalin test. The non-subtype selective CB receptor agonist WIN 55,212-2 was tested concurrently as a positive control. In the hot plate test, neither intrathecal (i.t.) HE nor WIN 55,212-2 significantly altered the latency to respond to noxious heat. By contrast, i.t. HE and WIN 55,212-2 significantly reduced pain-related behaviors in the formalin test. Possible HE functionality as a CB1 receptor antagonist at the spinal level was evaluated in the formalin test. Intrathecal pretreatment with HE did not attenuate the antinociceptive effect of i.t. WIN 55,212-2. However, pretreatment with the CB1 receptor antagonist rimonabant did; i.t. rimonabant pretreatment was not antinociceptive. Potential supraspinal antinociceptive activity of HE was also evaluated. Whereas intracerebroventricular (i.c.v.) injection of WIN 55,212-2 reduced pain-related behaviors in the formalin test, interestingly, i.c.v. HE increased behaviors. In the current study, an antinociceptive effect with the CB receptor ligand HE was obtained under the specific condition of tissue injury and not in the uninjured state. Thus, HE could be a useful analgesic peptide with a novel spinal mechanism of action. PMID:21958947
Central glucocorticoid receptors regulate the upregulation of spinal cannabinoid-1 receptors after peripheral nerve injury in rats.

PubMed

Wang, Shuxing; Lim, Grewo; Mao, Ji; Sung, Backil; Yang, Liling; Mao, Jianren

2007-09-01

Previous studies have shown that peripheral nerve injury upregulated both glucocorticoid receptors (GR) and cannabinoid-1 receptors (CB1R) within the spinal cord dorsal horn in rats. However, the relationship between the expression of spinal GR and CB1R after nerve injury remains unclear. Here, we examined the hypothesis that the upregulation of spinal CB1R induced by chronic constriction nerve injury (CCI) in rats would be regulated by spinal GR. CCI induced the upregulation of spinal CB1R primarily within the ipsilateral spinal cord dorsal horn as revealed by Western blot and immunohistochemistry. The expression of CB1R in CCI rats was substantially attenuated by intrathecal treatment with either the GR antagonist RU38486 or a GR antisense oligonucleotide given twice daily for postoperative day 1-6, whereas the expression of spinal CB1R was enhanced following intrathecal administration of a GR sense oligonucleotide twice daily for postoperative day 1-6. Furthermore, the upregulation of spinal CB1R after nerve injury was prevented in adrenalectomized rats, which was at least partially restored with the intrathecal administration of an exogenous GR agonist dexamethasone, indicating that corticosteroids (endogenous GR agonists) were critical to spinal GR actions. Since the development of neuropathic pain behaviors in CCI rats was attenuated by either RU38486 or a GR antisense oligonucleotide, these results suggest that CB1R is a downstream target for spinal GR actions contributory to the mechanisms of neuropathic pain.
Fatty acid amide hydrolase–morphine interaction influences ventilatory response to hypercapnia and postoperative opioid outcomes in children

PubMed Central

Chidambaran, Vidya; Pilipenko, Valentina; Spruance, Kristie; Venkatasubramanian, Raja; Niu, Jing; Fukuda, Tsuyoshi; Mizuno, Tomoyuki; Zhang, Kejian; Kaufman, Kenneth; Vinks, Alexander A; Martin, Lisa J; Sadhasivam, Senthilkumar

2017-01-01

Aim: Fatty acid amide hydrolase (FAAH) degrades anandamide, an endogenous cannabinoid. We hypothesized that FAAH variants will predict risk of morphine-related adverse outcomes due to opioid–endocannabinoid interactions. Patients & methods: In 101 postsurgical adolescents receiving morphine analgesia, we prospectively studied ventilatory response to 5% CO2 (HCVR), respiratory depression (RD) and vomiting. Blood was collected for genotyping and morphine pharmacokinetics. Results: We found significant FAAH–morphine interaction for missense (rs324420) and several regulatory variants, with HCVR (p < 0.0001) and vomiting (p = 0.0339). HCVR was more depressed in patients who developed RD compared with those who did not (p = 0.0034), thus FAAH–HCVR association predicts risk of impending RD from morphine use. Conclusion: FAAH genotypes predict risk for morphine-related adverse outcomes. PMID:27977335
The Use of Cannabis for Headache Disorders

PubMed Central

Lochte, Bryson C.; Beletsky, Alexander; Samuel, Nebiyou K.; Grant, Igor

2017-01-01

Abstract Headache disorders are common, debilitating, and, in many cases, inadequately managed by existing treatments. Although clinical trials of cannabis for neuropathic pain have shown promising results, there has been limited research on its use, specifically for headache disorders. This review considers historical prescription practices, summarizes the existing reports on the use of cannabis for headache, and examines the preclinical literature exploring the role of exogenous and endogenous cannabinoids to alter headache pathophysiology. Currently, there is not enough evidence from well-designed clinical trials to support the use of cannabis for headache, but there are sufficient anecdotal and preliminary results, as well as plausible neurobiological mechanisms, to warrant properly designed clinical trials. Such trials are needed to determine short- and long-term efficacy for specific headache types, compatibility with existing treatments, optimal administration practices, as well as potential risks. PMID:28861505
Endocannabinoids and the Immune System in Health and Disease.

PubMed

Cabral, Guy A; Ferreira, Gabriela A; Jamerson, Melissa J

2015-01-01

Endocannabinoids are bioactive lipids that have the potential to signal through cannabinoid receptors to modulate the functional activities of a variety of immune cells. Their activation of these seven-transmembranal, G protein-coupled receptors sets in motion a series of signal transductional events that converge at the transcriptional level to regulate cell migration and the production of cytokines and chemokines. There is a large body of data that supports a functional relevance for 2-arachidonoylglycerol (2-AG) as acting through the cannabinoid receptor type 2 (CB2R) to inhibit migratory activities for a diverse array of immune cell types. However, unequivocal data that supports a functional linkage of anandamide (AEA) to a cannabinoid receptor in immune modulation remains to be obtained. Endocannabinoids, as typical bioactive lipids, have a short half-life and appear to act in an autocrine and paracrine fashion. Their immediate effective action on immune function may be at localized sites in the periphery and within the central nervous system. It is speculated that endocannabinoids play an important role in maintaining the overall "fine-tuning" of the immune homeostatic balance within the host.
Cannabinoids in glaucoma II: the effect of different cannabinoids on intraocular pressure of the rabbit.

PubMed

ElSohly, M A; Harland, E C; Benigni, D A; Waller, C W

1984-06-01

Thirty-two different cannabinoids were tested for their ability to reduce intraocular pressure (IOP) in the rabbit. These included many of delta 9- and delta 8-THC derivatives and metabolites along with other natural and synthetic cannabinoids. In addition, some non-cannabinoid constituents of Cannabis were screened using the same model. All compounds were administered intravenously, while only a few were tested topically in mineral oil. Water soluble derivatives of delta 9- and delta 8-THC were prepared and tested topically in aqueous solution. The data revealed that certain derivatives of delta 9-and delta 8-THC were more active in lowering IOP than the parent cannabinoids. In addition, compounds other than delta 9- and delta 8-THC and their derivatives were shown to have activity.
Therapeutic potential of cannabinoids in counteracting chemotherapy-induced adverse effects: an exploratory review.

PubMed

Ostadhadi, Sattar; Rahmatollahi, Mahdieh; Dehpour, Ahmad-Reza; Rahimian, Reza

2015-03-01

Cannabinoids (the active constituents of Cannabis sativa) and their derivatives have got intense attention during recent years because of their extensive pharmacological properties. Cannabinoids first developed as successful agents for alleviating chemotherapy associated nausea and vomiting. Recent investigations revealed that cannabinoids have a wide range of therapeutic effects such as appetite stimulation, inhibition of nausea and emesis, suppression of chemotherapy or radiotherapy-associated bone loss, chemotherapy-induced nephrotoxicity and cardiotoxicity, pain relief, mood amelioration, and last but not the least relief from insomnia. In this exploratory review, we scrutinize the potential of cannabinoids to counteract chemotherapy-induced side effects. Moreover, some novel and yet important pharmacological aspects of cannabinoids such as antitumoral effects will be discussed. Copyright © 2014 John Wiley & Sons, Ltd.
Effects of Cannabinoids on T-cell Function and Resistance to Infection

PubMed Central

Eisenstein, Toby K.

2015-01-01

This review examines the effects of cannabinoids on immune function, with a focus on effects on T-cells, as well as on resistance to infection. The paper considers the immune modulating capacity of marijuana, of Δ9-THC extracted from the marijuana plant, and synthetic cannabinoids. Of particular interest are synthetic compounds that are CB2 receptor (CB2R) selective agonists. As the CB2R is principally expressed on cells of the immune system, agonists that target this receptor, and not CB1 (which is mainly expressed on neurons), have the possibility of altering immune function without psychoactive effects. The overall conclusion of the studies discussed in this review is that cannabinoids that bind to the CB2 receptor, including Δ9-THC and CB2 selective agonists are immunosuppressive. The studies provide objective evidence for potentially beneficial effects of marijuana and Δ9-THC on the immune system in conditions where it is desirable to dampen immune responses. Evidence is also reviewed supporting the conclusion that these same compounds can sensitize to some infections through their immunosuppressive activities, but not to others. An emerging area of investigation that is reviewed is evidence to support the conclusion that CB2 selective agonists are a new class of immunosuppressive and anti-inflammatory compounds that may have exceptional beneficial effects in a variety of conditions, such as autoimmune diseases and graft rejection, where it is desirable to dampen the immune response without psychoactive effects. PMID:25876735
Endocannabinoid contribution to Δ9-tetrahydrocannabinol discrimination in rodents

PubMed Central

Wiley, Jenny L.; Walentiny, D. Matthew; Wright, M. Jerry; Beardsley, Patrick M.; Burston, James J.; Poklis, Justin L.; Lichtman, Aron H.; Vann, Robert E.

2014-01-01

The mechanism through which marijuana produces its psychoactive effects is Δ9- tetrahydrocannabinol (THC)-induced activation of cannabinoid CB1 receptors. These receptors are normally activated by endogenous lipids, including anandamide and 2-arachidonoyl glycerol (2-AG). A logical “first step” in determination of the role of these endocannabinoids in THC’s psychoactive effects is to investigate the degree to which pharmacologically induced increases in anandamide and/or 2-AG concentrations through exogenous administration and/or systemic administration of inhibitors of their metabolism, fatty acid amide hydrolase (FAAH) or monoacylglycerol lipase (MAGL), respectively, share THC’s discriminative stimulus effects. To this end, adult male mice and rats were trained to discriminate THC (5.6 and 3 mg/kg, respectively). In Experiment 1, exogenous administration of anandamide or 2-AG did not substitute for THC in mice nor was substitution enhanced by co-administration of the FAAH or MAGL inhibitors, URB597 and N-arachidonyl maleimide (NAM), respectively. Significant decreases in responding may have prevented assessment of adequate endocannabinoid doses. In mice trained at higher baseline response rates (Experiment 2), the FAAH inhibitor PF3845 (10 mg/kg) enhanced anandamide substitution for THC without producing effects of its own. The MAGL inhibitor JZL184 increased brain levels of 2-AG in vitro and in vivo, increased THC-like responding without co-administration of 2-AG. In rats, neither URB597 nor JZL184 engendered significant THC-appropriate responding, but co-administration of these two enzyme inhibitors approached full substitution. The present results highlight the complex interplay between anandamide and 2-AG and suggest that endogenous increases of both endocannabinoids are most effective in elicitation of THC-like discriminative stimulus effects. PMID:24858366
Mechanisms involved in oleamide-induced vasorelaxation in rat mesenteric resistance arteries.

PubMed

Sudhahar, Varadarajan; Shaw, Sean; Imig, John D

2009-04-01

Fatty acid amides are a new class of signaling lipids that have been implicated in diverse physiological and pathological conditions. Oleamide is a fatty acid amide that induces vasorelaxation. Here, we investigated the mechanisms behind the vasorelaxation effect of oleamide in rat mesenteric resistance arteries. Oleamide-induced concentration dependent (0.01 microM-10 microM) vasorelaxation in mesenteric resistance arteries. This relaxation was unaffected by the presence of the fatty acid amide hydrolase (FAAH) inhibitors. The cannabinoid type 1 (CB1) receptor antagonist, AM251 and the non-CB1/CB2 cannabinoid receptor antagonist, O-1918, attenuated the oleamide vasodilatory response, however the cannabinoid CB2 receptor antagonist, AM630, did not affect the vascular response. Moreover, inhibition of the transient receptor potential vanilloid (TRPV) 1 receptor with capsazepine shifted the oleamide-induced vasorelaxation response to the right. In agreement with the vascular functional data, the cannabinoid CB1 and TRPV1 receptor proteins were expressed in mesenteric resistance arteries but cannabinoid CB2 receptors and the FAAH enzyme were not. In endothelium-denuded arteries, the oleamide-mediated vasorelaxation was attenuated and cannabinoid CB1 or non-CB1/CB2 cannabinoid receptor blockade did not further reduce the dilatory response whereas TRPV1 antagonism further decreased the response. These findings indicate that cannabinoid receptors on the endothelium and endothelium-independent TRPV1 receptors contribute to the oleamide vasodilatory response. Taken together, these results demonstrate that the oleamide-induced vasorelaxation is mediated, in part, by cannabinoid CB1 receptors, non-CB1/CB2 cannabinoid receptors, and TRPV1 receptors in rat mesenteric resistance arteries. These mechanisms are overlapping in respect to oleamide-induced mesenteric resistance artery dilation.
Mechanisms involved in oleamide-induced vasorelaxation in rat mesenteric resistance arteries

PubMed Central

Sudhahar, Varadarajan; Shaw, Sean; Imig, John D.

2009-01-01

Fatty acid amides are a new class of signaling lipids that have been implicated in diverse physiological and pathological conditions. Oleamide is a fatty acid amide that induces vasorelaxation. Here, we investigated the mechanisms behind the vasorelaxation effect of oleamide in rat mesenteric resistance arteries. Oleamide-induced concentration dependent (0.01 μM–10μM) vasorelaxation in mesenteric resistance arteries. This relaxation was unaffected by the presence of the fatty acid amide hydrolase (FAAH) inhibitors. The cannabinoid type 1 (CB1) receptor antagonist, AM251 and the non-CB1/CB2 cannabinoid receptor antagonist, O-1918, attenuated the oleamide vasodilatory response, however the cannabinoid CB2 receptor antagonist, AM630, did not affect the vascular response. Moreover, inhibition of the transient receptor potential vanilloid (TRPV) 1 receptor with capsazepine shifted the oleamide-induced vasorelaxation response to the right. In agreement with the vascular functional data, the cannabinoid CB1 and TRPV1 receptor proteins were expressed in mesenteric resistance arteries but cannabinoid CB2 receptors and the FAAH enzyme were not. In endothelium-denuded arteries, the oleamide-mediated vasorelaxation was attenuated and cannabinoid CB1 or non-CB1/CB2 cannabinoid receptor blockade did not further reduce the dilatory response whereas TRPV1 antagonism further decreased the response. These findings indicate that cannabinoid receptors on the endothelium and endothelium-independent TRPV1 receptors contribute to the oleamide vasodilatory response. Taken together, these results demonstrate that the oleamide-induced vasorelaxation is mediated, in part, by cannabinoid CB1 receptors, non-CB1/CB2 cannabinoid receptors, and TRPV1 receptors in rat mesenteric resistance arteries. These mechanisms are overlapping in respect to oleamide-induced mesenteric resistance artery dilation. PMID:19326479
Synthetic cannabinoids found in "spice" products alter body temperature and cardiovascular parameters in conscious male rats.

PubMed

Schindler, Charles W; Gramling, Benjamin R; Justinova, Zuzana; Thorndike, Eric B; Baumann, Michael H

2017-10-01

The misuse of synthetic cannabinoids is a persistent public health concern. Because these drugs target the same cannabinoid receptors as the active ingredient of marijuana, Δ 9 -tetrahydrocannabinol (THC), we compared the effects of synthetic cannabinoids and THC on body temperature and cardiovascular parameters. Biotelemetry transmitters for the measurement of body temperature or blood pressure (BP) were surgically implanted into separate groups of male rats. THC and the synthetic cannabinoids CP55,940, JWH-018, AM2201 and XLR-11 were injected s.c., and rats were placed into isolation cubicles for 3h. THC and synthetic cannabinoids produced dose-related decreases in body temperature that were most prominent in the final 2h of the session. The rank order of potency was CP55,940>AM2201=JWH-018>THC=XLR-11. The cannabinoid inverse agonist rimonabant antagonized the hypothermic effect of all compounds. Synthetic cannabinoids elevated BP in comparison to vehicle treatment during the first h of the session, while heart rate was unaffected. The rank order of potency for BP increases was similar to that seen for hypothermia. Hypertensive effects of CP55,940 and JWH-018 were not antagonized by rimonabant or the neutral antagonist AM4113. However, the BP responses to both drugs were antagonized by pretreatment with either the ganglionic blocker hexamethonium or the α 1 adrenergic antagonist prazosin. Our results show that synthetic cannabinoids produce hypothermia in rats by a mechanism involving cannabinoid receptors, while they increase BP by a mechanism independent of these sites. The hypertensive effect appears to involve central sympathetic outflow. Published by Elsevier B.V.
Evaluation of first generation synthetic cannabinoids on binding at non-cannabinoid receptors and in a battery of in vivo assays in mice

PubMed Central

Wiley, Jenny L.; Lefever, Timothy W.; Marusich, Julie A.; Grabenauer, Megan; Moore, Katherine N.; Huffman, John W.; Thomas, Brian F.

2016-01-01

Anecdotal reports suggest that abused synthetic cannabinoids produce cannabis-like “highs,” but some of their effects may also differ from traditional cannabinoids such as Δ9-tetrahydrocannabinol (THC). This study examined the binding affinities of first-generation indole-derived synthetic cannabinoids at cannabinoid and noncannabinoid receptors and their effects in a functional observational battery (FOB) and drug discrimination in mice. All seven compounds, except JWH-391, had favorable affinity (≤ 159 nM) for both cannabinoid receptors. In contrast, binding at noncannabinoid receptors was absent or weak. In the FOB, THC and the six active compounds disrupted behaviors in CNS activation and muscle tone/equilibrium domains. Unlike THC, however, synthetic cannabinoids impaired behavior across a wider dose and domain range, producing autonomic effects and signs of CNS excitability and sensorimotor reactivity. In addition, mice acquired JWH-018 discrimination, and THC and JWH-073 produced full substitution whereas the 5-HT2B antagonist mianserin did not substitute in mice trained to discriminate JWH-018 or THC. Urinary metabolite analysis showed that the compounds were extensively metabolized, with metabolites that could contribute to their in vivo effects. Together, these results show that, while first-generation synthetic cannabinoids shared some effects that were similar to those of THC, they also possessed effects that differed from traditional cannabinoids. The high nanomolar (or absent) affinities of these compounds at receptors for most major neurotransmitters suggests that these divergent effects may be related to the greater potencies and/or efficacies at CB1 receptors; however, action(s) at noncannabinoid receptors yet to be assessed or via different signaling pathways cannot be ruled out. PMID:27449567

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