Category Archives: Endocannabinoid System

The phylogenetic distribution and evolutionary origins of endocannabinoid signalling.

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Abstract

“The endocannabinoid signalling system in mammals comprises several molecular components, including cannabinoid receptors (e.g. CB1, CB2), putative endogenous ligands for these receptors [e.g. anandamide, 2-arachidonoylglycerol (2-AG)] and enzymes involved in the biosynthesis and inactivation of anandamide (e.g. NAPE-PLD, FAAH) and 2-AG (e.g. DAG lipase, MGL). In this review we examine the occurrence of these molecules in non-mammalian organisms (in particular, animals and plants) by surveying published data and by basic local alignment search tool (BLAST) analysis of the GenBank database and of genomic sequence data from several vertebrate and invertebrate species. We conclude that the ability of cells to synthesise molecules that are categorised as “endocannabinoids” in mammals is an evolutionarily ancient phenomenon that may date back to the unicellular common ancestor of animals and plants. However, exploitation of these molecules for intercellular signalling may have occurred independently in different lineages during the evolution of the eukaryotes. The CB1- and CB2-type receptors that mediate effects of endocannabinoids in mammals occur throughout the vertebrates, and an orthologue of vertebrate cannabinoid receptors was recently identified in the deuterostomian invertebrate Ciona intestinalis (CiCBR). However, orthologues of the vertebrate cannabinoid receptors are not found in protostomian invertebrates (e.g. Drosophila, Caenorhabditis elegans). Therefore, it is likely that a CB1/CB2-type cannabinoid receptor originated in a deuterostomian invertebrate. This phylogenetic information provides a basis for exploitation of selected non-mammalian organisms as model systems for research on endocannabinoid signalling”

.http://www.ncbi.nlm.nih.gov/pubmed/16596778

Cannabinoid signalling in the enteric nervous system.

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Abstract

“Cannabinoid signalling is an important mechanism of synaptic modulation in the nervous system. Endogenous cannabinoids (anandamide and 2-arachidonyl-glycerol) are synthesized and released via calcium-activated biosynthetic pathways. Exogenous cannabinoids and endocannabinoids act on CB1 and CB2 receptors. CB1 receptors are neuronal receptors which couple via G-proteins to inhibition of adenylate cyclase or to activation or inhibition of ion channels. CB2 receptors are expressed by immune cells and cannabinoids can suppress immune function. In the central nervous system, the endocannabinoids may function as retrograde signals released by the postsynaptic neuron to inhibit neurotransmitter release from presynaptic nerve terminals. Enteric neurons also express CB receptors. Exogenously applied CB receptor agonists inhibit enteric neuronal activity but it is not clear if endocannabinoids released by enteric neurons can produce similar responses in the enteric nervous system (ENS). In this issue of Neurogastroenterology and Motility, Boesmans et al. show that CB1 receptor activation on myenteric neurons maintained in primary culture can suppress neuronal activity, inhibit synaptic transmission and mitochondrial transport along axons. They also provide initial evidence that myenteric neurons (or other cell types present in the cultures) release endocannabinoids and which activate CB1 receptors constitutively. These data provide new information about targets for cannabinoid signalling in the ENS and highlight the potential importance of CB receptors as drug targets. It is necessary that future work extends these interesting findings to intact tissues and ideally to the in vivo setting.”

http://www.ncbi.nlm.nih.gov/pubmed/19689654

The neurobiology and evolution of cannabinoid signalling.

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Abstract

“The plant Cannabis sativa has been used by humans for thousands of years because of its psychoactivity. The major psychoactive ingredient of cannabis is Delta(9)-tetrahydrocannabinol, which exerts effects in the brain by binding to a G-protein-coupled receptor known as the CB1 cannabinoid receptor. The discovery of this receptor indicated that endogenous cannabinoids may occur in the brain, which act as physiological ligands for CB1. Two putative endocannabinoid ligands, arachidonylethanolamide (‘anandamide’) and 2-arachidonylglycerol, have been identified, giving rise to the concept of a cannabinoid signalling system. Little is known about how or where these compounds are synthesized in the brain and how this relates to CB1 expression. However, detailed neuroanatomical and electrophysiological analysis of mammalian nervous systems has revealed that the CB1 receptor is targeted to the presynaptic terminals of neurons where it acts to inhibit release of ‘classical’ neurotransmitters. Moreover, an enzyme that inactivates endocannabinoids, fatty acid amide hydrolase, appears to be preferentially targeted to the somatodendritic compartment of neurons that are postsynaptic to CB1-expressing axon terminals. Based on these findings, we present here a model of cannabinoid signalling in which anandamide is synthesized by postsynaptic cells and acts as a retrograde messenger molecule to modulate neurotransmitter release from presynaptic terminals. Using this model as a framework, we discuss the role of cannabinoid signalling in different regions of the nervous system in relation to the characteristic physiological actions of cannabinoids in mammals, which include effects on movement, memory, pain and smooth muscle contractility. The discovery of the cannabinoid signalling system in mammals has prompted investigation of the occurrence of this pathway in non-mammalian animals. Here we review the evidence for the existence of cannabinoid receptors in non-mammalian vertebrates and invertebrates and discuss the evolution of the cannabinoid signalling system. Genes encoding orthologues of the mammalian CB1 receptor have been identified in a fish, an amphibian and a bird, indicating that CB1 receptors may occur throughout the vertebrates. Pharmacological actions of cannabinoids and specific binding sites for cannabinoids have been reported in several invertebrate species, but the molecular basis for these effects is not known. Importantly, however, the genomes of the protostomian invertebrates Drosophila melanogaster and Caenorhabditis elegans do not contain CB1 orthologues, indicating that CB1-like cannabinoid receptors may have evolved after the divergence of deuterostomes (e.g. vertebrates and echinoderms) and protostomes. Phylogenetic analysis of the relationship of vertebrate CB1 receptors with other G-protein-coupled receptors reveals that the paralogues that appear to share the most recent common evolutionary origin with CB1 are lysophospholipid receptors, melanocortin receptors and adenosine receptors. Interestingly, as with CB1, each of these receptor types does not appear to have Drosophila orthologues, indicating that this group of receptors may not occur in protostomian invertebrates. We conclude that the cannabinoid signalling system may be quite restricted in its phylogenetic distribution, probably occurring only in the deuterostomian clade of the animal kingdom and possibly only in vertebrates.”

http://www.ncbi.nlm.nih.gov/pubmed/11316486

Cannabinoid receptors: nomenclature and pharmacological principles.

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Abstract

“The CB1 and CB2 cannabinoid receptors are members of the G protein-coupled receptor (GPCR) family that are pharmacologically well defined. However, the discovery of additional sites of action for endocannabinoids as well as synthetic cannabinoid compounds suggests the existence of additional cannabinoid receptors. Here we review this evidence, as well as the current nomenclature for classifying a target as a cannabinoid receptor. Basic pharmacological definitions, principles and experimental conditions are discussed in order to place in context the mechanisms underlying cannabinoid receptor activation. Constitutive (agonist-independent) activity is observed with the overexpression of many GPCRs, including cannabinoid receptors. Allosteric modulators can alter the pharmacological responses of cannabinoid receptors. The complex molecular architecture of each of the cannabinoid receptors allows for a single receptor to recognize multiple classes of compounds and produce an array of distinct downstream effects. Natural polymorphisms and alternative splice variants may also contribute to their pharmacological diversity. As our knowledge of the distinct differences grows, we may be able to target select receptor conformations and their corresponding pharmacological responses. Importantly, the basic biology of the endocannabinoid system will continue to be revealed by ongoing investigations.”

http://www.ncbi.nlm.nih.gov/pubmed/22421596

Cannabis and cannabinoid receptors.

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Abstract

“Cannabis and cannabinoids exert many of their biological functions through receptor-mediated mechanisms. Two types of cannabinoid receptors have been identified, namely CB(1) and CB(2), both coupled to a G protein. CB(1) receptors have been detected in the central nervous system (where they are responsible for the characteristic effects of Cannabis, including catalepsy, depression of motor activity, analgesia and feelings of relaxation and well being) and in peripheral neurons (where their activation produces a suppression in neurotransmitter release in the heart, bladder, intestine and vas deferens). Cannabinoid CB(2) receptors have only been detected outside the central nervous system, mostly in cells of the immune system, presumably mediating cannabinoid-induced immunosuppression and antinflammatory effects. With the discovery of cannabinoid receptors for exogenous cannabinoids, also endogenous cannabinoids (anandamide, 2-arachidonylglycerol) have been described.”

http://www.ncbi.nlm.nih.gov/pubmed/10930707

CB₁-independent mechanisms of Δ⁹-THCV, AM251 and SR141716 (rimonabant).

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Abstract

“WHAT IS KNOWN AND OBJECTIVE:

The potential beneficial therapeutic effects of cannabinoid CB₁ receptor antagonists or partial agonists have driven drug discovery and development efforts and have led to clinical candidates. It is generally assumed that these compounds are CB₁ ‘selective’ and produce their effects exclusively via CB₁ receptors.

METHODS:

A literature search was conducted of preclinical publications containing information about non-CB₁ receptor pharmacology of these agents. The information was summarized and evaluated from the perspective of contribution to a fuller understanding of this aspect of these compounds.

RESULTS AND DISCUSSION:

A number of recent studies have revealed that these compounds have CB₁-independent pharmacological actions. We highlight the evidence regarding effects produced in cells lacking CB₁ receptors, effects on neuronal membranes from CB₁ receptor-deficient mutant KO ‘knockout’ mice and affinity for μ-opioid receptors.

WHAT IS NEW AND CONCLUSION:

CB₁ ‘selective’ antagonists and partial agonists have been studied for their anorexigenic and other potential therapeutic uses. An awareness of CB₁-independent mechanism(s) of these agents might contribute to a better understanding of the pharmacologic and toxicologic profiles of these agents.”

http://www.ncbi.nlm.nih.gov/pubmed/21740450

Cannabis reinforcement and dependence: role of the cannabinoid CB1 receptor.

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Abstract

“Awareness of cannabis dependence as a clinically relevant issue has grown in recent years. Clinical and laboratory studies demonstrate that chronic marijuana smokers can experience withdrawal symptoms upon cessation of marijuana smoking and have difficulty abstaining from marijuana use. This paper will review data implicating the cannabinoid CB1 receptor in regulating the behavioral effects of Δ9-tetrahydrocannobinol (THC), the primary psycho-active component of cannabis, across a range of species. The behavioral effects that will be discussed include those that directly contribute to the maintenance of chronic marijuana smoking, such as reward, subjective effects, and the positive and negative reinforcing effects of marijuana, THC and synthetic cannabinoids. The role of the CB1 receptor in the development of marijuana dependence and expression of withdrawal will also be discussed. Lastly, treatment options that may alleviate withdrawal symptoms and promote marijuana abstinence will be considered.”

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2731704/

The cannabis withdrawal syndrome.

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Abstract

“PURPOSE OF REVIEW:

The demand for treatment for cannabis dependence has grown dramatically. The majority of the people who enter the treatment have difficulty in achieving and maintaining abstinence from cannabis. Understanding the impact of cannabis withdrawal syndrome on quit attempts is of obvious importance. Cannabis, however, has long been considered a ‘soft’ drug, and many continue to question whether one can truly become dependent on cannabis. Skepticism is typically focused on whether cannabis use can result in ‘physiological’ dependence or withdrawal, and whether withdrawal is of clinical importance.

RECENT FINDINGS:

The neurobiological basis for cannabis withdrawal has been established via discovery of an endogenous cannabinoid system, identification of cannabinoid receptors, and demonstrations of precipitated withdrawal with cannabinoid receptor antagonists. Laboratory studies have established the reliability, validity, and time course of a cannabis withdrawal syndrome and have begun to explore the effect of various medications on such withdrawal. Reports from clinical samples indicate that the syndrome is common among treatment seekers.

SUMMARY:

A clinically important withdrawal syndrome associated with cannabis dependence has been established. Additional research must determine how cannabis withdrawal affects cessation attempts and the best way to treat its symptoms.”

http://www.ncbi.nlm.nih.gov/pubmed/16612207

Regulation of nausea and vomiting by cannabinoids.

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“Anti-emetic effects of cannabinoids in human clinical trials”

  “Considerable evidence demonstrates that manipulation of the endocannabinoid system regulates nausea and vomiting in humans and other animals. The anti-emetic effect of cannabinoids has been shown across a wide variety of animals that are capable of vomiting in response to a toxic challenge. CB1 agonism suppresses vomiting, which is reversed by CB1 antagonism, and CB1 inverse agonism promotes vomiting. Recently, evidence from animal experiments suggests that cannabinoids may be especially useful in treating the more difficult to control symptoms of nausea and anticipatory nausea in chemotherapy patients, which are less well controlled by the currently available conventional pharmaceutical agents. Although rats and mice are incapable of vomiting, they display a distinctive conditioned gaping response when re-exposed to cues (flavours or contexts) paired with a nauseating treatment. Cannabinoid agonists (Δ9-THC, HU-210) and the fatty acid amide hydrolase (FAAH) inhibitor, URB-597, suppress conditioned gaping reactions (nausea) in rats as they suppress vomiting in emetic species. Inverse agonists, but not neutral antagonists, of the CB1 receptor promote nausea, and at subthreshold doses potentiate nausea produced by other toxins (LiCl). The primary non-psychoactive compound in cannabis, cannabidiol (CBD), also suppresses nausea and vomiting within a limited dose range. The anti-nausea/anti-emetic effects of CBD may be mediated by indirect activation of somatodendritic 5-HT1A receptors in the dorsal raphe nucleus; activation of these autoreceptors reduces the release of 5-HT in terminal forebrain regions. Preclinical research indicates that cannabinioids, including CBD, may be effective clinically for treating both nausea and vomiting produced by chemotherapy or other therapeutic treatments.”

“The cannabis plant has been used for several centuries for a number of therapeutic applications, including the attenuation of nausea and vomiting. Ineffective treatment of chemotherapy-induced nausea and vomiting prompted oncologists to investigate the anti-emetic properties of cannabinoids in the late 1970s and early 1980s, before the discovery of the 5-HT3 antagonists. The first cannabinoid agonist, nabilone (Cesamet), which is a synthetic analogue of Δ9-THC was specifically licensed for the suppression of nausea and vomiting produced by chemotherapy. Furthermore, synthetic Δ9-THC, dronabinol, entered the clinic as Marinol in 1985 as an anti-emetic and in 1992 as an appetite stimulant. In these early studies, several clinical trials compared the effectiveness of Δ9-THC with placebo or other anti-emetic drugs. Comparisons of oral Δ9-THC with existing anti-emetic agents generally indicated that Δ9-THC was at least as effective as the dopamine antagonists, such as prochlorperazine.”

“There is some evidence that cannabis-based medicines may be effective in treating the more difficult to control symptoms of nausea and delayed nausea and vomiting in children. Abrahamov et al. (1995) evaluated the anti-emetic effectiveness of Δ8-THC, a close but less psychoactive relative of Δ9-THC, in children receiving chemotherapy treatment. Two hours before the start of each cancer treatment and every six hours thereafter for 24 h, the children were given Δ8-THC as oil drops on the tongue or in a bite of food. After a total of 480 treatments, the only side effects reported were slight irritability in two of the youngest children (3.5 and 4 years old); both acute and delayed nausea and vomiting were controlled.”

“Chemotherapy-induced vomiting is well controlled in most patients by conventionally available drugs, nausea (acute, delayed and anticipatory) continues to be a challenge. Nausea is often reported as more distressing than vomiting, because it is a continuous sensation. Indeed, this distressing symptom of chemotherapy treatment (even when vomiting is pharmacologically controlled) can become so severe that as many as 20% of patients discontinue the treatment. Both preclinical and human clinical research suggests that cannabinoid compounds may have promise in treating nausea in chemotherapy patients.”

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3165951/

Mechanism of action of cannabinoids: how it may lead to treatment of cachexia, emesis, and pain.

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Image result for The Journal of Supportive Oncology

“Many patients with life-threatening diseases such as cancer experience severe symptoms that compromise their health status and deny them quality of life. Patients with cancer often experience cachexia, pain, and depression,which translate into an unacceptable quality of life. The discovery of the endocannabinoid system has led to a renewed interest in the use of cannabinoids for the management of nausea, vomiting, and weight loss arising either from cancer or the agents used to treat cancer. The endocannabinoid system has been found to be a key modulator of systems involved in pain perception, emesis, and reward pathways. As such, it represents a target for development of new medications for controlling the symptoms associated with cancer. Although the cannabinoid receptor agonist tetrahydrocannabinol and one of its analogs are currently the only agents approved for clinical use, efforts are under way to devise other strategies for activating the endocannabinoid system for therapeutic uses.”

http://www.ncbi.nlm.nih.gov/pubmed/15357514