Tag Archives: Cannabinoids

Cannabis and the brain.

Posted on by

Abstract

“The active compound in herbal cannabis, Delta(9)-tetrahydrocannabinol, exerts all of its known central effects through the CB(1) cannabinoid receptor. Research on cannabinoid mechanisms has been facilitated by the availability of selective antagonists acting at CB(1) receptors and the generation of CB(1) receptor knockout mice. Particularly important classes of neurons that express high levels of CB(1) receptors are GABAergic interneurons in hippocampus, amygdala and cerebral cortex, which also contain the neuropeptides cholecystokinin. Activation of CB(1) receptors leads to inhibition of the release of amino acid and monoamine neurotransmitters. The lipid derivatives anandamide and 2-arachidonylglycerol act as endogenous ligands for CB(1) receptors (endocannabinoids). They may act as retrograde synaptic mediators of the phenomena of depolarization-induced suppression of inhibition or excitation in hippocampus and cerebellum. Central effects of cannabinoids include disruption of psychomotor behaviour, short-term memory impairment, intoxication, stimulation of appetite, antinociceptive actions (particularly against pain of neuropathic origin) and anti-emetic effects. Although there are signs of mild cognitive impairment in chronic cannabis users there is little evidence that such impairments are irreversible, or that they are accompanied by drug-induced neuropathology. A proportion of regular users of cannabis develop tolerance and dependence on the drug. Some studies have linked chronic use of cannabis with an increased risk of psychiatric illness, but there is little evidence for any causal link. The potential medical applications of cannabis in the treatment of painful muscle spasms and other symptoms of multiple sclerosis are currently being tested in clinical trials. Medicines based on drugs that enhance the function of endocannabinoids may offer novel therapeutic approaches in the future.”

http://www.ncbi.nlm.nih.gov/pubmed/12764049

Multiple roles for the endocannabinoid system during the earliest stages of life: pre- and postnatal development.

Posted on by

Abstract

“The endocannabinoid system, including its receptors (CB(1) and CB(2)), endogenous ligands (‘endocannabinoids’), synthesising and degrading enzymes, as well as transporter molecules, has been detected from the earliest stages of embryonic development and throughout pre- and postnatal development. In addition, the endocannabinoids, notably 2-arachidonyl glycerol, are also present in maternal milk. During three distinct developmental stages (i.e. embryonic implantation, prenatal brain development and postnatal suckling), the endocannabinoid system appears to play an essential role for development and survival. Thus, during early pregnancy, successful embryonic passage through the oviduct and implantation into the uterus both require critical enzymatic control of optimal anandamide levels at the appropriate times and sites. During foetal life, the cannabinoid CB(1) receptor plays a major role in brain development, regulating neural progenitor differentiation into neurones and glia and guiding axonal migration and synaptogenesis. Postnatally, CB(1) receptor blockade interferes with the initiation of milk suckling in mouse pups, by inducing oral motor weakness, which exposes a critical role for CB(1) receptors in the initiation of milk suckling by neonates, possibly by interfering with innervation of the tongue muscles. Manipulating the endocannabinoid system by pre- and/or postnatal administration of cannabinoids or maternal marijuana consumption, has significant, yet subtle effects on the offspring. Thus, alterations in the dopamine, GABA and endocannabinoid systems have been reported while enhanced drug seeking behaviour and impaired executive (prefrontal cortical) function have also been observed. The relatively mild nature of the disruptive effects of prenatal cannabinoids may be understood in the framework of the intricate timing requirements and frequently biphasic effects of the (endo)cannabinoids. In conclusion, the endocannabinoid system plays several key roles in pre- and postnatal development. Future studies should further clarify the mechanisms involved and provide a better understanding of the adverse effects of prenatal exposure, in order to design strategies for the treatment of conditions such as infertility, mental retardation and failure-to-thrive.”

http://www.ncbi.nlm.nih.gov/pubmed/18426504

The endocannabinoid-CB(1) receptor system in pre- and postnatal life.

Posted on by

Abstract

“Recent research suggests that the endogenous cannabinoids (“endocannabinoids”) and their cannabinoid receptors have a major influence during pre- and postnatal development. First, high levels of the endocannaboid anandamide and cannabinoid receptors are present in the preimplantation embryo and in the uterus, while a temporary reduction of anandamide levels is essential for embryonal implantation. In women accordingly, an inverse association has been reported between fatty acid amide hydrolase (the anandamide degrading enzyme) in human lymphocytes and miscarriage. Second, CB(1) receptors display a transient presence in white matter areas of the pre- and postnatal nervous system, suggesting a role for CB(1) receptors in brain development. Third, endocannabinoids have been detected in maternal milk and activation of CB(1) receptors appears to be critical for milk sucking by newborn mice, apparently activating oral-motor musculature. Fourth, anandamide has neuroprotectant properties in the developing postnatal brain. Finally, prenatal exposure to the active constituent of marihuana (Delta(9)-tetrahydrocannabinol) or to anandamide affects prefrontal cortical functions, memory and motor and addictive behaviors, suggesting a role for the endocannabinoid CB(1) receptor system in the brain structures which control these functions. Further observations suggest that children may be less prone to psychoactive side effects of Delta(9)-tetrahydrocannabinol or endocannabinoids than adults. The medical implications of these novel developments are far reaching and suggest a promising future for cannabinoids in pediatric medicine for conditions including “non-organic failure-to-thrive” and cystic fibrosis.”

http://www.ncbi.nlm.nih.gov/pubmed/15464041

The endocannabinoid-CB receptor system: Importance for development and in pediatric disease.

Posted on by

Abstract

“Endogenous cannabinoids (endocannabinoids) and their cannabinoid CB1 and CB2 receptors, are present from the early stages of gestation and play a number of vital roles for the developing organism. Although most of these data are collected from animal studies, a role for cannabinoid receptors in the developing human brain has been suggested, based on the detection of “atypically” distributed CB1 receptors in several neural pathways of the fetal brain. In addition, a role for the endocannabinoid system for the human infant is likely, since the endocannabinoid 2-arachidonoyl glycerol has been detected in human milk. Animal research indicates that the Endocannabinoid-CB1 Receptor (‘ECBR’) system fulfills a number of roles in the developing organism: 1. embryonal implantation (requires a temporary and localized reduction in anandamide); 2. in neural development (by the transient presence of CB1 receptors in white matter areas of the nervous system); 3. as a neuroprotectant (anandamide protects the developing brain from trauma-induced neuronal loss); 4. in the initiation of suckling in the newborn (where activation of the CB1 receptors in the neonatal brain is critical for survival). 5. In addition, subtle but definite deficiencies have been described in memory, motor and addictive behaviors and in higher cognitive (‘executive’) function in the human offspring as result of prenatal exposure to marihuana. Therefore, the endocanabinoid-CB1 receptor system may play a role in the development of structures which control these functions, including the nigrostriatal pathway and the prefrontal cortex. From the multitude of roles of the endocannabinoids and their receptors in the developing organism, there are two distinct stages of development, during which proper functioning of the endocannabinoid system seems to be critical for survival: embryonal implantation and neonatal milk sucking. We propose that a dysfunctional Endocannabinoid-CB1 Receptor system in infants with growth failure resulting from an inability to ingest food, may resolve the enigma of “non-organic failure-to-thrive” (NOFTT). Developmental observations suggest further that CB1 receptors develop only gradually during the postnatal period, which correlates with an insensitivity to the psychoactive effects of cannabinoid treatment in the young organism. Therefore, it is suggested that children may respond positively to medicinal applications of cannabinoids without undesirable central effects. Excellent clinical results have previously been reported in pediatric oncology and in case studies of children with severe neurological disease or brain trauma. We suggest cannabinoid treatment for children or young adults with cystic fibrosis in order to achieve an improvement of their health condition including improved food intake and reduced inflammatory exacerbations.”

http://www.ncbi.nlm.nih.gov/pubmed/15159678

Cannabinoid signalling in the enteric nervous system.

Posted on by

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.

Posted on by

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.

Posted on by

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.

Posted on by

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

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

Posted on by

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/

Cannabis–1988.

Posted on by

Abstract

“In this updating review of research on cannabis particular attention has been paid to the increasing number of studies of the disposition of the components of cannabis in man, as well as possible effects on health. Specific binding sites for cannaboids have not been demonstrated. Approximately 80 metabolites of tetrahydrocannabiol (THC) have been discovered, of which 11-OH-THC is the main metabolite, but it contributes little to the overall effect when the drug is smoked or given intravenously. The minimum plasma level of THC associated with the psychotropic effect is 25 ng/ml. Cannabis may produce directly an acute panic reaction, a toxic delirium, and acute paranoid state, or acute mania. Cannabis use may aggrevate schizophrenia, but it is much less certain whether it can lead to sociopathy or even to “amotivational syndrome”. Despite widespread use of cannabis in virtually all parts of the world, no catastrophic effects on health have been noted. Cannabis appears to be relatively safe as compared with current social drugs. It is, however, still too early in the history of the present episode of cannabis use to be sanguine about possible bad effects.”

http://www.ncbi.nlm.nih.gov/pubmed/2852450