Distribution of cannabinoid receptors in the central and peripheral nervous system.
01 Jan 2005-Handbook of experimental pharmacology (Springer Berlin Heidelberg)-Vol. 168, Iss: 168, pp 299-325
TL;DR: There is the need for detailed anatomical studies of brain regions important in the therapeutic actions of drugs that modify the endocannabinoid system and the determination of the localization of the enzymes that synthesize, degrade, and transport the endOCannabinoids.
Abstract: CB1 cannabinoid receptors appear to mediate most, if not all of the psychoactive effects of delta-9-tetrahydrocannabinol and related compounds. This G protein-coupled receptor has a characteristic distribution in the nervous system: It is particularly enriched in cortex, hippocampus, amygdala, basal ganglia outflow tracts, and cerebellum—a distribution that corresponds to the most prominent behavioral effects of cannabis. In addition, this distribution helps to predict neurological and psychological maladies for which manipulation of the endocannabinoid system might be beneficial. CB1 receptors are primarily expressed on neurons, where most of the receptors are found on axons and synaptic terminals, emphasizing the important role of this receptor in modulating neurotransmission at specific synapses. While our knowledge of CB1 localization in the nervous system has advanced tremendously over the past 15 years, there is still more to learn. Particularly pressing is the need for (1) detailed anatomical studies of brain regions important in the therapeutic actions of drugs that modify the endocannabinoid system and (2) the determination of the localization of the enzymes that synthesize, degrade, and transport the endocannabinoids.
Citations
More filters
01 Jan 1999
TL;DR: In this article, anandamide attenuates the pain behavior produced by chemical damage to cutaneous tissue by interacting with CB1-like cannabinoid receptors located outside the central nervous system.
Abstract: The potent analgesic effects of cannabis-like drugs and the presence of CB1-type cannabinoid receptors in pain-processing areas of the brain and spinal cord, indicate that endogenous cannabinoids such as anandamide may contribute to the control of pain transmission within the central nervous system (CNS). Here we show that anandamide attenuates the pain behaviour produced by chemical damage to cutaneous tissue by interacting with CB1-like cannabinoid receptors located outside the CNS. Palmitylethanolamide (PEA), which is released together with anandamide from a common phospholipid precursor, exerts a similar effect by activating peripheral CB2-like receptors. When administered together, the two compounds act synergistically, reducing pain responses 100-fold more potently than does each compound alone. Gas-chromatography/mass-spectrometry measurements indicate that the levels of anandamide and PEA in the skin are enough to cause a tonic activation of local cannabinoid receptors. In agreement with this possibility, the CB1 antagonist SR141716A and the CB2 antagonist SR144528 prolong and enhance the pain behaviour produced by tissue damage. These results indicate that peripheral CB1-like and CB2-like receptors participate in the intrinsic control of pain initiation and that locally generated anandamide and PEA may mediate this effect.
918 citations
TL;DR: An introduction to the endocannabinoid system is provided with an emphasis on its role in synaptic plasticity and how the ECS is perturbed in schizophrenia.
698 citations
TL;DR: It is believed that the therapeutic significance of cannabinoids is masked by the adverse effects and here alternative strategies are discussed to take therapeutic advantage of cannabinoids.
Abstract: The biological effects of cannabinoids, the major constituents of the ancient medicinal plant Cannabis sativa (marijuana) are mediated by two members of the G-protein coupled receptor family, cannabinoid receptors 1 (CB1R) and 2. The CB1R is the prominent subtype in the central nervous system (CNS) and has drawn great attention as a potential therapeutic avenue in several pathological conditions, including neuropsychological disorders and neurodegenerative diseases. Furthermore, cannabinoids also modulate signal transduction pathways and exert profound effects at peripheral sites. Although cannabinoids have therapeutic potential, their psychoactive effects have largely limited their use in clinical practice. In this review, we briefly summarized our knowledge of cannabinoids and the endocannabinoid system, focusing on the CB1R and the CNS, with emphasis on recent breakthroughs in the field. We aim to define several potential roles of cannabinoid receptors in the modulation of signaling pathways and in association with several pathophysiological conditions. We believe that the therapeutic significance of cannabinoids is masked by the adverse effects and here alternative strategies are discussed to take therapeutic advantage of cannabinoids.
617 citations
Cites background from "Distribution of cannabinoid recepto..."
...Whereas regions like the thalamus and the ventral horn of spinal cord have low CB1R expression [59]....
[...]
...The brain regions with highest levels of CB1R expression include olfactory bulb, hippocampus, basal ganglia, and cerebellum [59]....
[...]
...Later, by using autoradiography, in situ hybridization, and immunohistochemistry, CB1R was proven to be the most widely-expressed receptor protein from the GPCR family in the brain [9,59]....
[...]
...Moderate CB1R expression is found in the cerebral cortex, septum, amygdala, hypothalamus, and parts of the brainstem and the dorsal horn of spinal cord [59]....
[...]
TL;DR: This review will discuss the reported tissue distribution of CB2 with a focus on CB2 in neurons, particularly those in the central nervous system as well as the implications of that presence.
Abstract: CB2 was first considered to be the ‘peripheral cannabinoid receptor’. This title was bestowed based on its abundant expression in the immune system and presumed absence from the central nervous system. However, multiple recent reports question the absence of CB2 from the central nervous system. For example, it is now well accepted that CB2 is expressed in brain microglia during neuroinflammation. However, the extent of CB2 expression in neurons has remained controversial. There have been studies claiming either extreme-its complete absence to its widespread expression-as well as everything in between. This review will discuss the reported tissue distribution of CB2 with a focus on CB2 in neurons, particularly those in the central nervous system as well as the implications of that presence. As CB2 is an attractive therapeutic target for pain management and immune system modulation without overt psychoactivity, defining the extent of its presence in neurons will have a significant impact on drug discovery. Our recommendation is to encourage cautious interpretation of data that have been presented for and against CB2's presence in neurons and to encourage continued rigorous study.
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
536 citations
Cites background from "Distribution of cannabinoid recepto..."
...CB1 is abundant within the brain, where it appears responsible for mediating the psychoactive effects of cannabis (Mackie, 2005)....
[...]
TL;DR: The endocannabinoid system consists of the endogenous cannabinoids (endocannabinoids), cannabinoid receptors and the enzymes that synthesise and degrade endOCannabinoids, although additional receptors may be involved, and partial agonism, functional selectivity and inverse agonism all play important roles in determining the cellular response to specific cannabinoid receptor ligands.
Abstract: The endocannabinoid system consists of the endogenous cannabinoids (endocannabinoids), cannabinoid receptors and the enzymes that synthesise and degrade endocannabinoids. Many of the effects of cannabinoids and endocannabinoids are mediated by two G protein-coupled receptors (GPCRs), CB(1) and CB(2), although additional receptors may be involved. CB(1) receptors are present in very high levels in several brain regions and in lower amounts in a more widespread fashion. These receptors mediate many of the psychoactive effects of cannabinoids. CB(2) receptors have a more restricted distribution, being found in a number of immune cells and in a few neurones. Both CB(1) and CB(2) couple primarily to inhibitory G proteins and are subject to the same pharmacological influences as other GPCRs. Thus, partial agonism, functional selectivity and inverse agonism all play important roles in determining the cellular response to specific cannabinoid receptor ligands.
475 citations
References
More filters
TL;DR: The cloning and expression of a complementary DNA that encodes a G protein-coupled receptor that is involved in cannabinoid-induced CNS effects (including alterations in mood and cognition) experienced by users of marijuana are suggested.
Abstract: Marijuana and many of its constituent cannabinoids influence the central nervous system (CNS) in a complex and dose-dependent manner. Although CNS depression and analgesia are well documented effects of the cannabinoids, the mechanisms responsible for these and other cannabinoid-induced effects are not so far known. The hydrophobic nature of these substances has suggested that cannabinoids resemble anaesthetic agents in their action, that is, they nonspecifically disrupt cellular membranes. Recent evidence, however, has supported a mechanism involving a G protein-coupled receptor found in brain and neural cell lines, and which inhibits adenylate cyclase activity in a dose-dependent, stereoselective and pertussis toxin-sensitive manner. Also, the receptor is more responsive to psychoactive cannabinoids than to non-psychoactive cannabinoids. Here we report the cloning and expression of a complementary DNA that encodes a G protein-coupled receptor with all of these properties. Its messenger RNA is found in cell lines and regions of the brain that have cannabinoid receptors. These findings suggest that this protein is involved in cannabinoid-induced CNS effects (including alterations in mood and cognition) experienced by users of marijuana.
4,806 citations
"Distribution of cannabinoid recepto..." refers background or methods in this paper
...Cloning the CB1 receptor (Matsuda et al. 1990) made it possible to identify CB1 synthesizing cells by in situ hybridization (Mailleux and Vanderhaeghen 1992;...
[...]
...robust expression in the granule cell layer (Matsuda et al. 1990; Herkenham et al. 1991; Glass et al. 1997; Tsou et al. 1998a; Egertová and Elphick 2000)....
[...]
3,359 citations
"Distribution of cannabinoid recepto..." refers background in this paper
...Basket cells canbe conveniently separated into twogroupsdistinguishedbyCCK or parvalbumin expression (Freund and Buzsaki 1996; Freund 2003)....
[...]
TL;DR: The results suggest that the presently characterized cannabinoid receptor mediates physiological and behavioral effects of natural and synthetic cannabinoids, because it is strongly coupled to guanine nucleotide regulatory proteins and is discretely localized to cortical, basal ganglia, and cerebellar structures involved with cognition and movement.
Abstract: A potent, synthetic cannabinoid was radiolabeled and used to characterize and precisely localize cannabinoid receptors in slide-mounted sections of rat brain and pituitary. Assay conditions for 3H-CP55,940 binding in Tris-HCl buffer with 5% BSA were optimized, association and dissociation rate constants determined, and the equilibrium dissociation constant (Kd) calculated (21 nM by liquid scintillation counting, 5.2 nM by quantitative autoradiography). The results of competition studies, using several synthetic cannabinoids, add to prior data showing enantioselectivity of binding and correlation of in vitro potencies with potencies in biological assays of cannabinoid actions. Inhibition of binding by guanine nucleotides was selective and profound: Nonhydrolyzable analogs of GTP and GDP inhibited binding by greater than 90%, and GMP and the nonhydrolyzable ATP analog showed no inhibition. Autoradiography showed great heterogeneity of binding in patterns of labeling that closely conform to cytoarchitectural and functional domains. Very dense 3H-CP55,940 binding is localized to the basal ganglia (lateral caudate-putamen, globus pallidus, entopeduncular nucleus, substantia nigra pars reticulata), cerebellar molecular layer, innermost layers of the olfactory bulb, and portions of the hippocampal formation (CA3 and dentate gyrus molecular layer). Moderately dense binding is found throughout the remaining forebrain. Sparse binding characterizes the brain stem and spinal cord. Densitometry confirmed the quantitative heterogeneity of cannabinoid receptors (10 nM 3H-CP55,940 binding ranged in density from 6.3 pmol/mg protein in the substantia nigra pars reticulata to 0.15 pmol/mg protein in the anterior lobe of the pituitary). The results suggest that the presently characterized cannabinoid receptor mediates physiological and behavioral effects of natural and synthetic cannabinoids, because it is strongly coupled to guanine nucleotide regulatory proteins and is discretely localized to cortical, basal ganglia, and cerebellar structures involved with cognition and movement.
2,070 citations
"Distribution of cannabinoid recepto..." refers background in this paper
...Expression of CB1 receptors in the thalamus is low (Herkenham et al. 1991; Jansen et al. 1992; Matsuda et al. 1993; Glass et al. 1997; Tsou et al. 1998a; Egertová and Elphick 2000)....
[...]
...robust expression in the granule cell layer (Matsuda et al. 1990; Herkenham et al. 1991; Glass et al. 1997; Tsou et al. 1998a; Egertová and Elphick 2000)....
[...]
...CB1 receptors are densely expressed in all regions of the cortex (Herkenham et al. 1991; Mailleux and Vanderhaeghen 1992; Matsuda et al. 1993; Glass et al. 1997; Tsou et al. 1998a; Egertová and Elphick 2000)....
[...]
...The first autoradiographic studies found very high levels of CB1 receptors in all subfields of the hippocampus as well as the dentate gyrus (Herkenham et al. 1991; Jansen et al. 1992)....
[...]
...nucleus of the lateral septum (Herkenham et al. 1991)....
[...]
TL;DR: Treatment of wild-type mice with the CB1 antagonist SR141716A mimicked the phenotype of CB1-deficient mice, revealing that CB1 is required at the moment of memory extinction, and proposes that endocannabinoids facilitate extinction of aversive memories through their selective inhibitory effects on local inhibitory networks in the amygdala.
Abstract: Acquisition and storage of aversive memories is one of the basic principles of central nervous systems throughout the animal kingdom. In the absence of reinforcement, the resulting behavioural response will gradually diminish to be finally extinct. Despite the importance of extinction, its cellular mechanisms are largely unknown. The cannabinoid receptor 1 (CB1) and endocannabinoids are present in memory-related brain areas and modulate memory. Here we show that the endogenous cannabinoid system has a central function in extinction of aversive memories. CB1-deficient mice showed strongly impaired short-term and long-term extinction in auditory fear-conditioning tests, with unaffected memory acquisition and consolidation. Treatment of wild-type mice with the CB1 antagonist SR141716A mimicked the phenotype of CB1-deficient mice, revealing that CB1 is required at the moment of memory extinction. Consistently, tone presentation during extinction trials resulted in elevated levels of endocannabinoids in the basolateral amygdala complex, a region known to control extinction of aversive memories. In the basolateral amygdala, endocannabinoids and CB1 were crucially involved in long-term depression of GABA (gamma-aminobutyric acid)-mediated inhibitory currents. We propose that endocannabinoids facilitate extinction of aversive memories through their selective inhibitory effects on local inhibitory networks in the amygdala.
1,641 citations
TL;DR: The results generally agree well with the previous studies using CB1 receptor autoradiography and messenger RNA in situ hybridization, but because of its greater resolution, immunohistochemistry allowed identification of particular neuronal cells and fibers that possess cannabinoid receptors.
1,561 citations