The Endocannabinoid System as an Emerging Target of Pharmacotherphy.pdf

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NIH Public Access

Author Manuscript

Pharmacol Rev . Author manuscript; available in PMC 2008 February 13.

Published in final edited form as:

Pharmacol Rev . 2006 September ; 58(3): 389–462.

The Endocannabinoid System as an Emerging Target of

Pharmacotherapy

PÁL PACHER , SÁNDOR BÁTKAI , and GEORGE KUNOS

Laboratory of Physiologic Studies, National Institute on Alcohol Abuse and Alcoholism, National

Institutes of Health, Bethesda, Maryland

Abstract

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 CB 1 receptors. However, this problem does not arise when the therapeutic aim is

achieved by treatment with a CB 1 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 CB 2 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.

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I. Introduction

Marijuana, or cannabis, is the most widely used illicit drug in Western societies and also the

one with the longest recorded history of human use. The popularity of marijuana as a

recreational drug is due to its ability to alter sensory perception and cause elation and euphoria,

most vividly described by the 19th century French poet, Charles Baudelaire, in his book Les

Paradis Artificiels (Iversen, 2000). However, the ability of extracts of the hemp plant

( Cannabis sativa ) to cause a variety of medicinal effects unrelated to its psychoactive properties

had been recognized as early as the third millennium BC, when Chinese texts described its

Address correspondence to: Dr. George Kunos, National Institutes of Health, NIAAA, Laboratory of Physiological Studies, 5625 Fishers

Lane, Room 2S-24, Bethesda, MD 20892-9413. E-mail: gkunos@mail.nih.gov.

P.P. and G.K. contributed equally to this work.

PACHER et al.

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usefulness in the relief of pain and cramps (Mechoulam, 1986). In ancient India, the anxiety-

relieving effect of bhang (the Indian term for marijuana ingested as food) had been recorded

more than 3000 years ago. The use of cannabis or hashish as a psychoactive substance reached

Europe and the Americas through the Arab world in the 19th century. During the same period,

cannabis extracts had gained widespread use for medicinal purposes until 1937, when concern

about the dangers of abuse led to the banning of marijuana for further medicinal use in the

United States. The rather turbulent history of marijuana and the recent resurgence of interest

in its medicinal properties have been the subject of excellent reviews (Mechoulam, 1986;

Iversen, 2000; Di Marzo et al., 2004; Howlett et al., 2004; Pertwee, 2005a; Piomelli, 2005; Di

Marzo and Petrocellis, 2006; Mackie, 2006; Pagotto et al., 2006). Added to this interest is the

emergence of the endocannabinoid system, offering not only new insights into the mechanisms

underlying the therapeutic actions of plant-derived phytocannabinoids but also novel molecular

targets for pharmacotherapy. In this overview, we will briefly summarize current thoughts

about the role of endocannabinoids in a given physiological or pathological process and then

survey attempts to exploit this role for therapeutic gain.

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II. The Pharmacology of Cannabinoids

A. Cannabinoid Receptors and Ligands

Up until the last two decades, marijuana research was a rather esoteric field, of interest to a

small number of scientists. A contributory factor was the highly lipophilic nature of the

biologically active ingredients, which led to the notion that marijuana elicits its effects

nonspecifically by perturbing membrane lipids (Lawrence and Gill, 1975). The first important

breakthrough that ultimately led to a rejection of this concept was the identification by Gaoni

and Mechoulam (1964) of the correct chemical structure of the main psychoactive ingredient

of marijuana, Δ 9 -tetrahydrocannabinol (THC 1 ), and the subsequent demonstration that

bioactivity resides in the l -stereoisomer of this compound (Mechoulam and Gaoni, 1967),

which is one of approximately 60 cannabinoids present in the plant (Dewey, 1986). This

discovery stimulated the generation of a whole range of synthetic analogs in the 1970s that

included not only compounds structurally similar to phytocannabinoids (Fig. 1A) but also

analogs with different chemical structures, including classic and nonclassic cannabinoids and

aminoalkylindoles (Fig. 1B) (Howlett et al., 2002), as well as the subsequently discovered

endogenous arachidonic acid derivatives or endocannabinoids (Fig. 1C), which are discussed

in more detail below. Studies of the biological effects of THC and its synthetic analogs revealed

strict structural selectivity (Hollister, 1974) as well as stereo-selectivity (Jones et al., 1974),

telltale signs of drug-receptor interactions. Definitive evidence for the existence of specific

cannabinoid receptors was followed soon by the demonstration of high-affinity, saturable,

stereospecific binding sites for the synthetic cannabinoid agonist [ 3 H]CP-55,940 in mouse

brain plasma membranes, which correlated with both the in vitro inhibition of adenylate cyclase

and the in vivo analgesic effect of the compound (Devane et al., 1988). The availability of a

radioligand also allowed the mapping of cannabinoid receptors in the brain by receptor

autoradiography (Herkenham et al., 1991b). This mapping turned out to be of key importance

in the subsequent identification of an orphan G protein-coupled receptor (GPCR) as the brain

receptor for cannabinoids (Matsuda et al., 1990), later named CB 1 receptor, based on the

overlapping regional distribution of the mRNA for this GPCR and [ 3 H]CP-55,940 binding

sites. CB 1 receptors are the most abundant receptors in the mammalian brain but are also present

at much lower concentrations in a variety of peripheral tissues and cells. A second cannabinoid

GPCR, CB 2 , is expressed primarily in cells of the immune and hematopoietic systems (Munro

et al., 1993) but recently were found to be present in the brain (Van Sickle et al., 2005; Gong

et al., 2006), in nonparenchymal cells of the cirrhotic liver (Julien et al., 2005), in the endocrine

pancreas (Juan-Pico et al., 2005), and in bone (Karsak et al., 2004; Idris et al., 2005; Ofek et

al., 2006). Two splice variants of CB 1 receptors have been also identified: CB 1A , which has

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an altered amino-terminal sequence (Shire et al., 1995), and CB 1B , which has an in-frame

deletion of 33 amino acids at the amino terminus (Ryberg et al., 2005). The mRNAs of both

splice variants are expressed at much lower levels than the CB 1 mRNA and, although the

receptors expressed from the cDNAs have unique pharmacology (Ryberg et al., 2005),

evidence for their natural expression has not been reported.

An interesting twist on the steric selectivity of cannabinoid receptors has emerged through

recent studies of the behaviorally inactive phytocannabinoid (−)-cannabidiol (CBD) and its

synthetic analogs, which have negligible affinity for either CB 1 or CB 2 receptors.

Paradoxically, some of the synthetic (+)-(+)-stereoisomers of these compounds were found to

bind potently to both CB 1 and CB 2 receptors (Bisogno et al., 2001) but to display only

peripheral and not centrally mediated cannabinoid-like bioactivity, suggesting that they may

act as antagonists rather than agonists at central, but not peripheral, CB 1 receptors (Fride et al.,

2005).

Another ligand that displays central versus peripheral selectivity is ajulemic acid, a metabolite

of THC that was found to have potent anti-inflammatory and analgesic properties without any

overt behavioral or psychoactive effects (Burstein et al., 1992; Dyson et al., 2005; Mitchell et

al., 2005). Ajulemic acid was reported to bind to both CB 1 and CB 2 receptors with reasonably

high affinity ( K d 100–200 nM) but only to activate the latter (Rhee et al., 1997), which may

explain its unique and therapeutically attractive pharmacological profile. A more recent study

indicated even higher affinities for CB 1 ( K i 6 nM) and CB 2 receptors ( K i 56 nM) and specified

the role of CB 1 in mediating its antihyperalgesic activity in neuropathic pain (Dyson et al.,

2005). This article also documented limited brain penetration of ajulemic acid compared with

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1 Abbreviations: THC or Δ 9 -THC, Δ 9 -tetrahydrocannabinol; CP-55,940, (1 R ,3 R ,4 R )-3-[2-hydroxy-4-(1,1-dimethylheptyl)phenyl]-4-(3-

hydroxypropyl)cyclohexan-1-ol; GPCR, G protein-coupled receptor; CB 1 or CB 2 , cannabinoid 1 or 2; CBD, cannabidiol; SR141716,

N -(piperidin-1-yl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1 H -pyrazole-3-carboximide hydrochloride (rimonabant);

AM251, N -(piperin-1-yl)-5-(4-iodophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1 H -pyrazole-3-carboxamide; TRPV 1 or VR 1 , transient

receptor potential vanilloid 1 or vanilloid 1; WIN 55,212-2, R -(+)-[2,3-dihydro-5-methyl-3-[(morpholinyl)methyl]pyrrolo-[1,2,3-

de ]-1,4-benzoxazinyl]-(1-naphthalenyl)methanone mesylate; GTP γ S, guanosine 5′- O -(3-thio)triphosphate; HU-210, Δ 8 -

tetrahydrocannabinol dimethyl heptyl; DARPP-32, dopamine- and cAMP-regulated phosphoprotein of 32 kDa; 2-AG, 2-

arachidonoylglycerol; NAPE; N- arachidonoyl phosphatidylethanolamide; PE, phosphatidylethanolamine; PL, phospholipase; DAG,

diacylglycerol; FAAH, fatty acid amide hydrolase; UCM707, N- (3-furanylmethyl)-5 Z ,8 Z ,11 Z ,14 Z -eicosatetraenamide; LY2318912, 5-

(4-azido-3-iodo-benzoylaminomethyl]-tetrazole-1-carboxylic acid dimethylamide; MGL, monoacylglyceride lipase; DSI,

depolarization-induced suppression of inhibition; SR144528, N -((1 S )-endo-1,3,3-trimethyl bicyclo heptan-2-yl]-5-(4chloro-3-

methylphenyl)-1-(4-methylbenzyl)-pyrazole-3-carboxamide); NPY, neuropeptide Y; MCH, melanin concentrating hormone; α -MSH,

α -melanocyte-stimulating hormone; CRH, corticotropin-releasing hormone; CART, cocaine- and amphetamine-related transcript;

AMPK, AMP-activated protein kinase; ACC1, acetyl CoA carboxylase-1; SREBP1c, sterol response element binding protein 1c; HDL,

high-density lipoprotein; LDL, low-density lipoprotein; CNS, central nervous system; HIV, human immunodeficiency virus; LPS,

lipopolysaccharide or endotoxin; TNF- α , tumor necrosis factor- α ; IL, interleukin; CXCL, CXC chemokine ligand; NMDA receptor, N-

methyl-D-aspartate receptor; HU-211, dexanabinol; TBI, traumatic brain injury; BAY 38-7271, (−)-( R )-3-(2-hydroxymethylindanyl-4-

oxy)phenyl-4,4,4-trifluoro-1-sulfonate; MCAo, middle cerebral artery occlusion; GABA, gamma-aminobutyric acid; GPe or GPi,

external or internal globus pallidus; HD, Huntington’s disease; HPA axis, hypothalamic-pituitary-adrenal axis; HU-211, dexanabinol;

ICAM-1, intercellular adhesion molecule-1; IL, interleukin; I/R, ischemia reperfusion; KA, kainic acid; LID, levodopa-induced

dyskinesia; methyl-D-aspartate receptor; NO, nitric oxide; PD, Parkinson’s disease; LY320135, [6-methoxy-2-(4-methoxyphenyl)benzo

[ b ]-thien-3-yl][4-cyanophenyl] methanone; MS, multiple sclerosis; SCI, spinal cord injury; EAE, experimental autoimmune

encephalomyelitis; JWH-133, 1,1-dimethylbutyl-1-deoxy-Δ 9 -tetrahydrocannabinol; PEA, palmitoylethanolamide; ACEA,

arachidonyl-2′-chloroethylamide/(all Z )- N -(2-cycloethyl)-5,8,11,14-eicosatetraenamide; JWH-015, (2-methyl-1-propyl-1 H -indol-3-

yl)-1-naphthalenylmethanone; OM-DM1, ( R )- N -oleoyl-(1′-hydroxybenzyl)-2′-ethanolamine; OMDM2, ( S )- N -oleoyl-(1′-

hydroxybenzyl)-2′-ethanolamine; SNr, substantia nigra pars reticulata; LID, levodopa-induced dyskinesia; GPe or GPi, external or

internal globus pallidus; HD, Huntington’s disease; ALS, amyotrophic lateral sclerosis; AM404, N -(4-hydroxyphenyl)-eicosa-5,8,11,14-

tetraenamide; VDM11, N -(4-hydroxy-2-methylphenyl) arachidonoyl amide; AM374, palmitylsulfonyl fluoride; TS, Gilles de la

Tourette’s syndrome; AD, Alzheimer’s disease; A β , β -amyloid; HPA, hypothalamic-pituitary-adrenal; URB597, cyclohexyl carbamic

acid 3′-carbamoyl-biphenyl-3-yl ester; 5-HT, 5-hydroxytryptamine (serotonin); VTA, ventral tegmental area; nAc, nucleus accumbens;

CPP, conditioned place preference; MDMA, 3,4-methylenedioxymethamphetamine (Ecstasy); SHR, spontaneously hypertensive rat(s);

WKY, Wistar-Kyoto; AM281, N -(morpholin-4-yl)-1-(2,4-dichlorophenyl)-5-(4-iodophenyl)-4-methyl-1 H -pyrazole-3-carboxamide;

AM630, 6-iodo-2-methyl-1-[2-(4-morpholinyl)ethyl]-1- H -indol-3-yl(4-methoxyphenyl)-methanone; IBD, inflammatory bowel disease;

PRS-211,092, [(+)-(6 aS ,10 aS )-6,6-dimethyl-3-(1,1-dimethylheptyl)-1-hydroxy-9-(1 H -imidazol-2-ylsulfanylmethyl]-6 a- ,7,10,10 a -

tetrahydro-6 H -dibenzo[ b , d ]pyran; RA, rheumatoid arthritis; HU-320, cannabidiol-dimethylheptyl-7-oic acid; HU-308, (+)-(1- aH ,3 H ,

5 aH )-4-[2,6-dimethoxy-4-(1,1-dimethylheptyl)phenyl]-6,6-dimethylbicyclo[3.1.1]hept-2-ene-2-carbinol.

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other cannabinoids, which may account for its favorable therapeutic profile. Ajulemic acid also

binds to peroxisome proliferator-activated receptor γ receptors with low (micromolar) affinity,

which was proposed to account for its effect on adipocyte differentiation (Liu et al., 2003b).

Among the 60 or so cannabinoids present in marijuana, only THC is psychoactive. However,

some of the other constituents, such as cannabidiol, have well-documented biological effects

of potential therapeutic interest, such as antianxiety, anticonvulsive, antinausea, anti-

inflammatory and antitumor properties (Mechoulam et al., 2002c; Grotenhermen, 2004;

Vaccani et al., 2005). Cannabidiol does not significantly interact with CB 1 or CB 2 receptors,

and its actions have been attributed to inhibition of anandamide degradation or its antioxidant

properties (Mechoulam and Hanus, 2002; Mechoulam et al., 2002c), or an interaction with as

yet unidentified cannabinoid receptors (see below). Another marijuana constituent of potential

therapeutic interest is tetrahydrocannabivarin (Markus, 1971), which has recently been shown

to have CB 1 antagonist properties (Thomas et al., 2005).

In addition to CB 1 and CB 2 receptors, pharmacological evidence has been accumulating over

the years to support the existence of one or more additional receptors for cannabinoids

(reviewed in Begg et al., 2005). Two of these possibilities have been more extensively explored:

an endothelial site involved in vasodilation and endothelial cell migration (Járai et al., 1999;

Begg et al., 2003; Mo et al., 2004), and a presynaptic site on glutamatergic terminals in the

hippocampus mediating inhibition of glutamate release (Hájos et al., 2001). Responses elicited

at both of these sites were reported to survive genetic ablation of CB 1 receptors, yet be sensitive

to inhibition by the CB 1 antagonist SR141716 or by pertussis toxin but not by the CB 1

antagonist AM251 (Járai et al., 1999; Hájos and Freund, 2002; Ho and Hiley, 2003; Offertáler

et al., 2003; O’Sullivan et al., 2004a,b). However, the two sites are apparently different. The

aminoalkylindol WIN 55,212-2 was found to be an agonist and capsazepine an antagonist at

the hippocampal (Hájos and Freund, 2002) but not at the endothelial receptor (Wagner et al.,

1999; Mukhopadhyay et al., 2002). On the other hand, certain atypical cannabinoids with no

affinity for CB 1 or CB 2 receptors behave as agonists (abnormal cannabidiol, O-1602) or

antagonists at the endothelial receptor (cannabidiol, O-1918) but not at the hippocampal

receptor (Begg et al., 2005). Arachidonoyl-L-serine, an endogenous lipid discovered in rat

brain, has been found to be a vasodilator acting at the endothelial cannabinoid receptor (Milman

et al., 2006), although its activity at the hippocampal receptor has not yet been evaluated. The

existence of this latter receptor has recently been called into question, as the ability of WIN

55,212-2 to suppress the same excitatory synapse as studied by Hájos et al. (2001) was found

to be absent in two different strains of CB 1 knockout mice, yet present in their respective wild-

type controls (Takahashi and Castillo, 2006). Atypical cannabinoid receptors with

pharmacological properties similar to those of the endothelial receptor have been postulated

to exist on microglia, where they mediate microglial migration (Walter et al., 2003), and on

neurons of the mouse vas deferens (Pertwee et al., 2002, 2005c). Activation of this latter

receptor by the CBD analog 7-OH-dimethylheptyl CBD, which is inactive at CB 1 , CB 2 , or

transient receptor potential vanilloid type 1 (TRPV 1 ) receptors, inhibits electrically evoked

contractions of the vas deferens, and the effect is selectively inhibited by CBD itself. A brain

cannabinoid receptor distinct from CB 1 was also indicated by the ability of anandamide and

WIN 55,212-2, but not other agonists, to stimulate GTP γ S binding in brain plasma membranes

from CB 1 knockout mice (Breivogel et al., 2001).

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Of interest are recent findings reported in the patent literature that the orphan receptor GPR-55

(Sawzdargo et al., 1999) recognizes a variety of cannabinoid ligands, but not WIN 55,212-2

(Brown and Wise, 2003; Drmota et al., 2004). However, GPR-55 is apparently not expressed

in the vascular endothelium and is sensitive to HU-210 (Drmota et al., 2004), a potent synthetic

cannabinoid devoid of vasorelaxant properties (Wagner et al., 1999). Furthermore, it couples

to G 12 /G 13 and ρ kinase, which have been linked to vasoconstrictor rather than vasodilator

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responses. This suggests that GPR-55 is not the abnormal cannabidiol-sensitive endothelial

receptor. Mice deficient in GPR-55 will help in defining the biological functions of this novel

cannabinoid-sensitive receptor.

Anandamide has been found to be an agonist ligand for the TRPV 1 ion channel, although its

affinity in the low micromolar range is lower than its affinity for CB 1 receptors (reviewed by

van der Stelt and Di Marzo, 2004). An in vitro study in rat mesenteric arteries provided evidence

that the endothelium-independent component of anandamide-induced vasodilation is mediated

via activation of capsaicin-sensitive TRPV 1 in sensory nerve terminals. This triggers the release

of CGRP, which then dilates the artery by activation of calcitonin gene-related peptide

receptors on the vascular smooth muscle (Zygmunt et al., 1999). However, this mechanism

does not contribute to the in vivo hypotensive action of anandamide, which is similar in wild-

type and TRPV 1 −/− mice (Pacher et al., 2004).

Both CB 1 and CB 2 receptors are G protein-coupled receptors. Surprisingly, they share little

sequence homology, only 44% at the protein level or 68% in the transmembrane domains,

which are thought to contain the binding sites for cannabinoids (Lutz, 2002). Despite this, THC

and most synthetic cannabinoids have similar affinities for the two receptors, and only recently

did synthetic ligands that discriminate between CB 1 and CB 2 receptors emerge. These include

agonists as well as antagonists, as listed in Fig. 2. The development of potent and highly

selective CB 1 and CB 2 receptor antagonists (Rinaldi-Carmona et al., 1994, 1998) is particularly

noteworthy as it provided critically important tools to explore the physiological functions of

endocannabinoids. For example, as it will be discussed later in this review, the appetite-

reducing effects of the CB 1 antagonist SR141716 in various rodent models was the first sign

to suggest that endocannabinoids may be tonically active orexigenic agents, representing the

endogenous counterpart of the “munchies” caused by marijuana smoking.

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However, these antagonists, as well as most of the other CB 1 and CB 2 antagonists developed

to date, have inverse agonist properties (Bouaboula et al., 1997, 1999), so their effects do not

necessarily reflect reversal of the tonic action of an endocannabinoid. For this reason, the

development of CB 1 and CB 2 receptor-deficient mouse strains (Ledent et al., 1999; Zimmer

et al., 1999; Buckley et al., 2000; Marsicano et al., 2002b; Robbe et al., 2002) was similarly

important, as the use of these animals in combination with receptor antagonists can reinforce

the putative regulatory roles of endocannabinoids. More recently, the development of

conditional mutant mice that lack the expression of CB 1 receptors only in certain types of

neurons represents another milestone, as it allows linking of specific neuronal populations with

a well-defined cannabinoid-modulated behavior (Marsicano et al., 2003).

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B. Cannabinoid Receptor Signaling

CB 1 and CB 2 receptors couple primarily to the G i/o subtypes of G protein, and their signaling

is remarkably complex. Although coupling to adenylate cyclase through G i/o usually results in

inhibition of cyclase activity through the release of G i α isoforms, cannabinoids can also

stimulate isoforms 2, 4, or 7 of adenylate cyclase via the release of βγ subunits (Rhee et al.,

1998). Activation of adenylate cyclase also occurs when CB 1 and dopamine D 2 receptors are

simultaneously activated (Glass and Felder, 1997), probably as a result of heterodimerization

of these two types of receptors (Kearn et al., 2005). Although direct evidence for the coupling

of CB 1 receptors to G q/11 had until recently been lacking (Howlett, 2004), the agonist WIN

55,212-2, but not other cannabinoids, was recently reported to increase intracellular calcium

in cultured hippocampal neurons and in human embryonic kidney 293 cells via coupling to

G q/11 proteins (Lauckner et al., 2005). Receptor dimerization may facilitate such coupling,

which may account for CB 1 -mediated mobilization of intracellular calcium in NG108-15

neuroblastoma glioma cells (Sugiura et al., 1999). Cannabinoids can also inhibit different types

of calcium channels (Mackie and Hille, 1992; Gebremedhin et al., 1999) and activate certain

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