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This article was downloaded by: [University Of South Australia Library]On: 11 August 2014, At: 11:25Publisher: Taylor & FrancisInforma Ltd Registered in England and Wales Registered Number: 1072954Registered office: Mortimer House, 37-41 Mortimer Street, London W1T 3JH,UK
Journal of Industrial HempPublication details, including instructions forauthors and subscription information:http://www.tandfonline.com/loi/wjih20
The Cannabinoid System-ABrief ReviewFranjo Grotenhermen aa nova-Institut , Goldenbergstrasse 2, Hürth,D-50354, GermanyPublished online: 25 Sep 2008.
To cite this article: Franjo Grotenhermen (2004) The Cannabinoid System-A BriefReview, Journal of Industrial Hemp, 9:2, 87-92, DOI: 10.1300/J237v09n02_09
To link to this article: http://dx.doi.org/10.1300/J237v09n02_09
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OTHER CONTRIBUTIONS
The Cannabinoid System–A Brief Review
Franjo Grotenhermen
ABSTRACT. ∆9-THC, the main psychoactive cannabinoid from theCannabis plant, binds to specific binding sites in humans, which are sit-uated in membranes of nerve and several other cells in both the centralnervous system and peripheral organs. Evidence for the existence of thespecific action of cannabinoids was presented in the late 1980s. Depend-ing on the kind of cells, on dose, and on the state of the body, activationof cannabinoid receptors (CB) may cause a multitude of effects includ-ing euphoria, anxiety, dry mouth, muscle relaxation, hunger and pain re-duction. In 1992 the first endogenous substance that binds to CB receptors,which causes similar effects as THC was detected. Five of these endo-cannabinoids and two subtypes of cannabinoid receptors are known sofar, constituting the endogenous cannabinoid system in humans andother animals. Several approaches are under investigation to influencethe cannabinoid system with therapeutic intent, including agonistic andantagonistic actions at CB receptors and modulation of endocanna-binoid concentrations. [Article copies available for a fee from The HaworthDocument Delivery Service: 1-800-HAWORTH. E-mail address: <[email protected]> Website: <http://www.HaworthPress.com> 2004 by TheHaworth Press, Inc. All rights reserved.]
Franjo Grotenhermen is affiliated with the nova-Institut, Goldenbergstrasse 2,D-50354 Hürth, Germany (E-mail: [email protected]).
Journal of Industrial Hemp, Vol. 9(2) 2004http://www.haworthpress.com/web/JIH
2004 by The Haworth Press, Inc. All rights reserved.Digital Object Identifier: 10.1300/J237v09n02_09 87
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KEYWORDS. Cannabis, THC, cannabinoids, anandamide, cannabinoidreceptors, endocannabinoids, therapeutic action
The mechanism of action for cannabinoids is currently investigatedfor ∆9-THC (THC) and other cannabinoids that bind to the cannabinoidreceptor. However, the mode of action of other cannabinoids of thera-peutic interest, such as CBD, the carboxy metabolite of THC (11-nor-9-carboxy-∆9-THC) and analogues are less well established.
The majority of THC effects are mediated through agonistic actionsat cannabinoid receptors. Agonistic action means that receptors are acti-vated in contrast to antagonistic action, where there is a blockade of re-ceptor effects.
Some non-cannabinoid receptors mediated the effects of THC, andsynthetic derivatives have also been described: e.g., effecting on the im-mune system, neuroprotective effects, and anti-emesis. It is also possi-ble that several effects previously thought to be non-receptor mediatedare mediated by cannabinoid receptor subtypes that have not yet beenidentified.
CANNABINOID RECEPTORS
To date two cannabinoid receptors have been identified, the CB1, andthe CB2 receptors. They differ in signaling mechanisms, tissue distribu-tion, and sensitivity to certain agonists and antagonists that show markedselectivity for one or the other receptor type. Activation of cannabinoidreceptors causes inhibition of adenylatcyclase, thus, inhibiting the con-version of ATP to cyclic AMP (cAMP). Other effects have also beenobserved: e.g., interaction with certain ion channels.
CB1 receptors are mainly found on nerve cells in the brain, spinalcord and in the peripheral nervous system, but are also present in certainperipheral organs and tissues, among them endocrine glands, leuko-cytes, spleen, heart and parts of the reproductive, urinary and gastroin-testinal tracts. One of its functions is inhibition of neurotransmitterrelease (Table 1). CB1 receptors are highly expressed in the basal gan-glia, cerebellum, hippocampus and dorsal primary afferent spinal cordregions, which reflect the importance of the cannabinoid system in mo-tor control, memory processing and pain modulation, while their ex-
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pression in the brainstem is low, which may account for the lack ofcannabis-related acute fatalities: e.g., due to depression of respiration.
CB2 receptors occur principally in immune cells, among them leuko-cytes, spleen and tonsils. Immune cells also express CB1 receptors butthere are markedly more CB2 than CB1 receptors in the immune system.One of the functions of CB receptors in the immune system is modulat-ing the release of cytokines, which are responsible for inflammation andregulation of the immune system. Activation of the CB1 receptor pro-duces cannabis-like effects on the psyche and circulation, while activa-tion of the CB2 receptor does not. Hence, selective CB2 receptor agonistshave become an investigated target for the therapeutic uses of canna-binoids, among them analgesic, anti-inflammatory and anti-cancer ac-tions.
There is increasing evidence for the existence of additional canna-binoid receptor subtypes in the brain and periphery. These receptors aremore likely to be functionally related to the known cannabinoid recep-
Franjo Grotenhermen 89
TABLE 1. Neurotransmitter functions under cannabinoid control
Neurotransmitter Associated disorder
Excitatory amino acids
Glutamate Epilepsy, nerve-cell death in ischemia and hypoxia(stroke, head trauma, nerve gas toxicity)
Inhibitory amino acids
GABA Spinal cord motor disorders, epilepsy, anxiety
Glycine Startle syndromes
Monoamines
Noradrenaline Autonomic homoeostasis, hormones, depression
Serotonin Depression, anxiety, migraine, vomiting
Dopamine Parkinson’s disease, schizophrenia, vomiting, pituitaryhormones, drug addiction
Acetylcholine Neuromuscular disorders, autonomic homeostasis(heart rate, blood pressure), dementia, parkinsonism,epilepsy, sleep-wake cycle
Neuropeptides Pain, movement, neural development, anxiety
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tors, rather than having a similar structure as CB1 and CB2, as there iscurrently no evidence for additional cannabinoid receptors in the humangenome.
ENDOCANNABINOIDS
The identification of cannabinoid receptors was followed by the de-tection of endogenous ligands for these receptors, called endocanna-binoids, a family of fatty acid derivates. To date five endocannabinoidshave been identified. These are N-arachidonylethanolamide (ananda-mide, AEA), 2-arachidonylglycerol (2-AG), 2-arachidonylglyceryl ether(noladin ether), O-arachidonyl-ethanolamine (virodhamine), and N-ara-chidonyl-dopamine (NADA).
Together, cannabinoid receptors and their endogenous ligands con-stitute the cannabinoid system which is teleologically millions of yearsold and has been found in other mammals and many other animal spe-cies. Endocannabinoids serve as neurotransmitters or neuromodulators.
Anandamide and NADA do not only bind to cannabinoid receptorsbut also stimulate vanilloid receptors (VR1), non-selective ion channelsassociated with hyperalgesia, i.e., increased pain sensitivity. Thus, thehistorical designation of anandamide as an “endocannabinoid” seems tobe only one part of the physiological reality, and cannabinoid receptorsseem to account for only some of the “anandamide receptors.”
The first two discovered endocannabinoids, anandamide and 2-AG,are best studied. They are produced “on demand” by cleavage of mem-brane lipid precursors and released from cells in a stimulus-dependentmanner. Endocannabinoids are produced by tissues that express canna-binoid receptors. After release, they are rapidly deactivated by uptakeinto cells and metabolized. Metabolism of anandamide and 2-AG oc-curs by enzymatic hydrolysis through fatty acid amide hydrolase (FAAH)and other metabolic processes.
AFFINITY TO THE CANNABINOID RECEPTOR
Cannabinoids show different affinities for CB1 and CB2 receptors.Synthetic cannabinoids have been developed that act as highly selectiveagonists or antagonists at each of these receptor subtypes. ∆9-THC hasapproximately equal affinity for the CB1 and CB2 receptors, while
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anandamide has only marginal selectivity for CB1 receptors. However,the efficacy of THC and anandamide is less at CB2 than at CB1 recep-tors.
TONIC ACTIVITY OF THE ENDOCANNABINOID SYSTEM
When administered by themselves, antagonists of the cannabinoidreceptor may behave as an inverse agonist in several bioassay systems.This means that they not only block the effects of endocannabinoids butproduce effects that are opposite in direction from those produced bycannabinoid receptor agonists: e.g., causing hyperalgesia, suggestingthat the cannabinoid system is tonically active. This tonic activity maybe due to a constant release of endocannabinoids or result from a portionof cannabinoid receptors that exist in a constitutively active state.
Tonic activity of the cannabinoid system has been demonstrated inseveral conditions. Endocannabinoid levels have been demonstrated tobe increased in a pain circuit of the brain (periaqueductal gray matter)following painful stimuli. Tonic control of spasticity by the endo-cannabinoid system has been observed in chronic relapsing experimen-tal autoimmune encephalomyelitis (CREAE) in mice, an animal modelof multiple sclerosis. An increase of cannabinoid receptors followingnerve damage was demonstrated in a rat model of chronic neuropathicpain and in a mouse model of intestinal inflammation. This increase inreceptor density may increase the potency of cannabinoid agonists usedfor the treatment of these conditions. Tonic activity has also been dem-onstrated with regard to appetite control and with regard to vomiting inemetic circuits of the brain.
THERAPEUTIC PROSPECTS
Mechanisms of action of cannabinoids are complex, not only involv-ing activation of and interaction at the cannabinoid receptor, but also acti-vation of vanilloid receptors, influence of endocannabinoid concentration,antioxidant activity, metabolic interaction with other compounds, andseveral other potential therapeutic effects. CB receptor antagonists(blockers) are currently under investigation for the treatment of obesityand nicotine dependence.
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Aside from phytocannabinoids and cannabis preparations, cannabin-oid analogues that do not bind to the CB1 receptor are attractive com-pounds for clinical research, among them dexanabinol and CT-3.Additional ideas for the separation of the desired therapeutic effectsfrom the psychotropic action comprise the concurrent administration ofTHC and CBD, the design of CB1 receptor agonists that do not cross theblood brain barrier, and the development of compounds that influenceendocannabinoid levels by inhibition of their membrane transport sys-tems (transport inhibitors) or enzymatic hydrolysis (FAAH inhibitors).For example, blockers of anandamide hydrolysis were able to reduceanxiety in animal tests. It is remarkable that FAAH inhibitors may al-ready be in clinical use. The non-steroidal anti-inflammatory agentfluriprofen inhibits the metabolism of FAAH and intrathecally adminis-trated fluriprofen reduced inflammatory pain by a mechanism that wasblocked by a CB1 receptor antagonist.
REFERENCES
Grotenhermen F. Clinical pharmacodynamics of cannabinoids. J Cannabis Ther 2004;4(1):29-78.
Grotenhermen F. Pharmacokinetics and pharmacodynamics of cannabinoids. ClinPharmacokin 2003;42(4):327-360.
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