Behavioral Neurobiology of the Endocannabinoid System: 1 (Current Topics in Behavioral Neurosciences)

A decrease of anandamide was found along the axis that contributed to basal hypersecretion of corticosterone ; in contrast, an increase of 2-AG was found in the amygdala after repeated stress, which was negatively correlated to magnitude of the corticosterone response. All effects were abolished by the CB 1 antagonist AM , supporting the conclusion that these effects were cannabinoid-receptor dependent.

Results suggest that glutamatergic cannabinoid receptors are not only responsible for mediating aggression, but produce an anxiolytic-like function by inhibiting excessive arousal: In contrast, GABAergic neurons appear to control an anxiogenic-like function by limiting inhibitory transmitter release. Taken together, these two sets of neurons appear to help regulate the organism's overall sense of arousal during novel situations.

Evidence suggests that endocannabinoids may function as both neuromodulators and immunomodulators in the immune system. Here, they seem to serve an autoprotective role to ameliorate muscle spasms, inflammation, and other symptoms of multiple sclerosis and skeletal muscle spasms.

These receptors have also been implicated in the proper migration of B cells into the marginal zone MZ and the regulation of healthy IgM levels. Historical records from ancient China and Greece suggest that preparations of Cannabis indica were commonly prescribed to ameliorate multiple sclerosis-like symptoms such as tremors and muscle pain.

Modern research has confirmed these effects in a study on diseased mice, wherein both endogenous and exogenous agonists showed ameliorating effects on tremor and spasticity. It remains to be seen whether pharmaceutical preparations such as dronabinol have the same effects in humans. Taken together, these studies point to the exciting possibility that cannabinoid treatment may not only be able to attenuate the symptoms of multiple sclerosis but also improve oligodendrocyte function reviewed in Pertwee, ; Mollna-Holgado et al. The developing embryo expresses cannabinoid receptors early in development that are responsive to anandamide secreted in the uterus.

This signaling is important in regulating the timing of embryonic implantation and uterine receptivity. In mice, it has been shown that anandamide modulates the probability of implantation to the uterine wall. For example, in humans, the likelihood of miscarriage increases if uterine anandamide levels are too high or low.

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Peripheral expression of cannabinoid receptors led researchers to investigate the role of cannabinoids in the autonomic nervous system. Research found that the CB 1 receptor is expressed presynaptically by motor neurons that innervate visceral organs.

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Cannabinoid-mediated inhibition of electric potentials results in a reduction in noradrenaline release from sympathetic nervous system nerves. Other studies have found similar effects in endocannabinoid regulation of intestinal motility, including the innervation of smooth muscles associated with the digestive, urinary, and reproductive systems. At the spinal cord, cannabinoids suppress noxious-stimulus-evoked responses of neurons in the dorsal horn, possibly by modulating descending noradrenaline input from the brainstem.

The endocannabinoid most researched in pain is palmitoylethanolamide. Palmitoylethanolamide is a fatty amine related to anandamide, but saturated and although initially it was thought that palmitoylethanolamide would bind to the CB1 and the CB2 receptor, later it was found that the most important receptors are the PPAR-alpha receptor , the TRPV receptor and the GPR55 receptor.

Palmitoylethanolamide has been evaluated for its analgesic actions in a great variety of pain indications [63] and found to be safe and effective. Basically these data are proof of concept for endocannabinoids and related fatty amines to be therapeutically useful analgesics; palmitoylethanolamide is available under the brand names Normast and PeaPure as nutraceuticals. Endocannabinoids are involved in placebo induced analgesia responses. Increased endocannabinoid signaling within the central nervous system promotes sleep-inducing effects.

Intercerebroventricular administration of anandamide in rats has been shown to decrease wakefulness and increase slow-wave sleep and REM sleep. Anandamide is an endogenous cannabinoid neurotransmitter that binds to cannabinoid receptors. In mice it was demonstrated that certain features of a runner's high depend on cannabinoid receptors. Pharmacological or genetic disruption of cannabinoid signaling via cannabinoid receptors prevents the analgesic and anxiety-reducing effects of running. Neuroscientists often utilize transgenic CB 1 knockout mice to discern novel roles for the endocannabinoid system.

While CB 1 knockout mice are healthy and live into adulthood, there are significant differences between CB 1 knockout and wild-type mice.

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When subjected to a high-fat diet, CB 1 knockout mice tend to be about sixty percent leaner and slightly less hungry than wildtype. The endocannabinoid system is by molecular phylogenetic distribution of apparently ancient lipids in the plant kingdom, indicative of biosynthetic plasticity and potential physiological roles of endocannabinoid-like lipids in plants, [77] and detection of arachidonic acid AA indicates chemotaxonomic connections between monophyletic groups with common ancestor dates to around million years ago silurian ; devonian.

From Wikipedia, the free encyclopedia. This article needs more medical references for verification or relies too heavily on primary sources. Please review the contents of the article and add the appropriate references if you can. Unsourced or poorly sourced material may be challenged and removed. Further information on receptor localization: This section provides insufficient context for those unfamiliar with the subject.

Please help improve the article with a good introductory style. January Learn how and when to remove this template message. The Journal of Sexual Medicine. European Journal of Pharmacology. The traditional view that PA engages the monoaminergic and endorphinergic systems has been challenged by the discovery of the endocannabinoid system ECS , composed of endogenous lipids, their target receptors, and metabolic enzymes.

Indeed, direct and indirect evidence suggests that the ECS might mediate some of the PA-triggered effects throughout the body. To our knowledge, the first experimental study aimed at investigating the influence of PA on ECS in humans was carried out in by Sparling and coworkers [63], who showed increased plasma AEA content after 45 min of moderate intensity exercise on a treadmill or cycle ergometer. Since then, other human studies have shown increased blood concentrations of AEA A dependence of the increase of AEA concentration on exercise intensity has also been documented.

Some Spice users have reported effects similar to or even stronger than those obtained by smoking cannabis, such as physical relaxation, changes in perception, and mild euphoria. The higher potency of action of these synthetic cannabinoids might be explained by in vitro experiments that have suggested that, while THC acts as a partial agonist on the CB1 receptor, JWH acts as a full and potent agonist Atwood et al. With respect to other products containing non-controlled plants and fungi and marketed as legal highs e.

Regrettably, safety information provided is sparse and of uncertain utility, with only a few products warnings about potential adverse effects or drug interactions. Spices are often referred to as legal highs, in that they are neither controlled by the Misuse of Drugs Act, nor licensed for legal use such as alcohol and nicotine. Both the use and possession of these drugs have been long officially authorized, and their supply tolerated as long as they are sold for purposes other than human consumption.

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The relatively recent identification of the first synthetic cannabinoids as not declared ingredients of Spice marked a significant turning point in this situation. Indeed, although structurally distinct from THC, synthetic cannabinoids are part of the well-characterized aminoalkylindole class of ligands that also bind and activate CB1 receptors.

Although their government regulation is still inconsistent or even lacking in many countries, Spice products are currently controlled in 14 European nations Austria, Denmark, Estonia, France, Germany, Ireland, Italy, Latvia, Lithuania, Luxembourg, Poland, Romania, Sweden, and UK , where they are classified as pharmaceuticals or narcotics.

Yet, they are still legal and uncontrolled in the remaining parts of Europe and many other countries, leading to heavy global marketing. In the USA, some states Alabama, Arkansas, Georgia, Kansas, Kentucky, and Missouri have taken legislative action against the distribution and use of Spice, and until recently, only one synthetic cannabinoid, namely HU, was considered a Schedule I substance unsafe, highly abused, no medical usage. On November 24, , the United States Drug Enforcement Administration temporarily added to the list the following synthetic cannabinoids: However, regulatory mechanisms are weak and difficult to enforce when controlled products are available on the Internet, because online retailers can evade easily national jurisdiction and supply Spice products to other countries but not their own.

In addition, experience has shown that, as legal authorities adopt control measures, other synthetic cannabinoids are soon added to existing Spice-like products, suggesting that the producers expect prohibition and are ready to synthesize an assortment of substitutes Lindigkeit et al. It looks like the producers are moving onto the next product, always one step ahead of the law Dargan et al.

This is not totally unexpected because there is a high demand for legal highs United Nations Office on Drugs and Crime, ; Zawilska, , implying that it will be satisfied by products containing chemical ingredients that are not yet prohibited. Lack of consistency in the measures adopted to control the market, ranging from medical legislation to formal drug control instruments, is another major point of concern in monitoring and responding to worldwide circulation of Spice ACMD, ; McLachlan, Marketed under the generic brand name of Spice, an increasing number of herbal mixtures are sold mainly on the Internet, and in some countries, in dedicated shops that offer legal alternatives to prohibited drugs.

As reported in a warning editorial by Griffiths et al. Because of their packaging resembling incense or tea and their scented smell, Spice products are far less noticeable as drugs, are not easily identified by parents or carers, and can comfortably be consumed at home. Lack of safety information could lead to the incorrect supposition that herbal mixtures are safe, especially amongst first-time users.

These herbal blends typically have a pleasurable smell and taste i.

Spice circumvents these limits by appearing as a safer alternative to cannabis. People that have been warned against using cannabis for legislative i. However, all Spice products introduced into the market lack any published in vivo testing, even in animal models, and very little information is available in international medical databases. Most of the synthetic cannabinoids added as not-listed ingredients to Spice products are very difficult to detect by commonly used drug screening procedures.

Apart from the analogs of THC such as HU, the structure of these new synthetic cannabinoids differs from that of THC, so that they probably will not trigger a positive test for cannabinoids in immunoassays of body fluids. This has important consequences, because it encourages not only cannabis users but also curious people with no previous experience of illicit drugs to use these products to attain cannabis-like effects, without having to fear prosecution. Furthermore, wherever drug screening is routinely performed to guarantee abstinence from drugs i.

Maximal research effort is currently focusing on the development of new analytical procedure for measuring urinary concentrations of synthetic cannabinoids and several potential metabolites of each Beuck et al. It is not easy to determine exactly what is in Spice products, due to the lack of reference samples and the presence of masking agents of natural origin such as tocopherol vitamin E , eugenol, or fatty acids Dresen et al. Spice is supposed to contain up to 15 different vegetal compounds, which gives rise to a wide variety of drug combinations Zuba et al.

Potentially psychoactive alkaloids, such as betonicine, aporphine, leonurine nuciferine, or nicotine, are often declared as ingredients in these products; yet, only some herbal mixtures have the constituents stated, and most samples of Spice contain inert vegetable matter. The synthetic psychoactive compounds added to Spice were initially almost unknown substances, which forensic laboratories had difficulties in recognizing and finding reference samples.

The active compounds present in Spice products are placed principally at the surface of the herbal ingredients, and the extraction procedure is able to remove them without significant contamination by the vegetable components of the herb. Unfortunately, trafficking and detection of these drugs is hampered by the fact that the exact content of many Spice products still remains unpredictable, because it changes constantly over time as a reaction to prevention and legal actions, leading to an ever-expanding array of synthetic cannabinoids being available on the market.

It is clear that comprehension of the clinical pharmacology of these compounds is essential for practitioners and scientists to discriminate the relative toxicity associated with the different synthetic cannabinoid mixtures and routes of administration. The major psychoactive ingredients of Spice products are illustrated in Figure 2.

Structures of most common psychoactive ingredients of Spice products: Unlike cannabis, Spice products do not contain the phytocannabinoids cannabidiol rarely THC but synthetic cannabinoid drugs, which originate from four chemically distinct groups: Huffman JWH in the s, of which JWH is the most studied and best characterized to date; ii the CP-compounds, a cyclohexylphenol series synthesized by Pfizer in the s, with the identified CP, and its modified version CP,C8 obtained by extending the dimethylheptyl side chain to dimethyloctyl ; iii the HU-compounds, synthesized in the s at the Hebrew University; and iv the benzoylindoles, such as AM and RCS-4 Huffman et al.

Behavioral Neurobiology of the Endocannabinoid System : Dave Kendall :

Contrary to nabilone, a synthetic analog of tetrahydrocannabinol approved by the US Food and Drug Administration FDA to treat chemotherapy-induced nausea and vomiting, no therapeutic effects have been documented so far for synthetic cannabinoids detected in these herbal mixtures. JWH naphthalenyl- 1-pentylindolyl methanone was first synthesized during an analysis aiming at developing new cannabimimetic indole compounds with potential therapeutic effects comparable with those of THC Chin et al.

Specifically, JWH dose-dependently inhibits glutamate release in autaptic excitatory hippocampal neurons, probably acting on the CB1 receptor, an effect reversed by administration of the CB1 receptor antagonist rimonabant Atwood et al. In vivo studies showing that JWH induces analgesia, catalepsy, hypomotility, and hypothermia, namely the tetrad of behaviors classically caused by cannabinoids administration Wiley et al. It is worth nothing that unlike metabolites of most synthetic cannabinoids, JWH hydroxylated metabolites retain in vitro and in vivo activity at CB1 receptors Brents et al.

The latter has been recently shown to act similarly to JWH, although it is less potent in inhibiting neurotransmission and slower in producing internalization of cannabinoid receptors Atwood et al. The CP, cannabinoid compound 2- 1R,3S hydroxycyclohexyl] 2-methyloctanyl phenol lacks the classical cannabinoid chemical structure tricyclic benzopyran system and is 3—28 times more potent than THC Weissman et al. The concentration—response curve of CP,C8 in inhibiting neurotransmission in autaptic hippocampal neuron cultures is nearly identical to that described for JWH Atwood et al.

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The classical cannabinoid HU [ 6aR,10aR hydroxymethyl -6,6-dimethyl 2-methyloctanyl -6a,7,10,10a-tetra-hydrobenzo[c] chromenol ], whose agonistic activity on the CB1 receptor has been long recognized, is an ingredient of herbal mixtures in the UK and USA European Monitoring Centre for Drugs and Drug Addiction EMCDDA, , where it has been placed under control since and , respectively. This synthetic analog of THC was shown to be a full non-selective agonist at the CB1 and CB2 receptors, and to possess intrinsic affinities for cannabinoid receptors that exceed those of the high-efficacy agonists, CP 55, and WIN 55, Howlett et al.

Notably, the pharmacological effects of HU in vivo are also exceptionally long lasting, and in animal models it has been shown to negatively affect learning Ferrari et al. Among the benzoylindoles, AM [ 1- 5-fluoropentyl 2-iodobenzoyl indole ] binds strongly to CB1 and CB2 receptors, and now represents an example of the latest synthetic cannabinoid agonists added to Spice that is currently available on the UK market, but still not controlled by current UK legislation Dargan et al.

On March 11, , it was banned as euphoriant substance by the Danish Ministry of Health It seems reasonable to hypothesize that additional compounds beside the above-mentioned might also contribute to the behavioral and subjective effects produced by smoking Spice, and that their different pharmacology might explain the different psychoactive effects experienced after smoking Spice.

Although the marijuana-like effects of smoked Spice products are probably due to activation of CB1 receptor, the potential role of CB2 receptors in such effects is still to be investigated. Currently, more than compounds with cannabimimetic activities are waiting for identification.

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Besides cannabinoids, other psychoactive substances can be part of Spice products, such as the synthetic opioid O -desmethyltramadol Dresen et al. This opioid is an active metabolite of the opioid tramadol, a centrally acting analgesic drug with suspected abuse liability Raffa, Indeed, in less than 1 year, consumption of Krypton had fatal results and caused the unintentional deaths of nine persons Kronstrand et al.

Oleamide cis-9,octadecenoamide , a fatty acid derivative with cannabinoid-like activity Leggett et al. Harmine and harmaline, two reversible inhibitors of the monoamine oxidase enzyme with stimulating central effects Fortunato et al. Benzophenone HM 40 is another undeclared substance found in an herbal mixture, although most likely it was not added purposely but rather should be considered a contamination from synthesis Dresen et al.

Many other ingredients are listed on the Spice packets, with their combinations greatly varying in number and concentration, often depending on the country of distribution. Notably, this product caused acute intoxication in two young girls, probably due to the co-presence of THC, JWH, and JWH identified among 15 other synthetic cannabinoids, whereas none of the listed ingredients were detectable Schneir et al. Conversely, some packets of Spice sold in the UK declare beach bean Canavalia maritima or Canavalia rosea , blue lotus Nelumbo nucifera , and dwarf skullcap Scutellaria nana as ingredients of the mixture, for which no safety data are available Burley, Other plants commonly used in Spice products in combination with synthetic cannabinoids included Marshmallow Althaea officinalis and Dog Rose or Rosehip Rosa canina ; Seely et al.

Not surprisingly, no natural cannabinoids were declared as constituents. Worryingly, very little is known about its pharmacology and toxicology in humans, and virtually nothing has been investigated thus far about the health implications of its use, either in humans or animals, which hampers appropriate medical treatment of Spice-induced side effects. The carcinogenic potential caused by inhaling smoke containing these substances has also not been evaluated EMCDDA, Only limited data on the pharmacological properties of CP, in animal models and on the metabolism of JWH in rat liver microsomes are available Compton et al.

It is noteworthy that CP, generalized with THC in drug discrimination studies in rats, that is, it produces subjective effects similar to those of THC, with an absolute threshold dose 3—14 times lower than that of THC Weissman et al. Very recently, JWH and CP, were found to significantly decrease the locomotor activity and increase the electroencephalogram power spectra in rats Uchiyama et al.

In general, the desired effects of Spice include a sense of empathy and well-being. On the Internet, it is possible to find a quantity of self-reports of users experiencing anxiety and psychotic symptoms after using synthetic cannabinoids 2. Finally, in the literature, there is one published case report of tolerance and withdrawal phenomena Zimmermann et al.

Spice blends are often described as energizing, euphoric, and disinhibiting Schifano et al. However, halting speech and avoidant eye contact were observed in a young student who smoked Spice for 3 weeks Benford and Caplan, Moreover, after chronic 8 months daily use, Spice can induce serious cognitive impairment Zimmermann et al. Loss of consciousness and confusion have also been described, as well as unresponsiveness, seizures, agitation, and irritation Seely et al.

Anxiety is one of the main side effects experienced during acute intoxication, which resolves within 1—2 h after consumption Schneir et al. A sense of extreme anxiety and sudden depression has been reported during withdrawal from chronic Spice use Zimmermann et al.

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