Tag Archives: 2-AG

Antidepressant-like effects of cannabidiol in mice: possible involvement of 5-HT1A receptors

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 “Extracts of the Cannabis sativa plant elicit in humans a complex subjective experience that includes euphoria, heightened sensitivity to external stimuli and relaxation. This plant contains more than 400 different compounds, of which 66 are termed cannabinoids. Δ9-tetrahydrocannabinol (Δ9-THC), one of the major constituents of C. sativa extracts is thought to account for most of the effects of cannabis through the activation of cannabinoid CB1 receptors in the brain….The major endogenous agonists of the CB1 receptor are anandamide and 2-arachidonoyl glycerol, referred to as endocannabinoids…”

“It has recently been suggested that the endocannabinoid system may be involved in the pathophysiology of depression. This is supported by several pieces of evidence showing that endocannabinoids and CB1 receptors are widely distributed in brain areas that are often related to affective disorders and that their expression is regulated by antidepressant drugs. Moreover, administration of inhibitors of anandamide uptake or metabolism, as well as CB1 receptor agonists induces antidepressant-like effects in different animal models. In accordance with these preclinical results, many patients report benefits from cannabis use in depressive syndromes…”

“Cannabidiol (CBD) is a non-psychotomimetic compound from Cannabis sativa that induces anxiolytic- and antipsychotic-like effects in animal models. Effects of CBD may be mediated by the activation of 5-HT1A receptors. As 5-HT1A receptor activation may induce antidepressant-like effects, the aim of this work was to test the hypothesis that CBD would have antidepressant-like activity in mice as assessed by the forced swimming test. We also investigated if these responses depended on the activation of 5-HT1A receptors and on hippocampal expression of brain-derived neurotrophic factor (BDNF).”

“Conclusion and implications:

CBD induces antidepressant-like effects comparable to those of imipramine. These effects of CBD were probably mediated by activation of 5-HT1A receptors.”

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2823358/

Increasing 2-arachidonoyl glycerol signaling in the periphery attenuates mechanical hyperalgesia in a model of bone cancer pain

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“Metastatic and primary bone cancers are usually accompanied by severe pain that is difficult to manage. In light of the adverse side effects of opioids, manipulation of the endocannabinoid system may provide an effective alternative for the treatment of cancer pain…

These data extend our previous findings with anandamide in the same model and suggest that the peripheral endocannabinoid system is a promising target for the management of cancer pain.

Taken together, the data demonstrate that peripheral 2-AG signaling may be a significant target to exploit for the management of cancer pain. In contrast to AEA, which inhibits nociception through CB1 receptors… Dual pharmacological modulation of peripheral AEA and 2-AG signaling that directly and indirectly affects DRG neurons may be a novel approach to reducing cancer pain without the side effects…”

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3104059/

 

Marijuana-like brain chemicals could be key to treating fragile X syndrome.

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“In an international collaboration of research centers from America and Europe, scientists have revealed that increasing chemicals in the brain that act similarly to marijuana can help repair the debilitating symptoms associated with fragile X syndrome.

The overall success of this study could lead to future treatments for the condition, which has been identified as the most common genetic basis for autism spectrum disorders.  The research was published in Nature Communications.

The marijuana-like compound, called 2-AG, is a part of a class of chemicals called endocannabinoid transmitters.    These compounds are naturally made by the brain, and they act by combining to receptor proteins in the brain that marijuana chemicals also bind with.

Fragile X syndrome is the result of a mutation of the FMR1 gene in the X chromosome passed on by the mother.   The condition occurs mostly in males because females typically have another X chromosome to compensate for the faulty X chromosome.  Symptoms of fragile X often include mental disability, walking and language delays and hyperactivity – as well as certain physical characteristics such as an elongated face and large ears.”

Read more: http://www.foxnews.com/health/2012/09/25/marijuana-like-brain-chemicals-could-be-key-to-treating-fragile-x-syndrome/#ixzz2DStbqb00

Marijuana- Like Compound in Brain Reduces Anxiety Associated With Fragile X Syndrome

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“Increasing levels of a marijuana-like compound in the brain may help reduce some behavioral problems seen in people with Fragile X Syndrome.
Researchers say that the marijuana-like compound may help reduce some of the anxiety and learning-related issues in people with this condition. The compound, called 2-AG, falls under a class of chemicals in the brain called endocannabinoids transmitters.

 Fragile X syndrome is a genetic disorder that causes learning disabilities. Children with this condition have characteristic physical features like long and narrow face, large forehead and ears, flexible fingers and flat feet that become more apparent as the child ages. The condition is caused by a change in the FMR1 gene that codes for a protein that helps the brain grow properly.”

Read more at http://www.medicaldaily.com/articles/12334/20120926/marijuana-compound-brain-reduces-anxiety-associated-fragile.htm#tFdDDvKazcBZ1gFG.99

  • mike

    “YES, finally its time… i have autistic spectrum and i have incorrect behaviors that cannot be fixed unless you tell yourself 24/7 and behaviors and thought process that is incorrect that you will never even know is incorrect. Ive tried marijuana before and the first time ive tried it ive done some self explaining to myself that was very different and i didnt know why. after using marijuana several times which i find relaxing if not used too much at once, i started realizing the difference in thought process and realizing the off things that i do and it got to the point where i actually started figuring out my problems with cannabis and i cant believe the correction in thought process when using this significant plant. there was never a cure for autism but this is the CLOSEST to it. i have a lot more things to say about this but it would take too long to write but all i have to say is this is THE best medication for personality disorders and autistic behaviors and correction to the thought process of such.”

Marijuana-Like Chemical May Help Autism And Fragile X Syndrome Symptoms

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“American and European researchers have found that increasing natural marijuana-like chemicals in the brain may help correct behavioral issues related to autism.

Daniele Piomelli of UC Irvine and Olivier Manzoni of INSERM, the French national research agency, led the study, which could result in treatments of anxiety and cognitive defects in individuals with fragile X syndrome, the most common known genetic cause of autism, according to a press release by UC Irvine.

The study examined 2-AG, which naturally occurs in the brain and is in a class of chemicals called endocannabinoid transmitters. These transmitters allow for the efficient transport of electrical signals at synapses, which is severely limited in people with fragile X syndrome.

The researchers treated mice that exhibited symptoms of fragile X syndrome with novel compounds that correct 2-AG protein signaling in the brain. And the results were promising–the mice showed “dramatic behavioral improvements in maze tests measuring anxiety and open-space acceptance,” UCI reports.

Piomelli said this is the first study to identify the role of naturally-occuring endocannabinoids, which share a similar chemical structure with THC, the primary psychoactive component of marijuana. “What we hope is to one day increase the ability of people with fragile X syndrome to socialize and engage in normal cognitive functions,” said Piomelli, a UCI professor of anatomy and neurobiology.

“It would be either an oral or injected drug but that’s at the very end stage of drug discovery, and we are at the very early stage of drug discovery,” Kwang Mook Jung, a researcher on the study and UCI professor, told The Huffington Post.

In addition, his study of endocannabinoids could result in new treatments for anxiety, pain, depression and obesity, according to UCI.”

http://www.huffingtonpost.com/2012/09/27/marijuana-chemical-autism-fragile-x_n_1920320.html

 

Abnormal mGlu 5 Receptor/Endocannabinoid Coupling in Mice Lacking FMRP and BC1 RNA

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“Transcriptional silencing of the gene encoding the fragile X mental retardation protein (FMRP) causes fragile X syndrome (FXS)…

Our data indicate for the first time that mGlu5R-driven endocannabinoid signaling in the striatum is under the control of both FMRP and BC1 RNA. The abnormal mGlu5R/2-AG coupling found in FMRP-KO mice emphasizes the involvement of mGlu5Rs in the synaptic defects of FXSand identifies the modulation of the endocannabinoid system as a novel target for the treatment of this severe neuropsychiatric disorder.

In conclusion, this is the first study addressing endocannabinoid system in a model of FXS. Our results show that dysfunctional mGlu5R signaling leads to abnormal 2-AG metabolism and physiological activity, and indicate that inhibition of 2-AG synthesis or activity at CB1Rs might be a useful treatment option in FXS patients. In this respect, recent investigations suggest that this modulation could be achieved not only by direct pharmacological blockade of CB1Rs, but also indirectly, for example through the inhibition of anandamide degradation or the stimulation of transient receptor potential vanilloid 1 (TRPV1) channels. These two components of the endocannabinoid system, in fact, have been shown to selectively interact with mGlu5R/2-AG coupling in striatal neurons, and might interfere with the synaptic alterations seen after FMRP ablation with less side effects than those of widespread pharmacological inhibition of CB1Rs, which control not only GABA but also glutamate synapses.”

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3055456/

Marijuana cannabinoids found to help combat autism

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“(NaturalNews) The cannabinoid compounds naturally found in many varieties of cannabis, also known more commonly as marijuana, may help children with autism spectrum disorders experience dramatic behavioral improvements, and potentially even full recovery from their symptoms. These are the findings of a new study published in the journal Nature Communications that help reinforce the growing body of evidence which shows that medicinal cannabinoids hold incredible potential in both treating and potentially curing chronic illness.

Daniele Piomelli from the University of California, Irvine (UCI) and her colleague Olivier Manzoni from Inserm, a French research agency, observed that marijuana cannabinoids are very closely related to the endocannabinoid transmitters naturally found in the brain that facilitate the transport of electrical signals between neurons. Known as 2-AG, these transmitters are responsible for regulating a whole host of important bodily processes, which include things like telling the body when it is hungry or when it is experiencing pain.

Children with autism spectrum disorders; however, including those who developed these disorders as a result of Fragile X syndrome, which is said to be the most commonly-known genetic cause of autism, often have poorly or non-functioning 2-AG, which necessitates chronic synaptic failure in the brain. Many children with Fragile X-induced autism end up becoming mentally disabled as a result of this synaptic failure, and have trouble developing basic motor skills like walking and talking, or learning how to behave in various social situations.

But taking marijuana cannabinoids, which as we pointed out in an earlier article are not psychoactive in the same way that tetrahydrocannabinol (THC) is (http://www.naturalnews.com/035759_cannabis_juicing_health.html), can help effectively block the enzymes that inhibit the proper function of 2-AG. In essence, marijuana cannabinoids essentially restore synaptic communication by feeding an ailing body the cannabinoids it lacks, which are absolutely vital for proper cell function and communication.

“Endocannabinoid compounds are created naturally in the body and share a similar chemical structure with THC … (and) are distinctive because they link with protein molecule receptors — called cannabinoid receptors — on the surface of cells,” explains the UCI report. “Because the body’s natural cannabinoids control a variety of factors — such as pain, mood and appetite — they’re attractive targets for drug discovery and development.””

Learn more: http://www.naturalnews.com/037445_marijuana_cannabinoids_autism.html#ixzz2DRNu5iDg

Cannabis-like chemical combats chief genetic cause of autism

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“Natural cannabis-like chemicals in the brain may help combat the leading genetic cause of autism, research has shown.

Scientists linked blockages in a signalling pathway dependent on the compounds, called 2-AG endocannabinoid transmitters, with symptoms of Fragile X syndrome.

Correcting the fault with drugs led to dramatic behavioural improvements in mice with a version of the condition.

Fragile X syndrome is the most common known genetic cause of autism.

It results from a mutation in the FMR1 gene on the female X chromosome. Men possess one copy of the chromosome, paired with a male Y chromosome, and women two.

Boys are much more likely to be born with Fragile X than girls. This is thought to be because with two X chromosomes, a defect in one may be compensated for by the other.

People with the syndrome suffer mental impairment, learning difficulties, and may be hyperactive or impulsive. They also possess notable physical characteristics such as an elongated face, flat feet and large ears.

“What we hope is to one day increase the ability of people with Fragile X syndrome to socialise and engage in normal cognitive functions,” said lead researcher Professor Daniele Piomelli, from the University of California at Irvine in the United States.

The study was the first to identify the role of endocannabinoids in the neurobiology of Fragile X, she said.

About endocannabinoids

Endocannabinoid compounds are created naturally in the body and share a similar chemical structure with THC, the primary psychoactive component of the marijuana plant, Cannabis.

Endocannabinoids are distinctive because they link with protein molecule receptors — called cannabinoid receptors — on the surface of cells. For instance, when a person smokes marijuana, the cannabinoid THC activates these receptors. And because the body’s natural cannabinoids control a variety of factors — such as pain, mood and appetite — they’re attractive targets for drug discovery and development.”

Read more: http://www.belfasttelegraph.co.uk/news/health/cannabis-chemical-combats-chief-genetic-cause-of-autism-16216090.html#ixzz2DRLsbjJO

Targeting CB2 receptors and the endocannabinoid system for the treatment of pain.

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Abstract

“The endocannabinoid system consists of the cannabinoid (CB) receptors, CB(1) and CB(2), the endogenous ligands anandamide (AEA, arachidonoylethanolamide) and 2-arachidonoylglycerol (2-AG), and their synthetic and metabolic machinery. The use of cannabis has been described in classical and recent literature for the treatment of pain, but the potential for psychotropic effects as a result of the activation of central CB(1) receptors places a limitation upon its use. There are, however, a number of modern approaches being undertaken to circumvent this problem, and this review represents a concise summary of these approaches, with a particular emphasis upon CB(2) receptor agonists. Selective CB(2) agonists and peripherally restricted CB(1) or CB(1)/CB(2) dual agonists are being developed for the treatment of inflammatory and neuropathic pain, as they demonstrate efficacy in a range of pain models. CB(2) receptors were originally described as being restricted to cells of immune origin, but there is evidence for their expression in human primary sensory neurons, and increased levels of CB(2) receptors reported in human peripheral nerves have been seen after injury, particularly in painful neuromas. CB(2) receptor agonists produce antinociceptive effects in models of inflammatory and nociceptive pain, and in some cases these effects involve activation of the opioid system. In addition, CB receptor agonists enhance the effect of mu-opioid receptor agonists in a variety of models of analgesia, and combinations of cannabinoids and opioids may produce synergistic effects. Antinociceptive effects of compounds blocking the metabolism of anandamide have been reported, particularly in models of inflammatory pain. There is also evidence that such compounds increase the analgesic effect of non-steroidal anti-inflammatory drugs (NSAIDs), raising the possibility that a combination of suitable agents could, by reducing the NSAID dose needed, provide an efficacious treatment strategy, while minimizing the potential for NSAID-induced gastrointestinal and cardiovascular disturbances. Other potential “partners” for endocannabinoid modulatory agents include alpha(2)-adrenoceptor modulators, peroxisome proliferator-activated receptor alpha agonists and TRPV1 antagonists. An extension of the polypharmacological approach is to combine the desired pharmacological properties of the treatment within a single molecule. Hopefully, these approaches will yield novel analgesics that do not produce the psychotropic effects that limit the medicinal use of cannabis.”

http://www.ncbi.nlm.nih.gov/pubmed/19150370

Alterations in endocannabinoid tone following chemotherapy-induced peripheral neuropathy: Effects of endocannabinoid deactivation inhibitors targeting fatty-acid amide hydrolase and monoacylglycerol lipase in comparison to reference analgesics following cisplatin treatment.

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Abstract

“Cisplatin, a platinum-derived chemotherapeutic agent, produces mechanical and cold allodynia reminiscent of chemotherapy-induced neuropathy in humans. The endocannabinoid system represents a novel target for analgesic drug development. The endocannabinoid consists of endocannabinoids (e.g. anandamide (AEA) and 2-arachidonoylglycerol (2-AG)), cannabinoid receptors (e.g. CB(1) and CB(2)) and the enzymes controlling endocannabinoid synthesis and degradation. AEA is hydrolyzed by fatty-acid amide hydrolase (FAAH) whereas 2-AG is hydrolyzed primarily by monoacylglycerol lipase (MGL). We compared effects of brain permeant (URB597) and impermeant (URB937) inhibitors of FAAH with an irreversible inhibitor of MGL (JZL184) on cisplatin-evoked behavioral hypersensitivities. Endocannabinoid modulators were compared with agents used clinically to treat neuropathy (i.e. the opioid analgesic morphine, the anticonvulsant gabapentin and the tricyclic antidepressant amitriptyline). Cisplatin produced robust mechanical and cold allodynia but did not alter responsiveness to heat. After neuropathy was fully established, groups received acute intraperitoneal (i.p.) injections of vehicle, amitriptyline (30mg/kg), gabapentin (100mg/kg), morphine (6mg/kg), URB597 (0.1 or 1mg/kg), URB937 (0.1 or 1mg/kg) or JZL184 (1, 3 or 8mg/kg). Pharmacological specificity was assessed by coadministering each endocannabinoid modulator with either a CB(1) (AM251 3mg/kg), CB(2) (AM630 3mg/kg), TRPV1 (AMG9810 3mg/kg) or TRPA1 (HC030031 8mg/kg) antagonist. Effects of cisplatin on endocannabinoid levels and transcription of receptors (CB(1), CB(2), TRPV1, TRPA1) and enzymes (FAAH, MGL) linked to the endocannabinoid system were also assessed. URB597, URB937, JZL184 and morphine reversed cisplatin-evoked mechanical and cold allodynia to pre-cisplatin levels. By contrast, gabapentin only partially reversed the neuropathy while amitriptyline, administered acutely, was ineffective. CB(1) or CB(2) antagonist completely blocked the anti-allodynic effects of both FAAH (URB597, URB937) and MGL (JZL184) inhibitors to mechanical and cold stimulation, while TRPV1 antagonist AMG9810 blocked only the anti-allodynic efficacy of both FAAH inhibitors, but not the MGL inhibitor. By contrast, the TRPA1 antagonist HC30031 did not attenuate anti-allodynic efficacy of any endocannabinoid modulator. When the levels of endocannabinoids were examined, cisplatin increased both anandamide (AEA) and 2-arachidonoylglycerol (2-AG) levels in the lumbar spinal cord and decreased 2-AG levels (but not AEA) in dorsal hind paw skin. RT-PCR showed that mRNA for FAAH, but not other markers, was upregulated by cisplatin treatment in dorsal root ganglia. The present studies demonstrate that cisplatin alters endocannabinoid tone and that inhibition of endocannabinoid hydrolysis alleviates chemotherapy-induced mechanical and cold allodynia. The anti-allodynic effects of FAAH and MGL inhibitors are mediated by CB(1) and CB(2) cannabinoid receptors, whereas TRPV1, but not TRPA1, -dependent mechanisms contribute to the anti-allodynic efficacy of FAAH (but not MGL) inhibitors. Strikingly, endocannabinoid modulators potently suppressed cisplatin-evoked allodynia with a rapid onset and showed efficacy that equaled or exceeded that of major classes of anti-neuropathic pain medications used clinically. Thus, inhibition of endocannabinoid hydrolysis, via FAAH or MGL inhibitors, represents an efficacious pharmacological approach for suppressing chemotherapy-induced neuropathic pain.”

http://www.ncbi.nlm.nih.gov/pubmed/23127915