Tag Archives: endocannabinoid system

The endocannabinoid nervous system: unique opportunities for therapeutic intervention.

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“The active principle in marijuana, Delta(9)-tetrahydrocannabinol (THC), has been shown to have wide therapeutic application for a number of important medical conditions, including pain, anxiety, glaucoma, nausea, emesis, muscle spasms, and wasting diseases. Delta(9)-THC binds to and activates two known cannabinoid receptors found in mammalian tissue, CB1 and CB2. The development of cannabinoid-based therapeutics has focused predominantly on the CB1 receptor, based on its predominant and abundant localization in the CNS.

Like most of the known cannabinoid agonists, Delta(9)-THC is lipophilic and relatively nonselective for both receptor subtypes.

Clinical studies show that nonselective cannabinoid agonists are relatively safe and provide therapeutic efficacy, but that they also induce psychotropic side effects. Recent studies of the biosynthesis, release, transport, and disposition of anandamide are beginning to provide an understanding of the role of lipid transmitters in the CNS. This review attempts to link current understanding of the basic biology of the endocannabinoid nervous system to novel opportunities for therapeutic intervention.

This new knowledge may facilitate the development of cannabinoid receptor-targeted therapeutics with improved safety and efficacy profiles.”

http://www.ncbi.nlm.nih.gov/pubmed/11448725

Worth Repeating: Marijuana Treats Anxiety and Depression

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HanusAndMechoulam.jpg
Lumír Ondřej Hanuš (left), discoverer of endogenous ligand, anandamide, from brain (1992) and Raphael Mechoulam (right), discoverer of psychoactive compound, (-)-trans-delta-9-tetrahydrocannabinol, from Cannabis sativa L. (1964). Both compounds bind to the CB1 and 2 cannabinoid receptors in the brain.
“This post is dedicated to these two great medical researchers. The fathers of homeostatic cannabinoid based medicine:
 
Lumír Ondřej Hanuš, discoverer of the endogenous ligand, anandamide, from the brain (1992) and Raphael Mechoulam, discoverer of the psychoactive compound, THC, from Cannabis sativa (1964). Both compounds bind to the CB1 and 2 cannabinoid receptors in the brain.
 
These two men need to be nominated and awarded the 2012  Nobel Prize in medicine for discovering the healing potential of cannabis. Their discoveries will save the human race a great deal of suffering. Thank you for your gift to humanity, gentlemen.”
 

Effects of cannabinoids on the anxiety-like response in mice.

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“Several pieces of anatomical, biochemical and pharmacological evidence indicate that the endocannabinoid system via CB1 receptors is implicated in the control of emotional behavior. However, previous studies have reported unclear and contradictory results concerning the role of cannabinoids in anxiety. The aim of the present study was to examine the influence of the cannabinoid agonist WIN 55,212-2, the CB1 antagonist AM 281, the inhibitor of anandamide hydrolysis AACOCF3  and the inhibitor of anandamide transporter AM404 on the anxiety-like response in mice in the light/dark box test…

  These results support the hypothesis that the endocannabinoid system is involved in the regulation of anxiety-like behavior, and also suggest that the inhibitors of anandamide hydrolysis might be potential anxiolytic drugs.”

http://www.ncbi.nlm.nih.gov/pubmed/16702621

Facilitation of endocannabinoid effects in the ventral hippocampus modulates anxiety-like behaviors depending on previous stress experience.

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“Although several pieces of evidence indicate that the endocannabinoid system modulates anxiety-like behaviors and stress adaptation, few studies have investigated the brain sites of these effects. The ventral hippocampus (VHC) has been related to anxiety behaviors and has a high expression of cannabinoid-1 (CB1) receptors. Moreover, endocannabinoid signaling in the hippocampus is proposed to regulate stress adaptation. In the present study we investigated the role of previous stressful experience on the effects of AM404, an anandamide uptake inhibitor, microinjected into the VHC of rats submitted to the elevated plus maze (EPM), a widely used animal model of anxiety…

These results suggest that facilitation of endocannabinoid system neurotransmission in the ventral hippocampus modulates anxiety-like behaviors and that this effect depends on previous stress experience.”

http://www.ncbi.nlm.nih.gov/pubmed/20167262

The endocannabinoid and endovanilloid systems interact in the rat prelimbic medial prefrontal cortex to control anxiety-like behavior.

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“Cannabinoid receptor 1 (CB(1)) agonists usually induce dose-dependent biphasic effects on anxiety-related responses. Low doses induce anxiolytic-like effects, whereas high doses are ineffective or anxiogenic, probably due to activation of Transient Receptor Potential Vanilloid Type 1 (TRPV(1)) channels.

 In this study we have investigated this hypothesis by verifying the effects of the CB(1)/TRPV(1) agonist ACEA injected into the prelimbic medial prefrontal cortex (PL) and the participation of endocannabinoids in the anxiolytic-like responses induced by TRPV(1) antagonism, using the elevated plus-maze (EPM) and the Vogel conflict test (VCT). Moreover, we verified the expression of these receptors in the PL by double labeling immunofluorescence. ACEA induced anxiolytic-like effect in the intermediate dose, which was attenuated by previous injection of AM251, a CB(1) receptor antagonist. The higher and ineffective ACEA dose caused anxiogenic- and anxiolytic-like effects, when injected after AM251 or the TRPV(1) antagonist 6-iodonordihydrocapsaicin (6-I-CPS), respectively. Higher dose of 6-I-CPS induced anxiolytic-like effects both in the EPM and the VCT, which were prevented by previous administration of AM251. In addition, immunofluorescence showed that CB(1) and TRPV(1) receptors are closely located in the PL.

These results indicate that the endocannabinoid and endovanilloid systems interact in the PL to control anxiety-like behavior.”

http://www.ncbi.nlm.nih.gov/pubmed/22691536

Reduced anxiety-like behaviour induced by genetic and pharmacological inhibition of the endocannabinoid-degrading enzyme fatty acid amide hydrolase (FAAH) is mediated by CB1 receptors.

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“Anandamide and 2-arachidonoyl glycerol, referred to as endocannabinoids (eCBs), are the endogenous agonists for the cannabinoid receptor type 1 (CB1). Several pieces of evidence support a role for eCBs in the attenuation of anxiety-related behaviours, although the precise mechanism has remained uncertain…

 The fatty acid amid hydrolase (FAAH), an enzyme responsible for the degradation of eCBs, has emerged as a promising target for anxiety-related disorders, since FAAH inhibitors are able to increase the levels of anandamide and thereby induce anxiolytic-like effects…

The present work provides genetic and pharmacological evidence supporting the inhibition of FAAH as an important mechanism for the alleviation of anxiety.

 In addition, it indicates an increased activation of CB1 receptors as a mechanism underlying the effects of FAAH inhibition in two models of anxiety.”

http://www.ncbi.nlm.nih.gov/pubmed/17709120

The endogenous cannabinoid anandamide has effects on motivation and anxiety that are revealed by fatty acid amide hydrolase (FAAH) inhibition

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“Converging evidence suggests that the endocannabinoid system is an important constituent of neuronal substrates involved in brain reward processes and emotional responses to stress.. It is known that the endocannabinoid system plays a modulatory role in emotional states such as anxiety and fear. Several studies utilizing rodent models of anxiety or depression showed that FAAH inhibition produced anxiolytic-like effects and anti-depressant-like effects…

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2213536/

Modulation of Fear and Anxiety by the Endogenous Cannabinoid System

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“The last decade has witnessed remarkable progress in the understanding of the mammalian cannabinoid system, from the cloning of the endogenous cannabinoid receptor to the discovery of new pharmacologic compounds acting on this receptor. Current and planned studies in humans include compounds with effects ranging from direct antagonists to inhibitors of reuptake and breakdown. This progress has been accompanied by a much greater understanding of the role of the cannabinoid system in modulating the neural circuitry that mediates anxiety and fear responses. This review focuses on the neural circuitry and pharmacology of the cannabinoid system as it relates to the acquisition, expression, and extinction of conditioned fear as a model of human anxiety.

 Preclinical studies suggest that these may provide important emerging targets for new treatments of anxiety disorders.

CONCLUSION

The last decade has witnessed an enormous amount of progress in the understanding of the molecular biology, physiology, pharmacology, and behavioral neuroscience underlying the endogenous cannabinoid system. These receptors and their ligands have ubiquitous roles ranging from appetite and pain response to modulation of fear and anxiety. A burgeoning understanding of their roles in regulating the extinction of fear responses may lead to a particularly important role in translation of the preclinical research to novel treatments of anxiety disorders.”

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2789283/

Endocannabinoid system and stress and anxiety responses.

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“Cannabinoid agonists induce complex and often contradictory effects on anxiety in humans and experimental animals. The data from animal tests provide evidence of dose-dependent bidirectional modulation of anxiety by the cannabinoid system and the importance of environmental context. The mechanisms mediating the effects of cannabinoids on anxiety-related responses appear to involve CB1 and non-CB1 cannabinoid receptors. In addition, the CRH, GABA(A), cholecystokinin, opioid and serotonergic systems have also been implicated. Brain regions such as the amygdala, hippocampus and cortex, directly involved in the regulation of emotional behavior, contain high densities of CB1 receptors. Mutant mice lacking CB1 receptors show anxiogenic-like and depressive-like phenotypes in several tests, as well as profound alterations in their adrenocortical activity. Pharmacological blockade of CB1 receptors induces anxiety in rats, and inhibition of anandamide metabolism produces anxiolytic-like effects.

Thus, the endocannabinoid system appears to play a pivotal role in the regulation of emotional states and may constitute a novel pharmacological target for anti-anxiety therapy.”

http://www.ncbi.nlm.nih.gov/pubmed/15927244

Pharmacological and pharmacokinetic characterization of the cannabinoid receptor 2 agonist, GW405833, utilizing rodent models of acute and chronic pain, anxiety, ataxia and catalepsy.

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“To date, two cannabinoid receptors have been identified, CB1 and CB2. Activation of these receptors with non-selective cannabinoid receptor agonists reduces pain sensitivity in animals and humans. However, activation of CB1 receptors is also associated with central side effects… More recently, a role for selective CB2 agonists in pain modification has been demonstrated…a selective CB2 agonist, was recently reported to partially reverse the inflammation and hyperalgesia in a rat model of acute inflammation. In the current report, we extend the characterization and therapeutic potential of this compound…

 These data support the tenet that selective CB2 receptor agonists have the potential to treat pain without eliciting the centrally-mediated side effects associated with non-selective cannabinoid agonists…”

http://www.ncbi.nlm.nih.gov/pubmed/15814101