Category Archives: Endocannabinoid System

Anandamide in primary sensory neurons: too much of a good thing?

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“The quest for possible targets for the development of novel analgesics has identified the activation of the cannabinoid type 1 (CB1) receptor outside the CNS as a potential means of providing relief from persistent pain, which currently constitutes an unmet medical need.

Increasing tissue levels of the CB1 receptor endogenous ligand N-arachidonoylethanolamine (anandamide), by inhibiting anandamide degradation through blocking the anandamide-hydrolysing enzyme fatty acid amide hydrolase, has been suggested to be used to activate the CB1 receptor.

However, recent clinical trials revealed that this approach does not deliver the expected relief from pain. Here, we discuss one of the possible reasons, the activation of the transient receptor potential vanilloid type 1 ion channel (TRPV1) on nociceptive primary sensory neurons (PSNs) by anandamide, which may compromise the beneficial effects of increased tissue levels of anandamide.

We conclude that better design such as concomitant blocking of anandamide hydrolysis and anandamide uptake into PSNs, to inhibit TRPV1 activation, could overcome these problems.”

http://www.ncbi.nlm.nih.gov/pubmed/24494681

Endocannabinoids and neuropathic pain: focus on neuron-glia and endocannabinoid-neurotrophin interactions.

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“Although originally described as a signalling system encompassing the cannabinoid CB1 and CB2 receptors, their endogenous agonists (the endocannabinoids), and metabolic enzymes regulating the levels of such agonists, the endocannabinoid system is now viewed as being more complex, and including metabolically related endocannabinoid-like mediators and their molecular targets as well.

The function and dysfunction of this complex signalling system in the molecular and cellular mechanisms of pain transduction and control has been widely studied over the last two decades.

In this review article, we describe some of the latest advances in our knowledge on the role of the endocannabinoid system, in its most recent and wider conception, in pain pathways, by focusing on: (1) neuron-glia interactions; and (2) emerging data on endocannabinoid cross-talk with neurotrophins, such as nerve growth factor and brain-derived neurotrophic factor.”

http://www.ncbi.nlm.nih.gov/pubmed/24494680

Neurotrophins, endocannabinoids and thermo-transient receptor potential: a threesome in pain signalling.

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“Although pain is multifactorial at cellular and molecular levels, it is widely accepted that neurotrophin (TrkA, p75NTR, Ret and GFRs), cannabinoid (CB1 and CB2), and thermo-transient receptor potential (TRPs; TRPV1, TRPA1 and TRPM8) receptors play a pivotal role.

…the available information confirms that pharmacological modulation of this signalling triad is a highly valuable therapeutic strategy for effectively treating pain syndromes.”

http://www.ncbi.nlm.nih.gov/pubmed/24494676

Basolateral amygdala CB1 cannabinoid receptors mediate nicotine-induced place preference.

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“In the present study, the effects of bilateral microinjections of cannabinoid CB1 receptor agonist and antagonist into the basolateral amygdala (intra-BLA) on nicotine-induced place preference were examined in rats.

Taken together, these findings support the possible role of endogenous cannabinoid system of the BLA in the acquisition and the expression of nicotine-induced place preference. Furthermore, it seems that there is a functional interaction between the BLA cannabinoid receptors and nicotine in producing the rewarding effects.”

http://www.ncbi.nlm.nih.gov/pubmed/24468643

Regulatory role of the Cannabinoid-2 receptor in stress-induced neuroinflammation in mice.

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“Stress-exposure produces excitoxicity and neuroinflammation, contributing to the cellular damage observed in stress-related neuropathologies. The endocannabinoid system is present in stress-responsive neural circuits and it is emerging as a homeostatic system. The aim of this study was to elucidate the possible regulatory role of cannabinoid-2 receptor in stress-induced excitotoxicity and neuroinflammation.

CONCLUSIONS AND IMPLICATIONS:

These results suggest that pharmacological manipulation of CB2 receptor is a potential therapeutic strategy for the treatment of stress-related pathologies with a neuroinflammatory component, such as depression.”

http://www.ncbi.nlm.nih.gov/pubmed/24467609

Peripheral interactions between cannabinoid and opioid systems contribute to the antinociceptive effect of crotalphine.

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“Crotalphine is an antinociceptive peptide… we evaluated the involvement of the peripheral cannabinoid system in the crotalphine effect and its interaction with the opioid system…

Crotalphine-induced antinociception involves peripheral CB2 cannabinoid receptors and local release of dynorphin A, which is dependent on CB2 receptor activation.

These results enhance our understanding of the mechanisms involved in the peripheral effect of crotalphine, as well as the interaction between the opioid and cannabinoid systems.”

http://www.ncbi.nlm.nih.gov/pubmed/24460677

Selective inhibition of FAAH produces antidiarrheal and antinociceptive effect mediated by endocannabinoids and cannabinoid-like fatty acid amides.

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“The endogenous cannabinoid system (ECS) plays a crucial role in multiple physiological processes in the central nervous system and in the periphery. The discovery that selective cannabinoid (CB) receptor agonists exert a potent inhibitory action on gastrointestinal (GI) motility and pain has placed the ECS in the center of attention as a possible target for the treatment of functional GI diseases…

These data expand our understanding of the ECS function and provide a novel framework for the development of future potential treatments of functional GI disorders.”

http://www.ncbi.nlm.nih.gov/pubmed/24460851

Cannabinoid system and neuroinflammation: implications for multiple sclerosis.

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“There is a growing amount of evidence suggesting that cannabinoids may be neuroprotective in central nervous system inflammatory conditions.

Advances in the understanding of the physiology and pharmacology of the cannabinoid system have potentiated the interest in cannabinoids as potential therapeutic targets.

…The effects of cannabinoids on cytokine brain work and on the regulation of neuroinflammatory processes may affect chronic inflammatory demyelinating diseases such as multiple sclerosis.”

http://www.ncbi.nlm.nih.gov/pubmed/18073512

5-Lipoxygenase and anandamide hydrolase (FAAH) mediate the antitumor activity of cannabidiol, a non-psychoactive cannabinoid.

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“It has been recently reported that cannabidiol (CBD), a non-psychoactive cannabinoid, is able to kill glioma cells, both in vivo and in vitro, independently of cannabinoid receptor stimulation.

…the present investigation indicates that CBD exerts its antitumoral effects through modulation of the LOX pathway and of the endocannabinoid system…”

http://www.ncbi.nlm.nih.gov/pubmed/18028339

Cannabinoids induce glioma stem-like cell differentiation and inhibit gliomagenesis.

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“Glioma stem-like cells constitute one of the potential origins of gliomas, and therefore, their elimination is an essential factor for the development of efficient therapeutic strategies.

Cannabinoids are known to exert an antitumoral action on gliomas that relies on at least two mechanisms: induction of apoptosis of transformed cells and inhibition of tumor angiogenesis…

The discovery of an endogenous cannabinoid system, together with the great improvement in our understanding of the signaling mechanisms responsible for cannabinoid actions, has fostered the interest in the potential therapeutic applications of cannabinoids.

Several studies have demonstrated a significant antitumoral action of cannabinoid ligands in animal models. Thus, cannabinoid administration to nude mice curbs the growth of different tumors, including gliomas…

Cannabinoids are known to exert an antitumoral action against gliomas…

Overall, our results demonstrate that cannabinoids target glioma stem-like cells, promote their differentiation, and inhibit gliomagenesis, thus giving further support to their potential use in the management of malignant gliomas.

In conclusion, our results demonstrate the action of cannabinoids on glioma stem-like cells and thus may open new avenues for cannabinoid-based antitumoral strategies.”

http://www.jbc.org/content/282/9/6854.long