Research Topic

The Canonical and Non-Canonical Endocannabinoid System as a Target in Cancer Diseases and Acute and Chronic Pain

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The endocannabinoid system (ECS) is currently a hot topic under investigation in the field of cancer and pain, respectively because of the tumor-regressive effects of cannabinoid ligands and the ability to inhibit behavioural responses to noxious stimuli and nociceptive processing.

The ECS includes ...

The endocannabinoid system (ECS) is currently a hot topic under investigation in the field of cancer and pain, respectively because of the tumor-regressive effects of cannabinoid ligands and the ability to inhibit behavioural responses to noxious stimuli and nociceptive processing.

The ECS includes the canonical two receptor subtypes CB1 and CB2 and endocannabinoids (anandamide and 2-arachidonoylglycerol), and an extended signalling network consisting of: (i) other fatty acid derivatives (2-AGE, NADA, OA); (ii) the defined “ionotropic cannabinoid receptors” (TRP channels); other GPCRs (GPR55, PPARα); (iii) enzymes involved in the biosynthesis and degradation of endocannabinoids (FAAH and MAGL); and iv) protein transporters (FABP family).

Several reports support the ECS (canonical and non canonical) as an effective target for treatment of different pathological conditions.

As for the canonical pathway, high CB1R expression correlated to poor prognosis in prostate, pancreatic, colorectal and ovarian cancer; high CB2R expression correlated to poor prognosis in HER2-positive breast cancer. Endocannabinoids such as AEA and 2-AG were found upregulated in different tumours (colorectal carcinomas) compared to healthy subjects. Different mechanisms have been suggested for the antitumorigenic activity of ligands such as AEA, 2-AG and other endocannabinoid –like compounds.

Indeed, AEA induced an antiproliferative effect via CB1R activation in prostate and breast cancers; R(+)-Methanandamide induced apoptosis through CB1R and CB2R activation in lymphoma cells and inhibited invasion of cancer cells in cervical and lung tumours via CB1R, CB2R and TRPV1. The antiproliferative effect of 2-AG was dependent on pathways involving CB1R-mediated p42/44 MAPK and AKT signalling. Conflicting results have been observed between MAGL and FAAH regulation and malignancies progression.

Recent studies have demonstrated the link existing between TRPV2 and CBD-induced autophagy in glioblastoma cells. Moreover, CB2R-GRP55 heteromers inducing cancer cell proliferation have been found suggesting the modulation of this cross-action could be useful to block cancer progression.

Additionally, cannabinoid receptors, endocannabinoid compounds, and enzymes controlling their production and degradation are located at different levels of the nociception axis, from the periphery to the CNS.

2-arachidonoyl glycerol (2-AG) and anandamide elicit long-term depression of both excitatory and inhibitory synapses thus increasing the neural circuit output. Endocannabinoid/TRPV signalling induces the sensitization of the shortening reflex due to direct stimulation of nearby nociceptive afferents cells or to noxious stimulation applied to skin several segments away. Moreover, CB1 and CB2 receptors are targeted in the treatment of pain; The CB2R selective agonist JWH-133 is able to exert antinociceptive effect during both the acute and inflammatory phases of the formalin test.

In conclusion, preclinical research has identified the ECS as an important target for the treatment of several pathological conditions suggesting that potential therapeutic approaches or ligands able to modulate the canonical and the not canonical cannabinoid pathways are worth investigating. With this Research Topic, we would like to highlight the different aspects of the ECS in acute and chronic pain and cancer research with a particular focus on new opportunities for potential treatments.


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