FIGURE 2.

The role of the endocannabinoid system (eCS) in the quadripartite synapse, its modulation by phytocannabinoids and alterations due to Neuropathic Pain. (A) Neurons, astrocytes, and microglial cells have the eCS components, and the endocannabinoid signaling through CB1R and CB2R leads to different outcomes in each cell. The presynaptic neuron expresses CB1R, TRPV1, TRPM8, and the endocannabinoid membrane transporter (EMT). Receptors are targeted by endocannabinoids (AEA and 2-AG). CB1R modulation activates signaling cascades that inhibit Ca²⁺ intracellular influx, which decreases the fusion of intracellular vesicles with the neuron membrane, changing the neurotransmitter release flow. The postsynaptic neuron also presents, besides the receptors, all the elements of the ECS, such as the AEA and 2-AG synthesis enzymes, respectively NAPE-PLD and DAGL, and the degradation enzymes, FAAH, MAGL, and other enzymes such as COX2. In green: Astrocyte takes part in the synapse and expresses different elements of the eCS such as endocannabinoids’ synthesis and degradation enzymes and cannabinoid receptors, where the activation of CB1R may favor the influx of Ca²⁺ ions. Microglia expresses components of the eCS; the CB2R expression is higher than CB1R, and its modulation is linked to the production and secretion of different cytokines. Phytocannabinoids modulate the eCS through many targets. THC and THCV are CB1R agonists, while CBD, CBDV, CBG, and THCV are TRPV1 agonists. The EMT transporter is the pharmacological target of the phytocannabinoids CBD, CBDV, CBG, and THCV. The phytocannabinoids also act over enzyme activity - CBD inhibits FAAH, CBDA inhibits COX-2 and CBDV, CBDA, THCVA and CBDVA inhibit DAGL. (B) In the Neuropathic Pain scenario, there is glial reactivity, leading to the increase of astrocyte and microglia next to neurons, especially in the dorsal spinal cord. The eCS is modulated and the levels of expression of your components change. There is a higher expression of CB1R and CB2R in neurons and glial cells. Enzymes such as FAAH, COX-2, and 5-LOX also increase their expression, and in result, there is a decrease of AEA levels and increase of pro-inflammatory mediators. CBD, cannabidiol; THC, tetrahydrocannabinol; CBDV; cannabidivarin; CBDA, cannabidiolic acid; THCVA, tetrahydrocannabivarinic acid; CBDVA, cannabidivarinic acid; THCV, tetrahydrocannabivarin; CBG, cannabigerol.