Cannabinoid Therapeutics in Chronic Neuropathic Pain: From Animal Research to Human Treatment

Abstract

Despite the importance of pain as a warning physiological system, chronic neuropathic pain is frequently caused by damage in the nervous system, followed by persistence over a long period, even in the absence of dangerous stimuli or after healing of injuries. Chronic neuropathic pain affects hundreds of millions of adults worldwide, creating a direct impact on quality of life. This pathology has been extensively characterized concerning its cellular and molecular mechanisms, and the endocannabinoid system (eCS) is widely recognized as pivotal in the development of chronic neuropathic pain. Scientific evidence has supported that phyto-, synthetic and endocannabinoids are efficient for pain management, while strong data arise from the therapeutic use of Cannabis-derived products. The use of medicinal Cannabis products is directed toward not only relieving symptoms of chronic pain, but also improving several aspects of patients' welfare. Here, we review the involvement of eCS, along with other cellular and molecular elements, in chronic neuropathic pain pathology and how this system can be targeted for pain management.

Keywords: THC; cannabidiol; cannabis; endocannabinoid; neuropathic pain.

FIGURE 1

Pain anatomical pathways and CB1R expression. Ascending pain pathways (in red) are carried from the body periphery through sensory neurons of dorsal root ganglia (DRG) that synapse mainly with laminaes I to III in the dorsal spinal cord. Projection neurons make connections with brain areas such as thalamus and cortex. The descending pathways (in blue), responsible for pain modulation, involve areas such as the periaqueductal gray matter and amygdala, ending in the dorsal spinal cord. The CB1R distribution is heterogeneous in pain pathway areas, being more concentrated in regions such as cortex and Central Amygdala (CeA). LA, lateral amygdala; CeA, central amygdala; BlA, basolateral amigdala.

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.