1.4.2 Additional ligands and receptors of the endocannabinoid system
In addition to CB1 and CB2, the ES may include additional ligands and receptors capable of binding to other pharmacological targets. The most studied of the receptors involved in this system are TRPV1, 5HT1A, PPARγ and PPARα, although some works have addressed the role of two GPRs, GPR55 and G protein-coupled receptor 18 (GPR18) [50-55].
TRPV1 is a cation-permeable ion channel activated by heat, acidic pH, and capsaicin (the pungent compound in the pepper Capsicum frutescens pepper). It is a ”vanilloid channel” or ”transient receptor potential cationic channel, subfamily V, member 1” [56], located in the GABAergic and glutamatergic terminals and in the perikarya of neurons in the hippocampus and cerebellum, being identified as an important target that may represent a potential treatment for some diseases [36, 57-60]. In models of epilepsy, for example, TRPV1 is believed to increase the excitability of central neurons. In this case, studies have shown that from a double blockade of FAAH/TRPV1 there was a mediation of the excitatory effects of anadamide. This strategy induced an increase in AEA, levels, selectively activating the CB1 receptor and inhibiting neuronal activity [56, 61, 62].
In short, TRPV1 has been identified as a receptor with high affinity for endogenous AEA having an opposite action to the CB1 receptor [47], since while the binding of anandamide to the CB1 receptor inhibits neuronal activity, activation of TRPV1 depolarizes neurons and promotes neuronal activity. release of neurotransmitters [50, 63-65].
As for 5HT1A, they are serotonin receptors coupled to a Gi/o protein and have been related to cannabinoids, including neuroprotective effects [66]. These receptors are considered autosomal and are located on presynaptic membranes and are also found postsynaptically in various areas of the brain [67]. From anin vivo study, the hypothesis emerged that 5HT1Awas a mediator that facilitated the neurotransmission of CBD, thus being an agonist of these cannabinoid receptors [68]. However, according to Campos et al [69] this agonist action was not corroborated in other subsequent studies, thus presenting the idea that 5HT1A-mediated effects of CBD would be caused by allosteric interactions with the receptor binding site and/or interference with intracellular pathways.
The antiaversive pharmacological effects of CBD were observed when CBD was injected systemically and in different areas of the brain, such as the dorsal periaqueductal gray matter, the medial hypothalamus and the medial prefrontal cortex, and in different animal models, including threat stress of predator [70-75]. Based on these and other findings, CBD has been proposed as a positive allosteric modulator for the 5HT1A receptor [76-78].
In addition to TRPV1 and 5HT1A receptors, investigations with PPARγ and PPARα have been presented in the literature. It is known that PPARα and PPARγ, an important class of nuclear hormone receptors (PPARs), are additional targets of endocannabinoids [79, 80]. Although the data are more significant for some cannabinoids, such as N-oleoylethanolamine (OEA) and N-palmitoylethanolamine (PEA), neuroprotection, anti-inflammatory and analgesic effects have been considered mediated, in part, by their activation to PPARs. However, there are a myriad of factors influencing interactions between cannabinoids and PPARs that need to be elucidated [81-83].
Interestingly, PEA (a compound related to cannabinoids) is currently used to treat pain and inflammation. Like other cannabinoid-related molecules, PEA has a very complex mechanism of action, which includes direct and/or indirect interaction with CB1, TRPV1, PPAR, GPR55 and GPR18, among other receptors [84]. It is known that GPR119, another putative receptor identified, can bind to PEA and also OEA compounds [85].
The list of non-cannabinoid receptors has been advancing. GPR18 and GPR55 have been presented as targets of various phytocannabinoids, synthetic cannabinoids and endocannabinoids [86-89]. Both are related to the modulation of several pathways of signaling of various metabolic disorders, being located mainly dispersed in the central and peripheral systems of the body, such as the brain and vascular system [90].
Moreover, GPR18 interact directly or indirectly with cannabinoids and seem to play an important role in inflammation, acting in the control of immune system activities, such as migration and apoptosis of leukocytes, and also in reducing intraocular pressure in mice. Its expression was evidenced in testes, spleen, peripheral blood leukocytes and lymph nodes [88].
Regarding GPR55, it has been shown to act in the nervous system, being a therapeutic target for Parkinson’s disease [91-93], Alzheimer’s disease (Medina-Vera et al, 2020), epilepsy (Gaston et al, 2016; Kaplan et al., 2017), in memory and spatial learning [94]. Furthermore, that it exerts antiproliferative effects through inhibition of protein kinase B (PKB) and extracellular signal-regulated kinase (ERK) in which CBD acts as a GPR55 antagonist [90], as well as, that PEA has high affinity for GPR55 as a full agonist [95]. Several interaction actions between endocannabinoids and GPR55 in the CNS have been studied recently, but many mechanisms need to be elucidated in order to obtain scientific evidence [15, 95].
An in vitro and in vivo study analyzed the affinity of eight compounds, namely, THC, ∆9-tetrahydrocannabinolic acid (THCA), ∆9- tetrahydrocannabivarin (THCV), CBD, cannabidiolic acid (CBDA), cannabidivarin (CBDV), canabigerol (CBG) and cannabichromene (CBC), with CB1 and CB2 receptors. The results demonstrated that many of these phytocannabinoids have a partial agonist activity on CB1 and/or CB2 receptors, and in vivo the interaction of phytocannabinoids often occurs with CB1 receptors [96].