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].