The cannabinoids mechanism of action: an overview

ABSTRACT

BACKGROUND AND OBJECTIVES:  The discovery of the psychoactive agent of Cannabis sativa (tetrahydrocannabinol - THC) in the second half of the 20^th century originated the research that later came to identify dozens of other substances from this plant, including cannabinoids, terpenes and flavonoids. Ensuing description of their interaction sites in animals and humans, together with endogenous ligands, transport proteins as well as synthesis and degradation enzymes, revealed what came to be known as the endocannabinoid system. Several receptors participate in this system.

CONTENTS:  The first receptors to be discovered were called CB1 and CB2, both are G protein-coupled (GPCR). It is noteworthy that CB1 receptors are among the most abundant and widely distributed GPCR in the mammalian brain, with marked expression in basal ganglia, cerebellum and hippocampus, for instance; on the other hand, they are scarce in areas of the brainstem related to breathing control. In light of the multiplicity of pharmacological effects of cannabinoids, concomitant with the lack of more clarifying studies on their mechanisms of action despite the great interest in research on their therapeutic application, it is necessary to deepen the knowledge in this area.

CONCLUSION:  Considering the literature research conducted for the composition of this article, it is possible to conclude that cannabinoids have a broad spectrum of action mechanisms in the human body, and that more robust clinical studies are needed to better understand their broad therapeutic potential.

Keywords: Cannabis; Cannabinoid receptor agonists; Cannabinoid receptor antagonists; Cannabinoids; Modulators; Neurobiology

RESUMO

JUSTIFICATIVA E OBJETIVOS:  A descoberta do princípio psicoativo da Cannabis sativa (tetrahidrocanabinol - THC) na segunda metade do século XX inaugurou pesquisas que posteriormente vieram a identificar dezenas de outras substâncias a partir dessa planta, incluindo canabinoides, terpenos e flavonoides. A subsequente descrição dos sítios de interação dessas substâncias em animais e humanos, assim como seus ligantes endógenos, proteínas de transporte e enzimas de síntese e degradação, revelou o que veio a ser conhecido como sistema endocanabinoide. Diversos receptores participam deste sistema.

CONTEÚDO:  Os primeiros receptores a serem descobertos foram denominados CB1 e CB2, ambos são acoplados à proteína G (GPCR). É importante ressaltar que os receptores CB1 estão entre os GPCRs mais abundantes e amplamente distribuídos do encéfalo de mamíferos, com marcada expressão, por exemplo, em gânglios da base, cerebelo e hipocampo; em contrapartida, são escassos em áreas do tronco cerebral relacionadas ao controle da respiração. Diante da multiplicidade de efeitos farmacológicos dos canabinoides, concomitante à falta de estudos mais esclarecedores sobre seus mecanismos de ação apesar do grande interesse na pesquisa de sua aplicação terapêutica, é preciso aprofundar o conhecimento nessa área.

CONCLUSÃO:  Considerando as pesquisas bibliográficas realizadas para a composição deste artigo, é possível concluir que os canabinoides possuem um amplo espectro de mecanismos de ação no organismo humano, e que mais estudos clínicos robustos são necessários para que seja possível entender melhor o seu amplo potencial terapêutico.

Descritores: Agonistas de receptores de canabinoides; Antagonistas de receptores de canabinoides; Cannabis; Canabinoides; Moduladores; Neurobiologia

HIGHLIGHTS

Knowledge of the endocannabinoid system allows for a better comprehension of its beneficial effects.

Clinical efficacy, positive or otherwise, is very much related to the functioning of this system of neurotransmitters, receptors, and enzymes.

INTRODUCTION

The discovery of Cannabis sativa psychoactive principle (tetrahydrocannabinol - THC) in the second half of the 20th century inaugurated research that later came to identify dozens of other substances from this plant, including cannabinoids, terpenes, and flavonoids¹,². The subsequent description of interaction sites for these substances in animals (most vertebrates, such as dogs, cats, horses, rabbits, and others) and humans, as well as their endogenous ligands, transport proteins, and synthesis and degradation enzymes, revealed what has come to be known as the endocannabinoid system¹.

Several receptors participate in this system. The first to be discovered were denominated CB1 and CB2, both of which are G protein-coupled receptors (GPCR)³. Therefore, they have extracellular binding sites and an intracellular guanine nucleotide binding protein. It is important to note that CB1 receptors are among the most abundant and widely distributed GPCRs in the mammalian brain⁴,⁵, with marked expression, for example, in basal ganglia, cerebellum and hippocampus⁶; on the other hand, they are scarce in brainstem areas related to respiration control⁵. CB1s, on the other hand, have significant expression in the medulla and peripheral nerve endings⁶, and have been identified at other sites, such as the cardiovascular system⁷, gastrointestinal tract⁸ and liver⁹. In turn, CB2 receptors are known to predominate in the immune system, especially in cells of macrophage origin, including microglia³, but are also present in lower expression in other tissues such as bone, reproductive system, cardiovascular, gastrointestinal¹⁰ and brain¹¹. Interestingly, some receptors also coupled to G protein with extracellular binding site, but with unknown endogenous ligands (hence being called orphan receptors - GPR), are also part of the system in question by having affinity for cannabinoids¹².

Also included in the endocannabinoid system are receptors with intracellular binding sites, the most important of which are the ionotropic vanilloid receptors (transient receptor potential -TRPV)¹³ and transcription factors such as the nuclear peroxisome proliferator-activated receptors (PPAR)¹⁴.

The main endogenous molecules that interact with cannabinoid receptors are anandamide (AEA) and 2-araquinodoylglycerol (2-AG)¹⁵,¹⁶,¹⁷. The effects of this interaction depend on the availability of these endocannabinoid substances in the cell, which, in turn, results from the balance between their synthesis and degradation². Both come from enzymatic activity on phospholipids. AEA can be synthesized by n-acetyltransferase (NAT), n-acyl-phosphatidylethanolamine phospholipase D (NAPE-PLD), glicero-phosphodiesterases¹⁸ and alpha/beta hydrolase¹⁹. The degradation of AEA is due to fatty acid amide hydrolase (FAAH) and n-acylethanolamine acid amidase (NAAA)²,²⁰. In turn, 2-AG is produced by diacylglycerol lipases alpha and beta (DAGL) and inactivated by monoacylglycerol lipase (MAGL)²,²⁰ and alpha/beta-beta hydrolases¹⁹.

This set of reactions needs to be highly precise, since endocannabinoids have a short half-life, approximately 15 minutes². Indeed, it is classically recognized that these substances are produced and released on demand. However, there is evidence that these processes are at least complemented by intracellular transport and storage²¹. This makes sense insofar as endocannabinoids participate both in extracellular signaling and at all levels of the intracellular space. Furthermore, these substances are lipidic, made to travel through the aqueous environments of cytosol and extracellular space, depending on carrier molecules²¹. The knowledge about these molecules is still rudimentary, and a chaperone (HSP70), albumin, and fatty acid-binding proteins (FABP)²²,²³, which are intracellular transporters, have been identified; there is a membrane transporter (EMT)²⁴ and in the extracellular compartment this movement occurs through microvesicles².

Notably, the kinetics and dynamics of endocannabinoids reveal that they are predominantly retrograde neurotransmitters²⁵,²⁶. Thus, their synthesis occurs in response to depolarization and increased calcium levels in postsynaptic cells, from where they are transported across the synaptic cleft to presynaptic cells²⁵,²⁶,²⁷. This model is interesting in the regulation of nociceptive pathways, so that the occurrence of a noxious stimulus transmitted to the postsynaptic neuron would cause it to synthesize and release endocannabinoids. These would reach presynaptic neurons by activating and inducing the expression of CB1 receptors, which, in turn, inhibit voltage-gated calcium channels and activate potassium channels. The result is restriction of the excitatory neurotransmitters release²⁸,²⁹. The activation of cannabinoid receptors, also via G protein coupled, determines the inhibition of enzyme adenylyl cyclase and synthesis of cyclic AMP, with consequent suppression of protein kinase A activity, an important intracellular signaling pathway in the production of energy through glycogenolysis and lipid metabolism²⁷.

This set of data indicates that cannabinoid system is widely involved in the suppression of neurotransmission and excitability, which is essential to control pathological states of excitotoxicity, such as chronic pain²⁹. This is in line with the evidence of this system participation in short- and long-term neuroplasticity³⁰. Finally, it is relevant to consider that the significant presence of CB1 receptors in areas essential to pain control, such as cortex, limbic system³¹, periaqueductal gray, rostral ventromedial medulla³², posterior grey column³³, trigeminal ganglion³⁴, dorsal root ganglia, and peripheral nerves³⁵, corroborates the endocannabinoid system importance in potential modification of somatic and affective aspects of pain²⁹.

Interestingly, cannabinoid receptors are able to interact with different forms of G-protein, leading to the activation of other important intracellular signaling pathways. Such is the case with mitogen-activated protein kinases (MAPKs), this diverse class of enzyme pathways is associated with cell proliferation, cell cycle and cell death. Its relationship with the cannabinoid system is of such complexity that depending on intracellular environment and the ligands involved, it can result in cell survival or death³⁶. There is still much to be known about the intracellular signaling pathways of cannabinoids, but it is already known that CB1 receptors also exist in this space, either by internalization of receptors originally located in cell membrane³⁷, or as part of a desensitization process in the interaction pathway with beta-arrestin independent of G protein³⁸, and finally, as receptors of diverse functionalities and originally expressed inside the cell³⁸. There is evidence, for example, of CB1 receptors in lysosomes, paradoxically associated with an intracellular increase of calcium³⁹, as well as in mitochondria, where they determine the reduction of cyclic AMP, mitochondrial respiration, neuroprotection, appetite and memory, according to studies on hypothalamic neurons⁴⁰.

At the same time that its wide distribution in nervous system indicates that CB1 can have several therapeutic applications, this same characteristic tends to restrict its clinical application by the potential for adverse effects³⁸. Although the distribution of CB1 receptors is very wide in central nervous system (CNS), leading to the think that it would have several therapeutic applications, however, this anatomical property leads to restrict its clinical application because it generates a significant potential for adverse effects, even though the expression of this receptor can oscillate in pathological states⁴¹. However, this restriction seems to be much smaller in the case of the CB2 receptor, whose expression is much more demand-dependent, so that tissues affected by diseases would be activated with greater selectivity⁴². Although this characteristic is advantageous in therapeutic terms, it constitutes a significant obstacle in the study of localization, structure, and function of these receptors. Despite advances in this understanding through studies with active and inactive models of these receptors, more details about the activation mechanisms of CB2 are still unclear⁴³.

Knowing that they are predominant in immune cells and other systems such as cardiovascular and digestive already indicates their potential for therapy, but more recently, CB2 receptor has also been identified in nervous system and studies point to its participation in pain modulation and neuroinflammation¹⁰. This is reinforced by the wide presence of cannabinoid receptors in glial cells as well, whose importance is increasingly recognized in the excitotoxicity present especially in neurodegenerative diseases⁴⁴.

The complexity of cannabinoid receptors also extends to their relationships with ligands. These can induce variable expressions of receptors, which can present a surprising multiplicity of conformations that, in turn, will lead to the activation of diverse signaling pathways⁴². Thus, there is a functional selectivity with great variability in affinity and response to different ligands. This makes the definition, research and development of agonists and antagonists complicated.

Studies on signaling of the endocannabinoid system suggest that 2-AG is probably the primary endogenous ligand of cannabinoid receptors, which is in line with the fact that this ligand has levels 1000 times higher than AEA in the brain³⁸. These substances also differ widely in terms of their relationship to the main receptors in this system. Traditionally, 2-AG is considered to act as a moderate affinity agonist for CB1 and CB2, whereas AEA is a partial agonist for CB1 and basically inactive for CB2⁴⁵. This does not mean that AEA is irrelevant, since it also acts on cannabinoid system, especially on ion channels via type 1 vanilloid receptors (TRPV1), and it can also act in an anterograde way⁴⁶.

Besides endocannabinoids, there are more than 100 substances derived from cannabis plant capable of interacting with cannabinoid receptors, which are the phytocannabinoids, among which tetrahydrocannabinol (THC) and cannabidiol (CBD) stand out. Tetrahydrocannabinol was the first phytocannabinoid to be discovered. It is the major responsible for cannabis psychoactive effects, through its agonist action on CB1 receptors and consequent interference in GABA/glutamate balance⁴⁷. It also causes release of dopamine with striato-limbic selectivity, although at lower levels than other substances of abuse, such as amphetamine and nicotine, as was demonstrated by a study using positron emission tomography⁴⁸. The wide distribution of CB1 in nervous system is compatible with the observation of multiple effects of THC.

One of the most important, known and interesting from a therapeutic point of view is certainly its antiemetic action. This is mainly due to the important expression of CB1 receptors in the dorsal vagal complex. However, there is evidence that central serotoninergic (5HT3) and vanilloid (TRPV1) receptors, as well as peripheral CB1s also participate⁴⁹. THC also has analgesic potential, both through CB1 receptors, whose presence in key sites of pain transmission and processing in CNS has already been cited; and through agonist action on CB2 receptors with anti-inflammatory results⁴⁷. However, the clinical use of THC is commonly limited by its psychoactive effects, including euphoria, anxiety, and even psychosis⁵⁰.

This is not the case with CBD, a phytocannabinoid discovered a few years after THC, which curiously acts as an antagonist for CB1 and CB2⁵¹ receptors, which offers an advantage not only by not giving it the adverse cognitive-behavioral effects of THC over CB1, but by being able to attenuate them⁵² when these substances are used in preparations that combine them. There is evidence that CBD acts on several other receptors. Its antiemetic, anxiolytic, and analgesic actions, at least in part, can be mediated by binding to serotonergic receptors, especially 5HT1A⁴⁷,⁵³. This same pathway would be involved in the reduction of excitotoxicity, oxidative stress, and proinflammatory activation, including microglial and lymphocytic.

Such effect would be compatible with the possible protective action of CBD in several diseases, such as neurodegenerative diseases (including Parkinson’s disease and Alzheimer’s disease), chronic pain, inflammatory, cardiac, hepatic, renal and gastrointestinal diseases, sepsis, and diabetes⁵³. One of the first applications discovered for CBD was its ability to contribute significantly to alleviating the suffering of patients with difficult to control epilepsy⁵⁴. An attempt is still being made to unravel the underlying mechanisms. Besides the action on 5HT1 receptors, it has been postulated that there is CBD activity on gabaergic receptors and ion channels⁵³.

Also of great interest is the possible contribution of CBD to antineoplastic therapy. At higher concentrations, it has been found to inhibit the proliferation of human cancer cells of various lineages, such as prostate, breast and colorectal⁵³. Several ways to explain this result have been suggested, including the participation of vanilloid receptors (TRPV1), CB2 and PPAR, compatible with the great pharmacological versatility of this phytocannabinoid⁵³. Still in this sense, there is evidence of CBD interaction with mu and delta opioid receptors, which, in association with its affinity for vanilloid receptors, reinforces its application in pain treatment⁴⁷,⁵⁵.

More recently, another phytocannabinoid has gained attention, cannabigerol (CBG), which has an intermediate pharmacological profile between THC and CBD. It shows agonism for both CB1 and CB2, but with much lower affinity than THC, and at the same time, it is able to associate with several vanilloid receptors (TRPV) like CBD, also with lower affinity⁵⁶. However, there are some peculiarities; CBG is a potent agonist of alpha-2 adrenergic receptors⁵⁶. The importance of these in blood pressure modulation, sedation and analgesia is well known. Its extensive distribution in the nervous system, with special emphasis on its participation in modulating prefrontal cortex activity, has attracted much interest about the use of alpha-2 adrenergic agonists in treatments for neuropsychiatric disorders, including attention deficit hyperactivity disorder⁵⁷. Another uniqueness of CBG is its antagonism to the 5HT1 receptor, unlike CBD and THC⁵⁶. All this considered, there is a need to better understand the interaction of CBG with the different subfamilies of the wide variety of receptors it is related to in order to safely elucidate its indications and limitations.

Such care, obviously, must be applied to the use of any group of substances. This is especially the case with cannabinoids, not only because the phytocannabinoids pharmacological diversity, of which there are more than a hundred, and of which only the best known are mentioned, but also because there are other groups of substances present in Cannabis sativa, such as the terpenes, hydrocarbons responsible for cannabis aroma, which also have therapeutic potential⁵⁸. Apparently, these substances do not act through the CB1 and CB2 receptors⁵⁹, but studies showing that extracts of the plant have superior effects compared to isolated phytocannabinoids, strongly suggest the existence of an “entourage effect”⁶⁰,⁶¹. This would correspond to a synergy between cannabis phytomolecules. If this occurs between phytocannabinoids or between terpenes, it is an intra-entourage effect, if on the other hand phytocannabinoids and terpenes participate in the synergy, it is an inter-entourage effect⁵⁸. The pharmacological processes by which these phenomena may occur are not known, but they are extremely interesting as future possibilities.

CONCLUSION

The great complexity of the endocannabinoid system, as well as its relationships with exogenous cannabinoids, the several types of receptors and systems in such a wide and varied distribution in the body, give a measure of the fascinating challenge of exploring so many possibilities, which can benefit the health of many people.

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Publication Dates

• Publication in this collection
  10 July 2023
• Date of issue
  2023

History

• Received
  13 Aug 2022
• Accepted
  24 Apr 2023