Despite the centuries of medicinal and recreational use of cannabis, the identity of its main psychotropic constituent remained unknown until 1964, when Rafael Mechoulam, Yechiel Gaoni, and Habib Edery, of the Institute of Weizmann Science in Rehovot (Israel), isolated Delta-9-tetrahydrocannabinol (THC) for the first time. Subsequently, it was established that this compound is responsible for the psychotropic effects of the plant. More than two decades later, it was discovered that the psychotropic effect occurs thanks to the interaction of cannabinoids with a series of specific receptors present in nerve cells.
It was not until 1988, during experiments using radio-marked CP55940, that the first of these receivers were finally identified . This receptor, called cannabinoid 1 (CB1), is mainly found in the Central Nervous System (CNS) and peripheral organs .
The second cannabinoid receptor (CB2) was discovered in 1993 using homologous cloning techniques. The CB2 receptor turns out to be different, both in the sequence of amino acids and in the distribution in our body, being mainly in peripheral tissues related to the immune system (especially in the B lymphocytes) but also, although in a lower quantity, in the nervous tissue .
THC is the main ligand of both receptors, having a higher affinity for CB1 than for CB2. 
Today we know that there are several other receptors related to the endocannabinoid system such as metabotropic receptors GPR55, GPR119, GPR18 and transient receptor potential vanilloid receptor (TRPV). 
They are mainly found in the central nervous system CNS, in greater proportions in the basal ganglia, cerebellum, neocortex and hippocampus, which is an essential area in the learning and memory processes (Herkenham et al., 1991) . They are also located in areas which are related to cognitive functions, memory, anxiety, pain, sensory perception, visceral perception, motor coordination and endocrine functions. They are found in low proportion in the immune system, peripheral nervous system, testicles, heart, small intestine, prostate, uterus, bone marrow, and vascular endothelium.
A close relationship can be seen between the distribution of CB1 receptors and the pharmacological effects produced by cannabinoids. The large presence of receptors in the basal ganglia correlates, for example, with the effects on the locomotive activity and the presence in areas of the hippocampus and cerebral cortex correlates with the effects on memory, learning and the anticonvulsant effect. (Kantona and Freund, 2012; Lu and Mackie., 2016; Mechoulam, 2016; Macarrone et al., 2015) . CB1 receptors are responsible for the psychoactive effect of cannabis.
Cannabinoid Receptors CB2
CB2 receptors are predominantly found in structures related to the immune system: Lymphoid line (lymphocytes B and T), myeloid line (monocytes, macrophages, Granulocítos, Mastócitos), glial cells of the CNS and spleen (Galiègue et al., 1995) . To a lesser extent, they are present in cells of other tissues and peripheral organs such as the heart, endothelium, bones, liver and pancreas. In the nervous tissue, the levels of CB2 are much lower than the levels of CB1. CB2 receptors of the CNS are present mainly in glial cells, increasing their presence significantly (about 100 times) in inflammation processes or after a tissue lesion (Benito et al., 2008; Di Marzo et al., 2015; Lu and Mackie., 2016)   . Its presence in neuronal progenitor cells and neurons of the cerebral cortex, hippocampus, pale globe, limbic areas and mesencephalic areas has also been described (Lanciego et al 2011; Zhang et al., 2016) . It is believed that CB2 receptors are responsible for the immune-modulatory properties of cannabis. It has not been observed that its activation produces psychoactive effects. 
The 5-HT1A are serotonin receptors distributed mainly in structures of the central nervous system like the cerebral cortex, hippocampus, tonsils and at lower levels also in the basal ganglia and the thalamus (12, 13,14). These receptors trigger different intracellular cascades of chemical messages that can produce a response both excitatory and inhibitory. In our body, they are involved in processes such as anxiety, addiction, appetite, sleep, the perception of pain, nausea and vomiting, among others. CBD at high doses can activate these receptors causing an anxiolytic effect (15, 16, 17), an antidepressant effect (17.18) and a neuroprotective effect (19.20), among others.
GPR55 and GPR119 type receptors
GPR-type receptors are distributed in adrenal glands, spleen, digestive system and widely in the CNS: Caudate Nucleus and Putamen, Hippocampus, Thalamus, Hypothalamus, Prefrontal Cortex and Cerebellum.
GPR’s could represent a bridge between the immune system, the nervous system, and the endocrine system, so their understanding leads to future therapies that could be directed at lipid metabolism, NA+/K+ homeostasis, or other ions, as well as regular hormonal profiles. A relationship between certain cannabinoids and carbohydrate intolerance has also been seen so it is being investigated whether these receptors could serve to treat syndromes related to energy metabolism.
GPR55 receptors are located in the regions of the brain that are involved in the control of functions such as memory, learning and motor coordination, such as dorsal striatum, caudate nucleus and putamen, as well as in various peripheral tissues including the ileum , testicles, spleen, tonsils, breasts, mental or adipose tissue, and even in some endothelial cell lines (21, 22). Due to its wide distribution in the CNS, it has attributed several functions that vary according to the location of the receiver (23):
- Caudate Nucleus → innervated by dopaminergic neurons/learning functions and memory/voluntary movement.
- Putamen Nucleus → functions related to learning and fine movement/ adiadokokinesis along with the cerebellum
- Hippocampus → memory, in relation to certain types/spatial memory and orientation/management anxiety/hyperactivity.
- Thalamus → Filters all sensitive stimuli minus smell/connects with the frontal lobe, emotions, hyperactivity-depression/regulates visceral activity.
- Hypothalamus → Regulates the release of hormones in pituitary/food behaviour, fluid intake, mating, aggressiveness/automatic visceral-endocrine regulation.
- Cerebellum → Motor functions, adiadokokinesis, balance/cognitive functions, attention, language, music.
- Prefrontal Cortex → Personalization of the individual, feelings/behaviours apathetic, depressive, compulsion/processes of attention.
There is evidence to indicate that the GPR55 receptor plays an important role in regulating bone metabolism, in the control of inflammatory pain, as well as in the proliferation of tumour cells. In tumours of different origins, a significantly higher expression has been observed in tissues transformed into healthy tissues. In addition, this elevated expression has been correlated with increased tumour aggressiveness and a worse prognosis for the patient (24) and is supposed to promote both growth, migration and invasion of tumour cells as the generation in vivo metastases (21).
Recent studies also attributed a possible involvement in the control of pain sensitivity. It was found that the mice GPR55-/-which lack the receptor did not present hyperalgesia (hypersensitivity to painful stimuli) mechanics in rodent models of inflammatory and neuropathic pain (25).
The GPR119 receptor shows a relatively narrow pattern of expression found predominantly in pancreatic and intestinal tissues (26, 27, 28).
Its localization in the β cells of the pancreatic islets and the Enteroendocrine intestinal L cells focuses attention on the possible involvement of the GPR119 in the control of the homeostasis of glucose (29) and obesity (30).
GPR119 and the treatment of obesity
In vitro studies and animal models have shown that their modulation produces beneficial effects on glucose homeostasis, reduces food intake (and thus limits body weight gain) and possibly helps to preserve beta-β cells Insulin-producing products in pancreatic islets (31).
GPR119 and the homeostasis of glucose
The expression of GPR119 in the β cells of the pancreatic islets has led to the hypothesis that this receptor could play a role in modulating insulin secretion. In studies with animals it has been seen that the stimulation of GPR119 exerts a double effect in the reduction of glucose in the blood, acting directly on the pancreatic β cell promoting the release of insulin, and indirectly through the whole Enteroendocrine cells, releasing incretins as GLP-1 (glucagon-like peptide) or other anti-hyperglycemic agents (32, 33, 34).
GPR119 and possible applications in the discovery of new drugs
The current data available on the effects of GPR119 agonists on animal models indicate that they could be important agents for the treatment of type 2 diabetes and obesity. The release of GPL-1 mediated by GPR119 stimulation improves the homeostasis of glucose while limiting the intake of food and the increase in body weight (35, 36, 37).
Transient Receptor Potential Vanilloid Receptors or TRPV
It is a family of ionic channels that modulate the flow of ions through the cell membrane, thus influencing the conductance of nerve impulses and the transmission, modulation and integration of harmful stimuli (38). The TRPV in mammals are formed by 6 members divided into 2 groups according to the degree of homology, TRPV1-4 and TRPV5-6 are involved in the recognition of thermal stimuli and nociceptive and modulating mechanisms of local inflammation (39, 44,45).
Its pattern of tissue distribution is very broad, being present in practically all tissues, especially in the central and peripheral nervous system. They are mediators of a wide variety of cellular functions like the initiation of pain, thermoregulation, salivary secretion, inflammation, the tone of the smooth musculature and homeostasis of calcium and magnesium, among others. (47). The fact that its function as an ionic channel is enhanced by pro-inflammatory mediators released during tissue damage, along with its wide distribution in different tissues, an important role in the modulation of inflammatory sensitization processes of nociceptors that cause hyperalgesia in the damaged area is attributed to these receptors (40, 41, 42,43). Currently, these receptors and their interrelation with the SEC are being investigated in order to develop new therapeutic targets directed to analgesic treatments.