Endocannabinoid system

The endocannabinoid system, broadly speaking, includes: • Endocannabinoids, which are the physiological ligands, or connecting substances, for the cannabinoid receptors. The main endocannabinoids are anandamide (N-arachidonoylethanolamide) and 2-AG (2-arachidonoylglycerol), which are in the same class of chemical compounds, called N-acylethanolamines (NAEs). Endocannabinoids are all eicosanoids, another class of compound. • The enzymes that synthesize (create) and degrade (break down) the endocannabinoids, including fatty acid amide hydrolase and monoacylglycerol lipase. • The cannabinoid receptors CB1 and CB2, two G protein-coupled receptors that are located in the central and peripheral nervous systems. The neurons, neural pathways, and other cells where these molecules, enzymes, and one or both cannabinoid receptor types are all localized together collectively comprise the endocannabinoid system. The endocannabinoid system has been studied using genetic and pharmacological methods. These studies have revealed that cannabinoids act as neuromodulators, or regulators of many neurons and neural signals, for a variety of processes, including motor learning, appetite, among other cognitive and physical processes. The CB1 receptor in the endocannabinoid system shows significant overlap with the orexinergic projection system, a network of hypothalamic projections that regulate many of the same physical and cognitive functions. where the CB1 and orexin receptor 1 (OX1) receptors physically and functionally join to form the CB1–OX1 receptor heterodimer. Expression of receptors Cannabinoid binding sites exist throughout the central and peripheral nervous systems. The two most relevant receptors for cannabinoids are the CB1 and CB2 receptors, which are expressed predominantly in the brain and immune system respectively. Density of expression varies based on species and correlates with the efficacy that cannabinoids will have in modulating specific aspects of behavior related to the site of expression. For example, in rodents, the highest concentration of cannabinoid binding sites are in the basal ganglia and cerebellum, regions of the brain involved in the initiation and coordination of movement. In humans, cannabinoid receptors exist in much lower concentration in these regions, which helps explain why cannabinoids possess a greater efficacy in altering rodent motor movements than they do in humans. A recent analysis of cannabinoid binding in CB1 and CB2 receptor knockout mice found cannabinoid responsiveness even when these receptors were not being expressed, indicating that an additional binding receptor may be present in the brain. In addition to CB1 and CB2, certain orphan receptors are known to bind endocannabinoids as well, including GPR18, GPR55 (a regulator of neuroimmune function), and GPR119. CB1 has also been noted to form a functional human receptor heterodimer in orexin neurons with OX1, the CB1–OX1 receptor, which mediates feeding behavior and certain physical processes such as cannabinoid-induced pressor responses which are known to occur through signaling in the rostral ventrolateral medulla. Endocannabinoid synthesis, release, and degradation During neurotransmission, the pre-synaptic neuron releases neurotransmitters into the synaptic cleft which bind to cognate receptors expressed on the post-synaptic neuron. Based upon the interaction between the transmitter and receptor, neurotransmitters may trigger a variety of effects in the post-synaptic cell, such as excitation, inhibition, or the initiation of second messenger cascades. Based on the cell, these effects may result in the on-site synthesis of endogenous cannabinoids anandamide or 2-AG by a process that is not entirely clear, but results from an elevation in intracellular calcium. This process is mediated by bile acids. In NAPE-phospholipase D (NAPEPLD)-knockout mice, cleavage of NAPE is reduced in low calcium concentrations, but not abolished, suggesting multiple, distinct pathways are involved in anandamide synthesis. The synthesis of 2-AG is less established and warrants further research. Once released into the extracellular space by a putative endocannabinoid transporter, messengers are vulnerable to glial cell inactivation. Endocannabinoids are taken up by a transporter on the glial cell and degraded by fatty acid amide hydrolase (FAAH), which cleaves anandamide into arachidonic acid and ethanolamine or monoacylglycerol lipase (MAGL), and 2-AG into arachidonic acid and glycerol. While arachidonic acid is a substrate for leukotriene and prostaglandin synthesis, it is unclear whether this degradative byproduct has unique functions in the central nervous system. Emerging data in the field also points to FAAH being expressed in postsynaptic neurons complementary to presynaptic neurons expressing cannabinoid receptors, supporting the conclusion that it is major contributor to the clearance and inactivation of anandamide and 2-AG after endocannabinoid reuptake. Binding and intracellular effects Cannabinoid receptors are G-protein coupled receptors located on the pre-synaptic membrane. While there have been some papers that have linked concurrent stimulation of dopamine and CB1 receptors to an acute rise in cyclic adenosine monophosphate (cAMP) production, it is generally accepted that CB1 activation via cannabinoids causes a decrease in cAMP concentration by inhibition of adenylyl cyclase and a rise in the concentration of mitogen-activated protein kinase (MAP kinase). Results from rat hippocampal gene chip data after acute administration of tetrahydrocannabinol (THC) showed an increase in the expression of transcripts encoding myelin basic protein, endoplasmic proteins, cytochrome oxidase, and two cell adhesion molecules: NCAM, and SC1; decreases in expression were seen in both calmodulin and ribosomal RNAs. In addition, CB1 activation has been demonstrated to increase the activity of transcription factors like c-Fos and Krox-24. This reduction in activity means that depolarization of affected cells is less likely to occur, and thus neural signalling is reduced. In the central nervous system, CB1 receptors influence neuronal excitability, reducing the incoming synaptic input. This mechanism, known as presynaptic inhibition, occurs when a postsynaptic neuron releases endocannabinoids in retrograde transmission, which then bind to cannabinoid receptors on the presynaptic terminal. CB1 receptors then reduce the amount of neurotransmitter released, so that subsequent excitation in the presynaptic neuron results in diminished effects on the postsynaptic neuron. It is likely that presynaptic inhibition uses many of the same ion channel mechanisms listed above, although recent evidence has shown that CB1 receptors can also regulate neurotransmitter release by a non-ion channel mechanism, i.e., through Gi/o-mediated inhibition of adenylyl cyclase and protein kinase A. Direct effects of CB1 receptors on membrane excitability have been reported, and strongly impact the firing of cortical neurons. A series of behavioral experiments demonstrated that NMDAR, an ionotropic glutamate receptor, and the metabotropic glutamate receptors (mGluRs) work in concert with CB1 to induce analgesia in mice, although the mechanism underlying this effect is unclear. ==Potential functions==