Anandamide was the first identified endocannabinoid, named after the Sanskrit 'ananda' for inner bliss. Anandamide is produced from lipids in cellular membranes throughout the body. In the brain, Anandamide is primarily involved in negative feedback, keeping brain activity in balance. In the body, Anandamide is implicated in the suppression of tumour growth, pain and vomiting and the stimulation of eating.
NAT: N-acyltransferase (Ca2+-dependent)
Produces NAPE from phospholipids.
iNAT: N-acyltransferase (Ca2+-independent)
Produces NAPE from phospholipids. Low abundant in brain.
NAPE-PLD: N-acyl-phosphatidylethanolamine (NAPE)-hydrolyzing phospholipase D
Produces Anandamide from NAPE
ABDH4: α/β-hydrolase 4
Lyso-PLD: lyso-phospholipase D
GDE1: glycerophosphodiester phosphodiesterase 1
PTPN22: protein tyrosine phosphatase, non-receptor type 22
Phospholipase C-mediated hydrolysis of NAPE
FAAH-1: fatty acid amide hydrolase-1
FAAH-2: fatty acid amide hydrolase-2
NAAA: N-acylethanolamine-hydrolyzing acid amidase
CytP450: cytochrome P450
Less abundant in brain than 2AG, also found in the liver
In one study in rats, chronic stimulation of the endocannabinoid system (Anandamide) reduced addictive behavior (cocaine seeking), suggesting a role for the endocannabinoid system in suppressing Addiction (Chauvet et al., 2014).
2AG and AEA are involved in food intake regulation (Fride, Bregman, & Kirkham, 2005).
DAGLα knockout mice showed a reduction of 80% of 2-AG, reduction of AEA and increased fear and Anxiety responses (Jenniches et al., 2016).
CB2 agonists as Anandamide or THC affect the inflammatory process of bone cancer cells by modulating interleukin, tumor necrosis factor α and nuclear factor-κB expression and cofilin-1 protein (Hsu et al., 2007; Lu et al., 2015; Yang et al., 2015).
However, the specific mechanism of the endocannabinoid system is not clear. Some studies suggest that Anandamide anti cancer properties depend on TRPV1 and not on CB1 or CB2 (Contassot et al., 2004; Ramer and Hinz, 2008).
In a rat study, Anandamide was found to induce bladder inflammation pain through TRPV1 suggesting this receptor might be a therapeutic target (Dinis et al., 2004). Interestingly, the opposite was found in another study where boosting Anandamide levels by preventing its breakdown exerted potent analgesic and anti-inflammatory effects (Wang et al., 2015). FAAH was responsible of breaking down Anandamide. Several studies found that CB2 was upregulated with Cystitis (Merriam et al., 2008; Tambaro et al., 2014) and that activation of CB2 with Anandamide or PEA attenuated pain and inflammation (Jaggar et al., 1998; Wang et al., 2013, 2014).
Anandamide levels (and to a lesser degree 2AG levels) and CB1 receptor availability are increased in the hippocampus (but not in the prefrontal cortex). Blocking the endocannabinoid system prevents the production of new neurons suggesting a role for cannabinoids in this process (Hill et al., 2010).
In an experimental mouse model of Eczema endocannabinoids AEA and PEA were increased and TRPV1 and PPARα were upregulated (Petrosino et al., 2010). PEA enhances AEA activity at CB1, CB2 and TRPV1 receptors and protects against keratinocyte inflammation in a TRPV1-, but not CB1, CB2 or PPARα-dependent way.
Anandamide reduces burst-firing in neurons (Evans et al., 2008).
Functional Gastro-Intestinal Disorders
Patients with Crohn’s Disease have significantly reduced levels of Anandamide, but not 2AG or PEA, supporting a role for the endocannabinoid system in Crohn’s Disease (Di Sabatino et al., 2011). Intracerebrovascular application of Anandamide and 2AG appeared gastro-protective in ethanol-induced ulcers suggesting the involvement of endocannabinoids in the central nervous system (Gyires and Zádori, 2016).
cannabinoid receptors CB1 and CB2 are upregulated and Endocannabinoids like AEA, 2-AG, OEA and PEA show increased levels after cerebral ischemia (England et al., 2015; Lara-Celador et al., 2013). AEA modulates the function of the glia increasing its pro-inflammatory response in the brain (Vázquez et al., 2015).
CB1 receptors mediated sleep effects caused by Anandamide in a rat model with in vivo microdialysis (Murillo-Rodriguez et al., 2003). Anandamide may interact with oleamide processes to induce sleep. CBD would act as an inhibitor of Anandamide uptake through TPRV1 receptor, suggesting a role in sleep (Bisogno et al., 2001; Mechoulam et al., 1997). Administration of a synthetic inhibitor of Anandamide uptake showed increased sleep in rats and enhanced c-Fos expression in sleep related brain areas (Murillo-Rodríguez et al., 2008).
Anandamide reduced parasitaemia and increased the survival rate of infected mice through the acceleration of eryptosis of infected erythrocytes (Bobbala et al., 2010).
Pre-administered Anandamide significantly reduced nociceptive behavior in rats, suggesting that migraine may actually be a manifestation of a dysfunctional endocannabinoid system (Greco et al., 2011), which in turn offers interesting possibilities for endo- and plant cannabinoids in the treatment of migraine.
endocannabinoids are derived from Poly Unsaturated Fatty Acids (PUFAs) with Anandamide and 2AG coming from Ω-6 PUFAs and EPA and DHA coming from Ω-3 PUFAs. The typical Western diet is low on PUFAs and has a low Ω-3/Ω-6 ratio. Shifting the balance to a higher Ω-3 content leads to weight loss, presumably through differential activation of the endocannabinoidsystem (Watkins and Kim, 2014)
In a mouse study, the endocannabinoid system was found to be required for the analgesic action of acetaminophen (paracetamol); FAAH breaks down acetaminophen to AM404 (first identified as synthetic cannabinoid but also displaying endocannabinoid activity), which in turn blocks re-uptake of Anandamide (Mallet et al., 2008). The analgesic effect of paracetamol thus seems to be due to increased ambient levels of Anandamide. Blocking CB1 completely prevents the analgesic action of paracetamol suggesting CB1 is required for analgesia (Bertolini et al., 2006). Similarly, ibuprofen was found to block the breakdown/hydrolysis of Anandamide (Fowler et al., 1999), which may contribute to the analgesic effect of ibuprofen (and similar substances).
Similarly, the endocannabinoid Anandamide strongly suppresses keratinocyte proliferation and induces cell death via sequential activation of CB1 and TRPV1 (Tóth et al., 2011), suggesting the endocannabinoid system normally keeps keratinocyte proliferation in check.
Regarding the molecular mechanisms of the comorbidity between cannabis and Schizophrenia, the endocannabinoid system has been related to Schizophrenia. endocannabinoids like Anandamide and 2-AG play an important role on Psychosis (Manseau and Goff, 2015). Some studies point to an Anandamide imbalance associated to Psychosis (Leweke, 2012). In unmedicated patients with acute Psychosis one of the body’s main endocannabinoids, Anandamide, is elevated 8-fold. This elevation is absent in patients on anti-psychotics and is inversely correlated with psychotic symptoms, suggesting Anandamide actually functions to suppress psychotic behavior (Giuffrida et al., 2004).
Similar to chronic stress, people with PTSD have 15-20% lower CB1 levels and more than 50% reduced Anandamide levels (Neumeister et al., 2013) which may form a mechanistic insight in the development of PTSD and/or depression.
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Several clinical trials have tested the therapeutic potential of cannabinoids after Stroke. Meta-analysis revealed that both endocannabinoids like AEA, OEA or PEA and plant cannabinoids like THC or CBD can significantly reduce neuronal degeneration after Stroke (England et al., 2015). Specifically activating CB1 and/or CB2 receptors had the strongest protective effect but other receptors such as 5-TH1a and PPARα are also likely to be involved.
England, T.J., Hind, W.H., Rasid, N.A., and O’Sullivan, S.E. (2015). cannabinoids in experimental Stroke: a systematic review and meta-analysis. J. Cereb. Blood Flow Metab. Off. J. Int. Soc. Cereb. Blood Flow Metab. 35, 348–358.