N-Arachidonoyl Dopamine : A Novel Endocannabinoid and Endovanilloid with Widespread Physiological and Pharmacological Activities
Urszula Grabiec and Faramarz Dehghani
Cannabis and Cannabinoid Research, 2017, 2, (1), 183-196
N-arachidonoyl dopamine (NADA) is a member of the family of endocannabinoids to which several other N-acyldopamines belong as well. Their activity is mediated through various targets that include cannabinoid receptors or transient receptor potential vanilloid (TRPV)1. Synthesis and degradation of NADA are not yet fully understood. Nonetheless, there is evidence that NADA plays an important role in nociception and inflammation in the central and peripheral nervous system. The TRPV1 receptor, for which NADA is a potent agonist, was shown to be an endogenous transducer of noxious heat. Moreover, it has been demonstrated that NADA exerts protective and antioxidative properties in microglial cell cultures, cortical neurons, and organotypical hippocampal slice cultures. NADA is present in very low concentrations in the brain and is seemingly not involved in activation of the classical pathways. We believe that treatment with exogenous NADA during and after injury might be beneficial. This review summarizes the recent findings on biochemical properties of NADA and other N-acyldopamines and their role in physiological and pathological processes. These findings provide strong evidence that NADA is an effective agent to manage neuroinflammatory diseases or pain and can be useful in designing novel therapeutic strategies.
Keywords : cannabinoid receptor 1; endocannabinoid; endovanilloid; N-arachidonoyl dopamine; transient receptor potential vanilloid 1
The endocannabinoid (EC) system consists of cannabinoid receptors, mediators, and enzymes responsible for the synthesis and degradation of endogenous ligands, namely ECs. ECs are lipid signaling molecules, which are involved in a diverse range of physiological and pathological processes.1–3 N-acyldopamines consist of a hydrocarbon tail and a polar head group capable of interacting with cell membranes, membrane proteins, or ion channels function. The best examined member of this group is N-arachidonoyl dopamine (NADA) next to endogenous N-oleoyl dopamine (OLDA), Npalmitoyl dopamine (PALDA), and N-stearoyl dopamine (STERDA) and synthetic N-octanoyl dopamine (NOD).4 The formation and inactivation of N-acyldopamines as well as their significance under physiological and pathological conditions are not fully understood yet. NADA was first synthesized as a pharmacological tool to study the EC system.5 Later NADA and other Nacyldopamines were identified as endogenous cannabinoids in the mammalian nervous tissue.6,7
Several lines of evidence identified NADA, next to anandamide (AEA), as a member of the endovanilloid family acting as an agonist with similar potency as capsaicin.6 NADA and OLDA act on transient receptor potential vanilloid (TRPV)1 and play an important role in nociception. It was postulated that endovanilloids such as AEA or NADA participate in the development of neuropathic pain and inflammatory hyperalgesia.8 Despite similarity in the structures of NADA and AEA, these two ECs vary in their functional activity: some of them will be mentioned later.
This review is divided in four sections. (1) The first section describes distribution and the current status of our understanding on the synthesis, transport, and degradation of N-acyldopamines. (2)
The second section summarizes our current knowledge on the pharmacology of N-acyldopamines and theirs receptors, such as cannabinoid (CB), CB-like, and TRP receptors, and coupled signal transduction pathways under physiological and pathological circumstances will be reported. (3)
The third section deals with N-acyldopamines mediated modulation of neuropathic pain and inflammatory hyperalgesia. (4) Finally, other effects of N-acyldopamines, protective versus toxic, with actions on immune and those in vascular system are mentioned.