Non-CB1, Non-CB2 Receptors for Endocannabinoids, Plant Cannabinoids, and Synthetic Cannabimimetics: Focus on G-protein-coupled Receptors and Transient Receptor Potential Channels

Abstract

The molecular mechanism of action of Delta(9)-tetrahydrocannabinol (THC), the psychotropic constituent of Cannabis, has been a puzzle during the three decades separating its characterization, in 1964, and the cloning, in the 1990s, of cannabinoid CB1 and CB2 receptors. However, while these latter proteins do mediate most of the pharmacological actions of THC, they do not seem to act as receptors for other plant cannabinoids (phytocannabinoids), nor are they the unique targets of the endogenous lipids that were originally identified in animals as agonists of CB1 and CB2 receptors, and named endocannabinoids. Over the last decade, several potential alternative receptors for phytocannabinoids, endocannabinoids, and even synthetic cannabimimetics, have been proposed, often based uniquely on pharmacological evidence obtained in vitro. In particular, the endocannabinoid anandamide, and the other most abundant Cannabis constituent, cannabidiol, seem to be the most "promiscuous" of these compounds. In this article, we review the latest data on the non-CB1, non-CB2 receptors suggested so far for endocannabinoids and plant or synthetic cannabinoids, and lay special emphasis on uncharacterized or orphan G-protein-coupled receptors as well as on transient receptor potential channels.

The endogenous cannabinoid system in the gut of patients with inflammatory bowel disease

“…8 CB1 are predominant in brain and vessels and mediate the psychoactive effects of cannabis, whereas CB2 are normally expressed on immune cells. 9,10 AEA shows higher affinity for CB1 over CB2, whereas 2-AG binds equally well to both CB1 and CB2. 7 -9 Other endocannabinoid-like compounds have been described to date, such as N -palmitoylethanolamine (PEA) and oleoylethanolamide, which are unable to bind with significant affinity to either CB1 and CB2.…”

The Endocannabinoid System and its Modulation by Phytocannabinoids

“…Unpublished electrophysiological evidence also exists for the antagonism of TRPM8 (Thomas Voets, personal communication). Nevertheless, the abovementioned thermo-TRPs, especially in the absence of other strong and specific exogenous/xenobiotic modulators, are now considered by all means bona fide "ionotropic cannabinoid receptors", whereas CB 1 R and CB 2 R would thus be defined as "metabotropic cannabinoid receptors" [3,17,18]. Importantly, several "endocannabinoid-like" mediators, such as, on the one hand, the anandamide congeners N-palmitoylethanolamine, N-oleoylethanolamine, and N-linoleoylethanolamine, as well as several N-acyl-dopamines and N-acyl-taurines, as direct or indirect activators [11,[19][20][21][22], and, on the other hand, some N-acyl-serotonins, as competitive antagonists [23,24], have been shown to interact with TRPV1 in in vitro and in vivo studies.…”

“…Abn-CBD = abnormal cannabidiol; DAG = diacylglycerol; PLCβ = phospholipase β. Adapted from Di Marzo [58] analogue, Δ 9 -tetrahydrocannabivarin (THCV), are capable of binding with high affinity to CB 1 R and CB 2 R (with agonist and antagonist activity for THC and THCV, respectively); hence, these 2 receptors should not be defined as "cannabinoid" receptors, but rather as THC/THCV receptors [alternatively the definition of "cannabinoid receptor" should also include those proteins that often bind to cannabinoids, such as the thermosensitive transient receptor potential (TRP) cation channels (thermo-TRPs) [3] (see below)]; 2) as a consequence, "endocannabinoids" should not be the endogenous ligands of CB 1 R and CB 2 R, but rather the ligands of all those "cannabinoid receptors" that uniquely and selectively bind to cannabinoids in general (thus, anandamide and 2-AG might not be the only endocannabinoids); and 3) again, as a consequence, "endocannabinoid enzymes" would not only be NAPE-PLD, the two DAGLs, FAAH, and MAGL, but also other enzymes responsible for the biosynthesis and inactivation of the other mediators to be eventually included in the list of the endocannabinoids.…”

Cannabinoids and Epilepsy

“…Increased levels of adenosine activate A2 receptors, which regulate striatal CB 1 Rs [120]. At high micromolar [73] levels, CBD also inhibits the uptake and enzymatic degradation of anandamide via FAAH, elevating anandamide extracellular concentrations [121]. Thus, dynamic interactions likely occur between the multiple plant cannabinoids such as CBD and Δ9-THC (see "Entourage Effect").…”