Cannabinoids throw up a conundrum

Abstract

The principal biologically active constituent of cannabis, D 9 -tetrahydrocannabinol (THC) and its synthetic analogues decrease neuronal signalling in the central, peripheral and enteric nervous systems (Martin, 2002). Some neural e ects produced by cannabinoids have potential clinical bene®ts, such as their analgesic and antiemetic actions. In the past decade, several arachidonic acid derivatives such as anandamide and 2-arachidonoylglycerol have been identi®ed as endogenous activators of two G protein-coupled cannabinoid receptors. Postsynaptic activity stimulates endocannabinoid synthesis, resulting in a retrograde action of endocannabinoids on cannabinoid receptors located on presynaptic terminals. Through the use of cannabinoid receptor knockout animals and the development of selective receptor antagonists, it has been possible to link many of the behavioural and peripheral e ects of cannabinoids to actions on the endocannabinoid system. Although cannabinoid receptors have been cloned and are well-characterized, pharmacological studies with cannabinoid ligands have continued to present conundrums. Some of the neuronal, cardiovascular and gastrointestinal actions of cannabinoids have been ascribed to mechanisms independent of cannabinoid CB 1 and CB 2 receptors (Kunos et al., 2000;Zygmunt et al., 2002). Moreover, anandamide appears to act as an agonist at vanilloid VR 1 receptors (Smart et al., 2000). Finally, the cannabimimetic eicosanoids, THC derivatives (such as CP-55,940) and aminoalkylindole-based cannabinoids (WIN-55,212-2 is an example) inhibit 5-HT evoked depolarization of rat nodose ganglion neurones. This e ect could not be attributed to cannabinoid receptors or indeed to a G protein-coupled receptor, but rather to the ionotropic 5-HT 3 receptor (Fan, 1995).Using 5-HT 3A receptor subunits expressed in HEK 293 cells, Barann et al. (this issue, 2002) report compelling evidence that cannabinoids allosterically modulate this ligand-gated ion channel. Chemically dissimilar cannabinoid agonists inhibited 5-HT-induced cation conductance with a rank order of potency that di ered from their potencies in stimulating cannabinoid receptors (Table 1). Moreover, the inhibitory actions of WIN-55,212 were resistant to the cannabinoid CB 1 receptor antagonist, SR-141716A and the presence of speci®c cannabinoid binding sites was not detected in HEK 293 cells. These results suggest that the inhibitory actions of cannabinoids are not mediated by cannabinoid receptors, yet their actions were potent and stereoselective. Thus, these lipophilic drugs appear to exert their actions directly on the 5-HT 3A receptor through a novel modulatory site.This modulatory action is non-competitive in nature, as pre-treatment of the recombinant 5-HT 3A receptor with the cannabinoid agonist WIN55,212-2 results in a suppression of the maximal current evoked by 5-HT. The mechanism of this antagonism is still not clear, although the required preincubation and the lack of use dependence would seem to rule out an open channel block. The al...

Cannabinoid receptor‐independent inhibition by cannabinoid agonists of the peripheral 5‐HT3 receptor‐mediated von Bezold–Jarisch reflex

“…The latter possibility could not be ruled out, when considering the lack of experiments with cannabinoid receptor antagonists in the study of Fan (1995). However, recently it was shown in a combined patch‐clamp and radioligand binding study on outside‐out patches and membrane preparations, respectively, of HEK 293 cells expressing recombinant human 5‐HT 3A (h5‐HT 3A ) receptors that cannabinoid receptor ligands directly act at the h5‐HT 3A receptor, probably by binding to an allosteric modulatory site (Barann et al ., 2002; see also Commentary by Townsend IV et al ., 2002).…”

Psychotropic and nonpsychotropic cannabis derivatives inhibit human 5-HT3A receptors through a receptor desensitization-dependent mechanism

“…The antiemetic action of cannabis has been proposed to occur partially via inhibition of 5-HT 3 receptors (Townsend et al ., 2002). However, whether or not CBD can inhibit h5-HT 3A Rs and the mechanism underlying cannabinoid inhibition have not been reported.…”

Endocannabinoids and the gastrointestinal tract: what are the key questions?

“… Anandamide and 2‐AG may also activate transient receptor potential vanilloid subtype 1 (TRPV1) receptors and cannabinoid ligands may inhibit 5‐hydroxytryptamine (5‐HT)‐induced depolarization of rat nodose ganglia and allosterically modulate the 5‐HT 3A receptor (see Townsend et al , 2002). The ability to activate both CB 1 and TRPV1 receptors is illustrated by experiments with anandamide, in which relatively low concentrations reduce electrically evoked cholinergically mediated contractions of guinea‐pig isolated ileum (longitudinal muscle‐myenteric plexus preparation) via CB 1 receptors sensitive to the selective CB 1 r‐antagonist rimonabant (SR141716), whereas at higher concentrations, anandamide increased basal ACh release in a manner reversible by the TRPV1 r‐antagonist capsazepine but not by rimonabant (Mang et al , 2001).…”