The CB2-preferring agonist JWH015 also potently and efficaciously activates CB1 in autaptic hippocampal neurons

Abstract

The G protein coupled receptors CB1 and CB2 are targets for the psychoactive constituents of cannabis, chief among them Δ9-THC. They are also key components of the multifunctional endogenous cannabinoid signaling system. CB1 and CB2 receptors modulate a wide variety of physiological systems including analgesia, memory, mood, reward, appetite and immunity. Identification and characterization of selective CB1 and CB2 receptor agonists and antagonists will facilitate understanding the precise physiological and pathophysiological roles of cannabinoid receptors in these systems. This is particularly necessary in the case of CB2 because these receptors are sparsely expressed and problematic to detect using traditional immunocytochemical approaches.1-Propyl-2-methyl-3-(1-naphthoyl)indole (JWH015) is an aminoalkylindole that has been employed as a “CB2-selective” agonist in more than 40 published papers. However, we have found that JWH015 potently and efficaciously activates CB1 receptors in neurons. Using murine autaptic hippocampal neurons, which express CB1, but not CB2 receptors, we find that JWH015 inhibits excitatory postsynaptic currents with an EC50 of 216nM. JWH015 inhibition is absent in neurons from CB1−/− cultures and is reversed by the CB1 antagonist, SR141716 [200nM]. Furthermore, JWH015 partially occludes CB1-mediated DSE (∼35% remaining), an action reversed by the CB2 antagonist, AM630 [1 and 3μM], suggesting that high concentrations of AM630 also antagonize CB1 receptors.We conclude that while JWH015 is a CB2-preferring agonist, it also activates CB1 receptors at experimentally encountered concentrations. Thus, CB1 agonism of JWH015 needs to be considered in the design and interpretation of experiments that use JWH015 to probe CB2-signaling.