Inhibition of Voltage-Gated Na+ Channels by the Synthetic Cannabinoid Ajulemic Acid

Abstract

Our data suggest that block of sodium channels can be a relevant mechanism by which ajulemic acid alleviates neuropathic pain. The potent inhibition of resurgent currents and the preserved block on local anesthetic-insensitive channels indicates that ajulemic acid interacts with a conserved but yet unknown site of sodium channels.

How much can synthetic cannabinoid damage the heart? A case of cardiogenic shock following resistant ventricular fibrillation after synthetic cannabinoid use

“…The dysrhythmia mechanism of SCs is not yet fully understood. SCs exhibit inhibitory effects on myocardial voltage–gated sodium channels and L‐type calcium channels, independently of CB1–2 receptor effects . These mechanisms were the probable cause of ventricular dysrhythmias in this case, and these substances are likely to cause resistant VF when consumed in large quantities, as with this patient.…”

“…SCs exhibit inhibitory effects on myocardial voltage-gated sodium channels and L-type calcium channels, independently of CB1-2 receptor effects. 13,14 These mechanisms were the probable cause of ventricular dysrhythmias in this case, and these substances are likely to cause resistant VF when consumed in large quantities, as with this patient. In addition to previously reported cases of prolonged QTc and Mobitz type II block associated with SC, SCs have also been described as a potential cause of lethal dysrhythmias.…”

The influence of voltage‐gated sodium channels on human gastrointestinal nociception

“…Serotonin selective reuptake inhibitors were shown to reduce the activity of some VGSCs (Na V 1.7 and Na V 1.8) evaluated in cell culture, while tricyclic antidepressants powerfully diminished mechanical and thermal somatosensory pain in a rat spinal cord injury model . The endocannabinoid, anandamide, and the synthetic cannabinoid, ajulemic acid, have both been shown to inhibit function of multiple VGSCs, including Na V 1.7 and Na V 1.8, while inducing analgesia . At least one murine model suggests that endogenous opioids appear to be necessary to facilitate Na V 1.7‐mediated visceral pain perception .…”

“…122 The endocannabinoid, anandamide, and the synthetic cannabinoid, ajulemic acid, have both been shown to inhibit function of multiple VGSCs, including Na V 1.7 and Na V 1.8, while inducing analgesia. 123,124 At least one murine model suggests that endogenous opioids appear to be necessary to facilitate Na V 1.7-mediated visceral pain perception. 125 Inflammatory mediators can also significantly alter VGSC expression and function.…”

Cannabinoids Modulate Neuronal Activity and Cancer by CB1 and CB2 Receptor-Independent Mechanisms

“…In the case of the synthetic cannabinoid, ajulemic acid that is structurally-related to THC, patch clamp studies of HEK293 and ND7/23 cells expressing various types of voltage-gated sodium channels demonstrated inhibition with potencies ranging from 1 to 10 μM (Foadi et al, 2014 ). These results suggest that the efficacy of ajulemic acid to reduce neuropathic pain may involve sodium channel inhibition.…”