Positive allosteric modulatory effects of ajulemic acid at strychnine-sensitive glycine α1- and α1β-receptors

The synthetic cannabinoid ajulemic acid (CT-3) is a potent cannabinoid receptor agonist which was found to reduce pain scores in neuropathic pain patients in the absence of cannabis-like psychotropic adverse effects. The reduced psychotropic activity of ajulemic acid has been attributed to a greater contribution of peripheral CB receptors to its mechanism of action as well as to non-CB receptor mechanisms. Loss of inhibitory synaptic transmission within the dorsal horn of the spinal cord plays a key role in the development of chronic pain following inflammation or nerve injury. Inhibitory postsynaptic transmission in the adult spinal cord involves mainly glycine. As we hypothesised that additional non-CB receptor mechanisms of ajulemic acid might contribute to its effect in neuropathic pain, we investigated the interaction of ajulemic acid with strychnine-sensitive alpha(1)-and alpha(1)beta-glycine receptors by using the whole-cell patch clamp technique. Ajulemic acid showed a positive allosteric modulating effect in a concentration range which can be considered close to clinically relevant concentrations (EC50 values: alpha(1)= 9.7 +/- 2.6 mu M and alpha(1)beta= 12.4 +/- 3.4 mu M). Direct activation of glycine receptors was observed at higher concentrations above 100 mu M (EC50 values: alpha(1)= 140.9 +/- 21.5 mu M and alpha(1)beta= 154.3 +/- 32.1 mu M). These in vitro results demonstrate that ajulemic acid modulates strychnine-sensitive glycine receptors in clinically relevant concentrations.