Positive allosteric modulatory effects of ajulemic acid at strychnine-sensitive glycine α1- and α1β-receptors
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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 α1- and α1β-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: α1 = 9.7 ± 2.6 μM and α1β = 12.4 ± 3.4 μM). Direct activation of glycine receptors was observed at higher concentrations above 100 μM (EC50 values: α1 = 140.9 ± 21.5 μM and α1β = 154.3 ± 32.1 μM). These in vitro results demonstrate that ajulemic acid modulates strychnine-sensitive glycine receptors in clinically relevant concentrations.
KeywordsGlycine receptor Neuropathic pain Cannabinoids Ajulemic acid (CT-3)
We are grateful to J. Kilian and A. Niesel, Dept. of Neurology, Hannover, for technical support and Prof. Dr. Sumner Burstein, Dept. of Biochemistry and Molecular Pharmacology, University of Massachusetts Medical School, USA, for his kind supply of AJA.
Conflict of interest statement
The authors declare that they have no conflict of interest.
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