Positive allosteric modulatory effects of ajulemic acid at strychnine-sensitive glycine alpha1- and alpha1beta-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 (EC(50) values: alpha(1) = 9.7 +/- 2.6 microM and alpha(1)beta = 12.4 +/- 3.4 microM). Direct activation of glycine receptors was observed at higher concentrations above 100 microM (EC(50) values: alpha(1) = 140.9 +/- 21.5 microM and alpha(1)beta = 154.3 +/- 32.1 microM). These in vitro results demonstrate that ajulemic acid modulates strychnine-sensitive glycine receptors in clinically relevant concentrations.
Ahrens
Jörg
J
Clinic for Anaesthesia and Critical Care Medicine, OE 8050, Hannover Medical School, Carl-Neuberg-Str. 1, 30623, Hannover, Germany. ahrens.j@mh-hannover.de
Leuwer
Martin
M
Demir
Reyhan
R
Krampfl
Klaus
K
de la Roche
Jeanne
J
Foadi
Nilufar
N
Karst
Matthias
M
Haeseler
Gertrud
G
D002460:Cell Line; D013759:Dronabinol / Q000031:analogs & derivatives* / Q000494:pharmacology; D055724:Electrophysiological Phenomena / Q000187:drug effects; D005998:Glycine / Q000494:pharmacology; D006801:Humans; D018408:Patch-Clamp Techniques; D011487:Protein Conformation / Q000187:drug effects; D018009:Receptors, Glycine / Q000819:agonists / Q000187:drug effects* / Q000235:genetics; D017981:Receptors, Neurotransmitter / Q000819:agonists / Q000187:drug effects / Q000235:genetics; D014162:Transfection
C114561:GLRB protein, human; D018009:Receptors, Glycine; D017981:Receptors, Neurotransmitter; C027822:strychnine receptor; D013759:Dronabinol; C471849:lenabasum; D005998:Glycine