Reduction and prevention of vincristine-induced neuropathic pain symptoms by the non-benzodiazepine anxiolytic etifoxine are mediated by 3α-reduced neurosteroids

The central processing of peripheral nociceptive messages is highly controlled by the activity of local inhibitory networks in the spinal cord and supraspinal centers. Recently, it has been shown that endogenous 3α-reduced neurosteroids (3αNS) exert a significant spinal antinociception by potentiating GABAA receptor function. Because endogenous 3αNS can be produced in many relay structures of the nociceptive system, we tested the potential analgesic efficacy of promoting the production of neurosteroids by using etifoxine (ETX, 50 mg/kg i.p.). This prescribed non-benzodiazepine anxiolytic was shown previously to stimulate neurosteroidogenesis in its early step after binding to the mitochondrial translocator protein complex (TSPO). Using an animal model of generalized neuropathic pain resulting from a 2- week treatment with the antitumoral agent vincristine sulfate (VCR, 0.1 mg/kg i.p.), we show that injections of ETX (50 mg/kg i.p.) given every day reduced the VCR-induced mechanical and thermal pain symptoms but also prevented their appearance, if used in prophylaxia 1 week before VCR. Both the curative and preventive effects of ETX on pain symptoms were mediated by the production of 3αNS as demonstrated in animals treated with the enzymatic inhibitor provera (6-medroxyprogesterone acetate; 20 mg/kg s.c.). Altogether, this study shows for the first time that promoting 3αNS could be a possible therapeutic strategy to treat neuropathic pain symptoms. Since ETX is already available as an anxiolytic, its use in humans, provided that its analgesic properties are confirmed, could be rapidly considered.