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Background: Pathological pain states are often associated with neuronal hyperexcitability in the spinal cord. Reducing this excitability could theoretically be achieved by amplifying the existing spinal inhibitory control mediated by GABAA receptors (GABAARs). In this study, we used the non-benzodiazepine anxiolytic etifoxine (EFX) to characterize its interest as pain killer and spinal mechanisms of action. EFX potentiates GABAAR function but can also increase its function by stimulating the local synthesis of 3α-reduced neurosteroids (3αNS), the most potent endogenous modulators of this receptor., Methods: The efficacy of EFX analgesia and the contribution of 3αNS were evaluated in a rat model of mononeuropathy. Spinal contribution of EFX was characterized through changes in pain symptoms after intrathecal injections, spinal content of EFX and 3αNS, and expression of FosB-related genes, a marker of long-term plasticity., Results: We found that a 2-week treatment with EFX (>5 mg/kg, i.p.) fully suppressed neuropathic pain symptoms. This effect was fully mediated by 3αNS and probably by allopregnanolone, which was found at a high concentration in the spinal cord. In good agreement, the level of EFX analgesia after intrathecal injections confirmed that the spinal cord is a privileged target as well as the limited expression of FosB/ΔFosB gene products that are highly expressed in persistent pain states., Conclusions: This preclinical study shows that stimulating the production of endogenous analgesics such as 3αNS represents an interesting strategy to reduce neuropathic pain symptoms. Since EFX is already prescribed as an anxiolytic in several countries, a translation to the human clinic needs to be rapidly evaluated., (© 2013 European Pain Federation - EFIC®)