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More than 450 million people worldwide suffer from diabetes, or 1 in 11 people. Chronic hyperglycemia degrades patients' quality of life and the development of neuropathic pain contributes to the burden of this disease. In this study, we used the mouse model of streptozocin-induced diabetic type 1 neuropathy to assess the analgesic potential of etifoxine. Etifoxine is a prescribed anxiolytic that increases GABAAA receptor function through a direct positive allosteric modulation effect and, indirectly, by stimulating the production of endogenous GABAA receptor positive modulators such as allopregnanolone-type neurosteroids. We show that a post-symptomatic or preventive treatment strongly and durably reduces mechanical hyperalgesia and anxiety in diabetic neuropathic mice. This analgesic and neuroprotective effect on painful symptoms and emotional comorbidities is promising and should now be clinically evaluated., Competing Interests: PP received financial support from Biocodex laboratories to investigate the molecular mechanisms of action of etifoxine. The financial support by Biocodex laboratories does not alter adherence to PLOS ONE policies on sharing data and materials. In good agreement, data could be filed in an open source depository. Moreover, the funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Neuropathic pain is frequently associated with anxiety and major depressive disorders, which considerably impact the overall patient experience. Favoring GABAergic inhibition through the pain matrix has emerged as a promising strategy to restore proper processing of nociceptive and affective information in neuropathic pain states. In this context, the non-benzodiazepine anxiolytic etifoxine (EFX), known to amplify GABAergic inhibition through positive modulation of GABA A receptors and neurosteroidogenesis, presents several advantages. Therefore, we sought to investigate the preclinical therapeutic potential of EFX on the somatosensory and affective components of neuropathic pain. Here, we used a murine model in which neuropathic pain was induced by the implantation of a compressive cuff around the sciatic nerve (mononeuropathy). We showed that the intraperitoneal EFX treatment for five consecutive days (50 mg/kg) relieved mechanical allodynia in a sustained manner. Besides its effect on evoked mechanical hypersensitivity, EFX also alleviated aversiveness of ongoing pain as well as anxiodepressive-like consequences of neuropathic pain following cuff-induced mononeuropathy. This effect was also seen 12 weeks after induction of the neuropathy when allodynia was no longer present. Analgesic and neuroprotective actions of EFX were also seen by the absence of neuropathic pain symptoms if a second sciatic nerve constriction injury was applied to the contralateral hindpaw. Mass spectrometry analysis revealed a normalization of brainstem serotonin levels in EFX-treated animals and an increase in norepinephrine. This study suggests that EFX presents promising therapeutic potential for the relief of both somatosensory and affective consequences of neuropathic pain, a beneficial effect that is likely to involve monoamine descending controls., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Inflammatory processes are critical promoting factors of chronic pain states, mostly by inducing peripheral and central sensitization of the nociceptive system. These processes are associated with a massive increase in glutamatergic transmission, sometimes facilitated by spinal disinhibition. In this study, we used etifoxine, a non-benzodiazepine anxiolytic known to amplify inhibition mediated by gamma-aminobutyric acid type A (GABA A ) receptors in pain processing regions, either directly (through allosteric modulation) or indirectly (through the synthesis of endogenous neurosteroids). We used different models of local inflammation to evaluate the possible direct action of etifoxine on analgesia and edema. Pain symptom and edema measurements were performed after intraplantar carrageenan injection or after topical ear inflammation. We found that etifoxine treatment was associated with reduced plantar surface temperature 24 h after intraplantar carrageenan injection. In this model, etifoxine also alleviated thermal hot and mechanical hyperalgesia. A similar finding was observed while analyzing pain symptoms in the late phase of the formalin test. In a model of ear inflammation, etifoxine appeared to have a moderate anti-edemic effect after topical application. This slight action of etifoxine on the limitation of inflammatory processes could be mediated in part by cyclo-oxygenase 1 activity inhibition. Etifoxine appears as a promising therapeutic tool contributing to the limitation of inflammatory pain symptoms. Since etifoxine is already prescribed as an anxiolytic in several countries, it could be a good candidate for the prevention of inflammatory-driven edema and hyperalgesia, although the precise mechanism of action relative to its anti-inflammatory potential remains to be elucidated., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Objectives: Anxiety and adjustment disorders are among the most prevalent mental health conditions. This review focuses on γ-aminobutyric acid receptor type A (GABA A R)-mediated anxiolysis, describing the action of both endogenous and exogenous modulators of GABA A R. Future directions and innovative strategies to alleviate anxiety symptoms are discussed, with a particular emphasis on etifoxine., Methods: We used available data from the recent literature to update the mode of action of anxiolytics. We focussed our search on anxiolytics acting at GABA A Rs, as well as on the pharmacological properties of formerly and currently prescribed anxiolytics., Results: Considering the adverse effects of current treatments aimed at increasing inhibitory controls, optimisation of existing pharmacotherapies is of crucial importance. Among the alternative compounds targeting the GABAergic system, translocator protein (TSPO) ligands, such as etifoxine (EFX), which promote endogenous neurosteroidogenesis, are emerging as promising candidates for anxiety relief. In several papers comparing the efficacy of benzodiazepines and EFX, EFX showed interesting properties with limited side effects. Indeed, neurosteroids are potent GABA A R modulators with highly underrated anxiolytic properties., Conclusions: Novel therapeutic strategies have been emerging following the recognition of neurosteroids as potent anxiolytics. Featured at the top of the list for well-tolerated anxiety relief, TSPO ligands such as etifoxine appear promising.

Etifoxine (EFX) is a non-benzodiazepine anxiolytic which potentiate GABAA receptor (GABAAR) function directly or indirectly via the production of 3α-reduced neurosteroids. The later effect is now recognized to account for the long-term reduction of pain symptoms in various neuropathic and inflammatory pain models. In the present study, we characterized the acute antinociceptive properties of EFX during spinal pain processing in naive and monoarthritic rats using in vivo electrophysiology. The topical application of EFX on lumbar spinal cord segment, at concentrations higher than 30 μM, reduced the excitability of wide dynamic range neurons receiving non-nociceptive and nociceptive inputs. Windup discharge resulting from the repetitive stimulation of the peripheral receptive field, and recognized as a short-term plastic process seen in central nociceptive sensitization, was significantly inhibited by EFX at these concentrations. In good agreement, mechanical nociceptive thresholds were also significantly increased following an acute intrathecal injection of EFX. The acute modulatory properties of EFX on spinal pain processing were never seen in the simultaneous presence of bicuculline. This result further confirmed EFX antinociception to result from the potentiation of spinal GABAA receptor function., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Inflammatory and degenerative diseases of the joint are major causes of chronic pain. Long-lasting pain symptoms are thought to result from a central sensitization of nociceptive circuits. These processes include activation of microglia and spinal disinhibition. Using a monoarthritic rat model of pain, we tried to potentiate neural inhibition by using etifoxine (EFX), a nonbenzodiazepine anxiolytic that acts as an allosteric-positive modulator of gamma-aminobutyric acid type A (GABAA) receptor function. Interestingly, EFX also can bind to the mitochondrial translocator protein (TSPO) complex and stimulate the synthesis of 3α-reduced neurosteroids, the most potent positive allosteric modulator of GABAA receptor function. Here we show that a curative and a preventive treatment with 50mg/kg of EFX efficiently reduced neuropathic pain symptoms. In the spinal cord, EFX analgesia was accompanied by a reduction in microglial activation and in the levels of proinflammatory mediators. Using electrophysiological tools, we found that EFX treatment not only amplified spinal GABAergic inhibition, but also prevented prostaglandin E2-induced glycinergic disinhibition and restored a "normal" spinal pain processing. Because EFX is already distributed in several countries under the trade name of Stresam for its anxiolytic actions in humans, new clinical trials are now required to further extend its therapeutic indications as pain killer., (Copyright © 2013 International Association for the Study of Pain. Published by Elsevier B.V. All rights reserved.)

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®)

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 3alpha-reduced neurosteroids (3alphaNS) exert a significant spinal antinociception by potentiating GABA(A) receptor function. Because endogenous 3alphaNS 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, 50mg/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, 0.1mg/kg i.p.), we show that injections of ETX (50mg/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 3alphaNS as demonstrated in animals treated with the enzymatic inhibitor provera (6-medroxyprogesterone acetate; 20mg/kg s.c.). Altogether, this study shows for the first time that promoting 3alphaNS 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.

We have investigated the effects of 2-ethylamino-6-chloro-4-methyl-4-phenyl-4H-3,1-benzoxazine hydrochloride (etifoxine) on GABA(A) receptor function. Etifoxine displaced [(35)S]TBPS (t-butylbicyclophosphorothionate) from GABA(A) receptors of rat cortical membranes with an IC(50) of 6.7+/-0.8 microM and [(3)H]PK11195 from peripheral (mitochondrial)-type benzodiazepine receptors (PBRs) of rat heart homogenates with an IC(50) of 27.3+/-1.0 microM. Etifoxine displayed anxiolytic properties in an anticonflict test in rats, and potentiated GABA(A) receptor-mediated membrane currents elicited by submaximal (5-10 microM) but not saturating (0.5 mM) concentrations of GABA in cultured rat hypothalamic and spinal cord dorsal horn neurones. In hypothalamic cultures, etifoxine induced a dose-dependent inward current for concentrations >1 microM which reflected the post-synaptic potentiation of a small ( approximately 20 pA) tonic and bicuculline-sensitive GABA(A) receptor-gated Cl(-) current. Etifoxine also increased the frequency of spontaneous and miniature GABAergic inhibitory post-synaptic currents without changing their amplitude and kinetic characteristics. Both effects of etifoxine were insensitive to flumazenil (10 microM), an antagonist of central-type benzodiazepine sites present at GABA(A) receptors, but were partly inhibited by PK11195 (10 microM) an antagonist of PBRs which control the synthesis of neurosteroids. Our results indicate that etifoxine potentiates GABA(A) receptor-function by a direct allosteric effect and by an indirect mechanism involving the activation of PBRs.