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 GABAA 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.