Mitochondrial Translocator-Protein Ligand Etifoxine Reduces Pain Symptoms and Protects Against Motor Dysfunction Development Following Peripheral Nerve Injury in Rats

Peripheral nerve injury enhances mitochondrial translocator protein (TSPO) expression in the spinal cord and dorsal root ganglia (DRG), which is associated with neuroinflammation and mitochondrial dysfunction contributing to chronic pain development. Here, we investigate the effect of TSPO ligand Etifoxine, on the development of chronic pain and motor dysfunction following sciatic nerve injury. Mechanical and thermal sensitivity, as well as motor function, were measured in rats before and after sciatic nerve crush (SNC). Rats were treated with the Etifoxine (50 mg/kg, twice daily) for one week. At the end of the experiment, RT-PCR and immunohistochemistry (IHC) were performed to assess mitochondrial stress and neuroinflammation. Additionally, high-resolution respirometry (O2k) was used to evaluate mitochondrial function in the spinal cord following mitochondrial permeability transition pore (mPTP) induction by Ca2+. Etifoxine treatment post-SNC alleviated mechanical and thermal hypersensitivity, as well as motor dysfunction in rats. In addition, Etifoxine treatment modulates neuroinflammation and mitochondrial stress. Specifically, we found a significant reduction in microglia presence and the transcription of pro-inflammatory cytokines (TNFα, IL-6, IL-1β) in the DRG and spinal cord of the SNC/etifoxine-treated group. Furthermore, Etifoxine treatment prevent the decline in mitochondrial respiration, including non-phosphorylation, ATP-linked respiration, and maximal respiration, after mPTP induction by Ca2+. Our findings suggest that TSPO-ligand Etifoxine protects against motor dysfunction and the development of chronic pain by reducing neuroinflammation and apoptosis in the DRG and spinal cord. Importantly, the beneficial effects of TSPO-ligands are reflected in the restoration of the mitochondrial function under challenging conditions.