Targeting Sigma-1 and Sigma-2 Receptors in Neuropathic Pain: Pharmacology, Ligand Development, and Translational Progress

Background: Neuropathic pain remains a major unmet clinical challenge. Growing evi- dence identifies sigma receptors (σRs) as pivotal intracellular modulators of maladaptive stress signaling, positioning them as promising non-opioid targets for chronic pain man- agement. Notably, despite the pleiotropic nature of σRs in regulating diverse cellular pathways—which might theoretically suggest a high risk of off-target effects—current se- lective antagonists have demonstrated remarkable safety and tolerability profiles. Sigma-1 and sigma-2 receptors (σ1R and σ2R) are molecularly and functionally distinct proteins that regulate neuronal excitability, proteostasis, and neuroimmune communication, all mechanisms that characterize neuronal excitability and cellular stress adaptation. σ1R acts as a ligand-operated molecular chaperone at the mitochondria-associated endoplasmic reticulum membrane. Extensive preclinical data demonstrate that σ1R antagonism atten- uates peripheral and central sensitization, suppresses neuroinflammation, and restores opioid analgesic efficacy. These findings are supported by the advanced clinical candi- date E-52862, which has shown efficacy and a favorable safety profile in neuropathic pain conditions. σ2R, identified as transmembrane protein 97 (σ2R/TMEM97), functions as a regulator of cholesterol trafficking, lysosomal integrity, and integrated stress response (ISR). σ2R modulation alleviates neuropathic pain by restoring proteostatic balance and reducing ISR-driven neuronal vulnerability rather than directly suppressing excitability. Emerging σ2R ligands such as FEM-1689, UKH-1114, and CM-398 provide compelling proof-of-concept for durable, disease-modifying analgesia. Methods: A structured litera- ture search was conducted using PubMed, Scopus, and Web of Science to identify studies published within the last decade describing σ1R and σ2R/TMEM97 biology, ligand de- velopment, and their preclinical or clinical evaluation in neuropathic pain. Reference lists were manually screened to ensure comprehensive coverage. Conclusions: This review synthesizes pharmacology, ligand development, and translational evidence supporting σRs as next-generation targets for neuropathic pain therapy, highlighting convergent roles of σ1R and σ2R in pain chronification and outlining future directions for structure-guided therapeutic strategies.