High-Throughput Screening for Next-Generation Analgesics: Charting Non-Opioid Pain Targets and Assay Innovations

Abstract

The growing burden of acute and chronic pain, coupled with the limitations of opioid-based therapies, has intensified the search for safer and more effective non-opioid analgesics. High-throughput screening (HTS) has emerged as a transformative strategy in analgesic drug discovery, enabling the rapid identification and characterization of novel compounds targeting peripheral pain pathways while minimizing central nervous system liabilities. This short communication highlights recent advances in HTS technologies and their role in accelerating the development of next-generation analgesics. We discuss the expanding landscape of non-opioid molecular targets, including voltage-gated sodium (NaV) channels, transient receptor potential (TRP) channels, non-opioid G protein-coupled receptors, and neuroimmune signalling pathways, alongside innovative screening platforms such as automated patch-clamp electrophysiology, human induced pluripotent stem cell (hiPSC)-derived nociceptor models, multi-electrode arrays, all-optical electrophysiology, and label-free mass spectrometry. We further examine the complementary roles of target-based and phenotypic screening approaches and consider the growing integration of artificial intelligence and machine learning in virtual screening, hit prioritization, and lead optimization. Collectively, these advances are reshaping the analgesic discovery pipeline by improving the physiological relevance, scalability, and predictive power of preclinical screening. As clinically validated non-opioid therapies continue to emerge, the convergence of advanced screening technologies and computational approaches offers a promising framework for the discovery of safer, more effective analgesics to address the global burden of pain.