G-protein Coupled Receptor Positive Allosteric Modulators for Chronic Pain Treatment
Abstract
Pain often occurs alongside inflammation, tissue damage, nerve injury, and multiple diseases. Persistent pain requires clinical attention and treatment. Despite chronic pain’s prevalence and profound influence on quality of life, its treatment remains a major unmet medical need. Current analgesics often have limited efficacy, undesirable adverse effects, and dependency risk, particularly with opioids. Therefore, safer, mechanism-based therapies are urgently needed. Emerging evidence suggests that positive allosteric modulators (PAMs) may provide relief in pathological pain conditions by enhancing endogenous pain-inhibitory receptor signaling without directly activating the receptor. This precise, targeted modulation offers greater temporal and spatial specificity in receptor activation than orthosteric agonists, thereby decreasing off-target effects and providing a promising alternative to conventional pain medications. Guanine nucleotide-binding protein-coupled receptors (GPCRs), which are closely associated with many disease pathways, are among the most promising druggable targets for pain control. This narrative review explores recent advances in GPCR-PAM research for pain management; highlights the therapeutic potential of key GPCR-PAMs in specific pathological pain conditions; and discusses the current technological landscape, challenges, and emerging opportunities for developing next-generation GPCR-PAM-based analgesics.
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