Cyclodextrins in chronic pain: Membrane cholesterol remodeling and neuroimmune signaling

BACKGROUND: Chronic pain remains challenging to treat, with current therapies offering incomplete relief and significant side effects. This narrative review examines cyclodextrins (CDs) beyond their conventional excipient role, focusing on their emerging function as membrane-active modulators of cholesterol-dependent signaling. METHOD/SCOPE: We integrate preclinical evidence linking CD-associated cholesterol remodeling to altered lipid raft organization, nociceptive ion channel regulation (e.g., TRPV1, TRPA1), and neuroimmune pathways implicated in selected chronic pain conditions. Direct support is strongest for cholesterol depletion and membrane reorganization, whereas downstream effects on transcription, epigenetics, central sensitization, and long-term outcomes remain indirect and hypothesis-generating. CONCLUSION: The reviewed evidence proposes membrane cholesterol remodeling as a useful mechanistic framework for interpreting CD actions on nociceptive and neuroimmune pathways. Rather than validating CDs as analgesics, the literature supports their consideration as promising preclinical platforms and candidates for mechanism-oriented investigation in selected chronic pain conditions. A central hypothesis is that membrane remodeling may influence persistent transcriptional and epigenetic programs relevant to pain, though direct evidence is limited. Further studies are needed to define compound-specific effects, safety, and translational relevance.