Cyclodextrins in chronic pain: Membrane cholesterol remodeling and neuroimmune signaling - 20/09/26
Abstract |
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.
Le texte complet de cet article est disponible en PDF.Graphical Abstract |
The figure summarizes a proposed multi-level framework linking cyclodextrin (CD)-associated membrane cholesterol remodeling to pain-related signaling. The initial biophysical interactions, indicated by solid arrows, represent the comparatively well-supported ability of cholesterol- extracting CDs to form inclusion complexes with membrane cholesterol and alter lipid-raft organization. Downstream connections, indicated by dotted arrows in the vertical pathway and gray arrows in the molecular pathway, represent indirect, context-dependent, or hypothesis-generating mechanisms that remain incompletely validated in pain models. These proposed links include modulation of membrane-associated signaling components such as TLR4, TRPV1, and CAV-1, with possible downstream effects on NF-κB, CREB, STAT3, neuroimmune signaling, and transcription-associated responses. The transition from membrane remodeling to persistent transcriptional or epigenetic changes and long-term pain states remains hypothetical and requires direct experimental validation. Thus, the figure distinguishes established membrane-level effects from proposed downstream mechanisms and presents CDs as mechanistic and preclinical platforms for investigating cholesterol-dependent pain signaling rather than as validated analgesic therapies.
The figure summarizes a proposed multi-level framework linking cyclodextrin (CD)-associated membrane cholesterol remodeling to pain-related signaling. The initial biophysical interactions, indicated by solid arrows, represent the comparatively well-supported ability of cholesterol- extracting CDs to form inclusion complexes with membrane cholesterol and alter lipid-raft organization. Downstream connections, indicated by dotted arrows in the vertical pathway and gray arrows in the molecular pathway, represent indirect, context-dependent, or hypothesis-generating mechanisms that remain incompletely validated in pain models. These proposed links include modulation of membrane-associated signaling components such as TLR4, TRPV1, and CAV-1, with possible downstream effects on NF-κB, CREB, STAT3, neuroimmune signaling, and transcription-associated responses. The transition from membrane remodeling to persistent transcriptional or epigenetic changes and long-term pain states remains hypothetical and requires direct experimental validation. Thus, the figure distinguishes established membrane-level effects from proposed downstream mechanisms and presents CDs as mechanistic and preclinical platforms for investigating cholesterol-dependent pain signaling rather than as validated analgesic therapies. Le texte complet de cet article est disponible en PDF.
Highlights |
• | Cyclodextrins modulate pain signaling via cholesterol-dependent membrane remodeling. |
• | Membrane disruption influences nociceptive ion channels like TRPV1/TRPA1. |
• | Direct evidence is strongest for membrane effects; broader consequences remain indirect. |
• | Cyclodextrins are promising preclinical tools for mechanism-oriented pain research. |
Keywords : Cyclodextrins, Membrane cholesterol remodeling, Lipid rafts, Nociceptive signaling, Neuroinflammation, Chronic pain
Plan
Vol 203
Article 119889- octobre 2026 Retour au numéro
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