title: Cholesterol level influences opioid signaling in cell models and analgesia in mice and humans.
abstract: Cholesterol regulates the signaling of µ-opioid receptor in cell models, but it has not been demonstrated in mice or humans. Whether cholesterol regulates the signaling by mechanisms other than supporting the entirety of lipid raft microdomains is still unknown. By modulating cholesterol-enriched lipid raft microdomains and/or total cellular cholesterol contents in human embryonic kidney cells stably expressing µ-opioid receptor, we concluded that cholesterol stabilized opioid signaling both by supporting the lipid raft's entirety and by facilitating G protein coupling. Similar phenomena were observed in the primary rat hippocampal neurons. In addition, reducing the brain cholesterol level with simvastatin impaired the analgesic effect of opioids in mice, whereas the opioid analgesic effect was enhanced in mice fed a high-cholesterol diet. Furthermore, when the records of patients were analyzed, an inverse correlation between cholesterol levels and fentanyl doses used for anesthesia was identified, which suggested the mechanisms above could also be applicable to humans. Our results identified the interaction between opioids and cholesterol, which should be considered in clinics as a probable route for drug-drug interaction. Our studies also suggested that a low cholesterol level could lead to clinical issues, such as the observed impairment in opioid functions.
authors.affiliation: Key Laboratory of Regenerative Biology, South China Institute for Stem Cell Biology and Regenerative Medicine, Guangzhou Institute of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, China. zheng_hui@gibh.ac.cn
authors.forename: Hui
authors.initials: H
authors.lastname: Zheng
authors.forename: Haibo
authors.initials: H
authors.lastname: Zou
authors.forename: Xiaopeng
authors.initials: X
authors.lastname: Liu
authors.forename: Ji
authors.initials: J
authors.lastname: Chu
authors.forename: Yali
authors.initials: Y
authors.lastname: Zhou
authors.forename: Horace H
authors.initials: HH
authors.lastname: Loh
authors.forename: Ping-Yee
authors.initials: PY
authors.lastname: Law
mesh_terms: D000698:Analgesia; D000701:Analgesics, Opioid / Q000378:metabolism* / Q000494:pharmacology; D000818:Animals; D002784:Cholesterol / Q000378:metabolism*; D002791:Cholesterol, Dietary / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D005260:Female; D005283:Fentanyl / Q000494:pharmacology; D057809:HEK293 Cells; D006801:Humans; D008297:Male; D021962:Membrane Microdomains / Q000187:drug effects; D051379:Mice; D009025:Morpholines / Q000494:pharmacology; D009474:Neurons / Q000166:cytology; D051381:Rats; D017450:Receptors, Opioid, mu / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D019821:Simvastatin / Q000494:pharmacology
chemical_list: D000701:Analgesics, Opioid; D002791:Cholesterol, Dietary; D009025:Morpholines; D017450:Receptors, Opioid, mu; C033110:RV 538; D002784:Cholesterol; D019821:Simvastatin; D005283:Fentanyl