Cholesterol regulates cannabinoid analgesia through glycine receptors. (15th October 2020)

• Record Type: Journal Article
• Authors: Yao, Lei; Liu, Chengyuan; Wang, Ning; Du, Feng; Fan, Sijia; Guo, Yujun; Zhang, Li; Pan, Yang; Xiong, Wei
• Is Part Of: Neuropharmacology. Volume 177(2020)
• Publication Date: 2020-10-15
• Subjects: Cholesterol -- Cannabinoid -- Glycine receptor -- Analgesia; Neuropsychopharmacology -- Periodicals; Autonomic Agents -- Periodicals; Neuropsychopharmacologie -- Périodiques; Neuropsychopharmacology; Periodicals; Electronic journals; 615.78
• DOI: 10.1016/j.neuropharm.2020.108242
• Languages: English
• ISSNs: 0028-3908

Abstract

Abstract: Cholesterol plays vital roles in many central physiological and pathological processes. As a key component in the cell membrane, cholesterol can regulate a variety of ion channels, including ligand-gated ion channels (LGICs). However, relatively little is known about the molecular detail and in vivo consequence of cholesterol-LGIC interaction. Here, we reveal that membrane cholesterol depletion significantly inhibits the potentiating effects of dehydroxylcannabidiol (DH-CBD) on glycine-activated currents (IGly ) in HEK 293T cells expressing α1/α3 glycine receptors (GlyRs). Simvastatin considerably decreases cholesterol levels and DH-CBD-induced potentiation of IGly in the spinal cord of mice. Simvastatin also significantly decreases DH-CBD analgesia in acute and chronic pain of mice. The cholesterol levels in the dorsal horn of spinal cord, measured by mass spectrometry imaging, are specifically correlated with cannabinoid potentiation of spinal GlyRs and cannabinoid-induced analgesia. These findings suggest that spinal cholesterol is critical for the efficacy of glycinergic cannabinoid-induced analgesia. Highlights: Membrane cholesterol modulates cannabinoid potentiation of glycine receptors. Simvastatin decreases cannabinoid analgesia in mice. Cannabinoid analgesic effects correlate with spinal cholesterol levels.