Cholesterol regulates cannabinoid analgesia through glycine receptors

Neuropharmacology. 2020 Oct 15:177:108242. doi: 10.1016/j.neuropharm.2020.108242. Epub 2020 Jul 24.

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.

Keywords: Analgesia; Cannabinoid; Cholesterol; Glycine receptor.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Analgesia / methods*
  • Animals
  • Cannabidiol / pharmacology*
  • Cholesterol / analysis
  • Cholesterol / metabolism*
  • Glycine / pharmacology
  • HEK293 Cells
  • Humans
  • Mice
  • Mice, Inbred C57BL
  • Organ Culture Techniques
  • Pain Measurement / drug effects
  • Pain Measurement / methods*
  • Receptors, Glycine / agonists
  • Receptors, Glycine / metabolism*
  • Reflex, Startle / drug effects
  • Reflex, Startle / physiology
  • Spinal Cord / drug effects
  • Spinal Cord / metabolism*

Substances

  • Receptors, Glycine
  • Cannabidiol
  • Cholesterol
  • Glycine