Cannabinoids suppress inflammatory and neuropathic pain by targeting α3 glycine receptors
Open Access
- 14 May 2012
- journal article
- Published by Rockefeller University Press in The Journal of Experimental Medicine
- Vol. 209 (6), 1121-1134
- https://doi.org/10.1084/jem.20120242
Abstract
Certain types of nonpsychoactive cannabinoids can potentiate glycine receptors (GlyRs), an important target for nociceptive regulation at the spinal level. However, little is known about the potential and mechanism of glycinergic cannabinoids for chronic pain treatment. We report that systemic and intrathecal administration of cannabidiol (CBD), a major nonpsychoactive component of marijuana, and its modified derivatives significantly suppress chronic inflammatory and neuropathic pain without causing apparent analgesic tolerance in rodents. The cannabinoids significantly potentiate glycine currents in dorsal horn neurons in rat spinal cord slices. The analgesic potency of 11 structurally similar cannabinoids is positively correlated with cannabinoid potentiation of the α3 GlyRs. In contrast, the cannabinoid analgesia is neither correlated with their binding affinity for CB1 and CB2 receptors nor with their psychoactive side effects. NMR analysis reveals a direct interaction between CBD and S296 in the third transmembrane domain of purified α3 GlyR. The cannabinoid-induced analgesic effect is absent in mice lacking the α3 GlyRs. Our findings suggest that the α3 GlyRs mediate glycinergic cannabinoid-induced suppression of chronic pain. These cannabinoids may represent a novel class of therapeutic agents for the treatment of chronic pain and other diseases involving GlyR dysfunction.Keywords
This publication has 64 references indexed in Scilit:
- Cannabinoids for treatment of chronic non‐cancer pain; a systematic review of randomized trialsBritish Journal of Clinical Pharmacology, 2011
- Cannabinoid potentiation of glycine receptors contributes to cannabis-induced analgesiaNature Chemical Biology, 2011
- Cannabinoid CB1 receptor facilitation of substance P release in the rat spinal cord, measured as neurokinin 1 receptor internalizationEuropean Journal of Neuroscience, 2010
- CHARMM general force field: A force field for drug‐like molecules compatible with the CHARMM all‐atom additive biological force fieldsJournal of Computational Chemistry, 2009
- CHARMM: The biomolecular simulation programJournal of Computational Chemistry, 2009
- Residual Dipolar Coupling Measurements of Transmembrane Proteins Using Aligned Low-q Bicelles and High-Resolution Magic Angle Spinning NMR SpectroscopyJournal of the American Chemical Society, 2008
- Peripherally acting mu-opioid receptor agonist attenuates neuropathic pain in rats after L5 spinal nerve injuryPain, 2008
- Molecular Dynamics Simulations of Ternary Membrane Mixture: Phosphatidylcholine, Phosphatidic Acid, and CholesterolThe Journal of Physical Chemistry B, 2007
- Scalable molecular dynamics with NAMDJournal of Computational Chemistry, 2005
- NMRPipe: A multidimensional spectral processing system based on UNIX pipesJournal of Biomolecular NMR, 1995