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Cannabinoid potentiation of glycine receptors contributes to cannabis-induced analgesia

Nature Chemical Biology volume 7, pages 296–303 (2011)Cite this article

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Abstract

Cannabinoids enhance the function of glycine receptors (GlyRs). However, little is known about the mechanisms and behavioral implication of cannabinoid-GlyR interaction. Using mutagenesis and NMR analysis, we have identified a serine at 296 in the GlyR protein critical for the potentiation of IGly by Δ9-tetrahydrocannabinol (THC), a major psychoactive component of marijuana. The polarity of the amino acid residue at 296 and the hydroxyl groups of THC are critical for THC potentiation. Removal of the hydroxyl groups of THC results in a compound that does not affect IGly when applied alone but selectively antagonizes cannabinoid-induced potentiating effect on IGly and analgesic effect in a tail-flick test in mice. The cannabinoid-induced analgesia is absent in mice lacking α3GlyRs but not in those lacking CB1 and CB2 receptors. These findings reveal a new mechanism underlying cannabinoid potentiation of GlyRs, which could contribute to some of the cannabis-induced analgesic and therapeutic effects.

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Figure 1: THC potentiation of IGly.
Figure 2: A distinct site of Ser296 is critical for THC potentiation of the α1 and α3 GlyRs.
Figure 3: NMR analysis.
Figure 4: Mutagenesis and correlation analysis.
Figure 5: Functional characterization of 5-desoxy-THC and di-desoxy-THC.
Figure 6: The critical role of the α3 GlyR in the THC analgesia in the TFR.

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Acknowledgements

We thank C.L. Cepko for providing α2−/− Glra mice. We especially thank D.M. Lovinger for critical comments on the manuscript. This work was supported by funds from the intramural program of the US National Institute on Alcohol Abuse and Alcoholism. We acknowledge the grant support (R37GM049202 to Y.X.) from the US National Institute of General Medical Sciences of the US National Institutes of Health.

Author information

Authors and Affiliations

  1. Laboratory for Integrative Neuroscience, US National Institute on Alcohol Abuse and Alcoholism, US National Institutes of Health, Bethesda, Maryland, USA

    Wei Xiong & Li Zhang

  2. Chemical Biological Research Branch, US National Institute on Drug Abuse, US National Institutes of Health, Bethesda, Maryland, USA

    KeJun Cheng & Kenner C Rice

  3. Department of Anesthesiology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA

    Tanxing Cui & Yan Xu

  4. Department of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA

    Tanxing Cui & Yan Xu

  5. Department of Structural Biology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA

    Tanxing Cui & Yan Xu

  6. Laboratory of Physiologic Studies, US National Institute on Alcohol Abuse and Alcoholism, US National Institutes of Health, Bethesda, Maryland, USA

    Grzegorz Godlewski

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  1. Wei Xiong
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Contributions

W.X. and L.Z. designed and conducted electrophysiology, biochemical and biophysical experiments and animal behavioral tests. K.-J.C. and K.C.R. synthesized cannabinoid chemicals. T-X.C. and Y.X. conducted protein expression, purification and NMR experiments of the full-length transmembrane domains of the α1 GlyR and carried out NMR analysis. G.G. conducted animal behavioral tests. L.Z. supervised the project and wrote the manuscript. Y.X. critically revised the manuscript.

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Correspondence to Li Zhang.

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Xiong, W., Cheng, K., Cui, T. et al. Cannabinoid potentiation of glycine receptors contributes to cannabis-induced analgesia. Nat Chem Biol 7, 296–303 (2011). https://doi.org/10.1038/nchembio.552

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