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Glycine receptors and glycine transporters: targets for novel analgesics?

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Abstract

Glycinergic neurotransmission has long been known for its role in spinal motor control. During the last two decades, additional functions have become increasingly recognized—among them is a critical contribution to spinal pain processing. Studies in rodent pain models provide proof-of-concept evidence that enhancing inhibitory glycinergic neurotransmission reduces chronic pain symptoms. Apparent strategies for pharmacological intervention include positive allosteric modulators of glycine receptors and modulators or inhibitors of the glial and neuronal glycine transporters GlyT1 and GlyT2. These prospects have led to drug discovery efforts in academia and in industry aiming at compounds that target glycinergic neurotransmission with high specificity. Available data show promising analgesic efficacy. Less is currently known about potential unwanted effects but the presence of glycinergic innervation in CNS areas outside the nociceptive system prompts for a careful evaluation not only of motor function, but also of potential respiratory impairment and addictive properties.

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Fig. 1

Modified from ref. [8]

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Acknowledgements

The authors thank Dr. Carlos F. Burgos, University of Concepción, Chile) for help with the glycine receptor model shown in Fig. 5. The authors’ work on glycine receptors has been supported by grants from the Swiss National Science Foundation (116064 and 131093) to HUZ and the Fondo Nacional de Desarrollo Científico y Tecnológico (FONDECYT 1170252) to GEY. MAA and GEY have partially been supported through fellowships from the rare disease initiative Zurich (RADIZ) (MAA) and by the Forschungskredit of the University of Zurich (GEY).

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  1. Institute of Pharmacology and Toxicology, University of Zurich, Winterthurerstrasse 190, 8057, Zurich, Switzerland

    Hanns Ulrich Zeilhofer & Mario A. Acuña

  2. Institute of Pharmaceutical Sciences, Swiss Federal Institute of Technology (ETH) Zürich, Vladimir-Prelog-Weg 1-5/10, 8093, Zurich, Switzerland

    Hanns Ulrich Zeilhofer

  3. Department of Neuroscience, Amgen Inc., Cambridge, MA, USA

    Jacinthe Gingras

  4. Department of Physiology, University of Concepción, Concepción, Chile

    Gonzalo E. Yévenes

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  1. Hanns Ulrich Zeilhofer
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Correspondence to Hanns Ulrich Zeilhofer.

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Zeilhofer, H.U., Acuña, M.A., Gingras, J. et al. Glycine receptors and glycine transporters: targets for novel analgesics?. Cell. Mol. Life Sci. 75, 447–465 (2018). https://doi.org/10.1007/s00018-017-2622-x

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