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Glycine Receptors in Spinal Nociceptive Control—An Update

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Glycine Receptors in Spinal Nociceptive Control—An Update biomolecules Review Glycine Receptors in Spinal Nociceptive Control—An Update Hanns Ulrich Zeilhofer 1,2,3,* , Karolina Werynska 1, Jacinthe Gingras 4 and Gonzalo E. Yévenes 5,6 1 Institute of Pharmacology and Toxicology, University of Zurich, Winterthurerstrasse 190, CH-8057 Zürich, Switzerland; [email protected] 2 Institute of Pharmaceutical Sciences, Swiss Federal Institute of Technology (ETH) Zurich, Vladimir Prelog Weg, CH-8093 Zürich, Switzerland 3 Drug Discovery Network Zurich, University of Zurich and ETH Zurich, Winterthurerstrasse 190, CH-8057 Zürich, Switzerland 4 Homology Medicines Inc., 1 Patriots Park, Bedford, MA 01730, USA; [email protected] 5 Department of Physiology, University of Concepción, Concepción 4070386, Chile; [email protected] 6 Millennium Nucleus for the Study of Pain (MiNuSPain), Santiago 8320000, Chile * Correspondence: [email protected]; Tel.: +41-44-63-55-912 Abstract: Diminished inhibitory control of spinal nociception is one of the major culprits of chronic pain states. Restoring proper synaptic inhibition is a well-established rational therapeutic approach explored by several pharmaceutical companies. A particular challenge arises from the need for site-specific intervention to avoid deleterious side effects such as sedation, addiction, or impaired motor control, which would arise from wide-range facilitation of inhibition. Specific targeting of glycinergic inhibition, which dominates in the spinal cord and parts of the hindbrain, may help reduce these side effects. Selective targeting of the α3 subtype of glycine receptors (GlyRs), which is highly enriched in the superficial layers of the spinal dorsal horn, a key site of nociceptive processing, may help to further narrow down pharmacological intervention on the nociceptive system and increase tolerability. This review provides an update on the physiological properties and functions of Citation: Zeilhofer, H.U.; Werynska, K.; Gingras, J.; Yévenes, G.E. Glycine α3 subtype GlyRs and on the present state of related drug discovery programs. Receptors in Spinal Nociceptive Control—An Update. Biomolecules Keywords: glycine; GABA; pain; inhibition; spinal cord; dorsal horn; hyperalgesia; allodynia; 2021, 11, 846. https://doi.org/ circuit; mouse 10.3390/biom11060846 Academic Editors: Robert Vandenberg and Robert Harvey 1. Introduction Inhibitory neurotransmission plays a crucial role in the maintenance of a physiolog- Received: 12 May 2021 ically meaningful state of pain sensitivity and helps separating innocuous and noxious Accepted: 3 June 2021 signal relay. Following injury and inflammation, reduced inhibition contributes to the Published: 6 June 2021 phenomena of hyperalgesia (an increased sensitivity to input from nociceptive fibers) and allodynia, which describes a painful sensation elicited by input from non-nociceptive fibers. Publisher’s Note: MDPI stays neutral While both phenomena may help protect injured tissue from further damage and may with regard to jurisdictional claims in foster its healing, under unfortunate conditions they outlast the healing process and may published maps and institutional affil- then severely compromise the quality of life of affected patients. The spinal dorsal horn is iations. a key site for endogenous pain control and maladaptive plasticity which underlies many chronic pain conditions. Various processes triggered by peripheral inflammation or nerve damage compromise synaptic inhibition at this site and in corresponding brainstem areas. Among these processes are alterations in the excitatory drive to inhibitory dorsal horn Copyright: © 2021 by the authors. neurons [1], a compromised electrochemical gradient of chloride ions [2,3], and altered Licensee MDPI, Basel, Switzerland. responsiveness of inhibitory neurotransmitter receptors [4]. While the first two mecha- This article is an open access article nisms are triggered by peripheral nerve damage and affect both GABAergic and glycinergic distributed under the terms and inhibition, peripheral inflammation has a specific impact on the function of dorsal horn conditions of the Creative Commons GlyRs. General aspects of glycinergic neurotransmission are illustrated in Figure1. Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/). Biomolecules 2021, 11, 846. https://doi.org/10.3390/biom11060846 https://www.mdpi.com/journal/biomolecules Biomolecules 2021,, 11,, 846x 2 2of of 13 Figure 1. Principles of glycinergic inhibition. ( A)) Schematic sagittal mouse brain section illustrating the distribution of glycinergic innervation innervation detected detected by by GlyT2 GlyT2 staining staining (in (in red). red). High High density density innervation innervation is found is found in the in brainstem the brainstem with withpar‐ particularlyticularly dense dense expression expression in the in medulla the medulla oblongata oblongata and pons, and pons, and generally and generally weaker weaker expression expression in the in midbrain the midbrain and parts and partsof the of thalamus. the thalamus. Dense Dense innervation innervation is also is also found found in the in the cerebellar cerebellar cortex, cortex, the the inferior inferior colliculus, colliculus, and and the the mesencephalic mesencephalic trigeminal nucleus. Cortex and hippocampus are virtually devoid of glycinergic innervation. In the spinal cord, glycinergic trigeminal nucleus. Cortex and hippocampus are virtually devoid of glycinergic innervation. In the spinal cord, glycinergic innervation is very widespread, with slightly less expression observed in the most dorsal laminae I and II. (B) Glycine innervation is very widespread, with slightly less expression observed in the most dorsal laminae I and II. (B) Glycine receptors are chloride permeable heteropentameric ion channels, composed from a repertoire of five (in humans four) subunitsreceptors each are chlorideencoded permeableby a separate heteropentameric gene (α4 is a pseudogene ion channels, in humans). composed Each from subunit a repertoire is composed of five of (in a large humans extracel four)‐ subunitslular domain each followed encoded byby a 4 separate transmembrane gene (α4 segments is a pseudogene connected in humans). by loop Eachstructures subunit and is composeda short extracellular of a large extracellular C‐terminus domain(see also followed Figures 2A by and 4 transmembrane 4). In the spinal segments cord, α1 connected subunit immunoreactivity by loop structures (blue) and is a shortfound extracellular throughout C-terminusthe grey matter, (see alsobut α Figures3 subunit 2A expression and 4). In the (green) spinal is cord, highlyα1 and subunit specifically immunoreactivity enriched in (blue) lamina is foundII. (C) throughoutSchematic representation the grey matter, of but a glyα3‐ subunitcinergic expressionsynapse. Glycine (green) is is released highly and from specifically a glycinergic enriched terminal in lamina and binds II. (C )to Schematic postsynaptic representation α/β heteromeric of a glycinergic receptors synapse.anchored Glycineto the postsynaptic is released from scaffolding a glycinergic protein terminal gephyrin. and bindsTheir toactivation postsynaptic by synapticα/β heteromeric release causes receptors an inhibitory anchored topostsynaptic the postsynaptic potential. scaffolding Glycine receptors protein gephyrin. are also found Their at activation extrasynaptic by synaptic and presynaptic release causes sites. anPresynaptic inhibitory glycine postsynaptic recep‐ tors lack β subunits and are not clustered by gephyrin. Activation of extrasynaptic glycine receptors cause a tonic inhibi‐ potential. Glycine receptors are also found at extrasynaptic and presynaptic sites. Presynaptic glycine receptors lack β tory membrane current, whereas the activation of presynaptic glycine receptors may enhance transmitter release. subunits and are not clustered by gephyrin. Activation of extrasynaptic glycine receptors cause a tonic inhibitory membrane current, whereas the activation of presynaptic glycine receptors may enhance transmitter release. 2. GlyRs in Inflammatory Hyperalgesia and Allodynia Cyclooxygenase‐2 (COX‐2) derived prostaglandin E2 (PGE2) is a pivotal mediator of inflammation2. GlyRs in Inflammatory and inflammatory Hyperalgesia hyperalgesia. and Allodynia In response to peripheral inflammatory in‐ sults,Cyclooxygenase-2 PGE2 is not only produced (COX-2) derivedin the periphery prostaglandin at the site E2 (PGE of inflammation,2) is a pivotal but mediator also in theof inflammation CNS, especially and in inflammatory the spinal dorsal hyperalgesia. horn, where In responseit contributes to peripheral to the phenomenon inflammatory of centralinsults, sensitization. PGE2 is not only A series produced of reports in the published periphery between at the site2002 of and inflammation, 2005 established but also the criticalin the CNS, role of especially α3 GlyRs in in the inflammation spinal dorsal and horn, PGE where2‐mediated it contributes central tosensitization. the phenomenon PGE2, butof central not other sensitization. prostaglandins A series including of reports PGD published2, PGI2, or PGF between2α, reduces 2002 and glycinergic 2005 established synaptic transmissionthe critical role in ofsuperficialα3 GlyRs dorsal in inflammation horn neurons and through PGE2-mediated a postsynaptic central mechanism sensitization. in‐ volvingPGE2, but the not activation other prostaglandins of EP2 receptors, including production PGD2 ,of PGI cAMP,2, or PGF and2 αsubsequent, reduces
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