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Biomolecules
Special Issues
Glycine Transporters and Receptors as Targets for Analgesics
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Glycine Transporters and Receptors as Targets for Analgesics

A special issue of Biomolecules (ISSN 2218-273X). This special issue belongs to the section "Molecular Medicine".

Deadline for manuscript submissions: closed (15 May 2021) | Viewed by 22455

Special Issue Editors

Prof. Dr. Robert Vandenberg

E-Mail Website
Guest Editor
School of Medical Sciences, Faculty of Medicine and Health, The University of Sydney, Sydney, NSW 2006, Australia
Interests: neurotransmitter transporters; drug discovery; protein structure and function;
Prof. Dr. Robert Harvey

E-Mail Website
Guest Editor
School of Health and Sport Sciences and Sunshine Coast Health Institute, University of the Sunshine Coast, Maroochydore DC, QLD 4558, Australia
Interests: neurotransmitter receptors; neurotransmitter transporters; autism; cognitive disorders; epilepsy; molecular and cellular biology

Special Issue Information

Dear Colleagues,

Professors Robert Harvey and Robert Vandenberg propose a themed issue for Biomolecules based on analysing the current information on the suitability of modulating glycinergic neurotransmission for the treatment of inflammatory and chronic pain. This area of research is gaining wider recognition as glycine receptors (GlyRs) and transporters (GlyT1 and GlyT2) are now considered potential therapeutic targets. This issue will explore a range of perspectives on this topic and we would like to include consideration of recent advances in: understanding the pathophysiology of glycine neurotransmission in pain states; structures and functions of transporters and receptors; mechanisms of transporter and receptor regulation; drug discovery programs; how potential drugs provide analgesia in animal models of pain; and the current state of clinical trials. We request that each author provide specific hypotheses about the key issues and how this field may be further developed. As part of this issue, Robert Vandenberg and Robert Harvey will provide an editorial highlighting the issues raised in the various articles and possible avenues for moving the field forward.

Prof. Dr. Robert Vandenberg
Prof. Dr. Robert Harvey
Guest Editors

Manuscript Submission Information

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Keywords

  • glycine
  • transporter
  • receptor
  • analgesic
  • pain
  • drug discovery
  • glycinergic neurotransmission
  • clinical trials

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Published Papers (6 papers)

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Editorial

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3 pages, 180 KiB  
Editorial
Glycine Transporters and Receptors as Targets for Analgesics
by Robert J. Harvey and Robert J. Vandenberg
Biomolecules 2021, 11(11), 1676; https://doi.org/10.3390/biom11111676 - 11 Nov 2021
Cited by 3 | Viewed by 1503
Abstract
The suitability of modulating glycinergic neurotransmission for the treatment of inflammatory and chronic pain has gained widespread recognition, with glycine receptors (GlyRs) and glycine transporters (GlyT1 and GlyT2) now considered key therapeutic targets [...] Full article
(This article belongs to the Special Issue Glycine Transporters and Receptors as Targets for Analgesics)

Research

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17 pages, 2649 KiB  
Article
Assessment of the Anti-Allodynic and Anti-Hyperalgesic Efficacy of a Glycine Transporter 2 Inhibitor Relative to Pregabalin, Duloxetine and Indomethacin in a Rat Model of Cisplatin-Induced Peripheral Neuropathy
by Andy Kuo, Laura Corradini, Janet R. Nicholson and Maree T. Smith
Biomolecules 2021, 11(7), 940; https://doi.org/10.3390/biom11070940 - 24 Jun 2021
Cited by 5 | Viewed by 3109
Abstract
Cisplatin, which is a chemotherapy drug listed on the World Health Organisation’s List of Essential Medicines, commonly induces dose-limiting side effects including chemotherapy-induced peripheral neuropathy (CIPN) that has a major negative impact on quality of life in cancer survivors. Although adjuvant drugs including [...] Read more.
Cisplatin, which is a chemotherapy drug listed on the World Health Organisation’s List of Essential Medicines, commonly induces dose-limiting side effects including chemotherapy-induced peripheral neuropathy (CIPN) that has a major negative impact on quality of life in cancer survivors. Although adjuvant drugs including anticonvulsants and antidepressants are used for the relief of CIPN, analgesia is often unsatisfactory. Herein, we used a rat model of CIPN (cisplatin) to assess the effect of a glycine transporter 2 (GlyT2) inhibitor, relative to pregabalin, duloxetine, indomethacin and vehicle. Male Sprague-Dawley rats with cisplatin-induced mechanical allodynia and mechanical hyperalgesia in the bilateral hindpaws received oral bolus doses of the GlyT2 inhibitor (3–30 mg/kg), pregabalin (3–100 mg/kg), duloxetine (3–100 mg/kg), indomethacin (1–10 mg/kg) or vehicle. The GlyT2 inhibitor alleviated both mechanical allodynia and hyperalgesia in the bilateral hindpaws at a dose of 10 mg/kg, but not at higher or lower doses. Pregabalin and indomethacin induced dose-dependent relief of mechanical allodynia but duloxetine lacked efficacy. Pregabalin and duloxetine alleviated mechanical hyperalgesia in the bilateral hindpaws while indomethacin lacked efficacy. The mechanism underpinning pain relief induced by the GlyT2 inhibitor at 10 mg/kg is likely due to increased glycinergic inhibition in the lumbar spinal cord, although the bell-shaped dose–response curve warrants further translational considerations. Full article
(This article belongs to the Special Issue Glycine Transporters and Receptors as Targets for Analgesics)
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Graphical abstract

13 pages, 2654 KiB  
Article
Modulation of Glycinergic Neurotransmission may Contribute to the Analgesic Effects of Propacetamol
by Lukas Barsch, Robert Werdehausen, Andreas Leffler and Volker Eulenburg
Biomolecules 2021, 11(4), 493; https://doi.org/10.3390/biom11040493 - 25 Mar 2021
Cited by 3 | Viewed by 3654
Abstract
Treating neuropathic pain remains challenging, and therefore new pharmacological strategies are urgently required. Here, the enhancement of glycinergic neurotransmission by either facilitating glycine receptors (GlyR) or inhibiting glycine transporter (GlyT) function to increase extracellular glycine concentration appears promising. Propacetamol is a N, [...] Read more.
Treating neuropathic pain remains challenging, and therefore new pharmacological strategies are urgently required. Here, the enhancement of glycinergic neurotransmission by either facilitating glycine receptors (GlyR) or inhibiting glycine transporter (GlyT) function to increase extracellular glycine concentration appears promising. Propacetamol is a N,N-diethylester of acetaminophen, a non-opioid analgesic used to treat mild pain conditions. In vivo, it is hydrolysed into N,N-diethylglycine (DEG) and acetaminophen. DEG has structural similarities to known alternative GlyT1 substrates. In this study, we analyzed possible effects of propacetamol, or its metabolite N,N-diethylglycine (DEG), on GlyRs or GlyTs function by using a two-electrode voltage clamp approach in Xenopus laevis oocytes. Our data demonstrate that, although propacetamol or acetaminophen had no effect on the function of the analysed glycine-responsive proteins, the propacetamol metabolite DEG acted as a low-affine substrate for both GlyT1 (EC50 > 7.6 mM) and GlyT2 (EC50 > 5.2 mM). It also acted as a mild positive allosteric modulator of GlyRα1 function at intermediate concentrations. Taken together, our data show that DEG influences both glycine transporter and receptor function, and therefore could facilitate glycinergic neurotransmission in a multimodal manner. Full article
(This article belongs to the Special Issue Glycine Transporters and Receptors as Targets for Analgesics)
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Graphical abstract

25 pages, 4375 KiB  
Article
A System for Assessing Dual Action Modulators of Glycine Transporters and Glycine Receptors
by Diba Sheipouri, Casey I. Gallagher, Susan Shimmon, Tristan Rawling and Robert J. Vandenberg
Biomolecules 2020, 10(12), 1618; https://doi.org/10.3390/biom10121618 - 30 Nov 2020
Cited by 6 | Viewed by 2681
Abstract
Reduced inhibitory glycinergic neurotransmission is implicated in a number of neurological conditions such as neuropathic pain, schizophrenia, epilepsy and hyperekplexia. Restoring glycinergic signalling may be an effective method of treating these pathologies. Glycine transporters (GlyTs) control synaptic and extra-synaptic glycine concentrations and slowing [...] Read more.
Reduced inhibitory glycinergic neurotransmission is implicated in a number of neurological conditions such as neuropathic pain, schizophrenia, epilepsy and hyperekplexia. Restoring glycinergic signalling may be an effective method of treating these pathologies. Glycine transporters (GlyTs) control synaptic and extra-synaptic glycine concentrations and slowing the reuptake of glycine using specific GlyT inhibitors will increase glycine extracellular concentrations and increase glycine receptor (GlyR) activation. Glycinergic neurotransmission can also be improved through positive allosteric modulation (PAM) of GlyRs. Despite efforts to manipulate this synapse, no therapeutics currently target it. We propose that dual action modulators of both GlyTs and GlyRs may show greater therapeutic potential than those targeting individual proteins. To show this, we have characterized a co-expression system in Xenopus laevis oocytes consisting of GlyT1 or GlyT2 co-expressed with GlyRα1. We use two electrode voltage clamp recording techniques to measure the impact of GlyTs on GlyRs and the effects of modulators of these proteins. We show that increases in GlyT density in close proximity to GlyRs diminish receptor currents. Reductions in GlyR mediated currents are not observed when non-transportable GlyR agonists are applied or when Na+ is not available. GlyTs reduce glycine concentrations across different concentration ranges, corresponding with their ion-coupling stoichiometry, and full receptor currents can be restored when GlyTs are blocked with selective inhibitors. We show that partial inhibition of GlyT2 and modest GlyRα1 potentiation using a dual action compound, is as useful in restoring GlyR currents as a full and potent single target GlyT2 inhibitor or single target GlyRα1 PAM. The co-expression system developed in this study will provide a robust means for assessing the likely impact of GlyR PAMs and GlyT inhibitors on glycine neurotransmission. Full article
(This article belongs to the Special Issue Glycine Transporters and Receptors as Targets for Analgesics)
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Review

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25 pages, 12270 KiB  
Review
Inhibition of Glycine Re-Uptake: A Potential Approach for Treating Pain by Augmenting Glycine-Mediated Spinal Neurotransmission and Blunting Central Nociceptive Signaling
by Christopher L. Cioffi
Biomolecules 2021, 11(6), 864; https://doi.org/10.3390/biom11060864 - 10 Jun 2021
Cited by 9 | Viewed by 4404
Abstract
Among the myriad of cellular and molecular processes identified as contributing to pathological pain, disinhibition of spinal cord nociceptive signaling to higher cortical centers plays a critical role. Importantly, evidence suggests that impaired glycinergic neurotransmission develops in the dorsal horn of the spinal [...] Read more.
Among the myriad of cellular and molecular processes identified as contributing to pathological pain, disinhibition of spinal cord nociceptive signaling to higher cortical centers plays a critical role. Importantly, evidence suggests that impaired glycinergic neurotransmission develops in the dorsal horn of the spinal cord in inflammatory and neuropathic pain models and is a key maladaptive mechanism causing mechanical hyperalgesia and allodynia. Thus, it has been hypothesized that pharmacological agents capable of augmenting glycinergic tone within the dorsal horn may be able to blunt or block aberrant nociceptor signaling to the brain and serve as a novel class of analgesics for various pathological pain states. Indeed, drugs that enhance dysfunctional glycinergic transmission, and in particular inhibitors of the glycine transporters (GlyT1 and GlyT2), are generating widespread interest as a potential class of novel analgesics. The GlyTs are Na+/Cl−-dependent transporters of the solute carrier 6 (SLC6) family and it has been proposed that the inhibition of them presents a possible mechanism by which to increase spinal extracellular glycine concentrations and enhance GlyR-mediated inhibitory neurotransmission in the dorsal horn. Various inhibitors of both GlyT1 and GlyT2 have demonstrated broad analgesic efficacy in several preclinical models of acute and chronic pain, providing promise for the approach to deliver a first-in-class non-opioid analgesic with a mechanism of action differentiated from current standard of care. This review will highlight the therapeutic potential of GlyT inhibitors as a novel class of analgesics, present recent advances reported for the field, and discuss the key challenges associated with the development of a GlyT inhibitor into a safe and effective agent to treat pain. Full article
(This article belongs to the Special Issue Glycine Transporters and Receptors as Targets for Analgesics)
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13 pages, 3688 KiB  
Review
Glycine Receptors in Spinal Nociceptive Control—An Update
by Hanns Ulrich Zeilhofer, Karolina Werynska, Jacinthe Gingras and Gonzalo E. Yévenes
Biomolecules 2021, 11(6), 846; https://doi.org/10.3390/biom11060846 - 6 Jun 2021
Cited by 23 | Viewed by 5199
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 [...] Read more.
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 α3 subtype GlyRs and on the present state of related drug discovery programs. Full article
(This article belongs to the Special Issue Glycine Transporters and Receptors as Targets for Analgesics)
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