Modulation of Glycine-Mediated Spinal Neurotransmission for the Treatment of Chronic Pain

Cioffi, Christopher L.

doi:10.1021/acs.jmedchem.7b00956

Cited by 35 publications

(50 citation statements)

References 243 publications

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“…Another approach to increase inhibition in pain pathways is by activating glycinergic inhibitory neurotransmission in the spinal trigeminal nucleus. Glycinergic neurons and their receptors are densely distributed in medullary dorsal horn and play an important role to maintain physiological levels of pain sensitivity together with GABAergic inhibition [102,103]. Dysfunction of glycinergic inhibition has been shown to produce mechanical allodynia, a hallmark of orofacial neuropathic pain [104].…”

Section: Therapies Targeting Central Nociceptive Circuit Dysfunctionmentioning

confidence: 99%

Pathological Mechanisms and Therapeutic Targets for Trigeminal Neuropathic Pain

Bista

Imlach

2019

Medicines

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Trigeminal neuropathic pain is a chronic pain condition caused by damage or inflammation of the trigeminal nerve or its branches, with both peripheral and central nervous system dysfunction contributing to the disorder. Trigeminal pain conditions present with diagnostic and therapeutic challenges to healthcare providers and often require multiple therapeutic approaches for pain reduction. This review will provide the overview of pathophysiology in peripheral and central nociceptive circuits that are involved in neuropathic pain conditions involving the trigeminal nerve and the current therapeutics that are used to treat these disorders. Recent advances in treatment of trigeminal pain, including novel therapeutics that target ion channels and receptors, gene therapy and monoclonal antibodies that have shown great promise in preclinical studies and clinical trials will also be described.

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Section: Therapies Targeting Central Nociceptive Circuit Dysfunctionmentioning

confidence: 99%

Pathological Mechanisms and Therapeutic Targets for Trigeminal Neuropathic Pain

Bista

Imlach

2019

Medicines

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“…Genetic, electrophysiological, and behavioral experiments have shown the presence of dysfunctional a3containing GlyRs in chronic pain of inflammatory origin (Harvey et al, 2004). Thus, the selective potentiation of a3GlyR activity through PAMs has emerged as a rational approach to restore glycinergic inhibition (Cioffi, 2018;Zeilhofer et al, 2018). One of the first evidences showing a GlyR-dependent analgesia comes from studies using the synthetic phytocannabinoid derivative de-hydroxylcannabidiol (DH-CBD).…”

Section: Glyrsmentioning

confidence: 99%

Pentameric Ligand-Gated Ion Channels as Pharmacological Targets Against Chronic Pain

et al. 2020

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Chronic pain is a common detrimental condition that affects around 20% of the world population. The current drugs to treat chronic pain states, especially neuropathic pain, have a limited clinical efficiency and present significant adverse effects that complicates their regular use. Recent studies have proposed new therapeutic strategies focused on the pharmacological modulation of G-protein-coupled receptors, transporters, enzymes, and ion channels expressed on the nociceptive pathways. The present work intends to summarize recent advances on the pharmacological modulation of pentameric ligandgated ion channels, which plays a key role in pain processing. Experimental data have shown that novel allosteric modulators targeting the excitatory nicotinic acetylcholine receptor, as well as the inhibitory GABA A and glycine receptors, reverse chronic painrelated behaviors in preclinical assays. Collectively, these evidences strongly suggest the pharmacological modulation of pentameric ligand-gated ion channels is a promising strategy towards the development of novel therapeutics to treat chronic pain states in humans.

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“…Inhibitors of GlyT2 have been shown to have analgesic actions in inflammatory and neuropathic pain models but have not been developed as therapeutics due to either poor pharmacokinetic, selectivity or reversibility profiles [56]. More recently, attention has turned to lipid inhibitors of GlyT2 based on the structure of N-arachidonyl-glycine, an endogenous lipid that is structurally related to anandamide [15,17,54,55,57,58], which show promising analgesic activity.…”

Section: Pharmacological Modulation Of the Glyr/glyt Co-expression Symentioning

confidence: 99%

A System for Assessing Dual Action Modulators of Glycine Transporters and Glycine Receptors

Sheipouri¹,

Gallagher²,

Shimmon³

et al. 2020

Preprint

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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.

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Modulation of Glycine-Mediated Spinal Neurotransmission for the Treatment of Chronic Pain

Cited by 35 publications

References 243 publications

Pathological Mechanisms and Therapeutic Targets for Trigeminal Neuropathic Pain

Pathological Mechanisms and Therapeutic Targets for Trigeminal Neuropathic Pain

Pentameric Ligand-Gated Ion Channels as Pharmacological Targets Against Chronic Pain

A System for Assessing Dual Action Modulators of Glycine Transporters and Glycine Receptors

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