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Review
. 2021 Jun 10;11(6):864.
doi: 10.3390/biom11060864.

Inhibition of Glycine Re-Uptake: A Potential Approach for Treating Pain by Augmenting Glycine-Mediated Spinal Neurotransmission and Blunting Central Nociceptive Signaling

Christopher L Cioffi  1
Affiliations
Review

Inhibition of Glycine Re-Uptake: A Potential Approach for Treating Pain by Augmenting Glycine-Mediated Spinal Neurotransmission and Blunting Central Nociceptive Signaling

Christopher L Cioffi. Biomolecules. .

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 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.

Keywords: GABA; N-methyl-d-aspartate (NMDA) receptor; allodynia; dorsal horn; glycine; glycine receptor (GlyR); glycine transporter (GlyT); hyperalgesia; inflammatory pain; neuropathic pain; nociceptor; spinal cord.

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Conflict of interest statement

The author declares no conflict of interest.

Figures

Figure 1
Figure 1
Glycinergic interneurons within the deep dorsal horn (laminae III) are part of a feed-forward inhibitory circuit that prevents innocuous Aβ fiber input from driving nociceptive pathways. Loss of segmental glycinergic inhibitory control via application of strychnine, nerve injury, or targeted ablation and silencing allows low threshold Aβ mechanosensor input to drive NS secondary order projection neurons, resulting in allodynia.
Figure 2
Figure 2
GlyT1 inhibitors studied in preclinical in vivo rodent pain assays.
Figure 3
Figure 3
GlyT2 inhibitors ALX1393 and ORG25543.
Figure 4
Figure 4
Potential functional consequences of GlyT inhibition. (A) Reversible GlyT1 inhibition with rapid dissociation (shown on the left) versus prolonged inhibition via slow dissociation (shown on the right) at an inhibitory glycinergic synapse. A slowly dissociating GlyT1 inhibitor (magenta square e.g., ALX5407) can potentially generate a sustained and excessive increase in synaptic glycine that can ultimately lead to robust and prolonged GlyR activity. This hyperglycinergic state is believed to underlie the severe motor impairment and respiratory depression observed for tight binding GlyT1 inhibitors. Reversible GlyT1 inhibitors (orange square, e.g., bitopertin), that slowed the clearance of synaptic glycine while also allowing for glycine reuptake, were found to exhibit significantly improved safety profiles. (B) Partial or reversible GlyT2 inhibition with rapid dissociation (shown on the left) versus full GlyT2 inhibition and slow dissociation (shown on the right) at an inhibitory glycinergic synapse. A slowly dissociating GlyT2 inhibitor (red square e.g., ORG25543) will initially generate an increase in synaptic glycine concentrations but will ultimately prevent glycine reloading of synaptic vesicles and reduce both glycine release and GlyR activity. A partial or reversible inhibitor that rapidly dissociates (blue square) will slow the clearance of synaptic glycine, increase GlyR activity, and also allow for glycine reuptake and reloading of vesicles.
Figure 5
Figure 5
Bioactive lipid GlyT2 inhibitors.
Figure 6
Figure 6
ORG25543-related GlyT2 inhibitors (17) and opiranserin (18).
Figure 7
Figure 7
Miscellaneous GlyT2 inhibitors.
Figure 8
Figure 8
Potential functional consequences of dual GlyT2 inhibition at an inhibitory glycinergic synapse. Shown on the left is a putative synergistic effect of co-application of sub-analgesic doses of ALX5407 (1 and 2 mg/kg, s.c.) and ORG25543 (2 mg/kg, s.c.). In addition to exhibiting a lack of efficacy in the rat PSNL model, the indicated sub-analgesic doses of ALX5407 or ORG25543 did not increase CSF glycine levels. However, co-application of ALX5407 (1 mg/kg, s.c.) and ORG25543 (2 mg/kg, s.c.) lead to significant analgesic activity coupled with robust elevations in CSF glycine. Minimal occupancy and subtle prohibition of glycine uptake by both compounds at their respective GlyTs may produce a synergistic effect, leading to significant increases in synaptic glycine concentrations and augmented inhibitory glycinergic signaling in the spinal dorsal horn. Further investigation into the analgesic efficacy of either combinations of reported GlyT1 and GlyT2 inhibitors devoid of adverse effects or the development of bispecific GlyT1/GlyT2 inhibitors is warranted.
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