Activity of novel lipid glycine transporter inhibitors on synaptic signalling in the dorsal horn of the spinal cord

Bryony L. Winters, Tristan Rawling, Robert J. Vandenberg, Macdonald J. Christie, Rebecca F Bhola, Wendy L Imlach

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7 Citations (Scopus)

Abstract

Background and Purpose: Inhibitory neurotransmission plays an important role in controlling excitability within nociceptive circuits of the spinal cord dorsal horn. Loss of inhibitory signalling is thought to contribute to the development of pathological pain. Preclinical studies suggest that increasing inhibitory glycinergic signalling is a good therapeutic strategy for treating pain. One approach to increase synaptic glycine is to inhibit the activity of the glycine transporter 2 (GlyT2) on inhibitory nerve terminals. These transporters are involved in regulating glycine concentrations and recycling glycine into presynaptic terminals. Inhibiting activity of GlyT2 increases synaptic glycine, which decreases excitability in nociceptive circuits and provides analgesia in neuropathic and inflammatory pain models. Experimental Approach: We investigated the effects of reversible and irreversible GlyT2 inhibitors on inhibitory glycinergic and NMDA receptor-mediated excitatory neurotransmission in the rat dorsal horn. The effect of these drugs on synaptic signalling was determined using patch-clamp electrophysiology techniques to measure glycine- and NMDA-mediated postsynaptic currents in spinal cord slices in vitro. Key Results: We compared activity of four compounds that increase glycinergic tone with a corresponding increase in evoked glycinergic postsynaptic currents. These compounds did not deplete synaptic glycine release over time. Interestingly, none of these compounds increased glycine-mediated excitatory signalling through NMDA receptors. The results suggest that these compounds preferentially inhibit GlyT2 over G1yT1 with no potentiation of the glycine receptor and without inducing spillover from inhibitory to excitatory synapses. Conclusions and Implications: GlyT2 inhibitors increase inhibitory neurotransmission in the dorsal horn and have potential as pain therapeutics.

Original languageEnglish
Pages (from-to)2337-2347
Number of pages11
JournalBritish Journal of Pharmacology
Volume175
Issue number12
DOIs
Publication statusPublished - Jun 2018

Keywords

  • Glycine
  • Pain
  • Spinal cord
  • Synaptic transmission
  • Dorsal horn
  • Inhibitory neurotransmission

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