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The lidocaine metabolite N-ethylglycine has antinociceptive effects in experimental inflammatory and neuropathic pain

Werdehausen, R; Mittnacht, S; McLaughlin, LA; Minett, MS; Armbruster, A; Bauer, I; Wood, JN; ... Eulenburg, V; + view all (2015) The lidocaine metabolite N-ethylglycine has antinociceptive effects in experimental inflammatory and neuropathic pain. PAIN , 156 (9) pp. 1647-1659. 10.1097/j.pain.0000000000000206. Green open access

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Abstract

Glycine transporter 1 (GlyT1) plays a crucial role in regulating extracellular glycine concentrations and might thereby constitute a new drug target for the modulation of glycinergic inhibition in pain signaling. Consistently with this view, inhibition of GlyT1 has been found to induce antinociceptive effects in various animal pain models. We have shown previously that the lidocaine metabolite N-ethylglycine (EG) reduces GlyT1-dependent glycine uptake by functioning as an artificial substrate for this transporter. Here we show that EG is specific for GlyT1 and that in rodent models of inflammatory and neuropathic pain, systemic treatment with EG results in an efficient amelioration of hyperalgesia and allodynia without affecting acute pain. There was no effect on motor coordination or the development of inflammatory edema. No adverse neurologic effects were observed following repeated high-dose application of EG. EG concentrations both, in blood and spinal fluid, correlated with an increase of glycine concentration in spinal fluid. The time courses of the EG and glycine concentrations corresponded well with the antinociceptive effect. Additionally, we found that EG reduced the increase in neuronal firing of wide-dynamic-range neurons caused by inflammatory pain induction. These findings suggest that systemically applied lidocaine exerts antihyperalgesic effects via its metabolite EG in vivo, by enhancing spinal inhibition of pain processing through GlyT1 modulation and subsequent increase of glycine concentrations at glycinergic inhibitory synapses. EG and other substrates of GlyT1, therefore, may be a useful therapeutic agent in chronic pain states involving spinal disinhibition.

Type: Article
Title: The lidocaine metabolite N-ethylglycine has antinociceptive effects in experimental inflammatory and neuropathic pain
Open access status: An open access version is available from UCL Discovery
DOI: 10.1097/j.pain.0000000000000206
Publisher version: http://dx.doi.org/10.1097/j.pain.0000000000000206
Language: English
Additional information: © 2015 International Association for the Study of Pain. This is an open access article distributed under the Creative Commons Attribution License 4.0 (CC BY), which permits unrestricted use,distribution,and reproduction in any medium,provided the original work is properly cited
UCL classification: UCL
UCL > Provost and Vice Provost Offices
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Cancer Institute
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Cancer Institute > Research Department of Cancer Bio
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Medicine
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Medicine > Wolfson Inst for Biomedical Research
URI: https://discovery.ucl.ac.uk/id/eprint/1467153
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