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. Consistent 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 neurological effects were observed after 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 through 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.