Received for publication January 7, 2008.
Revised April 27, 2008.
Accepted for publication April 29, 2008.

Spinal Anti-Allodynia Action of Glycine Transporter Inhibitors in Neuropathic Pain Models in Mice

Abstract

Neuropathic pain is refractory against conventional analgesics and thus novel medicaments are desired for the treatment. Glycinergic neurons are localized in specific brain regions, including the spinal cord, where they play an important role in the regulation of pain signal transduction. Glycine transporter (GlyT) 1, present in glial cells, and GlyT2, located in neurons, play roles in modulating glycinergic neurotransmission by clearing synaptically released glycine or supplying glycine to the neurons and thus could modify pain signal transmission in the spinal cord. Here we demonstrated that intravenous or intrathecal administration of GlyT1 inhibitors, ORG 25935 or sarcosine, and GlyT2 inhibitors, ORG 25543 and ALX 1393, or knockdown of spinal GlyTs by siRNA of GlyTs mRNA produced a profound anti-allodynia effect in a partial peripheral nerve ligation model and other neuropathic pain models in mice. The anti-allodynia effect is mediated through spinal glycine receptor 3. These results established GlyTs as the target molecules for the development of medicaments for neuropathic pain. These manipulations to stimulate glycinergic neuronal activity, however, were without effect during the 4 days post-nerve injury, while manipulations to inhibit glycinergic neuronal activity protected against the development of allodynia in this phase. The results implied that the timing of medication with their inhibitors should be considered, because glycinergic control of pain was reversed in the critical period of 3 to 4 days post-surgery. This may also provide important information for understanding the underlying molecular mechanisms of the development of neuropathic pain.

Key words: RNA interference, analgesics, anti-allodynia, glycine, neuropathic pain, transporter