Glycine transporter inhibitors as a novel drug discovery strategy for neuropathic pain.Pharmacol Ther 2009; 123(1):54-79P&T
Injury to peripheral or spinal nerves following either trauma or disease has several consequences including the development of neuropathic pain. This syndrome is often refractory against conventional analgesics; and thus, novel medicaments are desired for its treatment. Recent studies have emphasized that dysfunction of inhibitory neuronal regulation of pain signal transduction may be relevant to the development of neuropathic pain. Glycinergic neurons are localized in specific brain regions and the spinal cord, where they play an important role in the prevention of pathological pain symptoms. Thus, an enhancement of glycinergic control in the spinal cord is a promising strategy for pain relief from neuropathic pain. Glycine transporter (GlyT) 1 and GlyT2, which are located in glial cells and neurons, respectively play important roles by clearing synaptically released glycine or supplying glycine to glycinergic neurons to regulate glycinergic neurotransmission. Thus, an inhibition of GlyTs could be used to modify pain signal transmission in the spinal cord. Recently developed specific inhibitors of GlyTs have made this possibility a reality. Both GlyT1 and GlyT2 inhibitors produced potential anti-nociceptive effect in various neuropathic pain models, chronic and acute inflammatory models in animals. Their anti-allodynia effects are mediated by the inhibition of GlyTs following activation of spinal glycine receptor alpha3. These results established GlyTs as target molecules for medicaments for neuropathic pain. Moreover, the phase-dependent anti-allodynia effects of GlyT inhibitors have provided important information on effective therapeutic strategies and also understanding the underlying molecular mechanisms of the development of neuropathic pain.