Antinociceptive effect of intracerebroventricular administration of glycine transporter-2 inhibitor ALX1393 in rat models of inflammatory and neuropathic pain

Glycinergic transmission has an important role in regulating nociception in the spinal cord. The glycine transporter-2 (GlyT2) is localized at presynaptic terminals of glycinergic neurons and eliminates glycine from the synaptic cleft to terminate glycinergic transmission. Systemic and intrathecal administration of GlyT2 inhibitors alleviate various types of pain. Although the GlyT2s and glycine receptors are widely distributed in the central nervous system, little is known about the role of glycinergic transmission in pain perception at supraspinal regions. The present study examined the antinociceptive effect of intracerebroventricular (i.c.v.) administration of the selective GlyT2 Inhibitor ALX1393 on inflammatory and neuropathic pain in experimental models. For i.c.v. administration, a guide cannula was implanted into the right lateral ventricle of male Sprague-Dawley rats. Normal rats were used to assess inflammatory nociception using the formalin test and motor function using the rotarod test. Chronic constriction injury (CCI) to the sciatic nerve was induced in the rats. The CCI rats were then used to assess mechanical, cold, and thermal hyperalgesia using the electronic von Frey test, cold plate test, and the plantar test, respectively. ALX1393 (25, 50, and 100 μg) was administered i.c.v. to examine its effects on supraspinal antinociception. Supraspinal ALX1393 in normal rats suppressed the late-phase response in the formalin test but did not affect motor performance. In the CCI rats, ALX1393 inhibited mechanical and cold hyperalgesia in a dose-dependent manner. The antihyperalgesic effects of ALX1393 (100 μg) were reversed completely by i.c.v. pretreatment with a glycine receptor antagonist strychnine (10 μg). These results suggest that GlyT2 contributes to nociceptive transmission at supraspinal level and that the selective GlyT2 Inhibitor is a promising candidate for the treatment of inflammatory and neuropathic pain without causing motor dysfunction.