title: Antinociceptive effect of intracerebroventricular administration of glycine transporter-2 inhibitor ALX1393 in rat models of inflammatory and neuropathic pain.
abstract: 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.
authors.affiliation: Department of Anesthesiology, School of Medicine, University of Occupational and Environmental Health, Kitakyushu, Japan.
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Takahashi
authors.affiliation: Department of Anesthesiology, School of Medicine, University of Occupational and Environmental Health, Kitakyushu, Japan. Electronic address: kojihara@med.uoeh-u.ac.jp.
authors.forename: Koji
authors.initials: K
authors.lastname: Hara
authors.affiliation: Department of Anesthesiology, School of Medicine, University of Occupational and Environmental Health, Kitakyushu, Japan.
authors.forename: Yasunori
authors.initials: Y
authors.lastname: Haranishi
authors.affiliation: Department of Anesthesiology, School of Medicine, University of Occupational and Environmental Health, Kitakyushu, Japan.
authors.forename: Tadanori
authors.initials: T
authors.lastname: Terada
authors.affiliation: Department of Anesthesiology, School of Medicine, University of Occupational and Environmental Health, Kitakyushu, Japan.
authors.forename: Goh
authors.initials: G
authors.lastname: Obara
authors.affiliation: Department of Anesthesiology, School of Medicine, University of Occupational and Environmental Health, Kitakyushu, Japan.
authors.forename: Takeyoshi
authors.initials: T
authors.lastname: Sata
mesh_terms: D000700:Analgesics / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use; D000818:Animals; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D050487:Glycine Plasma Membrane Transport Proteins / Q000037:antagonists & inhibitors*; D006930:Hyperalgesia / Q000150:complications / Q000188:drug therapy; D007249:Inflammation / Q000150:complications / Q000188:drug therapy*; D057967:Infusions, Intraventricular; D008297:Male; D009437:Neuralgia / Q000188:drug therapy*; D010146:Pain / Q000150:complications* / Q000188:drug therapy*; D010147:Pain Measurement; D051381:Rats; D045442:Rotarod Performance Test; D012694:Serine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000037:antagonists & inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D013331:Strychnine / Q000494:pharmacology
chemical_list: C539864:ALX 1393; D000700:Analgesics; D050487:Glycine Plasma Membrane Transport Proteins; C493269:Slc6a5 protein, rat; D012694:Serine; D013331:Strychnine
keywords: Central nervous system; Chronic constriction injury; Glycinergic transmission; Nociceptive transmission