title: Potent antihyperalgesic activity without tolerance produced by glycine site antagonist of N-methyl-D-aspartate receptor GV196771A.
abstract: Central sensitization is a condition of enhanced excitability of spinal cord neurons that contributes to the exaggerated pain sensation associated with chronic tissue or nerve injury. N-methyl-D-aspartate (NMDA) receptors are thought to play a key role in central sensitization. We have tested this hypothesis by characterizing in vitro and in vivo a novel antagonist of the NMDA receptor acting on its glycine site, GV196771A. GV196771A exhibited an elevated affinity for the NMDA glycine binding site in rat cerebral cortex membranes (pKi = 7.56). Moreover, GV196771A competitively and potently antagonized the activation of NMDA receptors produced by glycine in the presence of NMDA in primary cultures of cortical, spinal, and hippocampal neurons (pKB = 7.46, 8. 04, and 7.86, respectively). In isolated baby rat spinal cords, 10 microM GV196771A depressed wind-up, an electrical correlate of central sensitization. The antihyperalgesic properties of GV196771A were studied in a model of chronic constriction injury (CCI) of the rat sciatic nerve and in the mice formalin test. In the CCI model GV196771A (3 mg/kg twice a day p.o.), administered before and then for 10 days after nerve ligature, blocked the development of thermal hyperalgesia. Moreover, GV196771A (1-10 mg/kg p.o.) reversed the hyperalgesia when tested after the establishment of the CCI-induced hyperalgesia. In the formalin test GV196771A (0.1-10 mg/kg p.o.) dose-dependently reduced the duration of the licking time of the late phase. These antihyperalgesic properties were not accompanied by development of tolerance. These observations strengthen the view that NMDA receptors play a key role in the events underlying plastic phenomena, including hyperalgesia. Moreover, antagonists of the NMDA glycine site receptor could represent a new analgesic class, effective in conditions not sensitive to classical opioids.
authors.affiliation: GlaxoWellcome S.p.A., Medicines Research Centre, Department of Pharmacology, Verona, Italy. mq7886@glaxowellcome.co.uk
authors.forename: M
authors.initials: M
authors.lastname: Quartaroli
authors.forename: C
authors.initials: C
authors.lastname: Carignani
authors.forename: G
authors.initials: G
authors.lastname: Dal Forno
authors.forename: M
authors.initials: M
authors.lastname: Mugnaini
authors.forename: A
authors.initials: A
authors.lastname: Ugolini
authors.forename: R
authors.initials: R
authors.lastname: Arban
authors.forename: L
authors.initials: L
authors.lastname: Bettelini
authors.forename: G
authors.initials: G
authors.lastname: Maraia
authors.forename: F
authors.initials: F
authors.lastname: Belardetti
authors.forename: A
authors.initials: A
authors.lastname: Reggiani
authors.forename: D G
authors.initials: DG
authors.lastname: Trist
authors.forename: E
authors.initials: E
authors.lastname: Ratti
authors.forename: R
authors.initials: R
authors.lastname: Di Fabio
authors.forename: M
authors.initials: M
authors.lastname: Corsi
mesh_terms: D018712:Analgesics, Non-Narcotic / Q000494:pharmacology*; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D001667:Binding, Competitive; D002540:Cerebral Cortex / Q000378:metabolism; D004361:Drug Tolerance; D004594:Electrophysiology; D004622:Embryo, Mammalian; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology*; D006930:Hyperalgesia / Q000188:drug therapy*; D066298:In Vitro Techniques; D007211:Indoles / Q000494:pharmacology*; D008297:Male; D051379:Mice; D010147:Pain Measurement / Q000187:drug effects; D018408:Patch-Clamp Techniques; D011758:Pyrroles / Q000494:pharmacology*; D011869:Radioligand Assay; D051381:Rats; D017207:Rats, Sprague-Dawley; D018009:Receptors, Glycine / Q000037:antagonists & inhibitors*; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors*; D013116:Spinal Cord / Q000187:drug effects
chemical_list: D018712:Analgesics, Non-Narcotic; D018691:Excitatory Amino Acid Antagonists; C119836:GV 196771A; D007211:Indoles; D011758:Pyrroles; D018009:Receptors, Glycine; D016194:Receptors, N-Methyl-D-Aspartate