title: Antinociceptive effects of MSVIII-19, a functional antagonist of the GluK1 kainate receptor.
abstract: The ionotropic glutamate receptor subunit, GluK1 (GluR5), is expressed in many regions of the nervous system related to sensory transmission. Recently, a selective ligand for the GluK1 receptor, MSVIII-19 (8,9-dideoxy-neodysiherbaine), was synthesized as a derivative of dysiherbaine, a toxin isolated from the marine sponge Lendenfeldia chondrodes. MSVIII-19 potently desensitizes GluK1 receptors without channel activation, rendering it useful as a functional antagonist. Given the high selectivity for GluK1 and the proposed role for this glutamate receptor in nociception, we sought to test the analgesic potential of MSVIII-19 in a series of models of inflammatory, neuropathic, and visceral pain in mice. MSVIII-19 delivered intrathecally dose-dependently reduced formalin-induced spontaneous behaviors and reduced thermal hypersensitivity 3 hours after formalin injection and 24 hours after complete Freund's adjuvant-induced inflammation, but had no effect on mechanical sensitivity in the same models. Intrathecal MSVIII-19 significantly reduced both thermal hyperalgesia and mechanical hypersensitivity in the chronic constriction injury model of neuropathic pain, but had no effect in the acetic acid model of visceral pain. Peripheral administration of MSVIII-19 had no analgesic efficacy in any of these models. Finally, intrathecal MSVIII-19 did not alter responses in Tail-flick tests or performance on the accelerating RotaRod. These data suggest that spinal administration of MSVIII-19 reverses hypersensitivity in several models of pain in mice, supporting the clinical potential of GluK1 antagonists for the management of pain.
authors.affiliation: Washington University Pain Center and Department of Anesthesiology, Washington University School of Medicine, St. Louis, MO, USA Department of Molecular Pharmacology and Biological Chemistry, Northwestern University Feinberg School of Medicine, Chicago, IL, USA Laboratory of Biostructural Chemistry, Graduate School of Life Sciences, Tohoku University, Aoba-ku, Sendai, Japan Faculty of Fisheries Science, Hokkaido University, Minato-cho, Hakodate, Japan.
authors.forename: Chang-Shen
authors.initials: CS
authors.lastname: Qiu
authors.forename: Leanne Lash-Van
authors.initials: LL
authors.lastname: Wyhe
authors.forename: Makoto
authors.initials: M
authors.lastname: Sasaki
authors.forename: Ryuichi
authors.initials: R
authors.lastname: Sakai
authors.forename: Geoffrey T
authors.initials: GT
authors.lastname: Swanson
authors.forename: Robert W
authors.initials: RW
authors.lastname: Gereau
mesh_terms: D000596:Amino Acids / Q000008:administration & dosage*; D000700:Analgesics / Q000008:administration & dosage*; D000818:Animals; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000008:administration & dosage*; D004195:Disease Models, Animal; D004333:Drug Administration Routes; D005620:Freund's Adjuvant / Q000009:adverse effects; D005727:Ganglia, Spinal / Q000473:pathology; D006930:Hyperalgesia / Q000188:drug therapy; D008124:Locomotion / Q000187:drug effects; D008297:Male; D008564:Membrane Potentials / Q000502:physiology; D051379:Mice; D009474:Neurons / Q000502:physiology; D010146:Pain / Q000145:classification / Q000188:drug therapy* / Q000209:etiology / Q000473:pathology; D058748:Pain Perception / Q000187:drug effects; D017288:Pain Threshold / Q000187:drug effects; D018408:Patch-Clamp Techniques / Q000379:methods; D018092:Kainic Acid Receptors / Q000037:antagonists & inhibitors*
chemical_list: D000596:Amino Acids; D000700:Analgesics; D019086:Bridged Bicyclo Compounds, Heterocyclic; D005620:Freund's Adjuvant; D018092:Kainic Acid Receptors; C511619:2-(2-amino-2-carboxyethyl)-hexahydrofuro(3,2-b)pyran-2-carboxylic acid