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: Chang-Shen Qiu, Leanne Lash-Van Wyhe, Makoto Sasaki, Ryuichi Sakai, Geoffrey T Swanson, Robert W Gereau 4th
• Journal: Pain (Pain) Vol. 152 Issue 5 Pg. 1052-1060 (May 2011) ISSN: 1872-6623 [Electronic] United States
• PMID: 21324591 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)
• Copyright: Copyright © 2011 International Association for the Study of Pain. Published by Elsevier B.V. All rights reserved.

Chemical References

• 2-(2-amino-2-carboxyethyl)-hexahydrofuro(3,2-b)pyran-2-carboxylic acid
• Amino Acids
• Analgesics
• Bridged Bicyclo Compounds, Heterocyclic
• Receptors, Kainic Acid
• Freund's Adjuvant

Topics

• Amino Acids (administration & dosage)
• Analgesics (administration & dosage)
• Animals
• Bridged Bicyclo Compounds, Heterocyclic (administration & dosage)
• Disease Models, Animal
• Drug Administration Routes
• Freund's Adjuvant (adverse effects)
• Ganglia, Spinal (pathology)
• Hyperalgesia (drug therapy)
• Locomotion (drug effects)
• Male
• Membrane Potentials (physiology)
• Mice
• Neurons (physiology)
• Pain (classification, drug therapy, etiology, pathology)
• Pain Perception (drug effects)
• Pain Threshold (drug effects)
• Patch-Clamp Techniques (methods)
• Receptors, Kainic Acid (antagonists & inhibitors)