Riluzole Normalizes Early-Life Stress-induced Visceral Hypersensitivity in Rats: Role of Spinal Glutamate Reuptake Mechanisms.
Gastroenterology. 2010 Mar 9;
Authors: Gosselin RD, O'Connor RM, Tramullas M, Julio-Pieper M, Dinan TG, Cryan JF
BACKGROUND & AIMS:: The molecular basis underlying visceral hypersensitivity in functional irritable bowel syndrome (IBS) remains elusive resulting in poor treatment effectiveness. Since alterations in spinal non-neuronal (astrocytic) glutamate reuptake are suspected to participate in chronic pain, we asked whether such processes occur in visceral hypersensitivity. METHODS:: Visceral hypersensitivity was induced in Sprague-Dawley rats by maternal separation. Separated adults were given a systemic administration of riluzole (5 mg/kg), an approved neuroprotective agent activating glutamate reuptake. Visceral hypersensitivity was assessed using colorectal distension (40mm/Hg). Somatic nociception was quantified using Hot Plate, Randall-Sellito and Hargreaves tests. Spinal proteins were quantified using immunofluorescence and western-blot. The dependence of visceral sensory function upon spinal glutamate transport was evaluated by intrathecal injection of glutamate transport antagonist DL-threo-beta-benzyloxyaspartate (TBOA). For in vitro testing of riluzole and TBOA, primary cultures of astrocytes were used. RESULTS:: We show that riluzole counteracts stress-induced visceral hypersensitivity, without affecting visceral response in non separated rats or altering nociceptive responses to somatic pain stimulation. In addition, maternal separation produces a reduction in glial excitatory amino acid transporter (EAAT)-1 with no change in EAAT-2 or gamma amino butyric acid (GABA) transporters. Stress was neither associated with changes in glial fibrillary acidic protein (GFAP) or astrocytic morphology per se. Furthermore, visceral normo-sensitivity relies on spinal EAAT, as intrathecal TBOA is sufficient to induce hypersensitivity in normal rats. CONCLUSIONS:: We identify spinal EAAT as a therapeutic target, and establish riluzole as a candidate to counteract gastrointestinal hypersensitivity in disorders such as IBS.
PMID: 20226190 [PubMed - as supplied by publisher]
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