TY - JOUR
T1 - Riluzole Normalizes Early-Life Stress-Induced Visceral Hypersensitivity in Rats
T2 - Role of Spinal Glutamate Reuptake Mechanisms
AU - Gosselin, Romain Daniel
AU - O'Connor, Richard M.
AU - Tramullas, Monica
AU - Julio-Pieper, Marcela
AU - Dinan, Timothy G.
AU - Cryan, John F.
N1 - Funding Information:
Funding JFC and TGD are supported in part by Science Foundation Ireland in the form of a Centre grant (Alimentary Pharmabiotic Centre).
Funding Information:
Conflicts of interest The authors disclose the following conflicts: The authors received industry support from GlaxoSmithKline. The Alimentary Pharmabiotic Centre is partly funded by GlaxoSmithKline .
PY - 2010/6
Y1 - 2010/6
N2 - Background & Aims: The molecular basis underlying visceral hypersensitivity in functional irritable bowel syndrome remains elusive, resulting in poor treatment effectiveness. Because 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 (40 mm 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-β-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 nonseparated 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 γ-amino butyric acid transporters. Stress was not associated with changes in glial fibrillary acidic protein or astrocytic morphology per se. Furthermore, visceral normosensitivity 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 irritable bowel syndrome.
AB - Background & Aims: The molecular basis underlying visceral hypersensitivity in functional irritable bowel syndrome remains elusive, resulting in poor treatment effectiveness. Because 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 (40 mm 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-β-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 nonseparated 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 γ-amino butyric acid transporters. Stress was not associated with changes in glial fibrillary acidic protein or astrocytic morphology per se. Furthermore, visceral normosensitivity 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 irritable bowel syndrome.
KW - Astrocytes
KW - Irritable Bowel Syndrome
KW - Maternal Separation
KW - Spinal Cord
UR - http://www.scopus.com/inward/record.url?scp=77952718405&partnerID=8YFLogxK
U2 - 10.1053/j.gastro.2010.03.003
DO - 10.1053/j.gastro.2010.03.003
M3 - Article
C2 - 20226190
AN - SCOPUS:77952718405
SN - 0016-5085
VL - 138
SP - 2418
EP - 2425
JO - Gastroenterology
JF - Gastroenterology
IS - 7
ER -