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Combinations of intrathecal gamma-amino-butyrate receptor agonists and N-methyl-d-aspartate receptor antagonists in rats with neuropathic spinal cord injury pain.

Abstract
Underlying below-level cutaneous hypersensitivity observed following spinal cord injury (SCI) is a concurrent loss of inhibition with an increase in excitation in the spinal dorsal horn. Thus, a dual pharmacological approach, increasing spinal γ-aminobutyrate (GABA) inhibition and decreasing N-methyl-d-aspartate (NMDA) receptor-mediated excitation, could be more beneficial than either approach alone. The current study evaluated the antinociceptive effects of lumbar intrathecal (i.t.) administration of GABA receptor agonists and NMDA receptor antagonists alone and in combination in rats with neuropathic SCI pain. Rats developed markedly decreased hind paw withdrawal thresholds following an acute thoracic spinal cord compression, indicative of below-level hypersensitivity. Separately, i.t. GABA(A) receptor agonist muscimol and GABA(B) receptor agonist baclofen demonstrated dose-dependent antinociception, whereas i.t. NMDA receptor antagonist ketamine and the endogenous peptide [Ser¹]histogranin, a putative NMDA receptor antagonist, demonstrated no efficacy. The combination of baclofen and ketamine resulted in a supra-additive (synergistic) antinociception whereas the combinations with muscimol were merely additive. Intrathecal pretreatment with the GABA(B) receptor antagonist CGP 35348 prevented the antinociceptive effect of the baclofen and ketamine combination. The data indicate that blocking spinal NMDA receptors alone is not sufficient to ameliorate SCI hypersensitivity, whereas a combined approach, simultaneous activation of spinal GABA(B) receptors and NMDA receptor blockade with ketamine, leads to significant antinociception. By engaging diverse pain modulating systems at the spinal level, combination drug treatment may be a useful approach in treating neuropathic SCI pain.
AuthorsAldric Hama, Jacqueline Sagen
JournalEuropean journal of pharmacology (Eur J Pharmacol) Vol. 683 Issue 1-3 Pg. 101-8 (May 15 2012) ISSN: 1879-0712 [Electronic] Netherlands
PMID22449374 (Publication Type: Comparative Study, Journal Article, Research Support, N.I.H., Extramural)
CopyrightCopyright © 2012 Elsevier B.V. All rights reserved.
Chemical References
  • GABA-A Receptor Agonists
  • GABA-B Receptor Agonists
  • GABA-B Receptor Antagonists
  • Proteins
  • Receptors, N-Methyl-D-Aspartate
  • histogranin
  • Muscimol
  • Ketamine
  • Baclofen
Topics
  • Analgesia, Epidural
  • Animals
  • Baclofen (administration & dosage, antagonists & inhibitors, therapeutic use)
  • Dose-Response Relationship, Drug
  • Drug Synergism
  • Drug Therapy, Combination
  • GABA-A Receptor Agonists (administration & dosage, therapeutic use)
  • GABA-B Receptor Agonists (administration & dosage, chemistry, therapeutic use)
  • GABA-B Receptor Antagonists (pharmacology)
  • Ketamine (administration & dosage, antagonists & inhibitors, therapeutic use)
  • Lumbar Vertebrae
  • Male
  • Muscimol (administration & dosage, therapeutic use)
  • Neuralgia (drug therapy, etiology)
  • Pain Threshold (drug effects)
  • Proteins (administration & dosage, therapeutic use)
  • Rats
  • Rats, Sprague-Dawley
  • Receptors, N-Methyl-D-Aspartate (antagonists & inhibitors)
  • Spinal Cord Injuries (physiopathology)

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