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.