The Journal of pharmacology and experimental therapeutics

Thermal hyperalgesia via supraspinal mechanisms in mice lacking glutamate decarboxylase 65.

PMID 19571163


Gamma-aminobutyric acid, which is synthesized by two isoforms of glutamate decarboxylase (GAD), inhibits the transfer of nociceptive signals from primary afferent fibers to the central nervous system. However, the roles of a 65-kDa isoform of GAD (GAD65)-mediated GABA in nociceptive processing are less clear. This study tested whether partial reductions in GABAergic inhibitory tone by GAD65 gene knockout [GAD65(-/-)] would contribute to the regulation of pain threshold in mice. Experiments were performed on male wild-type (WT) mice and GAD65(-/-) mice. Acute nociception and inflammatory pain tests were compared between WT mice and GAD65(-/-) mice. GABA(A) receptor-mediated inhibitory postsynaptic currents were also examined by use of the whole-cell patch-clamp method in somatosensory cortical neurons in brain slices. In the hot plate test, which reflects supraspinal sensory integration, a significant reduction in the latency was observed for GAD65(-/-) mice. Intraperitoneal administration of the GABA transporter 1 inhibitor, 1-[2-[[(diphenylmethylene)imino]oxy]ethyl]-1,2,5,6-tetrahydro-3-pyridinecarboxylic acid hydrochloride (C(21)H(22)N(2)O(3).HCl; NO-711), dose-dependently prolonged the latency in both genotypes, suggesting that GABA concentration contributes to acute thermal nociception. However, there was no genotype difference in responses to the tail-immersion test or the von Frey test, indicating that spinal reflex and mechanical nociception are kept intact in GAD65(-/-) mice. There was no genotype difference in responses to chemical inflammatory nociception (formalin test and carrageenan test). Although properties of the phasic component of inhibitory postsynaptic currents were similar in both genotypes, tonic inhibition was significantly reduced in GAD65(-/-) mice. These results support the hypothesis that GAD65-mediated GABA synthesis plays relatively small but significant roles in nociceptive processing via supraspinal mechanisms.

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NO-711 hydrochloride, ≥98% (HPLC)
C21H22N2O3 · HCl