Sensory thresholds and the antinociceptive effects of GABA receptor agonists in mice lacking the β 3 subunit of the GABA A receptor

Abstract

A line of mice was recently created in which the gabrb3 gene, which encodes the β 3 subunit of the GABA A receptor, was inactivated by gene-targeting. The existence of mice with a significantly reduced population of GABA A receptors in the CNS enabled an investigation of the role of GABA and GABA A receptors in nociception. The present study examined the sensory thresholds of these mice, as well as the antinociceptive effects of subcutaneously or intrathecally administered GABA A and GABA B receptor agonists. Homozygous null (β 3 −/−) mice displayed enhanced responsiveness to low-intensity thermal stimuli in the tail-flick and hot-plate test compared to C57BL/6J and 129/SvJ progenitor strain mice, and their wild-type (β 3 +/+) and heterozygous (β 3 +/−) littermates. The β 3 −/− mice also exhibited enhanced responsiveness to innocuous tactile stimuli compared to C57BL/6J, 129/SvJ and to their β 3 +/+ littermates as assessed by von Frey filaments. The presence of thermal hyperalgesia and tactile allodynia in β 3 −/− mice is consistent with a loss of inhibition mediated by presynaptic and postsynaptic GABA A receptors in the spinal cord. As expected, subcutaneous administration of the GABA A receptor agonist 4,5,6,7-tetrahydroisoxazolo-(5,4-c)pyridin-3-ol did not produce antinociception in β 3 −/− mice, whereas it produced a dose-dependent increase in hot-plate latency in C57BL/6J, 129/SvJ, β 3 +/+ and β 3 +/− mice. However, the antinociceptive effect of the GABA B receptor agonist baclofen in the tail-flick and hot-plate tests was also reduced in β 3 −/− mice compared to the progenitor strains, β 3 +/+ or β 3 +/− mice after either subcutaneous or intrathecal administration. This finding was unexpected and suggests that a reduction in GABA A receptors can affect the production of antinociception by other analgesic drugs as well.