Baclofen and midazolam alter c- fos induction by peripheral noxious or innocuous stimulation in the spinal cord of normal and monoarthritic rats

Abstract

In order to further clarify the role of γ-aminobutyric acid (GABA) receptors in spinal sensory processing we have studied the effects of baclofen, a GABA B agonist, and midazolam, a benzodiazepine agonist, on the activation of spinal neurones by peripheral innocuous or noxious stimulation, in normal or monoarthritic rats, as signalled by the induction of the proto-oncogene c- fos. Baclofen (10 mg/kg, i.v.) caused a significant reduction in the number of Fos-positive neurones following noxious stimulation of both normal and monoarthritic animals, which was prevented by the GABA B antagonist CGP 35348 (200 mg/kg, i.v.). The latter caused an increase of c- fos expression in normal animals subject to noxious stimulation, suggesting an endogenous tonic activation of GABA B receptors. This effect was not observed in monoarthritic animals. Baclofen also reduced the number of Fos-positive neurones in monoarthritic animals subject to innocuous stimulation. Midazolam (5 mg/kg, i.v.) had no effect in normal animals, but caused an increase in c- fos expression induced by noxious stimulation in monoarthritic animals. Flumazenil (1 mg/kg, i.v.), a benzodiazepine antagonist, prevented the effect of midazolam, and if given alone evoked a decrease in Fos-positive neurones. It can be concluded that although GABA B receptors modulate sensory input at the spinal level, high doses of systemic baclofen are required to inhibit nociceptive-induced c- fos expression. The paradoxical facilitation of c- fos expression by midazolam in monoarthritic animals, may be due to the reported increase in spinal GABA levels found in those animals.