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

In order to further clarify the role of gamma-aminobutyric acid (GABA) rece ptors in spinal sensory processing we have studied the effects of baclofen, a GABA(B) agonist, and midazolam, a benzodiazepine agonist, on the activat ion of Spinal neurones by peripheral innocuous or noxious stimulation, in n ormal or monoarthritic rats, as signalled by the induction of the proto-onc ogene c-fos. Baclofen (10 mg/kg, i.v.) caused a significant reduction in th e number of Fos-positive neurones following noxious stimulation of both nor mal and monoarthritic animals, which was prevented by the GABA(B) antagonis t CGP 35348 (200 mg/kg, i.v.). The latter caused an increase of c-fos expre ssion in normal animals subject to noxious stimulation, suggesting an endog enous tonic activation of GABA(B) receptors. This effect was not observed i n monoarthritic animals. Baclofen also reduced the number of Fos-positive n eurones in monoarthritic animals subject to innocuous stimulation. Midazola m (5 mg/kg, i.v.) had no effect in normal animals, but caused an increase i n c-fos expression induced by noxious stimulation in monoarthritic animals. Flumazenil (1 mg/kg, i.v.), a benzodiazepine antagonist, prevented the eff ect of midazolam, and if given alone evoked a decrease in Fos-positive neur ones. 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 th e reported increase in spinal GABA levels found in those animals. (C) 1999 Elsevier Science Ltd. All rights reserved.