Direct spinal effect of intrathecal and extradural midazolam on visceral noxious stimulation in rabbits

We measured alterations in a noxious visceromotor reflex in rabbits subjected to intestinal distension, after i.m., extradural or intrathecal injection of midazolam or saline. Spinal catheters were inserted and tunnelled surgically and the animals allowed to recover for 2 weeks. A balloon catheter was placed in the distal part of the descending colon, in the awake rabbit. Intraluminal pressures were increased continuously by water instillation until a sudden withdrawal of the pelvis was observed. Pressure values at withdrawal threshold were recorded immediately before the injection and after 5, 15 and 30 min. Pain thresholds were unaltered after saline. Extradural midazolam 12.5-250 micrograms kg-1 produced a dose-dependent increase in the percent maximum possible effect ranging from 7% after the smallest dose to 80%. Similar dose-dependent effects were observed after intrathecal injection of midazolam 25-62.5 micrograms kg-1. Extradural and intrathecal, but not i.v. injection of flumazenil 25 micrograms kg-1 (a benzodiazepine receptor antagonist) reduced the antinociceptive effect of extradural and intrathecal midazolam to pretreatment levels. A segmental effect of intrathecal midazolam was demonstrated using transcutaneous electrical stimulation in the areas of the neck and the lower back. The effect of intrathecal midazolam 62.5 microrgrams kg-1 was restricted to the lumbar region, demonstrating a selective action on the spinal cord. Thus extradural and intrathecal midazolam produced a dose-dependent effect on the reflex response to visceral distension in rabbits. This effect is caused by a direct spinal action on benzodiazepine receptors in the spinal cord.