THE SPINAL POTENTIATING EFFECT AND THE SUPRASPINAL INHIBITORY EFFECT OF MIDAZOLAM ON OPIOID-INDUCED ANALGESIA IN RATS

The authors investigated the effects of spinal and supraspinal adminis tration of the benzodiazepine receptor agonist midazolam alone and wit h opioids on tests of nociception (tail-flick and hot-plate tests) and motor function (catalepsy) in rats. At the spinal level, the dose-res ponse curves for peak effect and area under the curve for morphine wer e shifted to the left (indicating potentiation) by a submaximal dose o f intrathecal (i.t.) midazolam (20 mu g) in both nociceptive tests. Ad ditionally, 2.5 mu g Of i.t. midazolam, a dose having no effect when g iven alone, increased antinociception in both tests when given with i. t. morphine. Isobolographic analysis confirmed that i.t. injection of midazolam potentiated antinociception induced by i.t. morphine. At the supraspinal level, intracerebroventricular (i.c.v.) injection of 4 mu g of midazolam inhibited morphine antinociception, i.e., the dose-res ponse curve for morphine in the hot-plate test shifted to the right. M idazolam did not affect morphine antinociception in the tail-flick tes t. Catalepsy occurred only when the highest doses of i.t. or i.c.v. mo rphine or midazolam were injected alone. The differing effect of midaz olam on morphine-induced antinociception suggests that different mecha nisms are involved in the spinal cord and brain.