MECHANISMS OF THE INFLUENCE OF MIDAZOLAM ON MORPHINE ANTINOCICEPTION AT SPINAL AND SUPRASPINAL LEVELS IN RATS

The mechanisms for the combined antinociceptive effect of midazolam an d morphine administered at spinal (intrathecal, i.t.) and supraspinal (intracerebroventricular, i.c.v.) levels were investigated in rats. No ciceptive test results showed that co-administration of midazolam and morphine at the spinal level potentiated morphine-induced antinocicept ion, and that this interaction was blocked by intraperitoneal (i.p.) n aloxone and reversed by i.t. bicuculline and i.p. flumazenil. Also, bi cuculline and flumazenil blocked midazolam-induced antinociception at the spinal level, and naloxone completely reversed morphine antinocice ption. In contrast, when drugs were injected intracerebroventricularly , midazolam inhibited the antinociceptive effect of morphine (as deter mined by the hot-plate test). The inhibitory effects of i.c.v. midazol am upon i.c.v. morphine antinociception were partly blocked by flumaze nil and bicuculline. Midazolam-induced antinociception was increased b y bicuculline and decreased by flumazenil; naloxone i.p. blocked both i.c.v. morphine antinociception and i.c.v. morphine-midazolam antinoci ception. Results after i.t. injection may be due to an interaction bet ween morphine and midazolam/GABA(A) receptor-activated systems. At the supraspinal level, this interaction may also activate other systems t hat are distinct from those governing the individual action of each ag onist.