Mechanisms of the influence of midazolam on morphine antinociception at spinal and supraspinal levels in rats

• Published in: European journal of pharmacology Vol. 271; no. 2; pp. 421 - 431
• Main Authors: Luger, Thomas J., Takahiko Hayashi, Lorenz, Ingo H., Hill, Harlan F.
• Format: Journal Article
• Language: English
• Published: Amsterdam Elsevier B.V 27.12.1994; Elsevier
• Subjects: Analgesia; Analgesics; Animals; Antinociception, i.c.v., i.t; Benzodiazepine; Biological and medical sciences; Drug Interactions; Flumazenil - pharmacology; GABA receptor antagonist; Injections, Intraventricular; Male; Medical sciences; Midazolam - administration & dosage; Midazolam - pharmacology; Morphine - administration & dosage; Morphine - pharmacology; Naloxone - pharmacology; Neuropharmacology; Nociceptive test; Opioid; Pharmacology. Drug treatments; Rats; Rats, Sprague-Dawley; Reaction Time - drug effects; Spinal Cord - drug effects; Opioid; Nociceptive test; GABA receptor antagonist; Antinociception, i.c.v., i.t; Benzodiazepine; Nociception; Drug combination; Rat; Rodentia; Morphine; Opiates; Cerebral ventricle; Narcotic analgesic; Intrathecal administration; Gabaergic receptor; Vertebrata; Mammalia; Analgesic; Animal; Intracerebral administration; Benzodiazepine derivatives; Drug interaction; Mechanism of action
• ISSN: 0014-2999; 1879-0712
• DOI: 10.1016/0014-2999(94)90802-8

The mechanisms for the combined antinociceptive effect of midazolam and morphine administered at spinal (intrathecal, i.t.) and supraspinal (intracerebroventricular, i.c.v.) levels were investigated in rats. Nociceptive test results showed that co-administration of midazolam and morphine at the spinal level potentiated morphine-induced antinociception, and that this interaction was blocked by intraperitoneal (i.p.) naloxone and reversed by i.t. bicuculline and i.p. flumazenil. Also, bicuculline and flumazenil blocked midazolam-induced antinociception at the spinal level, and naloxone completely reversed morphine antinociception. In contrast, when drugs were injected intracerebroventricularly, midazolam inhibited the antinociceptive effect of morphine (as determined by the hot-plate test). The inhibitory effects of i.c.v. midazolam upon i.c.v. morphine antinociception were partly blocked by flumazenil and bicuculline. Midazolam-induced antinociception was increased by bicuculline and decreased by flumazenil; naloxone i.p. blocked both i.c.v. morphine antinociception and i.c.v. morphine-midazolam antinociception. Results after i.t. injection may be due to an interaction between morphine and midazolam/GABA A receptor-activated systems. At the supraspinal level, this interaction may also activate other systems that are distinct from those governing the individual action of each agonist.