Effects of an intrathecally administered benzodiazepine receptor agonist, antagonist and inverse agonist on morphine-induced inhibition of a spinal nociceptive reflex.
1. The effects of an intrathecally administered benzodiazepine receptor (BZR) agonist (midazolam, up to 50 micrograms), antagonist (flumazenil, Ro 15-1788, 5 micrograms) and inverse agonist (Ro 19-4603, 15 micrograms) on nociception and on morphine-induced antinociception were studied in rats. 2. By themselves, none of these compounds significantly altered pain threshold. 3. The BZR agonist midazolam enhanced the morphine-induced antinociceptive effect whereas the antagonist flumazenil did not alter it. In contrast, the BZR inverse agonist Ro 19-4603 decreased the morphine-induced antinociceptive effect. 4. Naloxone (1 mg kg-1 i.p.) completely reversed all these effects. 5. These results demonstrate that BZR agonists and inverse agonists are able to affect, by allosteric up- or down-modulation of gamma-aminobutyric acidA (GABAA)-receptors, the transmission of nociceptive information at the spinal cord level, when this transmission is depressed by mu-opioid receptor activation.
D000818:Animals; D014151:Anti-Anxiety Agents / Q000494:pharmacology*; D001381:Azepines / Q000494:pharmacology; D005442:Flumazenil / Q000494:pharmacology; D007278:Injections, Spinal; D008297:Male; D008874:Midazolam / Q000494:pharmacology; D009020:Morphine / Q000494:pharmacology*; D009619:Nociceptors / Q000187:drug effects* / Q000502:physiology; D051381:Rats; D011919:Rats, Inbred Strains; D011930:Reaction Time / Q000187:drug effects; D011963:Receptors, GABA-A / Q000187:drug effects*
D014151:Anti-Anxiety Agents; D001381:Azepines; D011963:Receptors, GABA-A; D005442:Flumazenil; D009020:Morphine; C056530:Ro 19-4603; D008874:Midazolam