Effects of an intrathecally administered benzodiazepine receptor agonist, antagonist and inverse agonist on morphine-induced inhibition of a spinal nociceptive reflex

Br J Pharmacol. 1988 Apr;93(4):964-8. doi: 10.1111/j.1476-5381.1988.tb11486.x.

Abstract

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.

MeSH terms

  • Animals
  • Anti-Anxiety Agents / pharmacology*
  • Azepines / pharmacology
  • Flumazenil / pharmacology
  • Injections, Spinal
  • Male
  • Midazolam / pharmacology
  • Morphine / pharmacology*
  • Nociceptors / drug effects*
  • Nociceptors / physiology
  • Rats
  • Rats, Inbred Strains
  • Reaction Time / drug effects
  • Receptors, GABA-A / drug effects*

Substances

  • Anti-Anxiety Agents
  • Azepines
  • Receptors, GABA-A
  • Flumazenil
  • Morphine
  • Ro 19-4603
  • Midazolam