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

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Abstract
1 The effects of an intrathecally administered benzodiazepine receptor (BZR) agonist (midazolam, up to 50 μg), antagonist (flumazenil, Ro 15–1788, 5 μg) and inverse agonist (Ro 19–4603, 15 μg) 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 γ-aminobutyric acidA (GABAA)-receptors, the transmission of nociceptive information at the spinal cord level, when this transmission is depressed by μ-opioid receptor activation.