Attenuation of opioid tolerance by ETA receptor antagonist, BQ123, administered intravenously in mice

Abstract

Intracerebroventricular injection of endothelin-A receptor antagonist BQ123 potentiates opioid analgesia and reverses analgesic tolerance. This study explores whether these effects can be replicated by injecting BQ123 intravenously. Male Swiss-Webster mice were used. Morphine tolerance was induced using 3- or 7-day dosing. Intravenous BQ123 (8mg/kg) was injected only once on Day 1, 2, 3 or 4 (3-day studies), and on Day 4, 6 or 8 (7-day studies). On Day 4 or 8, respectively, tail-flick and hot-plate latencies were measured following a morphine challenge dose. Intravenous BQ123 increased the potency and duration of morphine antinociceptive responses. In the 3-day study, the antinociceptive response was unaffected by BQ123 given on Days 1 or 2. BQ123 treatment on Day 3 or 4 (Day 4, BQ123 given 15-min before morphine) significantly potentiated antinociceptive response versus vehicle-treated tolerant mice. In 7-day studies, the antinociceptive response was unaffected by BQ123 given on Day 4. BQ123 given on Day 6 or 8 (Day 8, BQ123 given 15-min before morphine) produced a >100% increase in antinociceptive response versus vehicle-treated tolerant mice for at least 48h. Intravenous administration of BQ123 is effective in potentiating morphine analgesia and restoring antinociceptive response in morphine-tolerant mice.