College of Pharmacy, Midwestern University, Downers Grove, IL 60515, USA.
Chicago College of Osteopathic Medicine, Midwestern University, Downers Grove, IL 60515, USA.
J Pharm Pharmacol. 2022 May 20;74(5):769-778. doi: 10.1093/jpp/rgac014.
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 (8 mg/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 48 h.
Intravenous administration of BQ123 is effective in potentiating morphine analgesia and restoring antinociceptive response in morphine-tolerant mice.
脑室注射内皮素 A 受体拮抗剂 BQ123 增强阿片类药物的镇痛作用，并逆转镇痛耐受。本研究探讨了通过静脉注射 BQ123 是否可以产生类似的效果。
使用雄性瑞士-韦伯斯特小鼠。采用 3 天或 7 天给药法诱导吗啡耐受。静脉注射 BQ123（8mg/kg）仅在第 1、2、3 天或第 4 天（3 天研究），或在第 4、6 或 8 天（7 天研究）注射一次。在第 4 或 8 天，分别在给予吗啡挑战剂量后测量尾巴闪烁和热板潜伏期。
静脉注射 BQ123 增加了吗啡镇痛反应的效力和持续时间。在 3 天研究中，BQ123 给药于第 1 天或第 2 天对镇痛反应没有影响。第 3 天或第 4 天（第 4 天，BQ123 在给予吗啡前 15 分钟给予）给予 BQ123 治疗显著增强了对接受载体治疗的耐受小鼠的镇痛反应。在 7 天研究中，BQ123 给药于第 4 天对镇痛反应没有影响。第 6 天或第 8 天（第 8 天，BQ123 在给予吗啡前 15 分钟给予）给予 BQ123 治疗，与接受载体治疗的耐受小鼠相比，镇痛反应增加了 100%以上，至少持续 48 小时。
静脉给予 BQ123 可有效增强吗啡镇痛作用，并恢复吗啡耐受小鼠的镇痛反应。
