Bhalla Shaifali, Matwyshyn George, Gulati Anil
Department of Biopharmaceutical Sciences (M/C 865), University of Illinois at Chicago, Chicago, IL 60612, USA.
Peptides. 2003 Apr;24(4):553-61. doi: 10.1016/s0196-9781(03)00110-4.
Several neurotransmitter mechanisms have been proposed to play a role in the development of morphine tolerance. The present study provides evidence for the first time that endothelin (ET) antagonists can restore morphine analgesia in morphine tolerant rats. Tolerance to morphine was induced by subcutaneous implantation of six morphine pellets during a 7-day period. The degree of tolerance to morphine was measured by determining analgesic response (tail-flick latency) and hyperthermic response to morphine sulfate (8 mg/kg, subcutaneously (s.c.)) in placebo and morphine pellet implanted rats. The maximal tail-flick latency in morphine pellet-vehicle treated rats (7.54 s) was significantly lower (P<0.05) when compared to placebo pellet-vehicle treated rats (10s), indicating that tolerance developed to the analgesic effect of morphine. In separate sets of experiments, ET antagonists, BQ123 (10 microg, intracerebroventricularly (i.c.v.)) and BMS182874 (50 microg, i.c.v.) were administered in placebo and morphine tolerant rats. BQ123 was injected twice daily for 7 days and once on day 8. BMS182874 was administered only on day 8. Morphine (8 mg/kg, s.c.) was administered 30min after BQ123 or BMS182874 administration. It was found that both BQ123 and BMS182874 potentiated morphine analgesia in placebo and morphine tolerant rats. BQ123 potentiated tail-flick latency by 30.0% in placebo tolerant rats and 94.5% in morphine tolerant rats compared to respective controls. BMS182874 potentiated tail-flick latency by 30.2% in placebo tolerant rats and 66.7% in morphine tolerant rats. Morphine-induced hyperthermic effect was also potentiated by BQ123 and BMS182874. The duration of analgesic action was also prolonged by BQ123 and BMS182874. The effect of BMS182874 was less as compared to BQ123. BQ123 and BMS182874 are selective ET(A) receptor antagonists. Therefore, it is concluded that ET(A) receptor antagonists restore morphine analgesia in morphine tolerant rats.
已有多种神经递质机制被提出在吗啡耐受性的形成中发挥作用。本研究首次提供证据表明，内皮素（ET）拮抗剂可恢复吗啡耐受大鼠的吗啡镇痛作用。通过在7天内皮下植入6粒吗啡缓释片诱导大鼠对吗啡产生耐受性。通过测定安慰剂组和植入吗啡缓释片大鼠对吗啡（8mg/kg，皮下注射）的镇痛反应（甩尾潜伏期）和体温升高反应，来衡量对吗啡的耐受程度。与安慰剂缓释片 - 赋形剂处理的大鼠（10秒）相比，吗啡缓释片 - 赋形剂处理的大鼠的最大甩尾潜伏期（7.54秒）显著降低（P<0.05），表明对吗啡的镇痛作用产生了耐受性。在单独的几组实验中，将ET拮抗剂BQ123（10μg，脑室内注射）和BMS182874（50μg，脑室内注射）分别给予安慰剂组和吗啡耐受大鼠。BQ123每天注射两次，共注射7天，第8天注射一次。BMS182874仅在第8天给药。在注射BQ123或BMS182874 30分钟后给予吗啡（8mg/kg，皮下注射）。结果发现，BQ123和BMS182874均可增强安慰剂组和吗啡耐受大鼠的吗啡镇痛作用。与各自的对照组相比，BQ123使安慰剂耐受大鼠的甩尾潜伏期提高了30.0%，使吗啡耐受大鼠的甩尾潜伏期提高了94.5%。BMS182874使安慰剂耐受大鼠的甩尾潜伏期提高了30.2%，使吗啡耐受大鼠的甩尾潜伏期提高了66.7%。BQ123和BMS182874还增强了吗啡诱导的体温升高效应。BQ123和BMS182874也延长了镇痛作用的持续时间。与BQ123相比，BMS182874的作用较小。BQ123和BMS182874是选择性ET(A)受体拮抗剂。因此，得出结论：ET(A)受体拮抗剂可恢复吗啡耐受大鼠的吗啡镇痛作用。
