Ibuki T, Dunbar S A, Yaksh T L
Department of Anesthesiology, University of California, San Diego, La Jolla 92093-0801, USA.
Pain. 1997 Apr;70(2-3):125-32. doi: 10.1016/s0304-3959(96)03283-6.
The magnitude of tolerance and dependence is defined in part by agonist concentration and duration of receptor exposure. Therefore, in the face of continued exposure to an opioid agonist, periodic reduction in opiate receptor occupancy should reduce tolerance. Alternately, we have shown that reversal of opiate agonist action yields increased glutamate release and NMDA-antagonist studies indicated that this release may lead to an exacerbation of tolerance. To address this issue, we observed the effect of transient daily antagonism by naloxone of otherwise continuous opioid receptor exposure on morphine tolerance development. Rats with intrathecal (i.t.) catheters and osmotic minipumps were assigned to one of the following 7-day infusion/treatment groups: group A: i.t. morphine (20 nmol/h) with daily subcutaneous (s.c.) injection of naloxone 0.6 mg/kg, group B: i.t. morphine (20 nmol/h) with daily s.c. saline, group C: i.t. saline (1 microl/h) with daily s.c. injection of naloxone 0.6 mg/kg, or, group D: i.t. saline (1 microl/h) with daily s.c. saline. Hot plate response latency was measured daily before and after the s.c. injection. The infusion was discontinued on day 7 and on day 8 the response of the rat to a probe dose of i.t. morphine (60 nmol) given as a bolus was observed. Elevated hot plate latencies were observed for groups A and B on day 1 of infusion and this declined over the following 3-4-day interval. Group B approached baseline, but by day 5 group A showed a mild hyperalgesia prior to each naloxone injection. Groups C and D showed no change in baseline latency. On day 8, 24 h after termination of morphine infusion, the magnitude of the analgesic response to the probe i.t. morphine was: group D = group C > group B > group A (P < 0.05, 1-way ANOVA). Thus, in contrast to the expectation that tolerance would be reduced by periodic blockade of opiate receptor occupancy, rats that had daily transient receptor antagonism showed a greater tolerance than rats with simple continuous receptor occupancy. These results are, however, consistent with work showing that (i) naloxone will evoke spinal glutamate release in spinal morphine tolerant rats and (ii) spinal NMDA receptor antagonism ameliorates loss of opiate effect in this spinal infusion model.
耐受性和依赖性的程度部分由激动剂浓度和受体暴露持续时间决定。因此，面对持续暴露于阿片类激动剂的情况，定期降低阿片受体占有率应能降低耐受性。另外，我们已经表明，阿片类激动剂作用的逆转会导致谷氨酸释放增加，而NMDA拮抗剂研究表明这种释放可能导致耐受性加剧。为了解决这个问题，我们观察了纳洛酮每日短暂拮抗对持续阿片受体暴露情况下吗啡耐受性发展的影响。将带有鞘内（i.t.）导管和渗透微型泵的大鼠分配到以下7天输注/治疗组之一：A组：鞘内注射吗啡（20 nmol/h），每日皮下（s.c.）注射纳洛酮0.6 mg/kg；B组：鞘内注射吗啡（20 nmol/h），每日皮下注射生理盐水；C组：鞘内注射生理盐水（1微升/h），每日皮下注射纳洛酮0.6 mg/kg；或D组：鞘内注射生理盐水（1微升/h），每日皮下注射生理盐水。每天在皮下注射前后测量热板反应潜伏期。在第7天停止输注，在第8天观察大鼠对一次性给予的鞘内吗啡探测剂量（60 nmol）的反应。在输注第1天，A组和B组观察到热板潜伏期延长，在接下来的3 - 4天间隔内有所下降。B组接近基线，但到第5天，A组在每次纳洛酮注射前出现轻度痛觉过敏。C组和D组的基线潜伏期没有变化。在第8天，吗啡输注终止24小时后，对鞘内吗啡探测剂量的镇痛反应程度为：D组 = C组 > B组 > A组（P < 0.05，单因素方差分析）。因此，与通过定期阻断阿片受体占有率会降低耐受性的预期相反，每日有短暂受体拮抗作用的大鼠比单纯持续受体占有率状态的大鼠表现出更大的耐受性。然而，这些结果与以下研究结果一致：（i）纳洛酮会在脊髓吗啡耐受的大鼠中引起脊髓谷氨酸释放，以及（ii）脊髓NMDA受体拮抗作用可改善该脊髓输注模型中阿片类药物作用的丧失。
