Wong C S, Cherng C H, Luk H N, Ho S T, Tung C S
Department of Anesthesiology, National Defense Medical Center and Tri-Service General Hospital, Taipei, Taiwan.
Eur J Pharmacol. 1996 Feb 15;297(1-2):27-33. doi: 10.1016/0014-2999(95)00728-8.
Past studies have shown antagonists of excitatory amino acid receptors, both N-methyl-D-aspartate (NMDA) and non-NMDA, to produce an antinociceptive effect in vitro and in vivo. Additionally, NMDA receptor antagonists have been demonstrated to prevent morphine tolerance. We had found that one NMDA receptor antagonist, ketamine, potentiates morphine's analgesic effect in post-operative patients. Our latest experiment was performed to examine the modulatory effect of competitive and non-competitive NMDA receptor antagonists on morphine antinociception and tolerance. A PE10 catheter was intrathecally (i.t.) implanted in male Sprague-Dawley rats for drug administration. The antinociceptive effect of morphine, D-(-)-2-amino-5-phosphonovaleric acid (D-AP5) and (+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d] cyclohepten-5,10-imine maleate (MK-801) was measured using the hot-water tail immersion test. Neither competitive nor non-competitive NMDA receptor antagonists had an antinociceptive effect by themselves, but they did potentiate the antinociceptive effect of morphine. Both D-AP5 (AD50 = 0.18 micrograms) and MK-801 (AD50 = 0.57 micrograms) shifted the antinociceptive dose-response curve of morphine (AD50 = 4.2 micrograms) to the left. Both D-AP5 (4 micrograms/h) and MK-801 (10 micrograms/h) when co-administered with i.t. morphine infusions (10 micrograms/h) also inhibited the development of tolerance. In [3H][D-Ala2,N-Me-Phe4,Gly5-ol]enkephalin ([3H]DAMGO) binding assays, MK-801 (Bmax = 32.90 +/- 3.33 fmol/mg) treatment prevented the down-regulation of mu-opioid receptor high-affinity sites induced by continuous morphine infusions alone (Bmax = 13.97 +/- 1.47 fmol/mg). D-AP5 (Bmax = 20.78 +/- 3.36 fmol/mg) did not prevent the reduction of mu-opioid receptor high-affinity sites. However, high-affinity sites in rats treated with D-AP5 and morphine displayed a higher affinity (KD = 0.45 +/- 0.09 nM) than those of control animals (KD = 0.95 +/- 0.08 nM). Results of this study indicate that competitive as well as non-competitive NMDA receptor antagonists enhance morphine's antinociceptive effect, and prevent the development of morphine tolerance. Thus, in our opinion, there opens a new frontier in clinical pain management, especially for those patients who require long-term opioid treatment for pain relief.
过去的研究表明，兴奋性氨基酸受体的拮抗剂，包括N-甲基-D-天冬氨酸（NMDA）受体拮抗剂和非NMDA受体拮抗剂，在体外和体内均能产生抗伤害感受作用。此外，NMDA受体拮抗剂已被证明可预防吗啡耐受性。我们发现一种NMDA受体拮抗剂氯胺酮可增强术后患者吗啡的镇痛效果。我们进行了最新实验，以研究竞争性和非竞争性NMDA受体拮抗剂对吗啡抗伤害感受及耐受性的调节作用。将一根PE10导管鞘内（i.t.）植入雄性Sprague-Dawley大鼠体内用于给药。使用热水甩尾试验测量吗啡、D-（-）-2-氨基-5-磷酸戊酸（D-AP5）和（+）-5-甲基-10,11-二氢-5H-二苯并[a,d]环庚烯-5,10-亚胺马来酸盐（MK-801）的抗伤害感受作用。竞争性和非竞争性NMDA受体拮抗剂自身均无抗伤害感受作用，但它们确实增强了吗啡的抗伤害感受作用。D-AP5（半数有效剂量AD50 = 0.18微克）和MK-801（AD50 = 0.57微克）均使吗啡的抗伤害感受剂量-反应曲线（AD50 = 4.2微克）向左移动。当D-AP5（4微克/小时）和MK-801（10微克/小时）与鞘内吗啡输注（10微克/小时）共同给药时，也抑制了耐受性的产生。在[3H][D-丙氨酸2，N-甲基苯丙氨酸4，甘氨酸5-醇]脑啡肽（[3H]DAMGO）结合试验中，MK-801（最大结合容量Bmax = 32.90±3.33飞摩尔/毫克）处理可防止仅连续输注吗啡所诱导的μ-阿片受体高亲和力位点的下调（Bmax = 13.97±1.47飞摩尔/毫克）。D-AP5（Bmax = 20.78±3.36飞摩尔/毫克）未能防止μ-阿片受体高亲和力位点的减少。然而，用D-AP5和吗啡处理的大鼠中的高亲和力位点显示出比对照动物更高的亲和力（解离常数KD = 0.45±0.09纳摩尔）（KD = 0.95±0.08纳摩尔）。本研究结果表明，竞争性和非竞争性NMDA受体拮抗剂均可增强吗啡的抗伤害感受作用，并防止吗啡耐受性的产生。因此，我们认为，这为临床疼痛管理开辟了一个新领域，特别是对于那些需要长期使用阿片类药物缓解疼痛的患者。
