Mao J, Price D D, Lu J, Mayer D J
Department of Anesthesiology, Medical College of Virginia, Virginia Commonwealth University, Richmond 23298, USA.
Neurosci Lett. 1998 Jul 10;250(3):193-6. doi: 10.1016/s0304-3940(98)00472-8.
Morphine has been used in previous studies that investigate interactions between the spinal cord mu-opioid and N-methyl-D-aspartate (NMDA) receptors in mechanisms of antinociceptive tolerance. Although morphine acts primarily on the mu-receptor, it also activates other subtypes of opioid receptors. In the present study, the selective mu-opioid agonist, D-Ala2-N-Me-Phe4,Gly-ol5-enkephalin (DAMGO), was used to further test the hypothesis. Repeated intrathecal (i.t.) administration of 6 microg DAMGO (twice daily) in rats for 7 days resulted in an approximately 17-fold rightward shift of the cumulative dose-response curve (the tail-flick test) on Day 8 compared to that on Day 1. This rightward shift of the dose-response curve was prevented by the i.t. co-administration with DAMGO of the NMDA receptor antagonist MK-801 (10 = 5 > 2.5 >> 1.25 nmol > saline). Further, a lower dose range of MK-801 (2.5 > 1.25 nmol > 0.625 > 0.313 = saline) was effective to prevent the antinociceptive tolerance to a lower dose (1.5 microg) of DAMGO using the same i.t. administration regimen. Thus, the present results provide further evidence supporting a cellular and intracellular model of opioid tolerance involving interactions between the mu-opioid and the NMDA receptors in the spinal cord.
吗啡已被用于先前的研究中，这些研究探讨脊髓μ-阿片受体与N-甲基-D-天冬氨酸（NMDA）受体之间在抗伤害感受性耐受机制中的相互作用。尽管吗啡主要作用于μ-受体，但它也会激活其他亚型的阿片受体。在本研究中，使用选择性μ-阿片激动剂D-Ala2-N-Me-Phe4，Gly-ol5-脑啡肽（DAMGO）来进一步验证该假设。在大鼠中，连续7天每天两次鞘内注射6μg DAMGO，与第1天相比，第8天的累积剂量-反应曲线（甩尾试验）向右移动了约17倍。NMDA受体拮抗剂MK-801（10 = 5 > 2.5 >> 1.25 nmol > 生理盐水）与DAMGO鞘内共同给药可防止剂量-反应曲线的这种右移。此外，使用相同的鞘内给药方案，较低剂量范围的MK-801（2.5 > 1.25 nmol > 0.625 > 0.313 = 生理盐水）可有效防止对较低剂量（1.5μg）DAMGO的抗伤害感受性耐受。因此，本研究结果提供了进一步的证据，支持了一种涉及脊髓中μ-阿片受体与NMDA受体相互作用的阿片耐受的细胞和细胞内模型。
