Chow Lok-Hi, Huang Eagle Y-K, Ho Shung-Tai, Lee Tak-Yu, Tao Pao-Luh
Graduate Institute of Medical Science, Department of Pharmacology, National Defense Medical Center, Tapei, Taiwan.
Can J Anaesth. 2004 Nov;51(9):905-10. doi: 10.1007/BF03018888.
Morphine is an effective analgesic, but adverse effects limit its clinical use in higher doses. The non-opioid antitussive, dextromethorphan (DM), can potentiate the analgesic effect of morphine and decrease the dose of morphine in acute postoperative pain, but the underlying mechanism remains unclear. We previously observed that DM increases the serum concentration of morphine in rats. Therefore, we investigated the effects of drugs administered at the spinal level to exclude possible pharmacokinetic interactions. As DM has widespread binding sites in the central nervous system [such as N-methyl-D-aspartate (NMDA) receptors, sigma receptors and alpha(3)ss(4) nicotinic receptors], we investigated whether the potentiation of morphine antinociception by DM at the spinal level is related to NMDA receptors.
We used MK-801 as a tool to block the NMDA channel first, and then studied the interaction between intrathecal (i.t.) morphine and DM. The tail-flick test was used to examine the antinociceptive effects of different combinations of morphine and other drugs in rats.
DM (2-20 microg) or MK-801 (5-15 microg) showed no significant antinociceptive effect by themselves. The antinociceptive effect of morphine (0.5 microg, i.t.) was significantly enhanced by DM and reached the maximal potentiation (43.7%-50.4%) at doses of 2 to 10 microg. Pretreatment with MK-801 (5 or 10 microg, i.t.) significantly potentiated morphine antinociception by 49.9% or 38.7%, respectively. When rats were pretreated with MK-801, DM could not further enhance morphine antinociception (45.7% vs 50.5% and 43.3%).
Our results suggest that spinal NMDA receptors play an important role in the effect of DM to potentiate morphine antinociception.
吗啡是一种有效的镇痛药，但不良反应限制了其在高剂量时的临床应用。非阿片类镇咳药右美沙芬（DM）可增强吗啡的镇痛作用，并在急性术后疼痛中降低吗啡剂量，但其潜在机制仍不清楚。我们之前观察到DM可提高大鼠体内吗啡的血清浓度。因此，我们研究了脊髓水平给药的药物作用，以排除可能的药代动力学相互作用。由于DM在中枢神经系统中有广泛的结合位点[如N-甲基-D-天冬氨酸（NMDA）受体、σ受体和α3β4烟碱受体]，我们研究了DM在脊髓水平对吗啡镇痛作用的增强是否与NMDA受体有关。
我们首先使用MK-801作为阻断NMDA通道的工具，然后研究鞘内（i.t.）注射吗啡与DM之间的相互作用。采用甩尾试验检测吗啡与其他药物不同组合对大鼠的镇痛作用。
DM（2-20微克）或MK-801（5-15微克）单独使用时均未显示出明显的镇痛作用。DM可显著增强吗啡（0.5微克，i.t.）的镇痛作用，在2至10微克剂量时达到最大增强效果（43.7%-50.4%）。MK-801（5或10微克，i.t.）预处理分别使吗啡镇痛作用显著增强49.9%或38.7%。当大鼠用MK-801预处理后，DM不能进一步增强吗啡的镇痛作用（45.7%对50.5%和43.3%）。
我们的结果表明，脊髓NMDA受体在DM增强吗啡镇痛作用中起重要作用。
