Yamada Hiroaki, Shimoyama Naohito, Sora Ichiro, Uhl George R, Fukuda Yasuichiro, Moriya Hideshige, Shimoyama Megumi
Department of Autonomic Physiology, Chiba University Graduate School of Medicine, 1-8-1 Inohana, Chuo-ku, Chiba, Chiba-ken 260-8670, Japan.
Brain Res. 2006 Apr 14;1083(1):61-9. doi: 10.1016/j.brainres.2006.01.095. Epub 2006 Mar 10.
Previous studies have demonstrated the virtual lack of analgesia in mu opioid receptor knockout mice after systemic administration of morphine. Thus, it has been suggested that analgesic actions of morphine are produced via the mu opioid receptor, despite its ability to bind to kappa and delta receptors in vitro. However, it is not clear whether the results of these studies reflect the effect of morphine in the spinal cord. In the present study, we report study of the analgesic actions of spinally-administered morphine and other opioid receptor agonists in mu opioid receptor knockout and wild type mice. Morphine produced a dose-dependent antinociceptive effect in the tail flick test in the knockout mice, although higher doses were needed to produce antinociception than in wild type mice. The antinociceptive effect of morphine was completely blocked by naloxone (a non-selective opioid antagonist) and nor-binaltorphimine (nor-BNI, a selective kappa-opioid receptor antagonist), but not by naltrindole (a selective delta-opioid receptor antagonist). U-50,488H (a selective kappa-opioid receptor agonist) also produced a dose-dependent antinociceptive effect in knockout mice but presented lower analgesic potency in knockout mice than in wild type mice. Analgesic effects of [d-Pen2,d-Pen5]enkephalin (DPDPE, a selective delta-opioid receptor agonist) were observed in wild type mice but abolished in knockout mice. SNC80 (a selective delta-opioid receptor agonist) was not antinociceptive even in wild type mice. The present study demonstrated that morphine can produce thermal antinociception via the kappa opioid receptor in the spinal cord in the absence of the mu opioid receptor. Lower potency of U50,488H in mu opioid receptor knockout mice suggests interaction between kappa and mu opioid receptors at the spinal level.
先前的研究表明，在对μ阿片受体基因敲除小鼠全身给予吗啡后，实际上不存在镇痛作用。因此，尽管吗啡在体外能够与κ和δ受体结合，但有人提出吗啡的镇痛作用是通过μ阿片受体产生的。然而，这些研究结果是否反映了吗啡在脊髓中的作用尚不清楚。在本研究中，我们报告了对脊髓给予吗啡和其他阿片受体激动剂在μ阿片受体基因敲除小鼠和野生型小鼠中的镇痛作用的研究。在基因敲除小鼠的甩尾试验中，吗啡产生了剂量依赖性的抗伤害感受作用，尽管与野生型小鼠相比需要更高的剂量才能产生抗伤害感受。吗啡的抗伤害感受作用被纳洛酮（一种非选择性阿片受体拮抗剂）和去甲二氢吗啡酮（nor-BNI，一种选择性κ阿片受体拮抗剂）完全阻断，但未被纳曲吲哚（一种选择性δ阿片受体拮抗剂）阻断。U-50,488H（一种选择性κ阿片受体激动剂）在基因敲除小鼠中也产生了剂量依赖性的抗伤害感受作用，但在基因敲除小鼠中的镇痛效力低于野生型小鼠。[d- Pen2，d- Pen5]脑啡肽（DPDPE，一种选择性δ阿片受体激动剂）在野生型小鼠中具有镇痛作用，但在基因敲除小鼠中则消失。SNC80（一种选择性δ阿片受体激动剂）即使在野生型小鼠中也没有抗伤害感受作用。本研究表明，在不存在μ阿片受体的情况下，吗啡可通过脊髓中的κ阿片受体产生热镇痛作用。U50,488H在μ阿片受体基因敲除小鼠中的效力较低，表明κ和μ阿片受体在脊髓水平存在相互作用。
