Investigation for mechanism of morphine-inducing spastic paraplegia after a non-injurious interval of spinal cord ischemia

(1)虽然在啮齿类动物主动脉阻断后短时间内注射吗啡可通过脊髓阿片受体偶联作用诱导短暂性痉挛性截瘫，但关于脊髓缺血后阿片受体亚型激活与神经功能之间关系的研究尚未见报道。为了确定这些阿片受体在脊髓缺血后运动功能障碍的脊髓机制中的作用，我们研究了不同阿片受体激动剂是否可以诱导大鼠脊髓缺血后非损伤期的麻痹。在Sprague-Dawley大鼠植入IT导管后，用主动脉内球囊诱导脊髓缺血6分钟。回流后30min，鞘内注射Mu （[D-Ala^2, N-Me Phe^4， Gly-ol^5]脑啡肽）、kappa （U50488H）或delta （p-Pen^<2,5>]脑啡肽）激动剂。另一组动物被用来研究对运动功能障碍的剂量反应效应。为此目的，缺血后在鞘内注射三剂量的mu， kappa或delta激动剂。注射IT后，定期用运动缺陷指数评估运动功能恢复情况（0 =完全恢复；6 =完全截瘫）。给药mu和delta而不是kappa激动剂在诱导大鼠痉挛性截瘫中产生剂量依赖效应。此外，由IT mu和delta激动剂引起的这种痉挛分别被IT纳洛酮和纳曲多完全逆转。这些结果表明，在非损伤性脊髓缺血后，各种阿片样物质对运动功能的影响取决于个体阿片样物质受体亚型。(2)本研究旨在探讨K+ATP通道打开剂尼可地尔与吗啡对脊髓缺血非损伤期大鼠运动功能的相互作用。用球囊导管阻断大鼠主动脉6 min诱导脊髓缺血。所有动物缺血1 h后鞘内注射吗啡（1 ~ 60 μg）。在鞘内注射吗啡的基础上，M组（对照动物）、MN组（吗啡与尼可地尔联用）、MNG组（吗啡、尼可地尔、格列本地尔联用）在再灌注150 min后分别给予鞘内盐水、尼可地尔（10 μg）和格列本脲（10 μg）、尼可地尔（10 μg）。鞘内吗啡对缺血后神经功能影响的quintal生物测定，计算再灌注3 h时诱导麻痹的50%有效剂量值（ED_<50>）。M组和MN组的ED_<50>分别为15.1±4.9 μg和2.9±1.0 μg （p < 0.05）。MNG组剂量-反应曲线右移，致瘫ED_<50>为11.6±4.7 μg。本研究提示鞘内注射低剂量吗啡联合尼可诱导大鼠脊髓缺血非损伤期后痉挛性截瘫。少

(1) Although intra hecal (IT) morphine after a short interval of aortic occlusion in a rodent model induced transient spastic paraparesis via opioid receptor-coupled effects in spinal cord, investigations on the relationship between the activation of opioid receptor subtypes and neurological function after spinal cord ischemia have not been reported. To determine the role of these opioid receptors in spinal mechanisms of motor dysfunction after spinal cord ischemia we investigated whether IT administration of various opioid receptor agonists can induce paraparesis after a noninjurious interval of spinal cord ischemia in rats. In Sprague-Dawley rats implanted with an IT catheter, spinal cord ischemia was induced for 6 min using an intraaortic balloon. Mu ([D-Ala^2, N-Me Phe^4, Gly-ol^5] enkephalin), kappa (U50488H) or delta (p-Pen^<2,5>] enkephalin) agonist was injected intrathecally at 30 min after reflow. A separate group of animals was used to investigate the dose-response effect on … More this motor dysfunction. For this purpose, three doses of mu, kappa, or delta agonist were injected intrathecally after ischemia. After IT injection, recovery of motor function was assessed periodically using the motor deficit index (0 = complete recovery; 6 = complete paraplegia). IT administration of mu and delta but not kappa agonists produced dose-dependent effects in induction of spastic paraparesis in the rat. In addition, this spasticity induced by IT mu and delta agonists was reversed completely by IT naloxone and naltrindole, respectively. These results suggested that the effect of various opioids on motor function after a noninjurious interval of spinal cord ischemia depends upon individual opioid receptor subtypes.(2) The purpose of this study is to investigate the interaction between K+ATP channel opener (nicorandil) and morphine on motor function after non-injurious interval of spinal cord ischemia in the rat. Spinal ischemia was induced by aortic occlusion for 6 min with a balloon catheter in Sprague-Dawley rats. All animals received intrathecal injection of morphine (1-60 μg) 1 h after ischemia. In addition to the intrathecal injection of morphine, group M (control animals), group MN (combination of morphine and nicorandil), and group MNG (combination of morphine, nicorandil, and glibenclamide) received intrathecal saline, nicorandil (10 μg) and both glibenclamide (10 μg) and nicorandil (10 μg) after 150 min of reperfusion, respectively. The quintal bioassay for the effect of intrathecal morphine on neurological function after ischemia was performed to calculate 50% effective dose values (ED_<50>) for inducing paraparesis at 3 h of reperfusion. The ED_<50> in the group M and group MN was 15.1± 4.9 μg and 2.9± 1.0 μg of IT morphine respectively (p < 0.05). In Group MNG, the dose-response curve shifted back to the right and the ED_<50> for inducing paraparesis was 11.6 ± 4.7 μg of IT morphine. The present study suggests that intrathecal low dose morphine combined with nicoranil could induce spastic paraparesis after non-injurious interval of spinal cord ischemia in the rat. Less