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

(1)虽然大鼠主动脉阻断后短时间内注射吗啡可通过阿片受体偶联效应在脊髓内引起一过性痉挛瘫痪，但有关脊髓缺血后阿片受体亚型激活与神经功能的关系尚未见报道。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IT应用不同的阿片受体激动剂是否能在大鼠脊髓缺血一段时间后引起瘫痪。在SD大鼠体内植入IT导管，用主动脉内球囊诱导脊髓缺血6min。复流后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^&lt；2，5&>)激动剂。另一组动物被用来研究…的剂量反应效应更多的是运动功能障碍。为此，在缺血后鞘内注射三种剂量的Mu、kappa或Delta激动剂。注射IT后，采用运动缺陷指数(0=完全恢复；6=完全截瘫)定期评定运动功能恢复情况。注射Mu和Delta，但不注射kappa激动剂，在诱发大鼠痉挛性瘫痪中产生剂量依赖效应。此外，IT MU和Delta激动剂引起的这种痉挛分别被IT纳洛酮和纳曲吲哚完全逆转。这些结果提示，不同阿片类药物对大鼠脊髓非损伤性缺血后运动功能的影响取决于阿片受体亚型。(2)本研究旨在探讨K+-ATP通道开放剂尼可地尔与吗啡对大鼠脊髓非损伤性缺血后运动功能的影响。用球囊导管阻断大鼠主动脉6min造成脊髓缺血模型。所有动物在缺血后1h鞘内注射吗啡(1~60μg)。再灌注150min后，除鞘内注射吗啡外，M组(对照组)、MN组(吗啡+尼可地尔)、MNG组(吗啡+尼可地尔+格列本脲)分别鞘内注射生理盐水、尼可地尔(10μg)和格列本脲(10μg)+尼可地尔(10μg)。采用鞘内注射吗啡对脑缺血后神经功能影响的定量生物测定法，计算再灌流3h后再灌流3h致瘫痪的半数有效剂量值(ED50&gt；)。M组和MN组的ED50分别为15.1±4.9μg和2.9±1.0μg(P<0.0 5)。MNG组剂量-反应曲线右移，其致瘫痪的ED50为11.6±4.7μg。提示鞘内注射小剂量吗啡联合尼可拉尼可诱导大鼠非损伤性脊髓缺血后痉挛性瘫痪。较少

(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