Potent suppression of stretch reflex activity after systemic or spinal delivery of tizanidine in rats with spinal ischemia-induced chronic spastic paraplegia.
Potent suppression of stretch reflex activity after systemic or spinal delivery of tizanidine in rats with spinal ischemia-induced chronic spastic paraplegia.
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DOI：
10.1016/j.neuroscience.2011.08.022
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发表时间：
2011-10-27
期刊：
影响因子：
3.3
通讯作者：
Marsala, M.
中科院分区：
文献类型：
--
作者：
Fuchigami, T.;Kakinohana, O.;Hefferan, M. P.;Lukacova, N.;Marsala, S.;Platoshyn, O.;Sugahara, K.;Yaksh, T. L.;Marsala, M.
痉挛和僵硬是与脊柱创伤或缺血性损伤相关的严重并发症。临床研究表明，替扎尼定（Tizanidine，Tiz）是一种有效的抗痉挛药物，但其作用机制尚不清楚。Tiz不仅与α2-肾上腺素受体（AR）结合，还与咪唑啉（I）受体结合。两种受体系统（AR+I）均存在于脊髓中间神经元和α-运动神经元中。本研究的目的是评估全身或脊髓（鞘内）提供的Tiz对缺血性痉挛动物牵张反射活动（SRA）的治疗效力，并描绘脊髓上或脊髓部位的Tiz行动。将动物暴露于10分钟的脊髓缺血以诱导SRA增加。在完全清醒的动物中，通过记录的EMG活动和在计算机控制的踝关节背屈（40°/3秒）期间测量的踝关节阻力的同时增加来确定SRA的增加。具有增加的SRA的动物被分成几个实验亚组，并如下处理：i）以lmg kg-1的剂量全身施用Tiz，或以10 μg或50 μg鞘内（IT）施用，作为单剂量递送; ii）用全身Tiz处理后全身注射媒介物，或全身注射对咪唑啉受体没有亲和力的非选择性AR拮抗剂;育亨宾（Yoh），α2A AR拮抗剂; BRL 44408（BRL），α2B AR拮抗剂; ARC 239（ARC），非选择性AR和I1受体拮抗剂;依法罗生（Efa），或非选择性AR和I2受体拮抗剂;咪唑克生（Ida）; iii）IT Tiz处理后IT注射选择性α2A AR拮抗剂;阿替美唑（Ati）。在另一组痉挛动物中，还研究了全身性Tiz治疗（1 mg/kg）或异氟烷麻醉对H反射活动的影响。全身和/或IT治疗与Tiz显着抑制SRA。BRL（5 mg kg-1）、Efa（1 mg kg-1）和Ida（1 mg kg-1）可逆转Tiz介导的抗SRA作用。Yoh（3 mg kg-1）或ARC（5 mg kg-1）治疗后未观察到逆转。IT Tiz（50 μ g）诱导的抗SRA可被IT注射Ati（50 μ g）逆转。分别在全身性Tiz治疗（1 mg/kg）或异氟烷（2%）麻醉后测量到H反射的显著抑制。免疫荧光染色显示痉挛动物脊髓切片中激活的星形胶质细胞α-2A受体表达上调。这些数据表明，α2A AR和I受体，而不是α2B AR主要介导Tiz诱导的抗痉挛作用。这种作用涉及脊髓和潜在的脊髓上部位，可能靶向脊髓神经元、初级传入神经和活化星形胶质细胞上存在的α2A受体。需要使用高选择性拮抗剂进行进一步研究，以阐明AR和咪唑啉受体的特定亚型参与Tiz治疗后观察到的抗痉挛作用。
Spasticity and rigidity are serious complications associated with spinal traumatic or ischemic injury. Clinical studies show that Tizanidine (Tiz) is an effective anti-spasticity agent, however, the mechanism of this effect is still not clear. Tiz binds not only to α2-adrenoreceptors (AR) but also to imidazoline (I) receptors. Both receptor systems (AR+I) are present in the spinal cord interneurons and α-motoneurons. The aim of the present study was to evaluate the therapeutic potency of systematically or spinally (intrathecally) delivered Tiz on stretch reflex activity (SRA) in animals with ischemic spasticity, and to delineate supraspinal or spinal sites of Tiz action. Animals were exposed to 10 min of spinal ischemia to induce an increase in SRA. Increase in SRA was identified by simultaneous increase in recorded EMG activity and ankle resistance measured during computer-controlled ankle dorsiflexion (40°/3 sec) in fully awake animals. Animals with increased SRA were divided into several experimental subgroups and treated as follows: i) Tiz administered systemically at the dose of 1 mg kg-1, or intrathecally (IT) at 10 μg or 50 μg delivered as a single dose; ii) Treatment with systemic Tiz was followed by the systemic injection of vehicle, or by non-selective AR antagonist without affinity for imidazoline receptors; Yohimbine (Yoh), α2A AR antagonist; BRL44408 (BRL), α2B AR antagonist; ARC239 (ARC), non-selective AR and I1 receptor antagonist; Efaroxan (Efa), or non-selective AR and I2 receptor antagonist; Idazoxan (Ida); iii) Treatment with IT Tiz was followed by the IT injection of selective α2A AR antagonist; Atipamezole (Ati). In a separate group of spastic animals the effect of systemic Tiz treatment (1 mg/kg) or isoflurane anesthesia on H-reflex activity was also studied. Systemic and/or IT treatment with Tiz significantly suppressed SRA. This Tiz-mediated anti-SRA effect was reversed by BRL (5 mg kg-1), Efa (1 mg kg-1) and Ida (1 mg kg-1). No reversal was seen after Yoh (3 mg kg-1) or ARC (5 mg kg-1) treatment. Anti-SRA induced by IT Tiz (50 μg) was reversed by IT injection of Ati (50 μg). Significant suppression of H-reflex was measured after systemic Tiz treatment (1mg/kg) or isoflurane (2%) anesthesia, respectively. Immunofluoresecene staining of spinal cord sections taken from animals with spasticity showed upregulation of α-2A receptor in activated astrocytes. These data suggest that α2A AR and I receptors, but not α2B AR primarily mediate the Tiz-induced anti-spasticity effect. This effect involves spinal and potentially supraspinal sites and likely targets α2A receptor present on spinal neurons, primary afferents and activated astrocytes Further studies using highly selective antagonists are needed to elucidate the involvement of specific subtypes of the AR and imidazoline receptors in the anti-spasticity effect seen after Tiz treatment.
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