Department of Anesthesiology, University of the Ryukyus, Okinawa, Japan.
Neuroscience. 2011 Oct 27;194:160-9. doi: 10.1016/j.neuroscience.2011.08.022. Epub 2011 Aug 16.
Spasticity and rigidity are serious complications associated with spinal traumatic or ischemic injury. Clinical studies show that tizanidine (Tiz) is an effective antispasticity 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 [IT]) 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 electromyography (EMG) activity and ankle resistance measured during computer-controlled ankle dorsiflexion (40°/3 s) 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 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 nonselective AR antagonist without affinity for I receptors; yohimbine (Yoh), α2A AR antagonist; BRL44408 (BRL), α2B AR antagonist; ARC239 (ARC), nonselective AR and I(1) receptor antagonist; efaroxan (Efa), or nonselective AR and I(2) 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 (1 mg/kg) or isoflurane (2%) anesthesia, respectively. Immunofluorescence staining of spinal cord sections taken from animals with spasticity showed upregulation of α2A receptor in activated astrocytes.
These data suggest that α2A AR and I receptors, but not α2B AR, primarily mediate the Tiz-induced antispasticity 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 I receptors in the antispasticity effect seen after Tiz treatment.
痉挛和僵硬是与脊髓创伤或缺血损伤相关的严重并发症。临床研究表明替扎尼定（Tiz）是一种有效的抗痉挛药物；然而，这种效果的机制仍不清楚。Tiz 不仅与 α2-肾上腺素能受体（AR）结合，还与咪唑啉（I）受体结合。这两个受体系统（AR+I）都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系统性或脊髓内（鞘内[IT]）给予 Tiz 对缺血性痉挛动物伸展反射活动（SRA）的治疗效果，并描绘 Tiz 作用的上位或脊髓部位。
动物暴露于 10 分钟的脊髓缺血以诱导 SRA 增加。SRA 的增加通过同时增加在完全清醒动物中计算机控制的踝关节背屈（40°/3s）期间记录的肌电图（EMG）活动和踝关节阻力来识别。SRA 增加的动物被分为几个实验组，并进行如下治疗：（i）以 1mg/kg 的剂量给予系统性 Tiz，或给予单次 IT 剂量 10μg 或 50μg；（ii）给予系统性 Tiz 治疗后，给予系统性注射载体，或给予无亲和力的非选择性 AR 拮抗剂；育亨宾（Yoh），α2A AR 拮抗剂；BRL44408（BRL），α2B AR 拮抗剂；ARC239（ARC），非选择性 AR 和 I（1）受体拮抗剂；efaroxan（Efa），或非选择性 AR 和 I（2）受体拮抗剂；伊达唑（Ida）；（iii）给予 IT Tiz 治疗后，给予选择性 α2A AR 拮抗剂；atipamezole（Ati）。在一组痉挛动物中，还研究了系统性 Tiz 治疗（1mg/kg）或异氟烷麻醉对 H 反射活动的影响。
系统性和/或 IT 给予 Tiz 显著抑制 SRA。这种 Tiz 介导的抗 SRA 作用被 BRL（5mg/kg）、Efa（1mg/kg）和 Ida（1mg/kg）逆转。Yoh（3mg/kg）或 ARC（5mg/kg）治疗后未见逆转。IT 给予 50μg Tiz 诱导的抗 SRA 被 IT 给予 50μg Ati 逆转。分别给予系统性 Tiz（1mg/kg）或异氟烷（2%）麻醉后，测量到 H 反射的显著抑制。从痉挛动物的脊髓切片进行免疫荧光染色显示，激活的星形胶质细胞中 α2A 受体上调。
这些数据表明，α2A AR 和 I 受体，但不是 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上位部位，可能靶向存在于脊髓神经元、初级传入和激活的星形胶质细胞上的 α2A 受体。需要使用高度选择性的拮抗剂进一步研究，以阐明 AR 和 I 受体的特定亚型在替扎尼定治疗后抗痉挛作用中的参与。
