Hains Bryan C, Everhart Alex W, Fullwood Steven D, Hulsebosch Claire E
Department of Anatomy and Neurosciences, Marine Biomedical Institute, University of Texas Medical Branch, 301 University Boulevard, Galveston 77555-1043, USA.
Exp Neurol. 2002 Jun;175(2):347-62. doi: 10.1006/exnr.2002.7892.
Spinal cord injury (SCI) results in abnormal locomotor and pain syndromes in humans. In a rodent SCI model, T13 unilateral spinal hemisection results in bilateral mechanical allodynia and thermal hyperalgesia, partly by interruption of tonic descending serotonin (5-HT) inhibition. In the current study, we examined changes in density and distribution of 5-HT and 5-HT(T) in cervical (C8) and lumbar (L5) enlargements after T13 spinal hemisection and studied the effects of intrathecally delivered 5-HT (10, 21, and 63 microg), 5-HT antagonist methysergide (125 microg/kg), and 5-HT reuptake inhibitor fluvoxamine (75 microg/kg) on pain-related behaviors. Thirty-day-old male Sprague-Dawley rats were spinally hemisected and sacrificed at 3 (n = 20) and 28 (n = 20) days postsurgery for immunohistochemistry, Western blot, and ELISA analysis and compared against sham-operated animals (n = 10). At day 3, C8 5-HT levels were not significantly changed but at L5 there was a significant decrease in ipsilateral 5-HT in laminae I-II followed by incomplete recovery at 28 days postinjury. At both 3 and 28 days postinjury, C8 5-HT(T) levels were not significantly changed, but at L5 there was significant ipsilateral up-regulation of 5-HT(T) in laminae I-II. A second group of animals (n = 30) was hemisected and, starting at 28 days postinjury, behaviorally tested with intrathecal compounds. Increasing doses of 5-HT attenuated both fore- and hindlimb mechanical allodynia and thermal hyperalgesia, and effects of endogenous 5-HT were attenuated by methysergide and enhanced with fluvoxamine, all without locomotor alterations. Sham controls (n = 10) were unaffected. Thus, permanent changes occur in 5-HT and 5-HT(T) after SCI, denervation 5-HT supersensitivity develops, and modulation of 5-HT attenuates pain-related behaviors. Insight gained by these studies may aid in the understanding of dynamic 5-HT systems which will be useful in treating chronic central pain after SCI.
脊髓损伤（SCI）会导致人类出现异常的运动和疼痛综合征。在啮齿动物SCI模型中，T13单侧脊髓半切会导致双侧机械性异常性疼痛和热痛觉过敏，部分原因是紧张性下行5-羟色胺（5-HT）抑制作用的中断。在本研究中，我们检查了T13脊髓半切后颈段（C8）和腰段（L5）膨大处5-HT和5-HT(T)的密度和分布变化，并研究了鞘内注射5-HT（10、21和63微克）、5-HT拮抗剂甲基麦角新碱（125微克/千克）和5-HT再摄取抑制剂氟伏沙明（75微克/千克）对疼痛相关行为的影响。30日龄雄性Sprague-Dawley大鼠接受脊髓半切手术，并在术后3天（n = 20）和28天（n = 20）处死，进行免疫组织化学、蛋白质印迹和酶联免疫吸附测定分析，并与假手术动物（n = 10）进行比较。术后3天，C8处的5-HT水平无显著变化，但在L5处，I-II层同侧的5-HT显著降低，损伤后28天未完全恢复。在损伤后3天和28天，C8处的5-HT(T)水平均无显著变化，但在L5处，I-II层同侧的5-HT(T)显著上调。第二组动物（n = 30）接受半切手术，并在损伤后28天开始用鞘内化合物进行行为测试。递增剂量的5-HT可减轻前肢和后肢的机械性异常性疼痛和热痛觉过敏，甲基麦角新碱可减弱内源性5-HT的作用，氟伏沙明可增强其作用，所有这些均无运动改变。假手术对照组（n = 10）未受影响。因此，SCI后5-HT和5-HT(T)会发生永久性变化，去神经支配的5-HT超敏反应会发展，5-HT的调节可减轻疼痛相关行为。这些研究获得的见解可能有助于理解动态5-HT系统，这将有助于治疗SCI后的慢性中枢性疼痛。
