Horiuchi Hideki, Ogata Tadanori, Morino Tadao, Takeba Jun, Yamamoto Haruyasu
Department of Orthopaedic Surgery, Ehime University School of Medicine, Shigenobu, 791-0295, Ehime, Japan.
Brain Res. 2003 Feb 14;963(1-2):312-20. doi: 10.1016/s0006-8993(02)04055-6.
Although dysesthesia is one of the most serious problems in patients with spinal cord injury, most of them being unresponsive to conventional treatments. In this study, we established a rat thoracic spinal cord mild-compression model that revealed thermal hyperalgesia in the hind limb. The thoracic spinal cord was compressed gently, using a 20 g weight for 20 min. The withdrawal latency of the thermal stimulation of the bilateral hind-limb was monitored using Hargreaves' Plantar test apparatus. In this model, thermal-hyperalgesia was observed for 1 week after the injury. The spinal cord injury-induced thermal-hyperalgesia was mimicked by the intrathecal application of metergoline, a non-selective 5-HT antagonist, 1-(2-methoxyphenyl)-4-[4-(2-phthalimido) butyl]-piperazine hydrobromide (NAN190), a selective 5-HT1 antagonist, and 3-tropanyl-3,5-dichlorobenzoate (MDL72222), a selective 5-HT3 antagonist. Intraperitoneal application of fluvoxamine maleate, a selective serotonin reuptake inhibitor, reduced the intensity of hyperalgesia induced by spinal cord injury. The inhibitory effect of fluvoxamine maleate on thermal hyperalgesia was prevented by the application of the aforementioned nonselective or selective 5-HT receptor antagonists. Intrathecal application of fluvoxamine maleate and selective 5-HT receptor agonists, i.e., 8-hydroxy-2-(di-n-proplyamino)-tetralin hydrobromide (8-OH-DPAT: 5HT-1 selective) and 2-methyl-5-hydroxytryptamine maleate (2-m-5-HT: 5HT-3 selective), inhibited the spinal cord injury-induced hyperalgesia. These results suggest that the change in the descending serotonergic signal plays an important role in hyperalgesia after the spinal cord injury, and that the application of selective serotonin reuptake inhibitors will be one of the candidates for new therapeutic methods against post-spinal cord injury dysesthesia.
尽管感觉异常是脊髓损伤患者最严重的问题之一，且大多数患者对传统治疗无反应。在本研究中，我们建立了大鼠胸段脊髓轻度压迫模型，该模型显示后肢出现热痛觉过敏。使用20 g的重物对胸段脊髓进行轻柔压迫20分钟。使用哈格里夫斯足底测试装置监测双侧后肢热刺激的缩足潜伏期。在该模型中，损伤后1周观察到热痛觉过敏。鞘内注射非选择性5-羟色胺拮抗剂美替拉酮、选择性5-HT1拮抗剂1-(2-甲氧基苯基)-4-[4-(2-邻苯二甲酰亚胺基)丁基]-哌嗪氢溴酸盐（NAN190）和选择性5-HT3拮抗剂3-托烷-3,5-二氯苯甲酸酯（MDL72222）可模拟脊髓损伤诱导的热痛觉过敏。腹腔注射选择性5-羟色胺再摄取抑制剂马来酸氟伏沙明可降低脊髓损伤诱导的痛觉过敏强度。上述非选择性或选择性5-HT受体拮抗剂可阻断马来酸氟伏沙明对热痛觉过敏的抑制作用。鞘内注射马来酸氟伏沙明和选择性5-HT受体激动剂，即8-羟基-2-(二正丙基氨基)-四氢萘氢溴酸盐（8-OH-DPAT：5HT-1选择性）和马来酸2-甲基-5-羟色胺（2-m-5-HT：5HT-3选择性），可抑制脊髓损伤诱导的痛觉过敏。这些结果表明，下行5-羟色胺能信号的变化在脊髓损伤后的痛觉过敏中起重要作用，且应用选择性5-羟色胺再摄取抑制剂将是对抗脊髓损伤后感觉异常新治疗方法的候选之一。
