Chen Yuhua, Oatway Mark A, Weaver Lynne C
Biotherapeutics Research Group, Robarts Research Institute, London, Ontario, Canada.
J Neurosci Res. 2009 Feb;87(2):418-24. doi: 10.1002/jnr.21860.
Chronic neuropathic pain is a frequent, serious outcome of spinal cord injury (SCI) that is highly refractory to treatment. Serotonin can contribute to neuropathic pain after SCI, as suggested by our previous observation that transient blockade of the 5-HT(3) receptor by intrathecal injections of the antagonist ondansetron reduces mechanical allodynia after SCI in rats. The current study determined whether intrathecal or intravenous infusion of ondansetron for 3 or 7 days, respectively, could cause sustained blockade of mechanical allodynia at and below the level of a twelfth thoracic clip compression injury in rats. Intrathecal 3-day infusion of ondansetron (2.0 microg/hr), targeted to the cord rostral to the SCI and commencing at 28 days after SCI, decreased at-level mechanical allodynia by 40% and below-level allodynia by 60% compared with saline-treated rats (controls). This reduction was sustained throughout drug delivery and for 1 day afterward. During the next 3 days, allodynia gradually returned toward the values of saline-treated rats. An initial experiment showed that bolus intravenous injections of ondansetron (20-100 microg) at 28 days after SCI decreased both at- and below-level allodynia for 90-120 min. Intravenous 7-day infusions (20 microg/hr), commencing at 28 days after SCI, significantly decreased at-level allodynia by 48% and below-level allodynia by 51% compared with controls. This reduction of allodynia lasted throughout the infusion and for 1-3 days afterward while pain responses gradually approached those of controls. These findings suggest a potential role of 5-HT(3) receptor antagonism in the relief of neuropathic pain after SCI in humans.
慢性神经性疼痛是脊髓损伤（SCI）常见且严重的后果，治疗起来极为棘手。血清素可能在脊髓损伤后引发神经性疼痛，正如我们之前观察到的，鞘内注射拮抗剂昂丹司琼对5-HT(3)受体进行短暂阻断后，大鼠脊髓损伤后的机械性异常性疼痛有所减轻。本研究旨在确定分别进行3天或7天的鞘内或静脉输注昂丹司琼，是否能持续阻断大鼠第十二胸椎夹伤水平及以下的机械性异常性疼痛。鞘内连续3天输注昂丹司琼（2.0微克/小时），针对脊髓损伤部位头端的脊髓，于脊髓损伤后28天开始，与生理盐水处理的大鼠（对照组）相比，损伤水平处的机械性异常性疼痛降低了40%，损伤水平以下的异常性疼痛降低了60%。这种降低在整个给药期间及之后的1天内持续存在。在接下来的3天里，异常性疼痛逐渐恢复到生理盐水处理大鼠的水平。一项初步实验表明，在脊髓损伤后28天静脉推注昂丹司琼（20 - 100微克），损伤水平处及以下的异常性疼痛在90 - 120分钟内均有所减轻。脊髓损伤后28天开始进行7天的静脉输注（20微克/小时），与对照组相比，损伤水平处的异常性疼痛显著降低了48%，损伤水平以下的异常性疼痛降低了51%。这种异常性疼痛的减轻在整个输注期间及之后的1 - 3天持续存在，同时疼痛反应逐渐接近对照组。这些发现表明5-HT(3)受体拮抗作用在缓解人类脊髓损伤后神经性疼痛方面可能具有潜在作用。
