罗哌卡因致大鼠脊髓神经毒性时Bax和Bcl-2表达的变化

目的 评价罗哌卡因致大鼠脊髓神经毒性时Bax和Bcl-2表达的变化,以探讨罗哌卡因脊髓神经毒性的机制.方法 清洁级雄性SD大鼠,体重260～300 g,按改良Yaksh法鞘内置入脊髓微导管,取鞘内置管成功的大鼠54只,随机分为3组(n=18):生理盐水组(NS组)、0.5%罗哌卡因组(R1组)和1%罗哌卡因组(R2组).R1组和R2组于置管后第7天经脊髓微导管分别注射0.5%、1%罗哌卡因0.12μl/g,注药速率10 μl/15 s,每隔1.5小时给药1次,给药期24 h,共注药16次,NS组注射等容量生理盐水.于最后1次鞘内注射罗哌卡因或生理盐水后,每隔10分钟行双下肢运动阻滞评分1次,共5次(T1-5),以评价运动阻滞效果;于鞘内注射罗哌卡因或生理盐水后6、12和24 h(T6-8)时随机取6只大鼠,处死后取脊髓,光镜和电镜下观察病理学结构,并测定脊髓组织Bax和Bcl-2的表达水平.结果 与NS组比较,R1组T1,2时、R2组,T1-3时大鼠双下肢运动阻滞评分升高,R1组脊髓组织Bax、Bcl-2表达均上调(P<0.05),Bcl-2/Bax比值差异无统计学意义(P>0.05),R2组脊髓组织Bax表达上调(P<0.05),Bcl-2表达差异无统计学意义(P>0.05),Bcl-2/Bax比值降低(P<0.05).R1组超微结构改变主要为线粒体和内质网轻度肿胀,而神经细胞未发生凋亡;R2组脊髓神经细胞出现了核固缩等早期凋亡改变.结论 罗哌卡因的脊髓神经毒性可能与激活神经细胞线粒体凋亡途径有关.     

胸段硬膜外阻滞对冠状动脉结扎大鼠心肌细胞凋亡的影响

目的 观察罗哌卡因胸段硬膜外阻滞对冠状动脉结扎大鼠心肌细胞凋亡的影响.方法 健康成年雄性SD大鼠72只,随机均分为生理盐水胸段硬膜外注射+结扎冠状动脉(A)组,罗哌卡因胸段硬膜外注射+结扎冠状动脉(B)组、假手术(C)组,分别在结扎操作后3、6 h检测心肌细胞凋亡指数(AI)和Caspase-3活性.结果 A、R组结扎冠状动脉后3、6 h AI、Caspase-3活性较C组明显升高(P<0.01),且A组高于R组(P<0.05).结论 罗哌卡因胸段硬膜外阻滞可减轻急性缺血诱发的大鼠心肌细胞凋亡.     

鞘内注射罗哌卡因对大鼠脊髓的神经毒性

目的 评价鞘内注射罗哌卡因对大鼠脊髓的神经毒性.方法 取鞘内置管成功的雄性SD大鼠60只,体重180～220 g,随机分为6组(n=10),分别鞘内注射0.75%布比卡因17 μl(A1组)、0.75%罗哌卡因20μl(A2组)、1%罗哌卡因15μl(A3组)、0.75%布比卡因34μl(B1组)、0.75%罗哌卡因40μl(B2组)和1%罗哌卡因30μl(B3组).注药后记录出现双后肢瘫痪时间和运动功能恢复情况.注药后6 h取腰膨大处脊髓,采用免疫组织化学法计数fos蛋白阳性细胞,测定fos蛋白表达;采用RT-PCR技术测定c-fos mRNA表达;透射电镜观察脊髓超微结构.结果 与A1组比较,A3组和B1组出现双后肢瘫痪时间缩短,B1组fos蛋白阳性细胞计数和fos蛋白表达升高(P<0.01);与A2组比较,A3组和B2组出现双后肢瘫痪时间缩短,B2组fos蛋白阳性细胞计数和fos蛋白表达升高(P<0.01);与A3组、B1组和B2组比较,B3组出现双后肢瘫痪时间缩短,双后肢运动功能恢复率降低,fos蛋白阳性细胞计数、fos蛋白表达和c-fos mRNA表达均升高(P<0.01),脊髓损伤加重.结论 鞘内注射0.75%罗哌卡因和小剂量1%罗哌卡因对大鼠无脊髓神经毒性;鞘内注射大剂量1%罗哌卡因对大鼠可产生脊髓神经毒性,但比大剂量0.75%布比卡因脊髓神经毒性小.     

罗哌卡因惊厥对大鼠海马细胞凋亡及学习记忆能力的影响

目的研究罗哌卡因惊厥EDso致单次惊厥对大鼠海马细胞凋亡及学习记忆能力的影响。方法110只SD大鼠按随机数字表法分为生理盐水组（Ns组,35只）和罗哌卡因组（R组,75只）。R组大鼠腹腔注射罗哌卡因惊厥ED。致单次惊厥。分别在R组惊厥后2h、6h、24h、3d、7d的5个时点,NS组和R组各取5只大鼠海马组织冠状切片行Bax、Bcl-2蛋白免疫组化检测,显微镜下观察单位面积内Bax和Bcl-2阳性表达细胞的形态和数目。在R组惊厥后8、39d两个时间点,Ns组和R组大鼠各进行1次Morris水迷宫实验（定位航行实验和空间搜索实验）。结果成年大鼠腹腔注射罗哌卡因惊厥ED。致单次惊厥后,惊厥潜伏期为（9．3±3．7）S,惊厥持续时间为（7．2±4．6）s。与NS组比较,R组Bax蛋白表达在惊厥后2h时即升高,24h时达峰后回落,7d时仍高于NS组（P〈0．05）;Bcl-2蛋白表达在惊厥后2h时反应滞后（P〈0．05）,6h时升高（P〈0．05）,24h时达峰后回落（尸≮0．05）,7d时恢复正常（P〉O．05）。惊厥近期R组逃避潜伏期和空间搜索成绩明显差于NS组（P〈O．05）,惊厥远期R组逃避潜伏期和空间搜索成绩与NS组比较差异无统计学意义（P〉0．05）。结论腹腔注射罗哌卡因惊厥ED50致单次惊厥可引起大鼠海马组织细胞凋亡增加、惊厥近期学习记忆能力下降,但对惊厥远期学习记忆能力影响不大。     

瑞芬太尼对大鼠肠缺血再灌注时肝细胞凋亡的影响

目的 评价瑞芬太尼对大鼠肠缺血再灌注时肝细胞凋亡的影响.方法 成年Wistar大鼠54只,随机分为3组(n=18):假手术组(S组)、肠缺血再灌注组(IIR组)和瑞芬太尼组(R组).IIR组及R组采用夹闭肠系膜上动脉1 h后再灌注的方法制备肠缺血再灌注模型,R组于缺血前10min开始静脉输注瑞芬太尼1 μg·kg-1·min-1至再灌注末,S组及IIR组给予等容量生理盐水.分别于再灌注1、3、6 h时处死6只大鼠,取肝组织,检测肝组织Bcl-2与Bax表达水平及肝细胞凋亡情况,计算肝细胞凋亡指数(AI).结果 与S组相比,IIR组和R组Bcl-2与Box表达上调,肝细胞AI升高,IIR组Bcl-2/Bax比值降低,R组Bcl-2/Bax比值升高(P<0.05);与IIR组相比,R组Bcl-2表达、Bcl-2/Bax比值升高,Box表达下调,肝细胞AI降低(P<0.05).结论 瑞芬太尼可抑制大鼠肠缺血再灌注时肝细胞凋亡,其机制与上调Bcl-2表达及抑制Bax表达上调有关.     

异丙酚联合缺血预处理对大鼠肺缺血再灌注损伤时细胞凋亡的影响

目的 探讨异丙酚联合缺血预处理对大鼠肺缺血苒灌注损伤时细胞凋亡的影响.方法 雄性SD大鼠50只,200～250 g,随机分为5组(n=10):假手术组(S组)、缺血再灌注组(IR组)、异丙酚组(P组)、缺血预处理组(IP组)和异丙酚+缺血预处理组(P+IP组).阻断右肺门1 h后再灌注2 h制备大鼠单肺原位热缺血再灌注模型,P组夹闭右肺门前30 min持续静脉输注异丙酚30 mg·kg-1·h-1;IP组夹闭右肺门前先进行夹闭5 min,再灌注5 min,反复3次的缺血预处理;P+IP组夹闭肺门前30 min静脉输注异丙酚30 mg·kg-1·h-1和缺血预处理.于再灌注2 h时处死大鼠,取右肺下叶肺组织,光镜下观察肺组织病理学结果 ,计算肺损伤定量评价指标(IQA);检测肺凋亡细胞,计算肺细胞凋亡指数(AI);采用免疫组化法检测Bcl-2、Bax蛋白表达;IQA、Bcl-2/Bax蛋白比值与AI作直线相关分析.结果 与S组比较,IR组、P组、IP组和P+IP组再灌注后IQA、AI均明显升高,IR组Bcl-2、Bax蛋白表达上调,Bcl-2/Bax蛋白比值降低(P<0.01);与IR组比较,P组、IP组和P+IP组IQA、AI均明显降低,Bcl-2蛋白表达水平、Bcl-2/Bax蛋白比值升高,IP组、P+IP组Bax蛋白表达下调(P<0.01),P组差异无统计学意义(P>0.05);与P组和IP组比较,P+IP组IQA及AI降低,Bcl-2/Bax蛋白比值升高(P<0.05);IQA与AI呈正相关(r=0.951,P<0.01);AI与Bcl-2/Bax蛋白比值呈负相关(r=-0.851,P<0.01).结论 异丙酚联合缺血预处理可通过调节Bcl-2和Bax蛋白的表达抑制细胞凋亡,减轻肺缺血再灌注损伤.     

鞘内注射罗哌卡因与布比卡因对大鼠的脊髓神经毒性

目的 评价鞘内注射罗哌卡因与布比卡因对大鼠的脊髓神经毒性.方法 清洁级雌性SD大鼠,体重240～330 g,取鞘内置管成功的大鼠54只,随机分为3组(n=18):NS组鞘内注射生理盐水30μl;Bu组和RO组分别鞘内注射2%布比卡因20μl和2.7%罗哌卡因20μl,随后注射10μl生理盐水冲洗导管.于鞘内注药前、注药后10、20、30、60和120 min时(T1～6)行双后肢运动阻滞评分;于鞘内注药后第4天取腰段脊髓组织,观察病理学结果并行损伤评分.结果 与NS组比较,BU组T2～5时、RO组T2～4时大鼠双后肢运动阻滞评分升高,两组脊髓组织损伤评分升高(P＜0.05),脊髓组织病理学损伤较重;与T2时比较,Bu组和RO组其余各时点双后肢运动阻滞评分降低(P＜0.05),两组T2时差异无统计学意义(P＞0.05);与BU组比较,RO组脊髓组织损伤评分升高(P＜0.05),脊髓组织病理学损伤较重.结论 鞘内注射2.7%罗哌卡因对大鼠的脊髓神经毒性强于2%布比卡因.     

氯普鲁卡因、布比卡因和罗哌卡因在下肢手术腰-硬联合麻醉中的比较

目的比较氯普鲁卡因、布比卡因和罗哌卡因在下肢手术腰-硬联合麻醉(CSEA)中的应用效果。方法择期行髋关节及以下部位手术患者300例,随机均分成三组:氯普鲁卡因组(C组)、布比卡因组(B组)和罗哌卡因组(R组),蛛网膜下腔分别给予1.5%氯普鲁卡因、0.5%布比卡因和0.5%罗哌卡因各2 ml。记录患者感觉阻滞起效时间、平面固定时间、阻滞平面、腰麻持续时间和运动阻滞效果。结果 C组阻滞平面固定时间、腰麻持续时间明显短于B、R组(P<0.05)。C组感觉阻滞起效时间短于B组,但长于R组(P<0.05)。C组最高阻滞平面明显高于B、R组(P<0.05)。结论与0.5%罗哌卡因和0.5%布比卡因比较,1.5%氯普鲁卡因具有起效快、阻滞完善和运动阻滞效果弱的特点,小剂量氯普鲁卡因可用于手术时间较短的CSEA中的脊麻。     

瑞芬太尼对大鼠肾缺血再灌注时细胞凋亡的影响

目的 评价瑞芬太尼对大鼠肾缺血再灌注时细胞凋亡的影响.方法 健康成年雄性SD大鼠75只,体重220～ 250 g,采用随机数字表法,将其分为3组(n=25)∶假手术组(S组)、肾缺血再灌注组(I/R组)和瑞芬太尼组(R组).I/R组和R组采用夹闭双侧肾动脉45 min时恢复灌注法建立肾缺血再灌注损伤模型.R组于缺血前15 min至再灌注30 min经尾静脉输注瑞芬太尼1.0μg· kg-1·min-1,S组和I/R组给予等容量生理盐水.于缺血前15 min(T0)、再灌注3 h(T1)、6 h(T2)、12h(T3)及24 h(T4)时取肾组织标本.采用流式细胞术检测肾细胞凋亡率及Bax、Bcl-2蛋白表达,采用RT-PCR检测Bax和Bcl-2的mRNA表达,计算Bcl-2/Bax蛋白及mRNA表达比值,采用Paller法行肾小管损伤评分.结果 与S组比较,I/R组和R组T1-4时肾小管损伤评分和肾细胞凋亡率升高,Bcl-2/Bax蛋白及mRNA表达比值T12时升高,T3,4时降低(P＜0.01);与I/R组比较,R组T1-4时肾小管损伤评分和肾细胞凋亡率降低,Bcl-2/Bax蛋白及mRNA表达比值升高(P＜0.05或0.01);与T0时比较,I/R组和R组T1-4时肾小管损伤评分和肾细胞凋亡率升高,Bcl-2/Bax蛋白及mRNA表达比值T1,2时升高,T3,4时降低(P＜0.01).结论 瑞芬太尼减轻大鼠肾缺血再灌注损伤的机制与其调节Bcl-2/Bax蛋白表达,抑制肾组织细胞凋亡有关.     

鞘内注射不同浓度甲磺酸罗哌卡因对大鼠脊髓的神经毒性

目的 评价鞘内注射不同浓度甲磺酸罗哌卡因对大鼠脊髓的神经毒性.方法 取鞘内置管成功的Wistar大鼠60只,体重210～220 g,雌雄不拘,随机分为5组(n=12),对照组(C组)鞘内注射0.9%NaCl溶液0.4 ml;不同浓度甲磺酸罗哌卡因组(R1～4组)鞘内注射甲磺酸罗哌卡因0.4 ml,浓度依次为0.224%、0.447%、0.671%、0.894%.记录阻滞起效时间(鞘内给药结束至鼠尾丧失运动的时间)和维持时间(鼠尾丧失运动至恢复运动的时间).鞘内给药后第7天处死大鼠,取L4.5脊髓节段,透射电镜下观察超微结构,并进行脊髓损伤评分.脊髓损伤评分≥2分为发生神经毒性,记录脊髓神经毒性的发生情况.结果 随甲磺酸罗哌卡因浓度的升高起效时间逐渐缩短,维持时间逐渐延长(P＜0.05或0.01).脊髓神经毒性发生率C组为0,R1组为0,R2组为17%,R3组为42%,R4组为100%;随甲磺酸罗哌卡因浓度的升高,脊髓神经毒性发生率逐渐增加(P＜0.05或0.01).结论 鞘内注射甲磺酸罗哌卡因对大鼠可产生脊髓神经毒性,且取决于其浓度.     

鞘内注射右旋美托咪啶对大鼠罗哌卡因蛛网膜下腔阻滞效果的影响

目的 探讨鞘内注射右旋美托咪啶对大鼠罗哌卡因蛛网膜下腔阻滞效果的影响.方法 清洁级雄性SD大鼠,体重250～300 g,取鞘内置管成功的大鼠36只,随机分为6组(n=6),C组:鞘内注射生理盐水20 μl;D组:鞘内注射右旋美托咪啶3 μg/kg 20 μl;R组:鞘内注射0.5%罗哌卡因20 μl;DR1组:鞘内注射右旋美托咪啶1 μg/kg+0.5%罗哌卡因20 μl;DR2组鞘内注射右旋美托咪啶2 μg/kg+0.5%罗哌卡因20 μl;DR3组鞘内注射右旋美托咪啶3 μg/kg+0.5%罗哌卡因20 μl.于鞘内注药前(基础状态)和鞘内注药后5、30、60、120和240 min时计算最大抗伤害效应百分比(MPE),测定机械缩足阈值(PWT),并进行倾斜板实验.于鞘内注药后第2周,取脊髓组织进行病理学观察,计算神经元异常率,行脊髓病理学评分和损伤分级.结果 与R组比较,DR1组鞘内注药后30、60 min时PWT升高,DR3组鞘内注药后120 min时PWT降低(P<0.05),DR2组各时点差异无统计学意义(P>0.05),DR1组鞘内注药后5～240 min时、DR2组鞘内注药后5和240 min时、DR3组鞘内注药后5 min时MPE升高,DR1组鞘内注药后30、60 min时下滑角度降低(P<0.05);DR2组与DR3组各时点上述指标差异无统计学意义(P>0.05);与C组比较,DR3组神经元异常率、脊髓病理学评分和损伤分级升高(P<0.05),其余各组差异无统计学意义(P>0.05).结论 右旋美托咪啶可增强0.5%罗哌卡因蛛网膜下腔阻滞的效果,且具有封顶效应.     

Intrathecal Ropivacaine in Rabbits: Pharmacodynamic and Neurotoxicologic Study

Background: Ropivacaine is available for spinal or intrathecal use in humans, although data on neurotoxicity after spinal injection are not yet available. The authors experimentally determined the relationship between doses of intrathecal ropivacaine and spinal effects and local neurotoxic effects.

Methods: Eighty rabbits equipped with an intrathecal lumbar catheter were studied. Sixty were randomly assigned to receive 0.2 ml of intrathecal solutions as a sole injection of: 0.2%, 0.75%, 1.0%, and 2.0% ropivacaine (doses from 0.4-4.0 mg; groups R0.2 to R2.0), 5.0% lidocaine (10 mg; group L), or 0.9% NaCl as control (group C). Twenty other rabbits received either repeated injections of 0.2 ml of 0.2% ropivacaine every 2 days during 2 weeks (total dose of 2.8 mg; group RINT); or a continuous intrathecal infusion of 0.2% ropivacaine at the rate of 1.8 ml/h over 45 min (2.7 mg; group RCONT). Injection rate was 30 s in all groups except Rcont. Time to onset, duration and extent of motor block, and variations of mean arterial blood pressure were recorded in all groups. Somatosensory evoked potentials were also recorded in group RCONT and RINT. Seven days after the last intrathecal injection spinal cord and nerves were sampled for histopathologic study.

Results: In groups R0.2 and RINT, the lowest dose of ropivacaine induced a clinically visible spinal block in only 50% of rabbits, but SEPs recorded in group RINT were decreased by 70% in the lumbar dermatome. Complete motor block was observed with doses greater than 1.5 mg of ropivacaine (group RCONT and R0.75 to R2.0). Onset time was shorter and duration of block increased as doses of ropivacaine increased. Significant hypotension was observed only with 4.0 mg of ropivacaine (concentration of 2.0%). Complete paralysis and hypotension were observed with 5.0% lidocaine. No neurologic clinical lesion was observed in rabbits receiving saline or ropivacaine within the 7 days after the last intrathecal injection, and histopathologic study revealed no sign of neurotoxicity in these groups. In contrast, intrathecal lidocaine induced clinical and histopathologic changes.     

Intrathecal ropivacaine in rabbits: pharmacodynamic and neurotoxicologic study

BACKGROUND: Ropivacaine is available for spinal or intrathecal use in humans, although data on neurotoxicity after spinal injection are not yet available. The authors experimentally determined the relationship between doses of intrathecal ropivacaine and spinal effects and local neurotoxic effects. METHODS: Eighty rabbits equipped with an intrathecal lumbar catheter were studied. Sixty were randomly assigned to receive 0.2 ml of intrathecal solutions as a sole injection of: 0.2%, 0.75%, 1.0%, and 2.0% ropivacaine (doses from 0.4-4.0 mg; groups R0.2 to R2.0), 5.0% lidocaine (10 mg; group L), or 0.9% NaCl as control (group C). Twenty other rabbits received either repeated injections of 0.2 ml of 0.2% ropivacaine every 2 days during 2 weeks (total dose of 2.8 mg; group RINT); or a continuous intrathecal infusion of 0.2% ropivacaine at the rate of 1.8 ml/h over 45 min (2.7 mg; group RCONT). Injection rate was 30 s in all groups except Rcont. Time to onset, duration and extent of motor block, and variations of mean arterial blood pressure were recorded in all groups. Somatosensory evoked potentials were also recorded in group RCONT and RINT. Seven days after the last intrathecal injection spinal cord and nerves were sampled for histopathologic study. RESULTS: In groups R0.2 and RINT, the lowest dose of ropivacaine induced a clinically visible spinal block in only 50% of rabbits, but SEPs recorded in group RINT were decreased by 70% in the lumbar dermatome. Complete motor block was observed with doses greater than 1.5 mg of ropivacaine (group RCONT and R0.75 to R2.0). Onset time was shorter and duration of block increased as doses of ropivacaine increased. Significant hypotension was observed only with 4.0 mg of ropivacaine (concentration of 2.0%). Complete paralysis and hypotension were observed with 5.0% lidocaine. No neurologic clinical lesion was observed in rabbits receiving saline or ropivacaine within the 7 days after the last intrathecal injection, and histopathologic study revealed no sign of neurotoxicity in these groups. In contrast, intrathecal lidocaine induced clinical and histopathologic changes. CONCLUSION: Ropivacaine induced dose-dependent spinal anesthesia, and did not induce any neurotoxicologic lesion in this experimental animal model.     

Hyperbaric spinal for elective Cesarean section--ropivacaine vs bupivacaine

PURPOSE: To compare hyperbaric spinal ropivacaine to hyperbaric spinal bupivacaine for elective cesarean delivery in a prospective, randomized, double blinded study. METHODS: With the University Ethics Committee approval, 66 parturients for elective cesarean deliveries received either 15 mg of hyperbaric ropivacaine (N = 33) or 11.25 mg of hyperbaric bupivacaine (N - 33) with 0.1 mg of preservative-free morphine and 0.01 mg fentanyl. The sensory and motor blockades were assessed at 3, 6, and 9 min after injection. The APGAR scores, umbilical cord gases, intra-operative side effects and the total duration of motor and sensory blockade, were recorded. RESULTS: The two groups had similar demographics, and similar times for sensory block to T6 and Bromage score 3 motor blockade. The median levels of sensory blockade were T3 and T2 for the ropivacaine and bupivacaine groups respectively. Duration of sensory block was shorter in the ropivacaine group (174 +/- 24 min vs 217 +/- 46 min; P < 0.001). Duration of motor block was shorter in the ropivacaine group (85 +/- 26 vs 159 +/- 56 min; P < 0.001). The obstetricians rated intra-operative anesthesia as excellent in both groups. None of neonates had Apgar scores less than 7. There was no difference in cord gases between the two groups. Side effects did not differ between the two groups. The ropivacaine patients expressed significantly higher satisfaction levels (P < 0.016). DISCUSSION: 15 mg of hyperbaric ropivacaine with 0.1 mg morphine and 0.01 mg fentanyl provided excellent anesthesia for cesarean delivery. The advantages of hyperbaric ropivacaine consist of faster regression of the block and higher patient satisfaction.     

The effects of an AMPA receptor antagonist on the neurotoxicity of tetracaine intrathecally administered in rabbits

We have reported that large concentrations of intrathecal local anesthetics increase glutamate concentrations in the cerebrospinal fluid (CSF) and cause neuronal injury in rabbits. In the current study we determined whether an alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) receptor antagonist, YM872, administered intrathecally, reduces neuronal injury caused by tetracaine. We first examined the effects of intrathecal YM872 10, 30, 100, or 300 mug in rabbits (n = 3 in each). YM872 produced reversible motor and sensory block in a dose-dependent manner. Then, we evaluated modulatory effects of YM872 (300 mug) on tetracaine-induced glutamate release and neuronal injury. Pretreatment of YM872 did not attenuate 1% or 2% tetracaine-induced increases in cerebrospinal fluid glutamate concentrations (n = 3 in each). For evaluation of neuronal injury, rabbits were assigned to 4 groups (n = 6 in each) and intrathecally received 1% tetracaine and saline (1%T), 1% tetracaine and YM872 (1%TY), 2% tetracaine and saline (2%T), or 2% tetracaine and YM872 (2%TY). The volume of saline, YM872, and tetracaine was 0.3 mL. Saline or YM872 was administered 30 min before tetracaine administration. Neurological and histopathological assessments were performed 1 wk after the administration. Two and 1 animals respectively, showed motor and sensory dysfunction in 1%T, whereas 5 animals showed both motor and sensory dysfunction in 2%T. YM872 improved 2% tetracaine-induced motor dysfunction and neuronal damage (chromatolytic neurons, identified by round-shaped cytoplasm with loss of Nissl substance from the central part of the cell and eccentric nuclei). In 2%TY, 3 animals showed normal motor function and 3 showed mild dysfunction (ability to hop, but not normally), whereas 4 animals showed moderate dysfunction (inability to hop) in 2%T (P = 0.042). Only 2 animals showed one chromatolytic neuron in 2%TY, whereas 5 animals showed 4-16 chromatolytic neurons in 2%T (P = 0.020). These results suggest that AMPA receptor activation is involved, at least in part, in the tetracaine-induced neurotoxicity in the spinal cord.     

The addition of epinephrine to tetracaine injected intrathecally sustains an increase in glutamate concentrations in the cerebrospinal fluid and worsens neuronal injury

We have reported that large concentrations of intrathecal tetracaine increase glutamate concentrations in the cerebrospinal fluid (CSF) and cause neuronal injury in the spinal cord. In this study, we investigated whether the addition of epinephrine to tetracaine modulates these events. New Zealand white rabbits were assigned into five groups (six rabbits in each group) and intrathecally received 0.3 mL of epinephrine 0.1 mg/mL in NaCl solution (control), 1% tetracaine dissolved in saline (1%T), 1% tetracaine with epinephrine (1%TE), 2% tetracaine (2%T), or 2% tetracaine with epinephrine (2%TE). Glutamate concentrations in the lumbar CSF were monitored by microdialysis. Neurologic and histopathologic assessments were performed 1 wk after the administration. Glutamate concentrations significantly increased in all four groups that received tetracaine, whereas no change was observed in the Control group. The addition of epinephrine to tetracaine sustained large concentrations of glutamate. Sensory and motor dysfunction was observed in the 1%TE, 2%T, and 2%TE groups, and the dysfunction tended to be progressively exacerbated in this order. Characteristic histologic changes in animals with sensory and motor dysfunction were vacuolation in the dorsal funiculus and chromatolytic damage of motor neurons. The vacuolation of the dorsal funiculus in the 1%TE group was significantly worse than in the 1%T group. These results suggest that the addition of epinephrine to tetracaine may increase its neurotoxicity, which may possibly be related to a sustained increase of glutamate concentrations in the CSF. IMPLICATIONS: Sustained increase of glutamate concentrations produced by the addition of epinephrine to intrathecal tetracaine can cause neuronal injury.