脊髓ERK活化在瑞芬太尼引起术后痛觉过敏中的作用
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摘要
阿片类药物为目前临床治疗急、慢性疼痛和癌痛的代表药物。阿片类药物有诸多不良反应,如耐受、依赖、成瘾。近年研究发现阿片类药物可引起痛觉过敏(opioids induced hyperalgesia, OIH),即增加患者的痛觉敏感性。从阿片类经典药物吗啡到近年用于临床的瑞芬太尼,不论长期使用(治疗慢性疼痛)还是短时间应用(在全麻中持续输注阿片类药物),均可出现OIH。
瑞芬太尼为新型超短效的μ-阿片受体激动剂,其起效快,消除半衰期短,通过血浆和组织中非特异性酯酶代谢,不依赖于肝肾,用于老年人和肝肾功能不良的病人无需担心苏醒延迟,为较理想的阿片类药物,研究发现该药和其它阿片类药物一样,持续给药亦可引起痛觉过敏。OIH增强痛觉感知,产生异常疼痛,降低药物的镇痛效果,影响术后镇痛治疗。瑞芬太尼起效迅速,镇痛作用亦很快消退,可导致较强的术后痛觉过敏。临床上常出现术后病人苏醒迅速,但疼痛强烈,常出现烦躁不安,影响术后镇痛治疗效果。
OIH的机制包括蛋白激酶C、N-甲基-D-天门冬氨酸(NMDA)受体通路的激活,强啡肽A(Dynorphin A)释放增加等。目前瑞芬太尼引起的痛觉过敏机制研究不多,且研究多集中在人类研究中。对志愿者的研究结果表明瑞芬太尼输注后引起痛觉敏感性增高,使原有的痛觉过敏区域加大。临床研究结果却不尽相同,有研究认为术中持续输注瑞芬太尼可以增强术后疼痛,增加术后镇痛药物用量,但也有研究表明瑞芬太尼不影响术后疼痛,瑞芬太尼临床应用中出现是否存在术后痛觉过敏有待进一步研究。
细胞外信号调节蛋白激酶(extracellular signal-regulated kinase, ERK)属于丝裂原活化蛋白激酶(Mitogen-activated protein kinase, MAPK)家族,将细胞外信号传递入细胞核内,引起细胞内特异蛋白的表达谱变化,从而影响细胞命运。脊髓ERK活化参与伤害性信号调制和中枢敏感化的形成,活化的ERK可将胞浆的多种靶蛋白磷酸化,同时也转移至核内以调节转录因子的活性。通过直接或间接磷酸化某些关键结构如受体,离子通道,激酶而调节膜兴奋性和突触后可塑性变化。瑞芬太尼为μ-阿片受体激动剂,通过激活阿片受体发挥其镇痛作用。研究表明阿片类药物通过G蛋白耦联受体(G protein coupled receptor, CPCR)激活ERK通路,发现ERK路径参与吗啡耐受形成及痛觉过敏的形成。瑞芬太尼引起痛觉过敏与ERK路径的相关性值得进一步研究和探讨。
术后痛觉过敏包括伤害性刺激所致及阿片类药物停药后引起的OIH。手术创伤伤害性刺激使神经系统敏感性增加,产生痛觉过敏,影响术后镇痛治疗效果。目前术后疼痛痛觉过敏机制尚不清楚,术后疼痛不同于一般的生理性疼痛,除外科手术的切口创伤对神经末梢的机械性损害引起伤害性感受外,组织损伤后周围和中枢神经系统敏感性改变也是引起术后疼痛的主要原因。大鼠切口疼痛模型为研究术后疼痛的理想动物模型,发现切口痛与神经病理性疼痛及炎性可能具有不同的机制,对于切口痛机制还需深入研究。
OIH和术后痛觉过敏是否具有相同或类似的路径,阿片类药物与伤害性刺激引起的痛觉过敏间可能互相增强,进一步加重痛觉过敏的程度。研究OIH和术后痛觉过敏的机制有助于防治阿片类药物引起的痛觉过敏,改善术后镇痛治疗效果。
本研究观测鞘内注射ERK上游抑制剂U1026对瑞芬太尼输注后痛觉过敏的影响,及瑞芬太尼输注后大鼠脊髓p-ERK免疫阳性细胞变化,研究脊髓ERK活化在大鼠瑞芬太尼引起痛觉过敏中的作用。建立大鼠切口痛模型,研究瑞芬太尼持续输注对大鼠切口痛觉过敏的影响,以及脊髓ERK活化在切口痛痛觉过敏及瑞芬太尼引起术后痛觉中的作用。
第一部分脊髓ERK活化在瑞芬太尼引起痛觉过敏中作用
目的观测输注瑞芬太尼输注后痛觉阈值变化,鞘内注射ERK上游MEK抑制剂U1026对瑞芬太尼引起痛觉过敏的影响,及脊髓p-ERK阳性细胞数目变化。研究脊髓ERK活化在瑞芬太尼痛觉过敏中的作用。
方法雄性SD大鼠32只,随机分为4组,每组8只。经PE-10导管鞘内注射PBS液20μl,30min后,通过静脉导管持续泵入生理盐水1.5ml·h-1,持续4h,为对照组(C组)；鞘内注射PBS液20μl,30min后,静脉泵入瑞芬太尼,速度1μg·min-1·kg-1,药物浓度10μg/ml,持续注射4h,为瑞芬太尼加PBS液组(R+P组)；鞘内注射DMSO10μl、PBS液10μl冲管后,静脉泵入瑞芬太尼,速度1μg·min-1·kg-1,药物浓度10μg/ml,持续注射4h,为瑞芬太尼加DMSO组(R+D组)；鞘内注射U102610μl、PBS液10μl冲管30min后,静脉泵入瑞芬太尼1μg·min-1·kg-1,药物浓度10μg/ml,持续注射4h,为瑞芬太尼加U1026组(R+U组)。分别于颈静脉置管及鞘内置管前(TO)、鞘内给药前(Tc)、停药后0.5h、1h、2h及24h(分别为T1-T4)不同时点测定右足的机械性痛觉阈值。
雄性SD大鼠16只,按上述分组方法随机分为4组,每组4只。每组在停药1h后,灌注,取脊髓,冰冻切片,应用免疫组化方法观察脊髓p-ERK阳性细胞数目。
采用SPSS13.0统计软件进行分析,计量资料用均数士标准差(x±s)表示,置管前后机械痛阈比较采用配对,检验,组间比较采用单因素方差分析,组内比较采用重复测量数据的方差分析,不同组间脊髓p-ERK阳性细胞数目比较采用单因素方差分析,多重比较采用LSD。P<0.05为差异有统计学意义。
结果应用重复测量的方差分析,组间主效应有显著差异P=0.043,输注瑞芬太尼对大鼠机械性痛阈有显著影响。不同时间点间机械性痛阈差异有显著性意义P=0.000。输注瑞芬太尼与时间点间有交互效应P=0.000。R+P组、R+D组、R+U组在停药后30min、1h和2h机械性痛阈显著低于术前基础痛阂值(P=0.000),其中停药后1h痛觉阂值降至最低(P=0.000),停药后2h痛阈升高,术后24h组痛阈恢复至基础水平。停药后30min、1h和2h,R+P组、R+D组及R+U三组比较无差异(P>0.05)。
瑞芬太尼输注后大鼠脊髓p-ERK阳性细胞数目无明显变化,鞘内注射U1026与DMSO,大鼠脊髓p-ERK阳性细胞数目亦无明显改变。
结论大鼠静脉持续输注瑞芬太尼4h,停药后出现痛觉过敏,鞘内注射ERK上游抑制剂U1026与其佐剂DMSO对瑞芬太尼输注引起的痛觉过敏无影响。瑞芬太尼持续输注不影响大鼠脊髓p-ERK阳性细胞数目。瑞芬太尼引起的痛觉过敏可能与脊髓ERK活化无关。
第二部分瑞芬太尼对大鼠切口痛痛觉过敏的影响
目的建立大鼠切口痛模型,观测持续静脉输注瑞芬太尼对切口痛大鼠机械痛阈的影响,研究持续输注瑞芬太尼对术后疼痛的影响。
方法雄性SD大鼠24只,随机分为3组,C组、I+N组和I+R组。C组未作任何操作,只吸入同样时间2%异氟烷。I+N组和I+R组建立大鼠右后足切口痛模型后,I+N组静脉持续生理盐水,速度1.5ml·h-1;I+R组泵入盐酸瑞芬太尼,剂量为1μg·min-1·kg-1,药物浓度10μg／ml；持续注射4h。于颈静脉置管前测基础痛觉阈值TO,手术前测痛觉阈值(TC),在停药后1h、1d、2d、3d及4d(分别为T1-T5)不同时点测定右足的机械性痛觉阈值。
采用SPSS13.0统计软件进行分析,计量资料用均数士标准差(x±s)表示,组内比较采用重复测量数据的方差分析,组间比较采用单因素方差分析,多重比较采用LSD。P<0.05为差异有统计学意义。
结果输注不同药物对大鼠机械性痛阈有显著影响(P=0.000)。不同时间点间痛觉阈值差异有显著性意义(P=0.000)。输注不同药物与时间点间有交互效应(P=0.000)。I+N组及I+R组内时间点间有显著差异(P=0.000)。I+N组在停药后1h、停药后1d和2d显著低于术前基础痛觉阈值(P<0.05),术后3d痛觉阈值与术前基础值无显著差异(P=0.276)。I+R组在停药后1h、停药后1d、停药后2d及停药后3d显著低于术前基础痛觉阈值(P<0.05),术后4d痛觉阈值与术前基础值无显著差异(P=0.332)。两组在停药后1h痛觉阈值降至最低。停药后1h、停药后1d、停药后2d,I+N组及I+R组机械性痛阈低于C组(P<0.05),I+R组低于I+N组(P<0.05)。停药3d后,I+R组显著低于I+N组(P=0.027)。
结论大鼠右足切开术引起术后痛觉过敏,持续输注瑞芬太尼可增强大鼠切开痛痛觉过敏强度,延长痛觉过敏持续时间。
第三部分脊髓ERK活化在大鼠切口痛及瑞芬太尼引起术后痛觉过敏中的作用
目的鞘内注射MEK抑制剂U0126,观察其对切开痛痛觉过敏及瑞芬太尼输注后切开痛痛觉过敏的影响,及脊髓p-ERK阳性细胞数目和p-ERK蛋白表达的变化,探讨脊髓ERK活化在切口痛痛觉过敏及瑞芬太尼引起痛觉过敏中的作用。
方法雄性SD大鼠48只,随机分为6组,每组8只。I+R+P组,鞘内注射PBS液20μl,30min后行右足切开,静脉泵入瑞芬太尼,速度1μg·min-1·kg-1,药物浓度10μg/ml; I+N+P组,鞘内注射PBS液20μl,30min后,行切口痛模型制作,静脉持续泵入生理盐水1.5ml·h-1;I+R+D组,鞘内注射DMSO10μl后行右足切开,静脉泵入瑞芬太尼,速度1μg·min-1·kg-1,药物浓度10μg/ml;I+R+D组,鞘内注射DMSO10μl后,行右足切开,静脉持续泵入生理盐水1.5m1·h-1；I+R+U组,鞘内注射U102610μl,30min后行右足切开,静脉泵入瑞芬太尼,速度1μg-min-1·kg-1,药物浓度10μg/ml。I+N+U组,鞘内注射U102610μl,30min后行右足切开,静脉持续泵入生理盐水1.5ml·h-1。各组在1d、2d、3d及4d鞘内注射药物30min后开始痛觉测定。于颈静脉置管及鞘内置管前T0、鞘内给药前Tc、停药后1h、1d、2d、3d及4d(分别为T1-T5)不同时点测定右足的机械性痛觉阈值。
选择56只大鼠,随机分为7组,每组8只,其中对照组(C组),只做静脉置管,输注NS。其他六组按上述分组,每组在停药后1h和1d后分别选4只,灌注固定,取L4-L5脊髓,冰冻切片,应用免疫组化方法观察脊髓p-ERK阳性细胞数目变化。
选择28只大鼠,随机分为7组,每组4只,其中对照组,只做静脉置管,输注NS。其他六组按上述分组,每组在停药后1h后,迅速断头处死,取L4-L5脊髓组织,应用Western Blot方法,测定脊髓p-ERK蛋白含量。
采用SPSS13.0统计软件进行分析,计量资料用均数土标准差(x±s)表示,置管前后机械痛阈比较采用配对t检验,组间比较采用单因素方差分析,组内比较采用重复测量数据的方差分析,多重比较采用LSD。脊髓p-ERK蛋白含量比较采用单因素方差分析,脊髓p-ERK阳性细胞数目相同时间点不同组件采用单因素方差分析,同组间不同时点采用独立样本t检验。P<0.05为差异有统计学意义。
结果鞘内注射不同药物对大鼠机械性痛阈有显著影响P=0.006。组内不同时间点间痛觉阈值差异有显著性意义P=0.000。鞘内注射不同药物与时间点间有交互效应P=0.000。停药后1h、1d、2d、3d,I+R+P组与I+R+D组均显著低于术前基础痛阈,停药后1h、1d、2d,I+P组与I+D组均显著低于术前基础痛阈,其中停药后1h最低。I+R+U组在停药后1h、1d、2d痛阈显著低于术前,术后3d和4d与术前无差异P=0.915。I+U组在停药后1h、1d痛阈显著低于术前,术后2d与术前无差异(P=0.670)。术前和术后4d各组间无显著差异。停药后1h、1d、2d和3d,I+R+P组痛阈低于I+R+U组。停药后1h、1d和2d,I+P组显著低于I+U组。I+R+P组与I+R+D组无显著差异,I+P组与I+D组差异无统计学意义。
I+R+P组、I+P组、I+R+U组、I+U组、I+R+D组和I+D组术后1d脊髓背角p-ERK阳性神经元数目均显著高于术后1h及对照组,术后1h,1d,I+R+P组脊髓p-ERK阳性细胞数目显著高于I+R+U组和I+P组,I+P组高于I+U组(P=0.000)。
I+R+P组脊髓p-ERK蛋白积分光密度值显著高于I+R+U组和I+P组(P=0.000、P=0.000),I+P组与I+U组有显著差异(P=0.000),I+R+P组与I+R+D组间无显著差异(P=0.098),I+P组与I+D组无统计学差异(P=0.065)。
结论静脉输注瑞芬太尼可增强大鼠切口痛觉过敏程度,延长切口痛觉过敏持续时间,进一步增加大鼠脊髓P-ERK阳性神经元数目及p-ERK蛋白的表达。鞘内注射U1026可减轻大鼠痛觉过敏,缩短痛觉过敏持续时间,减少大鼠脊髓ERK磷酸化,表明大鼠切口痛觉过敏及瑞芬太尼引起术后痛觉过敏与脊髓ERK活化有关。
Opioids are the cornerstone therapy for alleviating moderate to severe pain. Opioids have long been used for alleviating acute and chronic pain and cancer pain. Common concerns regarding the use of opioids are the potential for detrimental side effects, such as tolerance, physical dependence,and addiction. However, recent research suggests that opioids may cause another problem, often referred to as opioid-induced hyperalgesia (OIH).Opioids were used to alleviated pain, somewhat paradoxically, may make patients become more sensitive to pain as a direct result of opioid therapy.From the classic opiate drugs morphine to the new opiate drugs remifentanil, regardless of long-term used (treatment of chronic pain) or a short application (in general anesthesia using a continuous infusion of opiates), may appear OIH.
Remifentanil is a new type of short actingμ-opioid receptor agonist of its rapid onset, short half-life of its elimination.It is predominantly metabolized by nonspecific esterases in plasma and tissue,and little dependent on liver and kidney. It is ideal analgesic drugs for the patients with liver and kidney dysfunction. In recent years, it was found that continuous infusion of remifentanil leads to a rapid hyperalgesia when withdrawal.OIH reduced the analgesic effect, decreased sensitivity to noxious stimuli, and resulting in abnormal pain, affecting the treatment of postoperative pain, limiting the clinical application of opioids.The analgesic effects of remifentanil were quickly disappeared after withdrawal and induce a strong hyperalgesia. Patients were awake rapidly, but with strong hyperalgesia. It is difficulty to treat postoperative pain in early.
Extracellular signal-regulated protein kinase (ERK) was belong to mitogen-activated protein kinase (MAPK) family, which is important for intracellular signal transduction and play critical roles in regulating neural plastictity and inflammatory responses.ERK activation in spinal cord neurons depends on nociceptive activity. Persistent noxious input such as imflammation pain and spinal injury and so on, could activate ERK in spinal cord.Activation of ERK may be the cytoplasm of a variety of target protein phosphorylation, and transfer to the nucleus to regulate the activity of transcription factors.This pathway is involved in pain mechanisms. Phosphorylated ERK can regulate ion channels, kinases and membrane excitability and synaptic plasticity, through direct or indirect phosphorylation of key structures such as receptors.In vitro studies showed that opioid receptor can activate ERK pathway by G protein-coupled receptor, and ERK pathway was involved in morphine tolerance and morphine induced hyperalgesia. Remifentanil is a short actingμ-opioid receptor agonists, by activating opioid receptors play its analgesic effect. Dose it induced hyperalgesia by activate the ERK in spinal cord?
Postoperative hyperalgesia can occur either due to nervous system sensitization by surgical nociception (nociception-induced hyperalgesia) or as an effect of anesthetic
drugs (opioids-induced hyperalgesia).The studies of remifentanil provide direct evidence for the existence of OIH in volunteers.But the results of whether remifentanil induced postoperative hyperalgesia are different. Is there same mechanism between remifentanil induced hyperalgesia and noxious stimulation caused allergic? The research of OIH and postoperative hyperalgesia mechanisms contribute to prevention of postoperative hyperalgesia, improvement analgesia effect of postoperative pain.
The present study was designed to investigate whether activation (phosphorylation) of ERK in the spinal cord is involved in remifentanil induced hyperalgesia and plantar incision induced hyperalgesia in the rat hind paw. Using immunohistochemical and behavioral approaches, we examined the correlation between the remifentanil induced hyperalgesia and activation of ERK in the spinal cord.We also investigated the preventive effects of intrathecal injection of MEK inhibitor, U1026,before remifentanil administer and plantar incision on mechanical hyperalgesia. Using immunohistochemical,behavioral approaches and western blot, we also examined the relation between the OIH,incision-induced hyperalgesia and ERK activation in the spinal cord.
Part 1 The role of activation of ERK in spinal cord in remifentanil induced hyperalgesia.
Objectives
To evaluate the influence of remifentanil on nociceptive sensitivity when withdrawal in rats.The role of activation of ERK in spinal cord on opioid-induced pronociception was also investigated.
Methods
Thirty-two adult male Sprague-Dawley rats were randomly divided into 4 groups. Control group (C group).Normal saline 1.5ml·h-1 'was injected through ntravenous after intrathecal injection of PBS solution 20μl,and it was continued for 4h. Remifentanil and PBS solution (R+P group),intravenous injection with remifentanil, speed 1μg-mirn-1-kg-1,after intrathecal injection of PBS solution 20μl,and it was continued for 4h. Remifentanil and DMSO (R+D group), intravenous injection with remifentanil, speed 1μg·min-1·kg-1,after intrathecal injection of DMSO solution 10μl, and it was continued for 4h. Remifentanil and U1026 (R+U group), continuous intravenous injection with remifentanil, speed 1μg·mim-1·kg-1,after intrathecal injection of U1026 solution 10μl, and it was continued for 4h.Mechanical hyperalgesia was evaluated by the paw pressure test before venipuncture (TO), before administration(Tc),0.5h, 1h,2h and 24h after drug withdrawal (respectively T1-T4). Using immunohistochemical, p-ERK positive cells in spinal cord were examined after drug withdrawal 1h.
Using SPSS 13.0 software for statistical treatment, measurement data were expressed as mean±standard deviation.Analysis of paired t test was used to evaluate pain threshold before and after catheterization.Comparisons among groups mechanical hyperalgesia were made by analysis of variance (ANOVA) and analysis of Repeated Measures. P-ERK positive cells in spinal cord were made by analysis of variance (ANOVA).Post Hoc multiple comparisons among each time spot in different groups and different time spots in each group were analyzed by using LSD test. P<0.05 was considered significant.
Results
In 0.5 h,1 h,2h after drug withdrawal,the paw-pressure threshold of R+P group, R+D group and R+U group were significantly decreased Compared to C group and baseline.The mechanical pain threshold of R+P group, R+D group and R+U group were minimized in 1h after drug withdrawal.There were no significant different of the paw-pressure threshold in 24h after treatment between four groups.Intrathecal injection of U1026 and DMSO caused no effect on hyperalgesia.
The numbers of p-ERK positive cells in rat spinal cord were no significant difference of between four groups.
Conclusions
Intrathecal injection of U1026 does not affect the hyperalgesia caused by remifentanil.The number of p-ERK positive cells in spinal cord had no effect by intravenous infusion of remifentanil.Activation of ERK in spinal cord may be unrelated to remifentanil induced hyperalgesia.
Part 2 The Study of Influence of Remifentanil on Mechanical Hyperalgesia of Incisional Pain in Rats
Objectives
To evaluated the influence of remifentanil used on nociceptive sensitivity of incisional pain in rats.
Methods
Twenty-four adult male Sprague-Dawley rats were randomly divided into 3 groups. Control group, incisional and remifentanil group, incisional and NS group, each consisting of eight rats.A catheter for the drug infusion was implanted into the jugular vein.Rats underwent right hind paw surgery combined with administration of saline(1.5ml·h-1) or remifentani(1μg·min-1·kg-1)for 4h. Nociception sensitivity was evaluated daily for 3 days using paw-pressure.
Using SPSS 13.0 software for statistical treatment, measurement data were expressed as mean±standard deviation. Analysis of paired t test was used to evaluate pain threshold before and after catheterization. Comparisons among groups mechanical hyperalgesia were made by analysis of variance (ANOVA) and analysis of Repeated Measures.Post Hoc multiple comparisons among each time spot in different groups and different time spots in each group were analyzed by using LSD test..P<0.05 was considered significant.
Results
The comparison of the pressure threshold before and after catheter implanted had no significant analgesic effect(P>0.05).Remifentanil enhanced mechanical hyperalgesia induced by surgery. The pressure threshold in R group were significantly reduced compared to C group at T2 to T5.Remifentanil induced a decrease in nociceptive thresholds in the left paw after Remifentanil infusion.
Conclusions
Intraoperative infusion of remifentanil significantly enhanced extent and duration of incisional pain in rats.
Part 3 The role of activation of ERK in spinal cord in remifentanil induced postoperative hyperalgesia
Objectives
The aim of the present study was to investigate the number of phosphorylated extracellular signal-regulated kinase (p-ERK) immunoreactive cells in the spinal dorsal horn after plantar incision, and the effects of intrathecal administration of MEK inhibitor U1026 on the behavior of pain in a rat model of incisional pain and remifentanil induced postoperative hyperalgesia.
Methods
Forty-eight adult male Sprague-Dawley rats were randomly divided into 6 groups. All rats were received a plantar incision surgery. (I+R+P group), intrathecal injection of PBS solution 20μl,intravenous injection with remifentanil.(I+N+P group) intrathecal injection of PBS solution 20μl, intravenous injection with normal saline. (I+R+D group), intrathecal injection of DMSO solution 10μl,intravenous injection with remifentanil.(I+N+D group), intrathecal injection of DMSO solution 10μl, intravenous injection with normal saline. (I+R+U group),intrathecal injection of U1026 solution 10μl, intravenous injection with remifentanil.(I+N+U group) intrathecal injection of U1026 solution 10μl,intravenous injection with normal saline. (and intrathecal DMSO group (D group).Mechanical hyperalgesia was evaluated by the pawpressure test before venipuncture (TO), before administration(Tc),0.5h,1h,2h and 24h after drug withdrawal (respectively T1-T4).Using immunohistochemical, p-ERK positive cells in spinal cord were examined after drug withdrawal 1h and 1d. Using western blot, protein of p-ERK were examined after drug withdrawal 1h.
SPSS 13.0 software was used for statistical, measurement data were expressed as mean±standard deviation. Analysis of paired t test was used to evaluate pain threshold before and after catheterization. Comparisons among groups mechanical hyperalgesia were made by analysis of variance (ANOVA) and analysis of Repeated Measures.P-ERK positive cells and IOD of p-ERK protein in spinal cord were made by analysis of variance (ANOVA).Post Hoc multiple comparisons among each time spot in different groups and different time spots in each group were analyzed by using LSD test.P<0.05 was considered significant.
Results
The paw-pressure threshold of I+R+P group in 1 h, ld,2d,3d after withdrawal were significantly decreased compared to I+R+U group and baseline of preoperative.I+P group was significantly lower than the I+U group in 1 h,1d,2d after withdrawal.I+R+P group and I+R+D group was no significant difference, I +P group and I+D group showed no significant difference.A significant increase in number of p-ERK immunoreactive cells was observed in the rat spinal cord form 1 h to Id in six groups. Intrathecal pretreatment of U1026 attenuated incision-induced mechanical hyperalgesia from 1 h to day 2 and significantly reduced activation of ERK in the spinal cord from 1h to 1 day after plantar incision. IOD of p-ERK protein in spinal cord in (I+R+P) group were significantly higher than the I+R+U group, and I+P group, I+P group than in I+U group.
Conclusions
Plantar incision-induced mechanical hyperalgesia can be prevented by the U1026. ERK activation in spinal cord play a role in incision-induced mechanical hyperalgesia and remifentanil induced postoperative hyperalgesia in rats.
瑞芬太尼为新型超短效的μ-阿片受体激动剂,其起效快,消除半衰期短,通过血浆和组织中非特异性酯酶代谢,不依赖于肝肾,用于老年人和肝肾功能不良的病人无需担心苏醒延迟,为较理想的阿片类药物,研究发现该药和其它阿片类药物一样,持续给药亦可引起痛觉过敏。OIH增强痛觉感知,产生异常疼痛,降低药物的镇痛效果,影响术后镇痛治疗。瑞芬太尼起效迅速,镇痛作用亦很快消退,可导致较强的术后痛觉过敏。临床上常出现术后病人苏醒迅速,但疼痛强烈,常出现烦躁不安,影响术后镇痛治疗效果。
OIH的机制包括蛋白激酶C、N-甲基-D-天门冬氨酸(NMDA)受体通路的激活,强啡肽A(Dynorphin A)释放增加等。目前瑞芬太尼引起的痛觉过敏机制研究不多,且研究多集中在人类研究中。对志愿者的研究结果表明瑞芬太尼输注后引起痛觉敏感性增高,使原有的痛觉过敏区域加大。临床研究结果却不尽相同,有研究认为术中持续输注瑞芬太尼可以增强术后疼痛,增加术后镇痛药物用量,但也有研究表明瑞芬太尼不影响术后疼痛,瑞芬太尼临床应用中出现是否存在术后痛觉过敏有待进一步研究。
细胞外信号调节蛋白激酶(extracellular signal-regulated kinase, ERK)属于丝裂原活化蛋白激酶(Mitogen-activated protein kinase, MAPK)家族,将细胞外信号传递入细胞核内,引起细胞内特异蛋白的表达谱变化,从而影响细胞命运。脊髓ERK活化参与伤害性信号调制和中枢敏感化的形成,活化的ERK可将胞浆的多种靶蛋白磷酸化,同时也转移至核内以调节转录因子的活性。通过直接或间接磷酸化某些关键结构如受体,离子通道,激酶而调节膜兴奋性和突触后可塑性变化。瑞芬太尼为μ-阿片受体激动剂,通过激活阿片受体发挥其镇痛作用。研究表明阿片类药物通过G蛋白耦联受体(G protein coupled receptor, CPCR)激活ERK通路,发现ERK路径参与吗啡耐受形成及痛觉过敏的形成。瑞芬太尼引起痛觉过敏与ERK路径的相关性值得进一步研究和探讨。
术后痛觉过敏包括伤害性刺激所致及阿片类药物停药后引起的OIH。手术创伤伤害性刺激使神经系统敏感性增加,产生痛觉过敏,影响术后镇痛治疗效果。目前术后疼痛痛觉过敏机制尚不清楚,术后疼痛不同于一般的生理性疼痛,除外科手术的切口创伤对神经末梢的机械性损害引起伤害性感受外,组织损伤后周围和中枢神经系统敏感性改变也是引起术后疼痛的主要原因。大鼠切口疼痛模型为研究术后疼痛的理想动物模型,发现切口痛与神经病理性疼痛及炎性可能具有不同的机制,对于切口痛机制还需深入研究。
OIH和术后痛觉过敏是否具有相同或类似的路径,阿片类药物与伤害性刺激引起的痛觉过敏间可能互相增强,进一步加重痛觉过敏的程度。研究OIH和术后痛觉过敏的机制有助于防治阿片类药物引起的痛觉过敏,改善术后镇痛治疗效果。
本研究观测鞘内注射ERK上游抑制剂U1026对瑞芬太尼输注后痛觉过敏的影响,及瑞芬太尼输注后大鼠脊髓p-ERK免疫阳性细胞变化,研究脊髓ERK活化在大鼠瑞芬太尼引起痛觉过敏中的作用。建立大鼠切口痛模型,研究瑞芬太尼持续输注对大鼠切口痛觉过敏的影响,以及脊髓ERK活化在切口痛痛觉过敏及瑞芬太尼引起术后痛觉中的作用。
第一部分脊髓ERK活化在瑞芬太尼引起痛觉过敏中作用
目的观测输注瑞芬太尼输注后痛觉阈值变化,鞘内注射ERK上游MEK抑制剂U1026对瑞芬太尼引起痛觉过敏的影响,及脊髓p-ERK阳性细胞数目变化。研究脊髓ERK活化在瑞芬太尼痛觉过敏中的作用。
方法雄性SD大鼠32只,随机分为4组,每组8只。经PE-10导管鞘内注射PBS液20μl,30min后,通过静脉导管持续泵入生理盐水1.5ml·h-1,持续4h,为对照组(C组)；鞘内注射PBS液20μl,30min后,静脉泵入瑞芬太尼,速度1μg·min-1·kg-1,药物浓度10μg/ml,持续注射4h,为瑞芬太尼加PBS液组(R+P组)；鞘内注射DMSO10μl、PBS液10μl冲管后,静脉泵入瑞芬太尼,速度1μg·min-1·kg-1,药物浓度10μg/ml,持续注射4h,为瑞芬太尼加DMSO组(R+D组)；鞘内注射U102610μl、PBS液10μl冲管30min后,静脉泵入瑞芬太尼1μg·min-1·kg-1,药物浓度10μg/ml,持续注射4h,为瑞芬太尼加U1026组(R+U组)。分别于颈静脉置管及鞘内置管前(TO)、鞘内给药前(Tc)、停药后0.5h、1h、2h及24h(分别为T1-T4)不同时点测定右足的机械性痛觉阈值。
雄性SD大鼠16只,按上述分组方法随机分为4组,每组4只。每组在停药1h后,灌注,取脊髓,冰冻切片,应用免疫组化方法观察脊髓p-ERK阳性细胞数目。
采用SPSS13.0统计软件进行分析,计量资料用均数士标准差(x±s)表示,置管前后机械痛阈比较采用配对,检验,组间比较采用单因素方差分析,组内比较采用重复测量数据的方差分析,不同组间脊髓p-ERK阳性细胞数目比较采用单因素方差分析,多重比较采用LSD。P<0.05为差异有统计学意义。
结果应用重复测量的方差分析,组间主效应有显著差异P=0.043,输注瑞芬太尼对大鼠机械性痛阈有显著影响。不同时间点间机械性痛阈差异有显著性意义P=0.000。输注瑞芬太尼与时间点间有交互效应P=0.000。R+P组、R+D组、R+U组在停药后30min、1h和2h机械性痛阈显著低于术前基础痛阂值(P=0.000),其中停药后1h痛觉阂值降至最低(P=0.000),停药后2h痛阈升高,术后24h组痛阈恢复至基础水平。停药后30min、1h和2h,R+P组、R+D组及R+U三组比较无差异(P>0.05)。
瑞芬太尼输注后大鼠脊髓p-ERK阳性细胞数目无明显变化,鞘内注射U1026与DMSO,大鼠脊髓p-ERK阳性细胞数目亦无明显改变。
结论大鼠静脉持续输注瑞芬太尼4h,停药后出现痛觉过敏,鞘内注射ERK上游抑制剂U1026与其佐剂DMSO对瑞芬太尼输注引起的痛觉过敏无影响。瑞芬太尼持续输注不影响大鼠脊髓p-ERK阳性细胞数目。瑞芬太尼引起的痛觉过敏可能与脊髓ERK活化无关。
第二部分瑞芬太尼对大鼠切口痛痛觉过敏的影响
目的建立大鼠切口痛模型,观测持续静脉输注瑞芬太尼对切口痛大鼠机械痛阈的影响,研究持续输注瑞芬太尼对术后疼痛的影响。
方法雄性SD大鼠24只,随机分为3组,C组、I+N组和I+R组。C组未作任何操作,只吸入同样时间2%异氟烷。I+N组和I+R组建立大鼠右后足切口痛模型后,I+N组静脉持续生理盐水,速度1.5ml·h-1;I+R组泵入盐酸瑞芬太尼,剂量为1μg·min-1·kg-1,药物浓度10μg／ml；持续注射4h。于颈静脉置管前测基础痛觉阈值TO,手术前测痛觉阈值(TC),在停药后1h、1d、2d、3d及4d(分别为T1-T5)不同时点测定右足的机械性痛觉阈值。
采用SPSS13.0统计软件进行分析,计量资料用均数士标准差(x±s)表示,组内比较采用重复测量数据的方差分析,组间比较采用单因素方差分析,多重比较采用LSD。P<0.05为差异有统计学意义。
结果输注不同药物对大鼠机械性痛阈有显著影响(P=0.000)。不同时间点间痛觉阈值差异有显著性意义(P=0.000)。输注不同药物与时间点间有交互效应(P=0.000)。I+N组及I+R组内时间点间有显著差异(P=0.000)。I+N组在停药后1h、停药后1d和2d显著低于术前基础痛觉阈值(P<0.05),术后3d痛觉阈值与术前基础值无显著差异(P=0.276)。I+R组在停药后1h、停药后1d、停药后2d及停药后3d显著低于术前基础痛觉阈值(P<0.05),术后4d痛觉阈值与术前基础值无显著差异(P=0.332)。两组在停药后1h痛觉阈值降至最低。停药后1h、停药后1d、停药后2d,I+N组及I+R组机械性痛阈低于C组(P<0.05),I+R组低于I+N组(P<0.05)。停药3d后,I+R组显著低于I+N组(P=0.027)。
结论大鼠右足切开术引起术后痛觉过敏,持续输注瑞芬太尼可增强大鼠切开痛痛觉过敏强度,延长痛觉过敏持续时间。
第三部分脊髓ERK活化在大鼠切口痛及瑞芬太尼引起术后痛觉过敏中的作用
目的鞘内注射MEK抑制剂U0126,观察其对切开痛痛觉过敏及瑞芬太尼输注后切开痛痛觉过敏的影响,及脊髓p-ERK阳性细胞数目和p-ERK蛋白表达的变化,探讨脊髓ERK活化在切口痛痛觉过敏及瑞芬太尼引起痛觉过敏中的作用。
方法雄性SD大鼠48只,随机分为6组,每组8只。I+R+P组,鞘内注射PBS液20μl,30min后行右足切开,静脉泵入瑞芬太尼,速度1μg·min-1·kg-1,药物浓度10μg/ml; I+N+P组,鞘内注射PBS液20μl,30min后,行切口痛模型制作,静脉持续泵入生理盐水1.5ml·h-1;I+R+D组,鞘内注射DMSO10μl后行右足切开,静脉泵入瑞芬太尼,速度1μg·min-1·kg-1,药物浓度10μg/ml;I+R+D组,鞘内注射DMSO10μl后,行右足切开,静脉持续泵入生理盐水1.5m1·h-1；I+R+U组,鞘内注射U102610μl,30min后行右足切开,静脉泵入瑞芬太尼,速度1μg-min-1·kg-1,药物浓度10μg/ml。I+N+U组,鞘内注射U102610μl,30min后行右足切开,静脉持续泵入生理盐水1.5ml·h-1。各组在1d、2d、3d及4d鞘内注射药物30min后开始痛觉测定。于颈静脉置管及鞘内置管前T0、鞘内给药前Tc、停药后1h、1d、2d、3d及4d(分别为T1-T5)不同时点测定右足的机械性痛觉阈值。
选择56只大鼠,随机分为7组,每组8只,其中对照组(C组),只做静脉置管,输注NS。其他六组按上述分组,每组在停药后1h和1d后分别选4只,灌注固定,取L4-L5脊髓,冰冻切片,应用免疫组化方法观察脊髓p-ERK阳性细胞数目变化。
选择28只大鼠,随机分为7组,每组4只,其中对照组,只做静脉置管,输注NS。其他六组按上述分组,每组在停药后1h后,迅速断头处死,取L4-L5脊髓组织,应用Western Blot方法,测定脊髓p-ERK蛋白含量。
采用SPSS13.0统计软件进行分析,计量资料用均数土标准差(x±s)表示,置管前后机械痛阈比较采用配对t检验,组间比较采用单因素方差分析,组内比较采用重复测量数据的方差分析,多重比较采用LSD。脊髓p-ERK蛋白含量比较采用单因素方差分析,脊髓p-ERK阳性细胞数目相同时间点不同组件采用单因素方差分析,同组间不同时点采用独立样本t检验。P<0.05为差异有统计学意义。
结果鞘内注射不同药物对大鼠机械性痛阈有显著影响P=0.006。组内不同时间点间痛觉阈值差异有显著性意义P=0.000。鞘内注射不同药物与时间点间有交互效应P=0.000。停药后1h、1d、2d、3d,I+R+P组与I+R+D组均显著低于术前基础痛阈,停药后1h、1d、2d,I+P组与I+D组均显著低于术前基础痛阈,其中停药后1h最低。I+R+U组在停药后1h、1d、2d痛阈显著低于术前,术后3d和4d与术前无差异P=0.915。I+U组在停药后1h、1d痛阈显著低于术前,术后2d与术前无差异(P=0.670)。术前和术后4d各组间无显著差异。停药后1h、1d、2d和3d,I+R+P组痛阈低于I+R+U组。停药后1h、1d和2d,I+P组显著低于I+U组。I+R+P组与I+R+D组无显著差异,I+P组与I+D组差异无统计学意义。
I+R+P组、I+P组、I+R+U组、I+U组、I+R+D组和I+D组术后1d脊髓背角p-ERK阳性神经元数目均显著高于术后1h及对照组,术后1h,1d,I+R+P组脊髓p-ERK阳性细胞数目显著高于I+R+U组和I+P组,I+P组高于I+U组(P=0.000)。
I+R+P组脊髓p-ERK蛋白积分光密度值显著高于I+R+U组和I+P组(P=0.000、P=0.000),I+P组与I+U组有显著差异(P=0.000),I+R+P组与I+R+D组间无显著差异(P=0.098),I+P组与I+D组无统计学差异(P=0.065)。
结论静脉输注瑞芬太尼可增强大鼠切口痛觉过敏程度,延长切口痛觉过敏持续时间,进一步增加大鼠脊髓P-ERK阳性神经元数目及p-ERK蛋白的表达。鞘内注射U1026可减轻大鼠痛觉过敏,缩短痛觉过敏持续时间,减少大鼠脊髓ERK磷酸化,表明大鼠切口痛觉过敏及瑞芬太尼引起术后痛觉过敏与脊髓ERK活化有关。
Opioids are the cornerstone therapy for alleviating moderate to severe pain. Opioids have long been used for alleviating acute and chronic pain and cancer pain. Common concerns regarding the use of opioids are the potential for detrimental side effects, such as tolerance, physical dependence,and addiction. However, recent research suggests that opioids may cause another problem, often referred to as opioid-induced hyperalgesia (OIH).Opioids were used to alleviated pain, somewhat paradoxically, may make patients become more sensitive to pain as a direct result of opioid therapy.From the classic opiate drugs morphine to the new opiate drugs remifentanil, regardless of long-term used (treatment of chronic pain) or a short application (in general anesthesia using a continuous infusion of opiates), may appear OIH.
Remifentanil is a new type of short actingμ-opioid receptor agonist of its rapid onset, short half-life of its elimination.It is predominantly metabolized by nonspecific esterases in plasma and tissue,and little dependent on liver and kidney. It is ideal analgesic drugs for the patients with liver and kidney dysfunction. In recent years, it was found that continuous infusion of remifentanil leads to a rapid hyperalgesia when withdrawal.OIH reduced the analgesic effect, decreased sensitivity to noxious stimuli, and resulting in abnormal pain, affecting the treatment of postoperative pain, limiting the clinical application of opioids.The analgesic effects of remifentanil were quickly disappeared after withdrawal and induce a strong hyperalgesia. Patients were awake rapidly, but with strong hyperalgesia. It is difficulty to treat postoperative pain in early.
Extracellular signal-regulated protein kinase (ERK) was belong to mitogen-activated protein kinase (MAPK) family, which is important for intracellular signal transduction and play critical roles in regulating neural plastictity and inflammatory responses.ERK activation in spinal cord neurons depends on nociceptive activity. Persistent noxious input such as imflammation pain and spinal injury and so on, could activate ERK in spinal cord.Activation of ERK may be the cytoplasm of a variety of target protein phosphorylation, and transfer to the nucleus to regulate the activity of transcription factors.This pathway is involved in pain mechanisms. Phosphorylated ERK can regulate ion channels, kinases and membrane excitability and synaptic plasticity, through direct or indirect phosphorylation of key structures such as receptors.In vitro studies showed that opioid receptor can activate ERK pathway by G protein-coupled receptor, and ERK pathway was involved in morphine tolerance and morphine induced hyperalgesia. Remifentanil is a short actingμ-opioid receptor agonists, by activating opioid receptors play its analgesic effect. Dose it induced hyperalgesia by activate the ERK in spinal cord?
Postoperative hyperalgesia can occur either due to nervous system sensitization by surgical nociception (nociception-induced hyperalgesia) or as an effect of anesthetic
drugs (opioids-induced hyperalgesia).The studies of remifentanil provide direct evidence for the existence of OIH in volunteers.But the results of whether remifentanil induced postoperative hyperalgesia are different. Is there same mechanism between remifentanil induced hyperalgesia and noxious stimulation caused allergic? The research of OIH and postoperative hyperalgesia mechanisms contribute to prevention of postoperative hyperalgesia, improvement analgesia effect of postoperative pain.
The present study was designed to investigate whether activation (phosphorylation) of ERK in the spinal cord is involved in remifentanil induced hyperalgesia and plantar incision induced hyperalgesia in the rat hind paw. Using immunohistochemical and behavioral approaches, we examined the correlation between the remifentanil induced hyperalgesia and activation of ERK in the spinal cord.We also investigated the preventive effects of intrathecal injection of MEK inhibitor, U1026,before remifentanil administer and plantar incision on mechanical hyperalgesia. Using immunohistochemical,behavioral approaches and western blot, we also examined the relation between the OIH,incision-induced hyperalgesia and ERK activation in the spinal cord.
Part 1 The role of activation of ERK in spinal cord in remifentanil induced hyperalgesia.
Objectives
To evaluate the influence of remifentanil on nociceptive sensitivity when withdrawal in rats.The role of activation of ERK in spinal cord on opioid-induced pronociception was also investigated.
Methods
Thirty-two adult male Sprague-Dawley rats were randomly divided into 4 groups. Control group (C group).Normal saline 1.5ml·h-1 'was injected through ntravenous after intrathecal injection of PBS solution 20μl,and it was continued for 4h. Remifentanil and PBS solution (R+P group),intravenous injection with remifentanil, speed 1μg-mirn-1-kg-1,after intrathecal injection of PBS solution 20μl,and it was continued for 4h. Remifentanil and DMSO (R+D group), intravenous injection with remifentanil, speed 1μg·min-1·kg-1,after intrathecal injection of DMSO solution 10μl, and it was continued for 4h. Remifentanil and U1026 (R+U group), continuous intravenous injection with remifentanil, speed 1μg·mim-1·kg-1,after intrathecal injection of U1026 solution 10μl, and it was continued for 4h.Mechanical hyperalgesia was evaluated by the paw pressure test before venipuncture (TO), before administration(Tc),0.5h, 1h,2h and 24h after drug withdrawal (respectively T1-T4). Using immunohistochemical, p-ERK positive cells in spinal cord were examined after drug withdrawal 1h.
Using SPSS 13.0 software for statistical treatment, measurement data were expressed as mean±standard deviation.Analysis of paired t test was used to evaluate pain threshold before and after catheterization.Comparisons among groups mechanical hyperalgesia were made by analysis of variance (ANOVA) and analysis of Repeated Measures. P-ERK positive cells in spinal cord were made by analysis of variance (ANOVA).Post Hoc multiple comparisons among each time spot in different groups and different time spots in each group were analyzed by using LSD test. P<0.05 was considered significant.
Results
In 0.5 h,1 h,2h after drug withdrawal,the paw-pressure threshold of R+P group, R+D group and R+U group were significantly decreased Compared to C group and baseline.The mechanical pain threshold of R+P group, R+D group and R+U group were minimized in 1h after drug withdrawal.There were no significant different of the paw-pressure threshold in 24h after treatment between four groups.Intrathecal injection of U1026 and DMSO caused no effect on hyperalgesia.
The numbers of p-ERK positive cells in rat spinal cord were no significant difference of between four groups.
Conclusions
Intrathecal injection of U1026 does not affect the hyperalgesia caused by remifentanil.The number of p-ERK positive cells in spinal cord had no effect by intravenous infusion of remifentanil.Activation of ERK in spinal cord may be unrelated to remifentanil induced hyperalgesia.
Part 2 The Study of Influence of Remifentanil on Mechanical Hyperalgesia of Incisional Pain in Rats
Objectives
To evaluated the influence of remifentanil used on nociceptive sensitivity of incisional pain in rats.
Methods
Twenty-four adult male Sprague-Dawley rats were randomly divided into 3 groups. Control group, incisional and remifentanil group, incisional and NS group, each consisting of eight rats.A catheter for the drug infusion was implanted into the jugular vein.Rats underwent right hind paw surgery combined with administration of saline(1.5ml·h-1) or remifentani(1μg·min-1·kg-1)for 4h. Nociception sensitivity was evaluated daily for 3 days using paw-pressure.
Using SPSS 13.0 software for statistical treatment, measurement data were expressed as mean±standard deviation. Analysis of paired t test was used to evaluate pain threshold before and after catheterization. Comparisons among groups mechanical hyperalgesia were made by analysis of variance (ANOVA) and analysis of Repeated Measures.Post Hoc multiple comparisons among each time spot in different groups and different time spots in each group were analyzed by using LSD test..P<0.05 was considered significant.
Results
The comparison of the pressure threshold before and after catheter implanted had no significant analgesic effect(P>0.05).Remifentanil enhanced mechanical hyperalgesia induced by surgery. The pressure threshold in R group were significantly reduced compared to C group at T2 to T5.Remifentanil induced a decrease in nociceptive thresholds in the left paw after Remifentanil infusion.
Conclusions
Intraoperative infusion of remifentanil significantly enhanced extent and duration of incisional pain in rats.
Part 3 The role of activation of ERK in spinal cord in remifentanil induced postoperative hyperalgesia
Objectives
The aim of the present study was to investigate the number of phosphorylated extracellular signal-regulated kinase (p-ERK) immunoreactive cells in the spinal dorsal horn after plantar incision, and the effects of intrathecal administration of MEK inhibitor U1026 on the behavior of pain in a rat model of incisional pain and remifentanil induced postoperative hyperalgesia.
Methods
Forty-eight adult male Sprague-Dawley rats were randomly divided into 6 groups. All rats were received a plantar incision surgery. (I+R+P group), intrathecal injection of PBS solution 20μl,intravenous injection with remifentanil.(I+N+P group) intrathecal injection of PBS solution 20μl, intravenous injection with normal saline. (I+R+D group), intrathecal injection of DMSO solution 10μl,intravenous injection with remifentanil.(I+N+D group), intrathecal injection of DMSO solution 10μl, intravenous injection with normal saline. (I+R+U group),intrathecal injection of U1026 solution 10μl, intravenous injection with remifentanil.(I+N+U group) intrathecal injection of U1026 solution 10μl,intravenous injection with normal saline. (and intrathecal DMSO group (D group).Mechanical hyperalgesia was evaluated by the pawpressure test before venipuncture (TO), before administration(Tc),0.5h,1h,2h and 24h after drug withdrawal (respectively T1-T4).Using immunohistochemical, p-ERK positive cells in spinal cord were examined after drug withdrawal 1h and 1d. Using western blot, protein of p-ERK were examined after drug withdrawal 1h.
SPSS 13.0 software was used for statistical, measurement data were expressed as mean±standard deviation. Analysis of paired t test was used to evaluate pain threshold before and after catheterization. Comparisons among groups mechanical hyperalgesia were made by analysis of variance (ANOVA) and analysis of Repeated Measures.P-ERK positive cells and IOD of p-ERK protein in spinal cord were made by analysis of variance (ANOVA).Post Hoc multiple comparisons among each time spot in different groups and different time spots in each group were analyzed by using LSD test.P<0.05 was considered significant.
Results
The paw-pressure threshold of I+R+P group in 1 h, ld,2d,3d after withdrawal were significantly decreased compared to I+R+U group and baseline of preoperative.I+P group was significantly lower than the I+U group in 1 h,1d,2d after withdrawal.I+R+P group and I+R+D group was no significant difference, I +P group and I+D group showed no significant difference.A significant increase in number of p-ERK immunoreactive cells was observed in the rat spinal cord form 1 h to Id in six groups. Intrathecal pretreatment of U1026 attenuated incision-induced mechanical hyperalgesia from 1 h to day 2 and significantly reduced activation of ERK in the spinal cord from 1h to 1 day after plantar incision. IOD of p-ERK protein in spinal cord in (I+R+P) group were significantly higher than the I+R+U group, and I+P group, I+P group than in I+U group.
Conclusions
Plantar incision-induced mechanical hyperalgesia can be prevented by the U1026. ERK activation in spinal cord play a role in incision-induced mechanical hyperalgesia and remifentanil induced postoperative hyperalgesia in rats.
引文
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