糖原合成酶激酶-3β和NMDA受体亚单位运输在切口痛—瑞芬太尼痛觉过敏大鼠脊髓中的变化及调节
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摘要
阿片类药物是临床疼痛治疗的代表性药物,主要用于急、慢性疼痛和癌痛的治疗。它们在镇痛的同时也产生诸多不良反应,其所致的痛觉过敏因为与其治疗初衷相悖,影响了这类药物的临床应用。瑞芬太尼是超短效的μ-阿片受体激动剂,因具有起效快、清除快、无蓄积等特点而被广泛应用于全身麻醉的镇痛,但据文献报告,其产生痛觉过敏的发生率明显高于其他阿片类药物。研究表明NMDA受体功能的改变在瑞芬太尼痛觉过敏的形成过程中发挥了重要的作用,但目前尚无关于NMDA受体亚单位运输与瑞芬太尼痛觉过敏机制关系的报告。糖元合成酶激酶-3(glycogen synthase kinase-3, GSK-3)是一个多功能的丝氨酸/苏氨酸类激酶,在真核生物中普遍存在。在哺乳动物中包括两个亚型,即GSK-3α和GSK-3β。该酶的作用主要包括调节糖原的合成代谢,参与细胞的分化与增殖等。近年来研究发现,GSK-3影响突触可塑性,并对NMDA受体运输有重要介导作用,即应用GSK-3抑制剂可以抑制NMDA受体在突触后膜的表达。而在瑞芬太尼痛觉过敏模型中,GSK-3的作用尚未见国内外研究报道。
本研究以大鼠切口痛-瑞芬太尼痛觉过敏模型为基础,通过评价大鼠脊髓GSK-3β mRNA表达水平及NMDA受体亚单位运输的变化,并给予δ-阿片受体抑制剂那曲吲哚和GSK-3β抑制剂TDZD-8,通过评价那曲吲哚对切口痛-瑞芬太尼痛觉过敏大鼠脊髓GSK-3β mRNA表达水平变化的影响,以及TDZD-8对切口痛-瑞芬太尼痛觉过敏大鼠脊髓NMDA受体亚单位运输变化的影响,探讨GSK-3β及NMDA受体亚单位运输的变化及调节在瑞芬太尼痛觉过敏形成机制中的作用。
第一部分：切口痛-瑞芬太尼痛觉过敏大鼠脊髓GSK-3β mRNA表达水平的变化
目的通过评价切口痛-瑞芬太尼痛觉过敏大鼠脊髓GSK-3βmRNA表达水平的变化,探讨GSK-3β在瑞芬太尼引发痛觉过敏中的可能机制。
方法尾静脉置管成功的雄性SD大鼠32只,质量240-260g,随机数字表法分为4组(n=8),瑞芬太尼组(R组)：经尾静脉置管输注瑞芬太尼1.2μ g·kg-1·min-1；切口痛组(Ⅰ组)：建立Brennan切口痛模型,同时经尾静脉置管输注等体积的生理盐水；瑞芬太尼+切口痛组(R+I组)：建立Brennan切口痛模型,同时经尾静脉置管输注瑞芬太尼1.2μ g·kg-1·min-1；对照组(C组)：经尾静脉置管输注等体积的生理盐水。瑞芬太尼和生理盐水的输注时间均为60min。于麻醉前24h、麻醉后2、6、24和48h,分别采用Von-Frey丝法和热板法测定机械刺激缩足阈值(PWT)和热刺激缩足潜伏期(PWL),最后一次测定痛阈后处死大鼠,取脊髓L4-6节段,采用实时定量聚合酶链式反应法测定脊髓GSK-3β mRNA表达水平的变化。
结果R组、I组、R+I组均发生痛觉过敏,且R+I组痛觉过敏的程度高于R组和Ⅰ组。4组中R+I组GSK-3β mRNA表达水平最高,是C组的4.4倍。
结论术中应用瑞芬太尼麻醉可加重切口痛导致的痛觉过敏；切口痛-瑞芬太尼痛觉过敏大鼠脊髓GSK-3β mRNA表达升高,该变化可能参与了切口痛-瑞芬太尼痛觉过敏形成的机制。
第二部分：切口痛-瑞芬太尼痛觉过敏大鼠脊髓NMDA受体亚单位运输的变化
目的通过评价切口痛-瑞芬太尼痛觉过敏大鼠脊髓NMDA受体亚单位运输的变化,探讨NMDA受体亚单位运输在瑞芬太尼引发痛觉过敏中的可能机制。
方法尾静脉置管成功的雄性SD大鼠32只,质量240-260g,随机数字表法分为4组(n=8),瑞芬太尼组(R组)：经尾静脉置管输注瑞芬太尼1.2μg·kg-1·min-1;切口痛组(Ⅰ组)：建立Brennan切口痛模型,同时经尾静脉置管输注等体积的生理盐水；瑞芬太尼+切口痛组(R+I组)：建立Brennan切口痛模型,同时经尾静脉置管输注瑞芬太尼1.2μg·kg-1·min-1;对照组(C组)：经尾静脉置管输注等体积的生理盐水。瑞芬太尼和生理盐水的输注时间均为60min。于麻醉前24h、麻醉后2、6、24和48h,分别采用Von-Frey丝法和热板法测定机械刺激缩足阈值(PWT)和热刺激缩足潜伏期(PWL),最后一次测定痛阈后处死大鼠,取脊髓L4-6节段,采用western blot法测定脊髓细胞膜(s)及胞浆内(i)NMDA受体NR1、NR2A及NR2B亚单位的表达,并计算sNR1/iNRl、sNR2A/iNR2A及sNR2B/iNR2B比值。
结果与C组比较,Ⅰ组、R组和R+I组PWT降低,PWL缩短,细胞膜NMDA受体NR1和NR2B亚单位表达上调,胞浆内NMDA受体NR1和NR2B亚单位表达下调,sNR1/iNR1及sNR2B/iNR2B比值增加(P<0.05)。与R组和Ⅰ组比较,R+I组PWT降低,PWL缩短,细胞膜NMDA受体NR1和NR2B亚单位表达上调,胞浆内NMDA受体NR1和NR2B亚单位表达下调,sNR1/iNR1及sNR2B/iNR2B比值增加(P<0.05)。各组细胞膜及胞浆内NMDA受体NR2A亚单位表达及sNR2A/iNR2A比值无显著性差异(P>0.05)。
结论术中应用瑞芬太尼麻醉可加重切口痛导致的痛觉过敏；切口痛-瑞芬太尼痛觉过敏大鼠脊髓NMDA受体NR1及NR2B亚单位从胞浆内向细胞膜的运输增加,该变化可能参与了切口痛-瑞芬太尼痛觉过敏形成的机制。
第三部分：GSK-3β抑制剂TDZD-8对切口痛-瑞芬太尼痛觉过敏大鼠脊髓NMDA受体亚单位运输变化的影响
目的评价GSK-3β对切口痛-瑞芬太尼痛觉过敏大鼠脊髓NMDA受体NR1及NR2B亚单位运输变化的影响。
方法尾静脉置管成功的雄性SD大鼠24只,体重240～260g,采用随机数字表法,将大鼠随机分为3组(n=8)：对照组(C组)静脉推注二甲基亚砜(DMSO)(2ml/kg),静脉输注与瑞芬太尼等容量生理盐水60min；瑞芬太尼+切口痛组(R+I组)静脉推注DMSO (2ml/kg),制备切口痛模型,模型制备前即刻开始静脉输注瑞芬太尼1.2μg·kg-1·min-160min；GSK-3β抑制剂组(TDZD-8组)静脉推注TDZD-8(1mg/kg),制备切口痛模型,模型制备前即刻开始静脉输注瑞芬太尼1.2μg·kg-1·min-160min。于静脉输注瑞芬太尼前24h、静脉给药后2、6、24和48h(T0～4)时测定机械刺激缩足阈值(PWT)和热刺激缩足潜伏期(PWL),最后一次测定痛阈后处死大鼠,取脊髓L4-6节段,采用western blot法测定脊髓细胞膜(s)及胞浆内(i)NMDA受体NR1及NR2B亚单位的表达,并计算sNR1/iNR1及sNR2B/iNR2B比值。
结果与C组比较,R+I组和TDZD-8组PWT降低,PWL缩短,sNR1和sNR2B表达增加,iNR1和iNR2B表达减少,sNR1/iNR1及sNR2B/iNR2B比值增加(P<0.05)。与R+I组比较,TDZD-8组PWT升高,PWL延长,sNR1和sNR2B表达减少,iNRl和iNR2B表达增加,sNR1/iNR1及sNR2B/iNR2B比值减小(P<0.05)。
结论GSK-3β参与调节切口痛-瑞芬太尼痛觉过敏大鼠脊髓NMDA受体NR1及NR2B亚单位运输。
第四部分：δ-阿片受体抑制剂那曲吲哚对切口痛-瑞芬太尼痛觉过敏大鼠脊髓GSK-3β mRNA表达水平变化的影响
目的评价δ-阿片受体对切口痛-瑞芬太尼痛觉过敏大鼠脊髓GSK-3βmRNA表达水平变化的影响。
方法尾静脉置管成功的雄性SD大鼠24只,体重240～260g,采用随机数字表法,将大鼠随机分为3组(n=8)：对照组(C组)腹腔内注射生理盐水,静脉输注与瑞芬太尼等容量生理盐水60min；瑞芬太尼+切口痛组(R+I组)腹腔内注射生理盐水,制备切口痛模型,模型制备前即刻开始静脉输注瑞芬太尼1.2μg·kg-1·min-160min;δ-阿片受体抑制剂组(naltrindole组)腹腔内注射那曲吲哚(0.1mg/kg),制备切口痛模型,模型制备前即刻开始静脉输注瑞芬太尼1.2μ g·kg-1·min-160min。于静脉输注瑞芬太尼前24h、静脉给药后2、6、24和48h(T0～4)时测定机械刺激缩足阈值(PWT)和热刺激缩足潜伏期(PWL),最后一次测定痛阈后处死大鼠,取脊髓L4-6节段,采用实时定量PCR法测定脊髓GSK-3βmRNA的表达。
结果与C组比较,R+I组和naltrindole组PWT降低,PWL缩短,大鼠脊髓GSK-3βmRNA表达增加(P<0.05)。与R+I组比较,naltrindole组PWT升高,PWL延长,大鼠脊髓GSK-3βmRNA表达减少(P<0.05)。
结论δ-阿片受体参与调节切口痛-瑞芬太尼痛觉过敏大鼠脊髓GSK-3βmRNA表达水平的变化。
Opioids have been regarded as the most effective analgesics for management of acute or chronic pain and cancer pain. However, they also produce a lot of adverse effects, including hyperalgesia, which limits their usefulness. Remifentanil is a potent short-acting μ-opioid receptor agonist, as it is a rapid-onset opioid and has short duration, remifentanil have been widely used as anagesic in clinical practice. Many researches show that the incidence rate of remifentanil-induced hyperalgesia is significantly higher than other opioids. There is increasing evidence that N-methyl-d-aspartate(NMDA) receptor play a critical role in the development of opioid-induced hyperalgesia. However, the change of NMDA receptor subunits trafficking in remifentanil-induced hyperalgesia has not been reported yet.Glycogen synthase kinase3(GSK-3) is a multifunctional serine/threonine protein kinase, ubiquitous in eukaryotes. GSK-3contained two subtypes GSK-3a and GSK-3β in mammals. The main function of this enzyme includes regulating the synthesis of glycogen metabolism, participate in cell differentiation and proliferation. Recent studies have found that, GSK-3affects synaptic plasticity, and has an important role in mediating NMDA receptor's trafficking that the application of GSK-3inhibitors can inhibit the NMDA receptor expression in the postsynaptic membrane. But in remifentanil-induced hyperalgesia model, the change of GSK-3has not been studied systematically.
In this study, using a rat model of postoperative pain, we investigated the changes of GSK-3(3expression and NMDA receptor subunits (NR1, NR2A, and NR2B) trafficking in rats'spinal cord when remifentanil-induced hyperalgesia developed. We also examined the impact of TDZD-8, a GSK-3(3inhibitor, on NMDA receptor subunits trafficking, and the impact of naltrindole, a DOR inhibitor, on GSK-3β expression in rats'spinal cord when remifentanil-induced hyperalgesia developed.
Part1Changes of glycogen synthase kinase-3β mRNA in spinal cord neurons in rats with incisional pain (IP)-remifentanil-induced hyperalgesia
Objective To investigate the changes in GSK-3β mRNA in spinal cord neurons in rats with IP-remifentanil-induced hyperalgesia.
Methods32SD male rats(240-260g) were randomly divided into4groups (n=8each):group R, remifentanil (1.2μg·kg-1·min-1); group I, IP+the same volume of saline infused; group R+I, IP+remifentanil; group C, the same volume of saline. IP was established as Brennan's description. Paw withdrawal threshold (PWT) and paw withdrawal latency (PWL) were measured24h before anesthesia and2h,6h,24h,48h after anesthesia. The rats were sacrificed after the last threshold measurement. The expressions of GSK-3β mRNA in rats'spinal cord neurons were determined by real-time PCR.
Results Remifentanil-induced hyperalgesia developed in group R, I and R+I. The expression of GSK-3(3mRNA in rats'spinal cord neurons was highest in group R+I.
Conclusion These data indicate that the increased GSK-3β mRNA in rats spinal cord neurons is involved in remifentanil-induced hyperalgesia.
Part2Changes in N-methyl-d-aspartate receptor subunits trafficking in spinal cord neurons in rats with IP-remifentanil-induced hyperalgesia
Objective To investigate the changes in N-methyl-d-aspartate receptor (NMDAR) subunits trafficking in spinal cord neurons in rats with IP-remifentanil-induced hyperalgesia.
Methods32SD male rats(240-260g) were randomly divided into4groups (n=8each):group R, remifentanil (1.2μg·kg-1·min-1); group I, IP+the same volume of saline; group R+I, IP+remifentanil (1.2μg·kg-1·min-1); group C, the same volume of saline. IP was established as Brennan's description. Paw withdrawal threshold (PWT) and paw withdrawal latency (PWL) were measured24h before anesthesia and2h,6h,24h,48h after anesthesia. The rats were sacrificed after the last threshold measurement. The surface and intracellular NMDAR subunits (NR1, NR2A, and NR2B) expressions in rats'spinal cord neurons were determined by western blot.The ratio of sNRl/iNRl, sNR2A/iNR2A and sNR2B/iNR2B were calculated.
Results Remifentanil-induced hyperalgesia developed in group R, I and R+I. The amount of surface NR1and NR2B protein increased in group R, I and R+I when compared with group C (P<0.05). As opposed to this increase in the surface pool, the amounts of intracellular NR1and NR2B in group R, I and R+I decreased when compared with group C (P<0.05). The ratio of sNRl/iNRl and sNR2B/iNR2B markedly increased in group R, I and R+I when compared with group C (P<0.05). The amount of surface NR1and NR2B protein increased, the amounts of intracellular NR1and NR2B decreased, the ratio of sNRl/iNRl and sNR2B/iNR2B markedly increased in group R+I when compared with group R and group I, respectively (P<0.05). NR2A showed no significant changes in either surface or intracellular pool (P>0.05).As a result, the ratio of sNR2A/iNR2A remained unchanged (P>0.05).
Conclusion These data indicate that the increased trafficking of NMDA receptors NR1and NR2B subunits from intracellular pool to surface pool in rats spinal cord neurons is involved in remifentanil-induced hyperalgesia.
Part3Effect of TDZD-8on NMDA receptor subunits (NRl and NR2B) trafficking in spinal cord in IP-remifentanil-induced hyperalgesia
Objective To investigate the regulation of Glycogen synthase kinase-3β on N-methyl-d-aspartate receptor NR1and NR2B subunits trafficking in spinal cord in a rat model of IP-remifentanil-induced hyperalgesia.
Methods Twenty-four male SD rats(240-260g,2-3months old) in which caudal vein catheter was successfully placed were randomly divided into3groups (n=8each):group C:DMSO+the same volume of saline; group R+I:DMSO+remifentanil+IP; group TDZD-8:TDZD-8+remifentanil+IP. TDZD-8(1mg/kg)/DMSO (2ml/kg) was infused intravenously just before remifentanil(1.2μg·kg-1·min-160min) infusion, IP was established as Brennan's description. Paw withdrawal threshold (PWT) and paw withdrawal latency (PWL) were measured24h before and2,6,24,48h after the infusion of intravenous remifentanil. The rats were sacrificed after the last threshold measurement. The surface and intracellular NMDAR NR1and NR2B subunits expressions in rats'spinal cord were determined by western blot. The ratio of sNR1/iNR1and sNR2B/iNR2B were calculated.
Results Compared with group C, PWT and PWL decreased, the amounts of surface NR1and NR2B proteins increased, the amounts of intracellular NR1and NR2B proteins decreased, the ratio of sNR1/iNR1and sNR2B/iNR2B increased in group R+I and group TDZD-8(P<0.05). Compared with groupR+I, PWT and PWL increased, the amounts of surface NR1and NR2B proteins decreased, the amounts of intracellular NR1and NR2B proteins increased, the ratio of sNR1/iNR1and sNR2B/iNR2B decreased in group TDZD-8(P<0.05)
Conclusion Glycogen synthase kinase-3β was involved in the regulation of N-methyl-d-aspartate receptor NR1and NR2B subunits trafficking in spinal cord in a rat model of IP-remifentanil-induced hyperalgesia.
Part4Effects of naltrindole on the changed expression of GSK-3β mRNA in spinal cord in IP-remifentanil-induced hyperalgesia
Objective To investigate the regulation of delta-opioid receptor (DOR) on the changed expression of GSK-3β mRNA in spinal cord in IP-remifentanil-induced hyperalgesia.
Methods Twenty-four male SD rats(240-260g,2-3months old) in which caudal vein catheter was successfully placed were randomly divided into3groups (n=8each):group C:saline+the same volume of saline; group R+I:saline+remifentanil+IP; group naltrindole:naltrindole+remifentanil+IP. Naltrindole (0.1mg/kg)/saline was administered intraperitoneally just before remifentanil(1.2μg·kg-1·min-160min) infusion, IP was established as Brennan's description. Paw withdrawal threshold (PWT) and paw withdrawal latency (PWL) were measured24h before and2,6,24,48h after the infusion of intravenous remifentanil. The rats were sacrificed after the last threshold measurement. The expressions of GSK-3β mRNA in rats' spinal cord neurons were determined by real-time PCR.
Results Compared with group C, PWT and PWL decreased, the expressions of GSK-3β mRNA increased in group R+I and group naltrindole (P<0.05). Compared with groupR+I, PWT and PWL increased, the expressions of GSK-3β mRNA decreased in group naltridole (P<0.05)
Conclusion Delta-opioid receptor was involved in the regulation of the expression of GSK-3β mRNA in spinal cord in a rat model of IP-remifentanil-induced hyperalgesia.
本研究以大鼠切口痛-瑞芬太尼痛觉过敏模型为基础,通过评价大鼠脊髓GSK-3β mRNA表达水平及NMDA受体亚单位运输的变化,并给予δ-阿片受体抑制剂那曲吲哚和GSK-3β抑制剂TDZD-8,通过评价那曲吲哚对切口痛-瑞芬太尼痛觉过敏大鼠脊髓GSK-3β mRNA表达水平变化的影响,以及TDZD-8对切口痛-瑞芬太尼痛觉过敏大鼠脊髓NMDA受体亚单位运输变化的影响,探讨GSK-3β及NMDA受体亚单位运输的变化及调节在瑞芬太尼痛觉过敏形成机制中的作用。
第一部分：切口痛-瑞芬太尼痛觉过敏大鼠脊髓GSK-3β mRNA表达水平的变化
目的通过评价切口痛-瑞芬太尼痛觉过敏大鼠脊髓GSK-3βmRNA表达水平的变化,探讨GSK-3β在瑞芬太尼引发痛觉过敏中的可能机制。
方法尾静脉置管成功的雄性SD大鼠32只,质量240-260g,随机数字表法分为4组(n=8),瑞芬太尼组(R组)：经尾静脉置管输注瑞芬太尼1.2μ g·kg-1·min-1；切口痛组(Ⅰ组)：建立Brennan切口痛模型,同时经尾静脉置管输注等体积的生理盐水；瑞芬太尼+切口痛组(R+I组)：建立Brennan切口痛模型,同时经尾静脉置管输注瑞芬太尼1.2μ g·kg-1·min-1；对照组(C组)：经尾静脉置管输注等体积的生理盐水。瑞芬太尼和生理盐水的输注时间均为60min。于麻醉前24h、麻醉后2、6、24和48h,分别采用Von-Frey丝法和热板法测定机械刺激缩足阈值(PWT)和热刺激缩足潜伏期(PWL),最后一次测定痛阈后处死大鼠,取脊髓L4-6节段,采用实时定量聚合酶链式反应法测定脊髓GSK-3β mRNA表达水平的变化。
结果R组、I组、R+I组均发生痛觉过敏,且R+I组痛觉过敏的程度高于R组和Ⅰ组。4组中R+I组GSK-3β mRNA表达水平最高,是C组的4.4倍。
结论术中应用瑞芬太尼麻醉可加重切口痛导致的痛觉过敏；切口痛-瑞芬太尼痛觉过敏大鼠脊髓GSK-3β mRNA表达升高,该变化可能参与了切口痛-瑞芬太尼痛觉过敏形成的机制。
第二部分：切口痛-瑞芬太尼痛觉过敏大鼠脊髓NMDA受体亚单位运输的变化
目的通过评价切口痛-瑞芬太尼痛觉过敏大鼠脊髓NMDA受体亚单位运输的变化,探讨NMDA受体亚单位运输在瑞芬太尼引发痛觉过敏中的可能机制。
方法尾静脉置管成功的雄性SD大鼠32只,质量240-260g,随机数字表法分为4组(n=8),瑞芬太尼组(R组)：经尾静脉置管输注瑞芬太尼1.2μg·kg-1·min-1;切口痛组(Ⅰ组)：建立Brennan切口痛模型,同时经尾静脉置管输注等体积的生理盐水；瑞芬太尼+切口痛组(R+I组)：建立Brennan切口痛模型,同时经尾静脉置管输注瑞芬太尼1.2μg·kg-1·min-1;对照组(C组)：经尾静脉置管输注等体积的生理盐水。瑞芬太尼和生理盐水的输注时间均为60min。于麻醉前24h、麻醉后2、6、24和48h,分别采用Von-Frey丝法和热板法测定机械刺激缩足阈值(PWT)和热刺激缩足潜伏期(PWL),最后一次测定痛阈后处死大鼠,取脊髓L4-6节段,采用western blot法测定脊髓细胞膜(s)及胞浆内(i)NMDA受体NR1、NR2A及NR2B亚单位的表达,并计算sNR1/iNRl、sNR2A/iNR2A及sNR2B/iNR2B比值。
结果与C组比较,Ⅰ组、R组和R+I组PWT降低,PWL缩短,细胞膜NMDA受体NR1和NR2B亚单位表达上调,胞浆内NMDA受体NR1和NR2B亚单位表达下调,sNR1/iNR1及sNR2B/iNR2B比值增加(P<0.05)。与R组和Ⅰ组比较,R+I组PWT降低,PWL缩短,细胞膜NMDA受体NR1和NR2B亚单位表达上调,胞浆内NMDA受体NR1和NR2B亚单位表达下调,sNR1/iNR1及sNR2B/iNR2B比值增加(P<0.05)。各组细胞膜及胞浆内NMDA受体NR2A亚单位表达及sNR2A/iNR2A比值无显著性差异(P>0.05)。
结论术中应用瑞芬太尼麻醉可加重切口痛导致的痛觉过敏；切口痛-瑞芬太尼痛觉过敏大鼠脊髓NMDA受体NR1及NR2B亚单位从胞浆内向细胞膜的运输增加,该变化可能参与了切口痛-瑞芬太尼痛觉过敏形成的机制。
第三部分：GSK-3β抑制剂TDZD-8对切口痛-瑞芬太尼痛觉过敏大鼠脊髓NMDA受体亚单位运输变化的影响
目的评价GSK-3β对切口痛-瑞芬太尼痛觉过敏大鼠脊髓NMDA受体NR1及NR2B亚单位运输变化的影响。
方法尾静脉置管成功的雄性SD大鼠24只,体重240～260g,采用随机数字表法,将大鼠随机分为3组(n=8)：对照组(C组)静脉推注二甲基亚砜(DMSO)(2ml/kg),静脉输注与瑞芬太尼等容量生理盐水60min；瑞芬太尼+切口痛组(R+I组)静脉推注DMSO (2ml/kg),制备切口痛模型,模型制备前即刻开始静脉输注瑞芬太尼1.2μg·kg-1·min-160min；GSK-3β抑制剂组(TDZD-8组)静脉推注TDZD-8(1mg/kg),制备切口痛模型,模型制备前即刻开始静脉输注瑞芬太尼1.2μg·kg-1·min-160min。于静脉输注瑞芬太尼前24h、静脉给药后2、6、24和48h(T0～4)时测定机械刺激缩足阈值(PWT)和热刺激缩足潜伏期(PWL),最后一次测定痛阈后处死大鼠,取脊髓L4-6节段,采用western blot法测定脊髓细胞膜(s)及胞浆内(i)NMDA受体NR1及NR2B亚单位的表达,并计算sNR1/iNR1及sNR2B/iNR2B比值。
结果与C组比较,R+I组和TDZD-8组PWT降低,PWL缩短,sNR1和sNR2B表达增加,iNR1和iNR2B表达减少,sNR1/iNR1及sNR2B/iNR2B比值增加(P<0.05)。与R+I组比较,TDZD-8组PWT升高,PWL延长,sNR1和sNR2B表达减少,iNRl和iNR2B表达增加,sNR1/iNR1及sNR2B/iNR2B比值减小(P<0.05)。
结论GSK-3β参与调节切口痛-瑞芬太尼痛觉过敏大鼠脊髓NMDA受体NR1及NR2B亚单位运输。
第四部分：δ-阿片受体抑制剂那曲吲哚对切口痛-瑞芬太尼痛觉过敏大鼠脊髓GSK-3β mRNA表达水平变化的影响
目的评价δ-阿片受体对切口痛-瑞芬太尼痛觉过敏大鼠脊髓GSK-3βmRNA表达水平变化的影响。
方法尾静脉置管成功的雄性SD大鼠24只,体重240～260g,采用随机数字表法,将大鼠随机分为3组(n=8)：对照组(C组)腹腔内注射生理盐水,静脉输注与瑞芬太尼等容量生理盐水60min；瑞芬太尼+切口痛组(R+I组)腹腔内注射生理盐水,制备切口痛模型,模型制备前即刻开始静脉输注瑞芬太尼1.2μg·kg-1·min-160min;δ-阿片受体抑制剂组(naltrindole组)腹腔内注射那曲吲哚(0.1mg/kg),制备切口痛模型,模型制备前即刻开始静脉输注瑞芬太尼1.2μ g·kg-1·min-160min。于静脉输注瑞芬太尼前24h、静脉给药后2、6、24和48h(T0～4)时测定机械刺激缩足阈值(PWT)和热刺激缩足潜伏期(PWL),最后一次测定痛阈后处死大鼠,取脊髓L4-6节段,采用实时定量PCR法测定脊髓GSK-3βmRNA的表达。
结果与C组比较,R+I组和naltrindole组PWT降低,PWL缩短,大鼠脊髓GSK-3βmRNA表达增加(P<0.05)。与R+I组比较,naltrindole组PWT升高,PWL延长,大鼠脊髓GSK-3βmRNA表达减少(P<0.05)。
结论δ-阿片受体参与调节切口痛-瑞芬太尼痛觉过敏大鼠脊髓GSK-3βmRNA表达水平的变化。
Opioids have been regarded as the most effective analgesics for management of acute or chronic pain and cancer pain. However, they also produce a lot of adverse effects, including hyperalgesia, which limits their usefulness. Remifentanil is a potent short-acting μ-opioid receptor agonist, as it is a rapid-onset opioid and has short duration, remifentanil have been widely used as anagesic in clinical practice. Many researches show that the incidence rate of remifentanil-induced hyperalgesia is significantly higher than other opioids. There is increasing evidence that N-methyl-d-aspartate(NMDA) receptor play a critical role in the development of opioid-induced hyperalgesia. However, the change of NMDA receptor subunits trafficking in remifentanil-induced hyperalgesia has not been reported yet.Glycogen synthase kinase3(GSK-3) is a multifunctional serine/threonine protein kinase, ubiquitous in eukaryotes. GSK-3contained two subtypes GSK-3a and GSK-3β in mammals. The main function of this enzyme includes regulating the synthesis of glycogen metabolism, participate in cell differentiation and proliferation. Recent studies have found that, GSK-3affects synaptic plasticity, and has an important role in mediating NMDA receptor's trafficking that the application of GSK-3inhibitors can inhibit the NMDA receptor expression in the postsynaptic membrane. But in remifentanil-induced hyperalgesia model, the change of GSK-3has not been studied systematically.
In this study, using a rat model of postoperative pain, we investigated the changes of GSK-3(3expression and NMDA receptor subunits (NR1, NR2A, and NR2B) trafficking in rats'spinal cord when remifentanil-induced hyperalgesia developed. We also examined the impact of TDZD-8, a GSK-3(3inhibitor, on NMDA receptor subunits trafficking, and the impact of naltrindole, a DOR inhibitor, on GSK-3β expression in rats'spinal cord when remifentanil-induced hyperalgesia developed.
Part1Changes of glycogen synthase kinase-3β mRNA in spinal cord neurons in rats with incisional pain (IP)-remifentanil-induced hyperalgesia
Objective To investigate the changes in GSK-3β mRNA in spinal cord neurons in rats with IP-remifentanil-induced hyperalgesia.
Methods32SD male rats(240-260g) were randomly divided into4groups (n=8each):group R, remifentanil (1.2μg·kg-1·min-1); group I, IP+the same volume of saline infused; group R+I, IP+remifentanil; group C, the same volume of saline. IP was established as Brennan's description. Paw withdrawal threshold (PWT) and paw withdrawal latency (PWL) were measured24h before anesthesia and2h,6h,24h,48h after anesthesia. The rats were sacrificed after the last threshold measurement. The expressions of GSK-3β mRNA in rats'spinal cord neurons were determined by real-time PCR.
Results Remifentanil-induced hyperalgesia developed in group R, I and R+I. The expression of GSK-3(3mRNA in rats'spinal cord neurons was highest in group R+I.
Conclusion These data indicate that the increased GSK-3β mRNA in rats spinal cord neurons is involved in remifentanil-induced hyperalgesia.
Part2Changes in N-methyl-d-aspartate receptor subunits trafficking in spinal cord neurons in rats with IP-remifentanil-induced hyperalgesia
Objective To investigate the changes in N-methyl-d-aspartate receptor (NMDAR) subunits trafficking in spinal cord neurons in rats with IP-remifentanil-induced hyperalgesia.
Methods32SD male rats(240-260g) were randomly divided into4groups (n=8each):group R, remifentanil (1.2μg·kg-1·min-1); group I, IP+the same volume of saline; group R+I, IP+remifentanil (1.2μg·kg-1·min-1); group C, the same volume of saline. IP was established as Brennan's description. Paw withdrawal threshold (PWT) and paw withdrawal latency (PWL) were measured24h before anesthesia and2h,6h,24h,48h after anesthesia. The rats were sacrificed after the last threshold measurement. The surface and intracellular NMDAR subunits (NR1, NR2A, and NR2B) expressions in rats'spinal cord neurons were determined by western blot.The ratio of sNRl/iNRl, sNR2A/iNR2A and sNR2B/iNR2B were calculated.
Results Remifentanil-induced hyperalgesia developed in group R, I and R+I. The amount of surface NR1and NR2B protein increased in group R, I and R+I when compared with group C (P<0.05). As opposed to this increase in the surface pool, the amounts of intracellular NR1and NR2B in group R, I and R+I decreased when compared with group C (P<0.05). The ratio of sNRl/iNRl and sNR2B/iNR2B markedly increased in group R, I and R+I when compared with group C (P<0.05). The amount of surface NR1and NR2B protein increased, the amounts of intracellular NR1and NR2B decreased, the ratio of sNRl/iNRl and sNR2B/iNR2B markedly increased in group R+I when compared with group R and group I, respectively (P<0.05). NR2A showed no significant changes in either surface or intracellular pool (P>0.05).As a result, the ratio of sNR2A/iNR2A remained unchanged (P>0.05).
Conclusion These data indicate that the increased trafficking of NMDA receptors NR1and NR2B subunits from intracellular pool to surface pool in rats spinal cord neurons is involved in remifentanil-induced hyperalgesia.
Part3Effect of TDZD-8on NMDA receptor subunits (NRl and NR2B) trafficking in spinal cord in IP-remifentanil-induced hyperalgesia
Objective To investigate the regulation of Glycogen synthase kinase-3β on N-methyl-d-aspartate receptor NR1and NR2B subunits trafficking in spinal cord in a rat model of IP-remifentanil-induced hyperalgesia.
Methods Twenty-four male SD rats(240-260g,2-3months old) in which caudal vein catheter was successfully placed were randomly divided into3groups (n=8each):group C:DMSO+the same volume of saline; group R+I:DMSO+remifentanil+IP; group TDZD-8:TDZD-8+remifentanil+IP. TDZD-8(1mg/kg)/DMSO (2ml/kg) was infused intravenously just before remifentanil(1.2μg·kg-1·min-160min) infusion, IP was established as Brennan's description. Paw withdrawal threshold (PWT) and paw withdrawal latency (PWL) were measured24h before and2,6,24,48h after the infusion of intravenous remifentanil. The rats were sacrificed after the last threshold measurement. The surface and intracellular NMDAR NR1and NR2B subunits expressions in rats'spinal cord were determined by western blot. The ratio of sNR1/iNR1and sNR2B/iNR2B were calculated.
Results Compared with group C, PWT and PWL decreased, the amounts of surface NR1and NR2B proteins increased, the amounts of intracellular NR1and NR2B proteins decreased, the ratio of sNR1/iNR1and sNR2B/iNR2B increased in group R+I and group TDZD-8(P<0.05). Compared with groupR+I, PWT and PWL increased, the amounts of surface NR1and NR2B proteins decreased, the amounts of intracellular NR1and NR2B proteins increased, the ratio of sNR1/iNR1and sNR2B/iNR2B decreased in group TDZD-8(P<0.05)
Conclusion Glycogen synthase kinase-3β was involved in the regulation of N-methyl-d-aspartate receptor NR1and NR2B subunits trafficking in spinal cord in a rat model of IP-remifentanil-induced hyperalgesia.
Part4Effects of naltrindole on the changed expression of GSK-3β mRNA in spinal cord in IP-remifentanil-induced hyperalgesia
Objective To investigate the regulation of delta-opioid receptor (DOR) on the changed expression of GSK-3β mRNA in spinal cord in IP-remifentanil-induced hyperalgesia.
Methods Twenty-four male SD rats(240-260g,2-3months old) in which caudal vein catheter was successfully placed were randomly divided into3groups (n=8each):group C:saline+the same volume of saline; group R+I:saline+remifentanil+IP; group naltrindole:naltrindole+remifentanil+IP. Naltrindole (0.1mg/kg)/saline was administered intraperitoneally just before remifentanil(1.2μg·kg-1·min-160min) infusion, IP was established as Brennan's description. Paw withdrawal threshold (PWT) and paw withdrawal latency (PWL) were measured24h before and2,6,24,48h after the infusion of intravenous remifentanil. The rats were sacrificed after the last threshold measurement. The expressions of GSK-3β mRNA in rats' spinal cord neurons were determined by real-time PCR.
Results Compared with group C, PWT and PWL decreased, the expressions of GSK-3β mRNA increased in group R+I and group naltrindole (P<0.05). Compared with groupR+I, PWT and PWL increased, the expressions of GSK-3β mRNA decreased in group naltridole (P<0.05)
Conclusion Delta-opioid receptor was involved in the regulation of the expression of GSK-3β mRNA in spinal cord in a rat model of IP-remifentanil-induced hyperalgesia.
引文
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