关节炎慢性吗啡耐受大鼠脊髓谷氨酸及其转运体的改变
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摘要
阿片类药物是用于治疗急慢性疼痛的重要药物，但长期应用可发生耐受现象，从而限制了阿片类药物的临床应用。关于阿片耐受机制的研究很多，各种阿片耐受模型的建立为阿片耐受机制的研究提供了基础。近年的研究证实，谷氨酸能系统参与阿片耐受的形成，并在其神经可塑性变化中发挥重要作用。该系统包括以谷氨酸为代表的兴奋性氨基酸、以NMDA受体为代表的各种兴奋性氨基酸受体和谷氨酸转运体等。脊髓是哺乳动物躯体和内脏感觉和运动的低级中枢。脊髓背角是机体接受伤害性信息传入，并对伤害性信息进行加工、整合处理的重要部位。研究发现脊髓的阿片敏感性传入神经元含有可释放的谷氨酸池，脊髓背角含有丰富的谷氨酸受体。本研究以新建立的关节炎吗啡耐受大鼠模型为基础，着重探讨谷氨酸及其转运体在吗啡耐受大鼠脊髓神经可塑性改变中的作用。期望这些研究结果能提供日后相关吗啡耐受治疗及研究的重要信息。
第一部分：关节炎大鼠慢性吗啡耐受模型的建立及谷氨酸在大鼠脊髓神经可塑性改变中的作用
目的：建立关节炎大鼠慢性吗啡耐受模型，探讨谷氨酸在关节炎慢性吗啡耐受大鼠脊髓神经可塑性改变中的作用。方法：雄性SD大鼠，300+20g，行鞘内置管，随机分为6组(n=5)，其中4组制成佐剂性关节炎模型，分别经鞘内给予生理盐水、吗啡10μg、吗啡20μg、吗啡10μg+纳洛酮10μg，另外两组非致炎大鼠分别经鞘内给予生理盐水、吗啡20μg。各组给药均为1日2次，连续7天。动态检测大鼠机械缩爪阈值及热板缩爪潜伏期，以痛觉过敏作为形成吗啡耐受的标志。测定各组大鼠脊髓谷氨酸的含量。在鞘内给予吗啡同时给予MK-801及外源性谷氨酸，测定大鼠机械缩爪阈值及热板缩爪潜伏期的改变。结果：机械痛敏和热痛敏检测证实经鞘内连续7天给予吗啡诱导出了吗啡耐受。在炎性痛导致大鼠脊髓谷氨酸含量增加的基础上，关节炎慢性吗啡耐受大鼠脊髓谷氨酸含量进一步增高，并且谷氨酸含量的增加随给药时间的进展呈现时间依赖性。MK-801及外源性谷氨酸分别阻断和增强了慢性吗啡诱导的痛觉过敏。结论：通过给关节炎大鼠鞘内反复注射吗啡，在以吗啡治疗炎性痛的背景下形成了吗啡耐受，标志炎性痛慢性吗啡耐受模型建立成功。慢性吗啡耐受产生的痛觉过敏与脊髓谷氨酸含量的增高、谷氨酸受体的过度激活及神经系统的兴奋性增强有关。
第二部分：脊髓谷氨酸转运体在慢性吗啡耐受中的作用
目的：观察谷氨酸转运体在关节炎慢性吗啡耐受大鼠脊髓背角的表达变化及谷氨酸转运体活性改变对大鼠行为学及痛觉调制物质的影响，探讨谷氨酸转运体在慢性吗啡耐受机制中的作用。方法：采用免疫组化、western blot及RT-PCR等方法检测上述分组的各组大鼠脊髓谷氨酸转运体的表达；动态检测鞘内给予谷氨酸转运体激动剂Riluzole和抑制剂PDC后大鼠机械缩爪阈值及热板缩爪潜伏期；采用RT-PCR法检测关节炎慢性吗啡耐受大鼠脊髓OFQ和BDNF mRNA的表达。结果：关节炎慢性吗啡耐受大鼠脊髓背角谷氨酸转运体GLAST和EAAC1蛋白及mRNA表达均下调；谷氨酸转运体激动剂和抑制剂在关节炎基础上对吗啡耐受所致的痛觉过敏具有减弱和增强作用，并且对吗啡耐受中参与痛觉调制相关物质BDNF及OFQ mRNA的表达具有调节作用。结论：谷氨酸转运体下调使细胞外谷氨酸含量增加，在吗啡耐受的痛觉过敏机制中发挥作用。调节谷氨酸转运体活性及表达有望成为治疗吗啡耐受引起的痛觉过敏的新方法。
第三部分：谷氨酸及其转运体在吗啡耐受诱导脊髓背角神经细胞凋亡中的作用
目的：探讨谷氨酸诱导脊髓神经细胞凋亡在慢性阿片耐受形成机制中的意义。方法：采用TUNEL染色方法观察关节炎慢性吗啡耐受大鼠脊髓背角凋亡细胞的分布，以western blot方法检测脊髓Bax、caspase-3及Bcl-2的表达。结果：慢性吗啡耐受可诱导脊髓背角神经细胞凋亡，使促凋亡因子Bax和caspase-3表达上调，抗凋亡因子Bcl-2表达下调，Riluzole和MK-801可减弱吗啡诱导的神经细胞凋亡，而PDC和外源性谷氨酸则加重了吗啡诱导的神经细胞凋亡。结论：脊髓神经细胞凋亡可能是慢性阿片耐受的神经基础，谷氨酸的神经毒性在吗啡耐受的神经细胞凋亡中发挥作用，Riluzole和PDC分别通过抑制和加重阿片诱导的脊髓背角神经凋亡而减弱和加重阿片诱导的痛觉过敏。
综上所述，关节炎慢性吗啡耐受大鼠是在以吗啡治疗炎性痛的背景下，形成的不同以往的吗啡耐受模型。本研究即在此模型基础上，发现谷氨酸及其转运体在慢性吗啡耐受的形成机制中发挥重要作用，提示我们可通过调节谷氨酸转运体的表达及活性来治疗吗啡耐受诱发的痛觉过敏，为日后相关吗啡耐受的治疗及研究提供了新的思路。
Opioids have been regarded as the most effective analgesics for management ofacute and chronic pain,however,opioid tolerance occurs following chronic drugexposure which limits their usefulness.Studies on mechanism of opioid tolerancehave been developing generally and various models of opioid tolerance areconstructed to provide the basis for such studies.Recent reports indicate thatglutamatergic system is involved in the development of opioid tolerance and plays animportant role in neural plasticity of opioid tolerance.The glutamatergic systemconsists of excitatory amino acids,excitatory amino acid receptors and glutamatetransporters.For mammalians,spinal cord is the lower centre of somatic and visceralsensation and motion,and spinal dorsal horn is an important location where afferentinformation of nociception is introduced,processed and integrated.It is reported thatreleasable pools of EAA are found in opioid-sensitive primary afferent neurons inspinal cord,and generous glutamate receptors in spinal dorsal horn.In the dissertation,a novel model of arthritis-chronic morphine tolerant rats is constructed.Based on thismodel,the effect of glutamate and transporters leading to neural plastic change in thespinal cord of morphine tolerant rats is explored.The results of this study areexpected to provide important information for future treatment and studies associatedwith morphine tolerance.
Part one:Construction of arthritis-chronic morphine tolerant rat model andimplication of glutamate in spinal nerve plasticity change of rats
Objective:To construct the rat model of arthritis-chronic morphine tolerance,discussthe implication of glutamate in spinal nerve plasticity change of rats witharthritis-chronic morphine tolerance.Methods:Healthy male SD rats,300±20g,wereimplanted intrathecal catheters and randomized into 6 groups.Amongst,the rats infour groups were made into model of adjuvant-induced arthritis and wereadministered intrathecally saline,morphine 10μg,morphine 20μg,morphine 10μg+naloxone 10μg,respectively.The rats in the other two groups without arthritis wereadministered intrathecally saline and morphine 20μg,respectively.The drugs wereadministered twice daily for 7 days.Mechanical withdrawal threshold (MWT) and thermal paw withdrawal latency (PWL) of rats was examined to evaluate theirbehavior.Hyperalgesia was concerned as the sign of genesis of morphine tolerance.The glutamate concentration in spinal cord tissue of rats was measured.MK-801 andexogenous glutamate was administered intrathecally concomitant with morphinerespectively,MWT and PWL was examined.Results:Mechanical and thermalhyperalgesia examination evinced that repeated intrathecal infusion of morphine forconsecutive 7 days induced tolerance.The spinal glutamate concentration furtherelevated in arthritis-chronic morphine tolerant rats on top of increasing in arthritis rats.The increasing of glutamate concentration was time-dependent as administration ofdrug.MK-801 and exogenous glutamate blokcked or enhanced hyperalgesia inducedby chronic morphine respectively.Conclusion:The rat model of arthritis-chronicmorphine tolerance is constructed successfully by repeatedly administering morphineintrathecally in the presence of painful arthritis,which develops morphine tolerancein the background of treating inflammatory pain.There is association between thehyperalgesia induced by chronic morphine tolerance and elevated spinal glutamateconcentration,excessive stimulation of glutamate receptor as well as the excitabilityof nervous system.
Part two:The effect of spinal glutamate transporters on chronic morphinetolerance
Objective:To observe the change of expression of glutamate transporters in spinaldorsal horn of arthritis-chronic morphine tolerant rats and effect of glutamatetransporter inhibitor and promoter on behavior and pain modulators,explore theeffect of glutamate transporters on morphine tolerance mechanism.Methods:Immunohistochemical stain,western blot and RT-PCR were used to measure theexpression of glutamate transporters in spinal cord of each group of rats divided asmentioned in Part one.MWT and PWL was examined for rats which wereintrathecally infused Riluzole and PDC.The expression of OFQ and BDNF mRNA ofspinal cord was measured by RT-PCR.Results:The expression of protein and mRNAof GLAST and EAAC1 in spinal dorsal horn of arthritis-chronic morphine tolerantrats was downregulated.Riluzole and PDC attenuated or enhanced hyperalgesia inopioid tolerance respectively,and regulated the expression of pain modulators such as BDNF and OFQ.Conclusion:The downregulation of glutamate transporters resultsin elevation of extracellular glutamate concentration,which plays an important role inmechanism of hyperalgesia induced by morphine tolerance.Regulation of activity orexpression of glutamate transporters promises to become a new strategy for treatingmorphine tolerance induced hyperalgesia.
Part three:The effect of glutamate and transporters on nerve cellular apoptosisof spinal dorsal horn induced by chronic morphine tolerance
Objective:To elucidate the implication of glutamate introducing nerve cellularapoptosis of spinal dorsal horn in chronic morphine tolerance.Methods:TUNELstaining was used to observe the distribution of apoptotic cells in spinal dorsal hom ofarthritis-chronic morphine tolerant rats.The expression of Bax、caspase-3 and Bcl-2in spinal cord were determined by western blot.Results:Chronic administration ofmorphine induced nerve cellular apoptosis of spinal dorsal horn.The expression ofBax and caspase-3 in spinal cord was upregulated,and that of Bcl-2 wasdownregulated.Riluzole and MK-801 attenuated apoptosis in spinal dorsal horninduced by chronic opioids while PDC and exogenous glutamate enhanced apoptosis.
Conclusion:Spinal neural apoptosis may be the basis of chronic opioid tolerancedeveloping.The neurotoxicity of glutamate contributes to nerve cellular apoptosis ofmorphine tolerance.Riluzole and PDC relieves or enhances hyperalgesia in opioidtolerance by inhibiting or enhancing neural apoptosis in spinal dorsal horn induced bychronic opioid.
In conclusion,arthritis rat with chronic morphine tolerance is a novel chronicmorphine tolerant model which is formed in the backdrop of treatment ofinflammatory pain with morphine.The present study was on the basis of this modeland detected the important effect of glutamate and its transporters on mechanism ofchronic morphine tolerance.The results enlighten us to treat the hyperalgesia inducedby morphine tolerance through regulating the expression and activity of glutamatetransporters.Moreover,it promises to provide a new strategy for treatment andresearch associated with morphine tolerance.
第一部分：关节炎大鼠慢性吗啡耐受模型的建立及谷氨酸在大鼠脊髓神经可塑性改变中的作用
目的：建立关节炎大鼠慢性吗啡耐受模型，探讨谷氨酸在关节炎慢性吗啡耐受大鼠脊髓神经可塑性改变中的作用。方法：雄性SD大鼠，300+20g，行鞘内置管，随机分为6组(n=5)，其中4组制成佐剂性关节炎模型，分别经鞘内给予生理盐水、吗啡10μg、吗啡20μg、吗啡10μg+纳洛酮10μg，另外两组非致炎大鼠分别经鞘内给予生理盐水、吗啡20μg。各组给药均为1日2次，连续7天。动态检测大鼠机械缩爪阈值及热板缩爪潜伏期，以痛觉过敏作为形成吗啡耐受的标志。测定各组大鼠脊髓谷氨酸的含量。在鞘内给予吗啡同时给予MK-801及外源性谷氨酸，测定大鼠机械缩爪阈值及热板缩爪潜伏期的改变。结果：机械痛敏和热痛敏检测证实经鞘内连续7天给予吗啡诱导出了吗啡耐受。在炎性痛导致大鼠脊髓谷氨酸含量增加的基础上，关节炎慢性吗啡耐受大鼠脊髓谷氨酸含量进一步增高，并且谷氨酸含量的增加随给药时间的进展呈现时间依赖性。MK-801及外源性谷氨酸分别阻断和增强了慢性吗啡诱导的痛觉过敏。结论：通过给关节炎大鼠鞘内反复注射吗啡，在以吗啡治疗炎性痛的背景下形成了吗啡耐受，标志炎性痛慢性吗啡耐受模型建立成功。慢性吗啡耐受产生的痛觉过敏与脊髓谷氨酸含量的增高、谷氨酸受体的过度激活及神经系统的兴奋性增强有关。
第二部分：脊髓谷氨酸转运体在慢性吗啡耐受中的作用
目的：观察谷氨酸转运体在关节炎慢性吗啡耐受大鼠脊髓背角的表达变化及谷氨酸转运体活性改变对大鼠行为学及痛觉调制物质的影响，探讨谷氨酸转运体在慢性吗啡耐受机制中的作用。方法：采用免疫组化、western blot及RT-PCR等方法检测上述分组的各组大鼠脊髓谷氨酸转运体的表达；动态检测鞘内给予谷氨酸转运体激动剂Riluzole和抑制剂PDC后大鼠机械缩爪阈值及热板缩爪潜伏期；采用RT-PCR法检测关节炎慢性吗啡耐受大鼠脊髓OFQ和BDNF mRNA的表达。结果：关节炎慢性吗啡耐受大鼠脊髓背角谷氨酸转运体GLAST和EAAC1蛋白及mRNA表达均下调；谷氨酸转运体激动剂和抑制剂在关节炎基础上对吗啡耐受所致的痛觉过敏具有减弱和增强作用，并且对吗啡耐受中参与痛觉调制相关物质BDNF及OFQ mRNA的表达具有调节作用。结论：谷氨酸转运体下调使细胞外谷氨酸含量增加，在吗啡耐受的痛觉过敏机制中发挥作用。调节谷氨酸转运体活性及表达有望成为治疗吗啡耐受引起的痛觉过敏的新方法。
第三部分：谷氨酸及其转运体在吗啡耐受诱导脊髓背角神经细胞凋亡中的作用
目的：探讨谷氨酸诱导脊髓神经细胞凋亡在慢性阿片耐受形成机制中的意义。方法：采用TUNEL染色方法观察关节炎慢性吗啡耐受大鼠脊髓背角凋亡细胞的分布，以western blot方法检测脊髓Bax、caspase-3及Bcl-2的表达。结果：慢性吗啡耐受可诱导脊髓背角神经细胞凋亡，使促凋亡因子Bax和caspase-3表达上调，抗凋亡因子Bcl-2表达下调，Riluzole和MK-801可减弱吗啡诱导的神经细胞凋亡，而PDC和外源性谷氨酸则加重了吗啡诱导的神经细胞凋亡。结论：脊髓神经细胞凋亡可能是慢性阿片耐受的神经基础，谷氨酸的神经毒性在吗啡耐受的神经细胞凋亡中发挥作用，Riluzole和PDC分别通过抑制和加重阿片诱导的脊髓背角神经凋亡而减弱和加重阿片诱导的痛觉过敏。
综上所述，关节炎慢性吗啡耐受大鼠是在以吗啡治疗炎性痛的背景下，形成的不同以往的吗啡耐受模型。本研究即在此模型基础上，发现谷氨酸及其转运体在慢性吗啡耐受的形成机制中发挥重要作用，提示我们可通过调节谷氨酸转运体的表达及活性来治疗吗啡耐受诱发的痛觉过敏，为日后相关吗啡耐受的治疗及研究提供了新的思路。
Opioids have been regarded as the most effective analgesics for management ofacute and chronic pain,however,opioid tolerance occurs following chronic drugexposure which limits their usefulness.Studies on mechanism of opioid tolerancehave been developing generally and various models of opioid tolerance areconstructed to provide the basis for such studies.Recent reports indicate thatglutamatergic system is involved in the development of opioid tolerance and plays animportant role in neural plasticity of opioid tolerance.The glutamatergic systemconsists of excitatory amino acids,excitatory amino acid receptors and glutamatetransporters.For mammalians,spinal cord is the lower centre of somatic and visceralsensation and motion,and spinal dorsal horn is an important location where afferentinformation of nociception is introduced,processed and integrated.It is reported thatreleasable pools of EAA are found in opioid-sensitive primary afferent neurons inspinal cord,and generous glutamate receptors in spinal dorsal horn.In the dissertation,a novel model of arthritis-chronic morphine tolerant rats is constructed.Based on thismodel,the effect of glutamate and transporters leading to neural plastic change in thespinal cord of morphine tolerant rats is explored.The results of this study areexpected to provide important information for future treatment and studies associatedwith morphine tolerance.
Part one:Construction of arthritis-chronic morphine tolerant rat model andimplication of glutamate in spinal nerve plasticity change of rats
Objective:To construct the rat model of arthritis-chronic morphine tolerance,discussthe implication of glutamate in spinal nerve plasticity change of rats witharthritis-chronic morphine tolerance.Methods:Healthy male SD rats,300±20g,wereimplanted intrathecal catheters and randomized into 6 groups.Amongst,the rats infour groups were made into model of adjuvant-induced arthritis and wereadministered intrathecally saline,morphine 10μg,morphine 20μg,morphine 10μg+naloxone 10μg,respectively.The rats in the other two groups without arthritis wereadministered intrathecally saline and morphine 20μg,respectively.The drugs wereadministered twice daily for 7 days.Mechanical withdrawal threshold (MWT) and thermal paw withdrawal latency (PWL) of rats was examined to evaluate theirbehavior.Hyperalgesia was concerned as the sign of genesis of morphine tolerance.The glutamate concentration in spinal cord tissue of rats was measured.MK-801 andexogenous glutamate was administered intrathecally concomitant with morphinerespectively,MWT and PWL was examined.Results:Mechanical and thermalhyperalgesia examination evinced that repeated intrathecal infusion of morphine forconsecutive 7 days induced tolerance.The spinal glutamate concentration furtherelevated in arthritis-chronic morphine tolerant rats on top of increasing in arthritis rats.The increasing of glutamate concentration was time-dependent as administration ofdrug.MK-801 and exogenous glutamate blokcked or enhanced hyperalgesia inducedby chronic morphine respectively.Conclusion:The rat model of arthritis-chronicmorphine tolerance is constructed successfully by repeatedly administering morphineintrathecally in the presence of painful arthritis,which develops morphine tolerancein the background of treating inflammatory pain.There is association between thehyperalgesia induced by chronic morphine tolerance and elevated spinal glutamateconcentration,excessive stimulation of glutamate receptor as well as the excitabilityof nervous system.
Part two:The effect of spinal glutamate transporters on chronic morphinetolerance
Objective:To observe the change of expression of glutamate transporters in spinaldorsal horn of arthritis-chronic morphine tolerant rats and effect of glutamatetransporter inhibitor and promoter on behavior and pain modulators,explore theeffect of glutamate transporters on morphine tolerance mechanism.Methods:Immunohistochemical stain,western blot and RT-PCR were used to measure theexpression of glutamate transporters in spinal cord of each group of rats divided asmentioned in Part one.MWT and PWL was examined for rats which wereintrathecally infused Riluzole and PDC.The expression of OFQ and BDNF mRNA ofspinal cord was measured by RT-PCR.Results:The expression of protein and mRNAof GLAST and EAAC1 in spinal dorsal horn of arthritis-chronic morphine tolerantrats was downregulated.Riluzole and PDC attenuated or enhanced hyperalgesia inopioid tolerance respectively,and regulated the expression of pain modulators such as BDNF and OFQ.Conclusion:The downregulation of glutamate transporters resultsin elevation of extracellular glutamate concentration,which plays an important role inmechanism of hyperalgesia induced by morphine tolerance.Regulation of activity orexpression of glutamate transporters promises to become a new strategy for treatingmorphine tolerance induced hyperalgesia.
Part three:The effect of glutamate and transporters on nerve cellular apoptosisof spinal dorsal horn induced by chronic morphine tolerance
Objective:To elucidate the implication of glutamate introducing nerve cellularapoptosis of spinal dorsal horn in chronic morphine tolerance.Methods:TUNELstaining was used to observe the distribution of apoptotic cells in spinal dorsal hom ofarthritis-chronic morphine tolerant rats.The expression of Bax、caspase-3 and Bcl-2in spinal cord were determined by western blot.Results:Chronic administration ofmorphine induced nerve cellular apoptosis of spinal dorsal horn.The expression ofBax and caspase-3 in spinal cord was upregulated,and that of Bcl-2 wasdownregulated.Riluzole and MK-801 attenuated apoptosis in spinal dorsal horninduced by chronic opioids while PDC and exogenous glutamate enhanced apoptosis.
Conclusion:Spinal neural apoptosis may be the basis of chronic opioid tolerancedeveloping.The neurotoxicity of glutamate contributes to nerve cellular apoptosis ofmorphine tolerance.Riluzole and PDC relieves or enhances hyperalgesia in opioidtolerance by inhibiting or enhancing neural apoptosis in spinal dorsal horn induced bychronic opioid.
In conclusion,arthritis rat with chronic morphine tolerance is a novel chronicmorphine tolerant model which is formed in the backdrop of treatment ofinflammatory pain with morphine.The present study was on the basis of this modeland detected the important effect of glutamate and its transporters on mechanism ofchronic morphine tolerance.The results enlighten us to treat the hyperalgesia inducedby morphine tolerance through regulating the expression and activity of glutamatetransporters.Moreover,it promises to provide a new strategy for treatment andresearch associated with morphine tolerance.
引文
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