GDNF在糖尿病神经病理性疼痛大鼠模型中的作用研究
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摘要
背景：糖尿病的全球发病率高达6-7％，且发病率逐年升高。糖尿病神经病变是糖尿病最常见的长期并发症之一，50％的患者可出现神经病变，其中以感觉神经病变即疼痛性糖尿病神经病变(PDN)最为常见，占16％-26％。PDN患者可因为慢性疼痛而活动减少，出现睡眠障碍和抑郁症状，降低正常工作和其他社会活动的能力，削弱心理和社会功能以及生活质量。而且PDN常难以治疗，目前的治疗策略首先是控制血糖，其次是对症治疗疼痛症状：常用的镇痛药物包括非甾体类抗炎药(NSAIDs)，三环类抗抑郁药，选择性5-羟色胺重摄取抑制剂，阿片类药物，抗惊厥药等，一般都有疗效但效果和耐受性较差。
胶质细胞源性神经生长因子(GDNF)对初级传入神经元具有营养和促进再生作用，而且可能与脊髓背角的伤害性感觉形成有关，一些实验动物模型也证实了GDNF可防止和逆转神经病理性疼痛的某些症状，其作用机制是使TTX敏感性钠离子通道的Ⅲα亚型的表达正常，抑制初级传入神经纤维的异常放电以及对细小伤害性感觉神经元的神经保护作用等，因此在各种疼痛状态中调节GDNF的合成和释放可能是缓解疼痛的有效工具。
本研究拟观察糖尿病神经病理性疼痛大鼠模型及应用有效镇痛治疗后大鼠DRG中GDNF的表达变化，从而探讨GDNF在糖尿病神经病理性疼痛中的作用，为临床应用神经营养因子制剂治疗PDN提供依据。
第一部分糖尿病大鼠模型的建立和GDNF的表达变化
目的：应用链脲霉素(STZ)诱导的糖尿病神经病理性疼痛大鼠模型，观察其背根神经节(DRG)中GDNF的表达变化，从而探讨GDNF在糖尿病神经病理性疼痛中的作用。
方法：雄性SD大鼠48只，随机分为正常对照组(n=12)和糖尿病组(36只)。糖尿病组大鼠左下腹腔一次性注射STZ 60mg／kg，一周后查血糖16.7mmol以上者列为DM大鼠，同时定期测定并记录大鼠的体重、血糖和机械痛阈；大鼠分别在模型制备后2周、4周处死，取双侧背根神经节进行Western Blot分析。
结果：79％的DM组大鼠的血糖高于16.7mmol／L，其体重均显著低于对照组大鼠。注射STZ后5天，大鼠即可出现疼痛行为的显著变化，对机械刺激的缩足反射阈值与对照组和基础值均具有显著的统计学差异，直至注射后28天。与同龄大鼠相比，注射STZ2周和4周后DRG中GDNF均发生下调，四周后GDNF的表达略低于两周时，但未见统计学差异。
结论：糖尿病神经病理性疼痛大鼠模型中，DRG中GDNF的表达出现下调，提示GDNF的改变与神经病理性疼痛形成或维持有关。
第二部分应用加巴喷丁治疗糖尿病神经病理性疼痛后GDNF的表达变化
目的：应用治疗疼痛的有效药物，如加巴喷丁，逆转糖尿病神经病理性疼痛大鼠的疼痛行为后观察GDNF的变化，从而推断GDNF在糖尿病神经病理性疼痛中发挥的作用。
方法：注射STZ的糖尿病大鼠模型，测定痛阈，出现疼痛行为的纳入实验，随机分为四组，每日两次分别腹腔内注射0.9％生理盐水0.6ml，加巴喷丁30mg／kg；加巴喷丁60mg／kg(约0.6ml)；或者加巴喷丁120mg／kg(约0.6ml)。每组大鼠在第一次注射药物后，每隔半小时测定其机械痛阈，持续4h。然后所有大鼠每周定时测痛阈、血糖和体重，注药三周后处死，取双侧背根神经节进行Western Blot分析。
结果：单次给药时，加巴喷丁呈剂量依赖性改善大鼠的疼痛症状。腹腔内注射加巴喷丁60mg／kg或120mg／kg后，60min达作用峰值，持续240min，与生理盐水组存在统计学差异。连续应用加巴喷丁60mg／kg，120mg／kg治疗14天后，大鼠机械痛阈较治疗前有显著改善，这种差异持续至治疗21天。DM大鼠应用加巴喷丁60mg／kg和120mg／kg治疗后，其DRG中GDNF表达显著高于与注射生理盐水组大鼠。
结论：加巴喷丁60mg／kg和120mg／kg可有效逆转糖尿病大鼠模型的疼痛行为，而疼痛行为改善后，大鼠DRG中的GDNF表达回升，提示GDNF在神经病理性疼痛发生过程中可能具有与加巴喷丁相关的保护性作用。
Background.
Diabetes mellitus(DM) is a common disorder and has a worldwide prevalence of6-7%. The neuropathies are among the most common of the long-time complications,affecting up to 50% patients with DM. Between 16% and 26% of diabetic patientsexperience chronic pain. This may be referred to as diabetic neuropathic pain (DNP)or painful diabetic neuropathy (PDN). Given that depression and other co-morbiditiesare commonly associated with pain, a broad approach to management is essential. Themechanisms of neuropathic pain are complex and the management is still quitedifficult. Optimisation of glycaemic control is recommended as initial step inmanagement. Tricyclic antidepressant, anticonvulsants, selective serotoninnoradrenaline re-uptake inhibitor are thought to be effective, together with opioidagonist. Irrespective of which treatment is offered, only about one third of patients arelikely to achieve more than 50% pain and many patients only achieve partial relieffrom therapy relief. Further research is needed to improve the diagnosis andmanagement of DPN.
Neurotrophic factors may play key roles in pathophysiological mechanisms ofhuman neuropathies. GDNF, Glial cell line-derived neurotrophic factor, was found to have potent survival-promoting effects on various types of neurons including primarysensory neurons. Immunohistochemical studies have revealed the existence of GDNFin the superficial layers of spinal cord, an area closely related to pain transmission.GDNF also reversed sensory abnormalities that developed in neuropathic pain models,without affecting pain-related behavior in normal animals, possibly through theregulation of sodium-channel subunits expression in DRG (dorsal root ganglion),reducing ectopic discharge of unmyelinated primary afferents, and preventing DRGneuron daeth. GDNF has been proved to play an important role in the modulation ofnociceptive signals. However, it is not clear whether and how endogenous GDNFcould be involved in the diabetic neuropathic pain model.
PartⅠ. Expression changes of glial cell line-derivedneurotrophie factor in DRG of streptozotocin-induced diabeticrats
Objective: To observe changes in the expressions of GDNF (glial cellline-derived neurotrophic factor) in STZ (streptozotocin) induced diabetic rat modelsof neuropathic pain.
Methods: Forty-eight male Sprague-Dawley rats were randomly divided into
2 groups: diabetes was induced in 36 rats with a single intraperitoneal injection ofstreptozotocin (60 mg/kg), another 12 rats were selected as controls. Diabetes wasconfirmed 5 days after injection by measurement of blood glucose levels. Tactileallodynia was determined by measuring paw withdrawal in response to probing with aseries of von Frey filaments. The expression of GDNF was examined by Western blotanalysis. The time points of analysis were selected as 2, and 4 weeks after STZinjection. At each time point, six animals of each group were used for every analysis.
Results: Five days after administration of STZ, glucose level of 79%animals increased up to 16.7mmol/L and remained high after 4 weeks. The weight of DM rats became significantly lower than that of controls by day 5 and did not changesignificantly up to week 4. The thresholds of paw withdrawal in response to themechanical stimulus began to decrease at day 5 and further decreased for more than 4weeks. Two weeks following STZ injection, the GDNF contents in DRG weremarkedly decreased and stayed at lower levels in the following two weeks.
Conclusions: The present results suggested that the changes of GDNF inthe nociceptive afferent system might contribute to the development and/ormaintenance of painful diabetic neuropathy.
PartⅡ. Changes of expression of GDNF in DRG ofpainful diabetic rats treated with gabapentin
Objective: To investigate changes of expression of GDNF in DRG aftergabapentin was administered in STZ-induced diabetic neuropathic pain rats.
Methods: Painful diabetic neuropathic rats were randomly divided into fourgroups and treated intraperitoneally with gabapentin (30, 60 and 120 mg/kg) or salinerespectively. The withdrawal threshold was measured for the next 4 hours. Then therats were treated twice with gabapentin (30, 60 and 120 mg/kg) or saline respectivelyevery day. And tactile sensitivity was measured every week using von Freymonofilaments following treatment with gabapentin (30, 60 and 120 mg/kg) or saline.Three weeks after gabapentin administration, Rats were sacrificed and Western Blot(n=6 in each group) analyses were used to observe the changes of GDNF expression.
Results: Gabapentin (60 and 120 mg/kg) produced significant dose-dependentanti-hyperalgesia or anti-allodynia in painful diabetic rats. After treated withGabapentin (60 and 120 mg/kg), the withdrawal threshold of rats was significantlyincreased an hour after injection, and lasted for about 4 hours. Saline and Gabapentin (30 mg/kg) injection had no significant effect on the withdrawal threshold. Comparedto salines controls, rats treated twice daily with gabapentin (60 and 120 mg/kg) hadsignificantly higher von Frey thresholds on day 14 and stayed at higher level until day21. The expressions of GDNF in DRG of rats with gabapentin (60 and 120mg/kg)were markedly higher than that of rats treated with gabapentin30mg/kg orsaline.
Conclusions: While the hyperalgeia and allodynia of diabetic rats werecompletely reversed by treatment with gabapentin, expression of GDNF in DRGincreased markedly, which indicated the correlation between GDNF and gabapentinein their anti-nociceptive effect.
胶质细胞源性神经生长因子(GDNF)对初级传入神经元具有营养和促进再生作用，而且可能与脊髓背角的伤害性感觉形成有关，一些实验动物模型也证实了GDNF可防止和逆转神经病理性疼痛的某些症状，其作用机制是使TTX敏感性钠离子通道的Ⅲα亚型的表达正常，抑制初级传入神经纤维的异常放电以及对细小伤害性感觉神经元的神经保护作用等，因此在各种疼痛状态中调节GDNF的合成和释放可能是缓解疼痛的有效工具。
本研究拟观察糖尿病神经病理性疼痛大鼠模型及应用有效镇痛治疗后大鼠DRG中GDNF的表达变化，从而探讨GDNF在糖尿病神经病理性疼痛中的作用，为临床应用神经营养因子制剂治疗PDN提供依据。
第一部分糖尿病大鼠模型的建立和GDNF的表达变化
目的：应用链脲霉素(STZ)诱导的糖尿病神经病理性疼痛大鼠模型，观察其背根神经节(DRG)中GDNF的表达变化，从而探讨GDNF在糖尿病神经病理性疼痛中的作用。
方法：雄性SD大鼠48只，随机分为正常对照组(n=12)和糖尿病组(36只)。糖尿病组大鼠左下腹腔一次性注射STZ 60mg／kg，一周后查血糖16.7mmol以上者列为DM大鼠，同时定期测定并记录大鼠的体重、血糖和机械痛阈；大鼠分别在模型制备后2周、4周处死，取双侧背根神经节进行Western Blot分析。
结果：79％的DM组大鼠的血糖高于16.7mmol／L，其体重均显著低于对照组大鼠。注射STZ后5天，大鼠即可出现疼痛行为的显著变化，对机械刺激的缩足反射阈值与对照组和基础值均具有显著的统计学差异，直至注射后28天。与同龄大鼠相比，注射STZ2周和4周后DRG中GDNF均发生下调，四周后GDNF的表达略低于两周时，但未见统计学差异。
结论：糖尿病神经病理性疼痛大鼠模型中，DRG中GDNF的表达出现下调，提示GDNF的改变与神经病理性疼痛形成或维持有关。
第二部分应用加巴喷丁治疗糖尿病神经病理性疼痛后GDNF的表达变化
目的：应用治疗疼痛的有效药物，如加巴喷丁，逆转糖尿病神经病理性疼痛大鼠的疼痛行为后观察GDNF的变化，从而推断GDNF在糖尿病神经病理性疼痛中发挥的作用。
方法：注射STZ的糖尿病大鼠模型，测定痛阈，出现疼痛行为的纳入实验，随机分为四组，每日两次分别腹腔内注射0.9％生理盐水0.6ml，加巴喷丁30mg／kg；加巴喷丁60mg／kg(约0.6ml)；或者加巴喷丁120mg／kg(约0.6ml)。每组大鼠在第一次注射药物后，每隔半小时测定其机械痛阈，持续4h。然后所有大鼠每周定时测痛阈、血糖和体重，注药三周后处死，取双侧背根神经节进行Western Blot分析。
结果：单次给药时，加巴喷丁呈剂量依赖性改善大鼠的疼痛症状。腹腔内注射加巴喷丁60mg／kg或120mg／kg后，60min达作用峰值，持续240min，与生理盐水组存在统计学差异。连续应用加巴喷丁60mg／kg，120mg／kg治疗14天后，大鼠机械痛阈较治疗前有显著改善，这种差异持续至治疗21天。DM大鼠应用加巴喷丁60mg／kg和120mg／kg治疗后，其DRG中GDNF表达显著高于与注射生理盐水组大鼠。
结论：加巴喷丁60mg／kg和120mg／kg可有效逆转糖尿病大鼠模型的疼痛行为，而疼痛行为改善后，大鼠DRG中的GDNF表达回升，提示GDNF在神经病理性疼痛发生过程中可能具有与加巴喷丁相关的保护性作用。
Background.
Diabetes mellitus(DM) is a common disorder and has a worldwide prevalence of6-7%. The neuropathies are among the most common of the long-time complications,affecting up to 50% patients with DM. Between 16% and 26% of diabetic patientsexperience chronic pain. This may be referred to as diabetic neuropathic pain (DNP)or painful diabetic neuropathy (PDN). Given that depression and other co-morbiditiesare commonly associated with pain, a broad approach to management is essential. Themechanisms of neuropathic pain are complex and the management is still quitedifficult. Optimisation of glycaemic control is recommended as initial step inmanagement. Tricyclic antidepressant, anticonvulsants, selective serotoninnoradrenaline re-uptake inhibitor are thought to be effective, together with opioidagonist. Irrespective of which treatment is offered, only about one third of patients arelikely to achieve more than 50% pain and many patients only achieve partial relieffrom therapy relief. Further research is needed to improve the diagnosis andmanagement of DPN.
Neurotrophic factors may play key roles in pathophysiological mechanisms ofhuman neuropathies. GDNF, Glial cell line-derived neurotrophic factor, was found to have potent survival-promoting effects on various types of neurons including primarysensory neurons. Immunohistochemical studies have revealed the existence of GDNFin the superficial layers of spinal cord, an area closely related to pain transmission.GDNF also reversed sensory abnormalities that developed in neuropathic pain models,without affecting pain-related behavior in normal animals, possibly through theregulation of sodium-channel subunits expression in DRG (dorsal root ganglion),reducing ectopic discharge of unmyelinated primary afferents, and preventing DRGneuron daeth. GDNF has been proved to play an important role in the modulation ofnociceptive signals. However, it is not clear whether and how endogenous GDNFcould be involved in the diabetic neuropathic pain model.
PartⅠ. Expression changes of glial cell line-derivedneurotrophie factor in DRG of streptozotocin-induced diabeticrats
Objective: To observe changes in the expressions of GDNF (glial cellline-derived neurotrophic factor) in STZ (streptozotocin) induced diabetic rat modelsof neuropathic pain.
Methods: Forty-eight male Sprague-Dawley rats were randomly divided into
2 groups: diabetes was induced in 36 rats with a single intraperitoneal injection ofstreptozotocin (60 mg/kg), another 12 rats were selected as controls. Diabetes wasconfirmed 5 days after injection by measurement of blood glucose levels. Tactileallodynia was determined by measuring paw withdrawal in response to probing with aseries of von Frey filaments. The expression of GDNF was examined by Western blotanalysis. The time points of analysis were selected as 2, and 4 weeks after STZinjection. At each time point, six animals of each group were used for every analysis.
Results: Five days after administration of STZ, glucose level of 79%animals increased up to 16.7mmol/L and remained high after 4 weeks. The weight of DM rats became significantly lower than that of controls by day 5 and did not changesignificantly up to week 4. The thresholds of paw withdrawal in response to themechanical stimulus began to decrease at day 5 and further decreased for more than 4weeks. Two weeks following STZ injection, the GDNF contents in DRG weremarkedly decreased and stayed at lower levels in the following two weeks.
Conclusions: The present results suggested that the changes of GDNF inthe nociceptive afferent system might contribute to the development and/ormaintenance of painful diabetic neuropathy.
PartⅡ. Changes of expression of GDNF in DRG ofpainful diabetic rats treated with gabapentin
Objective: To investigate changes of expression of GDNF in DRG aftergabapentin was administered in STZ-induced diabetic neuropathic pain rats.
Methods: Painful diabetic neuropathic rats were randomly divided into fourgroups and treated intraperitoneally with gabapentin (30, 60 and 120 mg/kg) or salinerespectively. The withdrawal threshold was measured for the next 4 hours. Then therats were treated twice with gabapentin (30, 60 and 120 mg/kg) or saline respectivelyevery day. And tactile sensitivity was measured every week using von Freymonofilaments following treatment with gabapentin (30, 60 and 120 mg/kg) or saline.Three weeks after gabapentin administration, Rats were sacrificed and Western Blot(n=6 in each group) analyses were used to observe the changes of GDNF expression.
Results: Gabapentin (60 and 120 mg/kg) produced significant dose-dependentanti-hyperalgesia or anti-allodynia in painful diabetic rats. After treated withGabapentin (60 and 120 mg/kg), the withdrawal threshold of rats was significantlyincreased an hour after injection, and lasted for about 4 hours. Saline and Gabapentin (30 mg/kg) injection had no significant effect on the withdrawal threshold. Comparedto salines controls, rats treated twice daily with gabapentin (60 and 120 mg/kg) hadsignificantly higher von Frey thresholds on day 14 and stayed at higher level until day21. The expressions of GDNF in DRG of rats with gabapentin (60 and 120mg/kg)were markedly higher than that of rats treated with gabapentin30mg/kg orsaline.
Conclusions: While the hyperalgeia and allodynia of diabetic rats werecompletely reversed by treatment with gabapentin, expression of GDNF in DRGincreased markedly, which indicated the correlation between GDNF and gabapentinein their anti-nociceptive effect.
引文
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