P2X4受体在慢性吗啡耐受中的作用机制
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摘要
吗啡是一种阿片类受体激动剂,在临床实践过程中常用于急慢性疼痛的治疗,特别是对神经病理性疼痛和癌痛的治疗。然而,患者长期反复使用吗啡将会产生对吗啡镇痛作用的耐受和依赖,其具体表现为镇痛作用下降、作用持续时间缩短、疼痛过敏及停药后疼痛加剧等,需要增加吗啡剂量才能达到耐受前的镇痛效果。由于吗啡存在上述弊端,使其临床应用受到了一定的限制。
近些年来,学者们对吗啡耐受的机制从细胞和分子水平进行了大量研究,为临床上更加有效应用吗啡治疗疼痛提供了重要理论依据。然而,到目前为止吗啡的镇痛和耐受机制尚不完全清楚。有研究发现中枢神经系统的P2X4受体和小胶质细胞在神经病理性疼痛中充当重要作用,p38MAPK信号通道也参与其作用过程,肿瘤坏死因子和白介素1β等细胞因子以及神经递质脑源性神经生长因子对神经病理性疼痛和吗啡耐受的形成也有一定的作用。而且,最近有文献报道,吗啡能够通过P2X4受体途径对小胶质细胞的迁徙产生影响。
由于神经病理性疼痛和吗啡耐受在发生和发展上有许多共同机制,因此本研究推断P2X4R/p38MAPK可能也参与吗啡耐受的形成,并发挥重要作用。为论证上述假说,本实验拟进行一下两方面的研究：(1)吗啡耐受对脊髓和背根神经节P2X4受体表达和小胶质细胞激活的影响；(2)探讨嘌呤受体拮抗剂TNP-ATP(P1-4受体拮抗剂)和PPADS(P1,2,3,5,7受体拮抗剂)对吗啡耐受的作用及其作用机制。本研究有助于进一步揭示吗啡耐受机制,特别是P2X4受体在吗啡耐受机制中的作用,并为研制开发新型的镇痛药提供理论依据。
目的
观察慢性吗啡耐受对大鼠痛阈的影响
方法
12只成年雄性SD大鼠,质量250-300g,鞘内置管成功后,随机分为2组(n=6),NS组：大鼠经鞘内置管并注入生理盐水；MOR组：大鼠并经鞘内置管注入吗啡10μg,每天两次。鞘内置管3d后,开始鞘内输注生理盐水或吗啡,鞘内注射5d后建立大鼠慢性吗啡耐受模型。
结果
与NS组比较,MOR组鞘内注射吗啡后大鼠第1天痛敏阈值明显上升,而第3,5,7天痛敏阈值逐渐下降,并在鞘内注射吗啡第7日降至最低点。
结论
连续7天鞘内注射吗啡能够导致大鼠发生慢性吗啡耐受。
目的
1.观察慢性吗啡耐受对大鼠脊髓背角小胶质细胞激活的影响
2.观察慢性吗啡耐受大鼠脊髓背角和背根神经节P2X4R表达的影响。
方法
36只成年雄性SD大鼠,质量250-300g,鞘内置管成功后,随机分为2组(n=18),NS组：大鼠经鞘内置管并注入生理盐水；MOR组：大鼠并经鞘内置管注入吗啡10μg,每天两次。鞘内置管3d后,开始鞘内输注生理盐水或吗啡,鞘内注射5d后建立大鼠吗啡耐受模型,鞘内注射吗啡1、3、7d后取脊髓腰膨大部和背根神经节,免疫组化测定检测P2X4R、OX-42的表达。
结果
免疫组化结果显示吗啡耐受大鼠脊髓小胶质细胞呈激活状态,P2X4R主要在小胶质细胞上表达,与盐水组相比较,吗啡组大鼠脊髓背角P2X4R阳性细胞数明显增多,而背根神经节P2X4R阳性细胞数变化不明显。
结论
吗啡耐受大鼠脊髓的P2X4R表达明显增加,提示脊髓小胶质细胞P2X4R可能参与吗啡耐受的发生。
目的
1.观察鞘内注射嘌呤受体拮抗剂TNP-ATP(P1-4受体拮抗剂)和PPADS(P1,2,3,5,7受体拮抗剂)对慢性吗啡耐受大鼠痛敏的影响。
2.观察鞘内注射嘌呤受体拮抗剂TNP-ATP和PPADS对慢性吗啡耐受大鼠脊髓P2X4R、OX-42、p-p38MAPK、BDNF表达的调节。
方法
114只成年雄性SD大鼠,质量250-300g,鞘内置管成功后,随机分为6组(n=18)。NS组：大鼠经鞘内置管注入生理盐水；MOR组：大鼠经鞘内置管并注入吗啡10μg；TNP-ATP组：大鼠经鞘内置管并注入TNP-ATP30nmol后注入吗啡10μg；TNP-ATP+NS组：大鼠经鞘内置管并注入TNP-ATP和生理盐水；PPADS组：大鼠经鞘内置管并注入PPADS30nmol后注入吗啡10μg;PPADS+NS组：大鼠经鞘内置管并注入PPADS和生理盐水。按各组处理,鞘内置管3d后开始分别鞘内输注生理盐水、吗啡、TNP-ATP和PPADS,鞘内注射5d后建立大鼠吗啡耐受模型,于1、3、5、7d测定大鼠的痛敏值,并在鞘内注射7d后取脊髓腰膨大部,Western Blot检测P2X4R、BDNF、p-p38MAPK蛋白表达,RT-PCR检测P2X4R、BDNF mRNA的表达,以及免疫组化测定P2X4R、OX42、p-p38MAPK、BDNF的表达。
结果
与MOR组比较, TNP-ATP组给药后第3-7天大鼠痛敏阈值增高,脊髓P2X4R、BDNF、OX42的表达明显下降。而PPADS组与MOR组比较大鼠痛敏阈值无明显差异,脊髓P2X4R、OX42、p-p38MAPK、BDNF的表达无明显差异。
结论
鞘内给予P1-4受体拮抗剂TNP-ATP能够明显延缓吗啡耐受的形成,同时下调脊髓P2X4R、BDNF、p-p38MAPK的表达和小胶质细胞活化,而鞘内给予P1,2,3,5,7受体拮抗剂PPADS对吗啡耐受没有明显作用,从而说明脊髓胶质P2X4R/p38MAPK/BDNF途径可能是参与吗啡耐受发生机制。
Opioids receptor agonist, such as morphine, are widely used as, effective analgesic drugs for acute and chronic pain in clinical practice, especially for neuropathic pain and cancer pain. However, repeated use of morphine could lead to the development of tolerance to analgesia including the attenuated analgesic efficacy, the shorted analgesic duration, hyperalgesia and withdrawal-induced pain enhancement. Therefore, its long-trem therapy is limited by the development of tolerance. In recent years, researchers have approached for the mechanisms of morphine tolerance on corpuscular and molecular level and gained much outcome. However, the mechanism is not fully understood in the present.
Recently, researches had confirmed that role of P2X4 receptor and glia in the CNS played the role of neuropathic pain and P38MAPK signal channel might be involved in it. Cytokines such as tumor necrosis factor-alpha, interleukinlβand neurotransmitters such as brain-derived neurotrophic factors participated in the development of neuropathic pain and morphine tolerance. Moreover, the latest literature reported that morphine enhances microglial migration through modulation of P2X4 receptor signaling.
Because morphine tolerance and neuropatic pain share similar mechanisms, we may assume that P2X4R/P38MAPK pathway might be involved in chronic morphine tolerance. To confirm the above hypothesis, we design to investigate:1) the effect of morphine tolerance on P2X4 receptor and microglial activation in the spinal cord; 2) the effect of P2X4 receptor antagonists TNP-ATP and PPADS on the morphine tolerance and the mechanisms. The data from our studies will provide new evidence for the mechanisms of morphine tolerance, moreover, it will provide theory for novel analgesic drugs exploitation.
Objectives
To examine the effects of morphine tolerance on pain threshold of the rats
Methods
12 male Sprague-Dawley (SD) rats (250-300g) fitted with intrathecal (i.t.)
Catheters, Randomly, rats were divided into 2 groups(n=6), NS group:rats were intrathecally administrated saline; MOR group:rats were intrathecally administrated morphine 10μg.3 days after intrathecal catheters implantation, rats were administrated NS or morphine. And 5 day after administration, the model of morphine tolerance was established. The rat hind paw withdrawal threshold (WT) to mechanical stimuli and withdrawal latency (WL) to radiant heat were determined from day 1 to 7 after administration.
Results
Compared with NS group, a significant increase on day 1 in WT and WL was observed in MOR group. From 3d to 7d WT decreased, and day 7 reached the lowest point.
Conclusion
Consecutive administration of morphine induced morphine tolerance.
Objectives
1. To examine spinal microglial activation induced by morphine tolerance in rats.
2. To examine spinal microglial activation induced by morphine tolerance in rats.
Methods
36 male Sprague-Dawley (SD) rats (250-300g) fitted with intrathecal (i.t.)
catheters. Randomly, rats were divided into 2 groups(n=18):normal control group, NS group:rats were intrathecally administrated saline; MOR group:rats were intrathecally administrated morphine 10μg.3 days after intrathecal catheters implantation, rats were administrated NS or morphine. And 5 day after administration, the model of morphine tolerance was established. The spinal cord around lumbar enlargement and dorsal root ganglion was removed. Spinal microglial activation was evaluated with OX-42 immunoreactivity and spinal P2X4R expression were determined by immunohistochemisty.
Results
Compared with NS group, spinal P2X4R、OX-42 expression were significantly increased, While P2X4R in DRG didn't changed.
Conclusion
Consecutive administration of morphine induced spinal P2X4R、OX-42 expression increase, which suggested that spinal glial P2X4R receptor may be involved in the development of morphine tolerance.
Objective
1. To examine the effects of morphine tolerance on pain threshold of the rats.
2. To examine spinal microglial activation and spinal P2X4R expression induced by morphine tolerance in rats.
Methods
114 male Sprague-Dawley(SD) rats(250-300g) fitted with intrathecal (i.t) catheters. Randomly, rats were divided into 7 groups(n=18):NS group:rats underwent were intrathecally administrated saline(NS); MOR group:rats were intrathecally morphine; TNP-ATP group:rats were intrathecally 30nmol TNP-ATP and morphine; TNP-ATP+NS group:rats were intrathecally TNP-ATP and NS; PPADS group:rats were intrathecally 30nmol PPADS and morphine; PPADS group+NS group: rats were intrathecally PPADS and NS.3 days after intrathecal catheters implantation, rats were administrated various intrathecal medicine. And 5 day after administration, the model of morphine tolerance was established. The rat hind paw withdrawal threshold(WT) to mechanical stimuli and withdrawal latency(WL) to radiant heat were determined from day 1 to 7.7 days after administration, the spinal cord around lumbar enlargement was removed. Spinal microglial activation was evaluated with OX-42 immunoreactivity and spinal P2X4R、p-p38MAPK、BDNF expression were determined by immunohistochemisty, P2X4R、BDNF、p-p38MAPK spinal expression were assessed by western blotting, spinal P2X4R、BDNF mRNA expression was assessed by reverse transcriptase polymerase chain reation (RT-PCR).
Results
Compared with MOR group, a significant increase in WT and WL was observed and spinal P2X4R、BDNF、OX42、p-p38MAPK expression were significantly decreased in TNP-ATP group On day 3 and day 7, while group PPADS did not.
Conclusion
Intrathecal TNP-ATP attenuated the morphine tolerance in rats, and suppressed spinal P2X4R、p-p38MAPK、BDNF expression and microglial activation, while PPADS could not. Therefore, the activation of spinal P2X4R/p38MAPK/BDNF pathway may be involved in the development of morphine tolerance.
近些年来,学者们对吗啡耐受的机制从细胞和分子水平进行了大量研究,为临床上更加有效应用吗啡治疗疼痛提供了重要理论依据。然而,到目前为止吗啡的镇痛和耐受机制尚不完全清楚。有研究发现中枢神经系统的P2X4受体和小胶质细胞在神经病理性疼痛中充当重要作用,p38MAPK信号通道也参与其作用过程,肿瘤坏死因子和白介素1β等细胞因子以及神经递质脑源性神经生长因子对神经病理性疼痛和吗啡耐受的形成也有一定的作用。而且,最近有文献报道,吗啡能够通过P2X4受体途径对小胶质细胞的迁徙产生影响。
由于神经病理性疼痛和吗啡耐受在发生和发展上有许多共同机制,因此本研究推断P2X4R/p38MAPK可能也参与吗啡耐受的形成,并发挥重要作用。为论证上述假说,本实验拟进行一下两方面的研究：(1)吗啡耐受对脊髓和背根神经节P2X4受体表达和小胶质细胞激活的影响；(2)探讨嘌呤受体拮抗剂TNP-ATP(P1-4受体拮抗剂)和PPADS(P1,2,3,5,7受体拮抗剂)对吗啡耐受的作用及其作用机制。本研究有助于进一步揭示吗啡耐受机制,特别是P2X4受体在吗啡耐受机制中的作用,并为研制开发新型的镇痛药提供理论依据。
目的
观察慢性吗啡耐受对大鼠痛阈的影响
方法
12只成年雄性SD大鼠,质量250-300g,鞘内置管成功后,随机分为2组(n=6),NS组：大鼠经鞘内置管并注入生理盐水；MOR组：大鼠并经鞘内置管注入吗啡10μg,每天两次。鞘内置管3d后,开始鞘内输注生理盐水或吗啡,鞘内注射5d后建立大鼠慢性吗啡耐受模型。
结果
与NS组比较,MOR组鞘内注射吗啡后大鼠第1天痛敏阈值明显上升,而第3,5,7天痛敏阈值逐渐下降,并在鞘内注射吗啡第7日降至最低点。
结论
连续7天鞘内注射吗啡能够导致大鼠发生慢性吗啡耐受。
目的
1.观察慢性吗啡耐受对大鼠脊髓背角小胶质细胞激活的影响
2.观察慢性吗啡耐受大鼠脊髓背角和背根神经节P2X4R表达的影响。
方法
36只成年雄性SD大鼠,质量250-300g,鞘内置管成功后,随机分为2组(n=18),NS组：大鼠经鞘内置管并注入生理盐水；MOR组：大鼠并经鞘内置管注入吗啡10μg,每天两次。鞘内置管3d后,开始鞘内输注生理盐水或吗啡,鞘内注射5d后建立大鼠吗啡耐受模型,鞘内注射吗啡1、3、7d后取脊髓腰膨大部和背根神经节,免疫组化测定检测P2X4R、OX-42的表达。
结果
免疫组化结果显示吗啡耐受大鼠脊髓小胶质细胞呈激活状态,P2X4R主要在小胶质细胞上表达,与盐水组相比较,吗啡组大鼠脊髓背角P2X4R阳性细胞数明显增多,而背根神经节P2X4R阳性细胞数变化不明显。
结论
吗啡耐受大鼠脊髓的P2X4R表达明显增加,提示脊髓小胶质细胞P2X4R可能参与吗啡耐受的发生。
目的
1.观察鞘内注射嘌呤受体拮抗剂TNP-ATP(P1-4受体拮抗剂)和PPADS(P1,2,3,5,7受体拮抗剂)对慢性吗啡耐受大鼠痛敏的影响。
2.观察鞘内注射嘌呤受体拮抗剂TNP-ATP和PPADS对慢性吗啡耐受大鼠脊髓P2X4R、OX-42、p-p38MAPK、BDNF表达的调节。
方法
114只成年雄性SD大鼠,质量250-300g,鞘内置管成功后,随机分为6组(n=18)。NS组：大鼠经鞘内置管注入生理盐水；MOR组：大鼠经鞘内置管并注入吗啡10μg；TNP-ATP组：大鼠经鞘内置管并注入TNP-ATP30nmol后注入吗啡10μg；TNP-ATP+NS组：大鼠经鞘内置管并注入TNP-ATP和生理盐水；PPADS组：大鼠经鞘内置管并注入PPADS30nmol后注入吗啡10μg;PPADS+NS组：大鼠经鞘内置管并注入PPADS和生理盐水。按各组处理,鞘内置管3d后开始分别鞘内输注生理盐水、吗啡、TNP-ATP和PPADS,鞘内注射5d后建立大鼠吗啡耐受模型,于1、3、5、7d测定大鼠的痛敏值,并在鞘内注射7d后取脊髓腰膨大部,Western Blot检测P2X4R、BDNF、p-p38MAPK蛋白表达,RT-PCR检测P2X4R、BDNF mRNA的表达,以及免疫组化测定P2X4R、OX42、p-p38MAPK、BDNF的表达。
结果
与MOR组比较, TNP-ATP组给药后第3-7天大鼠痛敏阈值增高,脊髓P2X4R、BDNF、OX42的表达明显下降。而PPADS组与MOR组比较大鼠痛敏阈值无明显差异,脊髓P2X4R、OX42、p-p38MAPK、BDNF的表达无明显差异。
结论
鞘内给予P1-4受体拮抗剂TNP-ATP能够明显延缓吗啡耐受的形成,同时下调脊髓P2X4R、BDNF、p-p38MAPK的表达和小胶质细胞活化,而鞘内给予P1,2,3,5,7受体拮抗剂PPADS对吗啡耐受没有明显作用,从而说明脊髓胶质P2X4R/p38MAPK/BDNF途径可能是参与吗啡耐受发生机制。
Opioids receptor agonist, such as morphine, are widely used as, effective analgesic drugs for acute and chronic pain in clinical practice, especially for neuropathic pain and cancer pain. However, repeated use of morphine could lead to the development of tolerance to analgesia including the attenuated analgesic efficacy, the shorted analgesic duration, hyperalgesia and withdrawal-induced pain enhancement. Therefore, its long-trem therapy is limited by the development of tolerance. In recent years, researchers have approached for the mechanisms of morphine tolerance on corpuscular and molecular level and gained much outcome. However, the mechanism is not fully understood in the present.
Recently, researches had confirmed that role of P2X4 receptor and glia in the CNS played the role of neuropathic pain and P38MAPK signal channel might be involved in it. Cytokines such as tumor necrosis factor-alpha, interleukinlβand neurotransmitters such as brain-derived neurotrophic factors participated in the development of neuropathic pain and morphine tolerance. Moreover, the latest literature reported that morphine enhances microglial migration through modulation of P2X4 receptor signaling.
Because morphine tolerance and neuropatic pain share similar mechanisms, we may assume that P2X4R/P38MAPK pathway might be involved in chronic morphine tolerance. To confirm the above hypothesis, we design to investigate:1) the effect of morphine tolerance on P2X4 receptor and microglial activation in the spinal cord; 2) the effect of P2X4 receptor antagonists TNP-ATP and PPADS on the morphine tolerance and the mechanisms. The data from our studies will provide new evidence for the mechanisms of morphine tolerance, moreover, it will provide theory for novel analgesic drugs exploitation.
Objectives
To examine the effects of morphine tolerance on pain threshold of the rats
Methods
12 male Sprague-Dawley (SD) rats (250-300g) fitted with intrathecal (i.t.)
Catheters, Randomly, rats were divided into 2 groups(n=6), NS group:rats were intrathecally administrated saline; MOR group:rats were intrathecally administrated morphine 10μg.3 days after intrathecal catheters implantation, rats were administrated NS or morphine. And 5 day after administration, the model of morphine tolerance was established. The rat hind paw withdrawal threshold (WT) to mechanical stimuli and withdrawal latency (WL) to radiant heat were determined from day 1 to 7 after administration.
Results
Compared with NS group, a significant increase on day 1 in WT and WL was observed in MOR group. From 3d to 7d WT decreased, and day 7 reached the lowest point.
Conclusion
Consecutive administration of morphine induced morphine tolerance.
Objectives
1. To examine spinal microglial activation induced by morphine tolerance in rats.
2. To examine spinal microglial activation induced by morphine tolerance in rats.
Methods
36 male Sprague-Dawley (SD) rats (250-300g) fitted with intrathecal (i.t.)
catheters. Randomly, rats were divided into 2 groups(n=18):normal control group, NS group:rats were intrathecally administrated saline; MOR group:rats were intrathecally administrated morphine 10μg.3 days after intrathecal catheters implantation, rats were administrated NS or morphine. And 5 day after administration, the model of morphine tolerance was established. The spinal cord around lumbar enlargement and dorsal root ganglion was removed. Spinal microglial activation was evaluated with OX-42 immunoreactivity and spinal P2X4R expression were determined by immunohistochemisty.
Results
Compared with NS group, spinal P2X4R、OX-42 expression were significantly increased, While P2X4R in DRG didn't changed.
Conclusion
Consecutive administration of morphine induced spinal P2X4R、OX-42 expression increase, which suggested that spinal glial P2X4R receptor may be involved in the development of morphine tolerance.
Objective
1. To examine the effects of morphine tolerance on pain threshold of the rats.
2. To examine spinal microglial activation and spinal P2X4R expression induced by morphine tolerance in rats.
Methods
114 male Sprague-Dawley(SD) rats(250-300g) fitted with intrathecal (i.t) catheters. Randomly, rats were divided into 7 groups(n=18):NS group:rats underwent were intrathecally administrated saline(NS); MOR group:rats were intrathecally morphine; TNP-ATP group:rats were intrathecally 30nmol TNP-ATP and morphine; TNP-ATP+NS group:rats were intrathecally TNP-ATP and NS; PPADS group:rats were intrathecally 30nmol PPADS and morphine; PPADS group+NS group: rats were intrathecally PPADS and NS.3 days after intrathecal catheters implantation, rats were administrated various intrathecal medicine. And 5 day after administration, the model of morphine tolerance was established. The rat hind paw withdrawal threshold(WT) to mechanical stimuli and withdrawal latency(WL) to radiant heat were determined from day 1 to 7.7 days after administration, the spinal cord around lumbar enlargement was removed. Spinal microglial activation was evaluated with OX-42 immunoreactivity and spinal P2X4R、p-p38MAPK、BDNF expression were determined by immunohistochemisty, P2X4R、BDNF、p-p38MAPK spinal expression were assessed by western blotting, spinal P2X4R、BDNF mRNA expression was assessed by reverse transcriptase polymerase chain reation (RT-PCR).
Results
Compared with MOR group, a significant increase in WT and WL was observed and spinal P2X4R、BDNF、OX42、p-p38MAPK expression were significantly decreased in TNP-ATP group On day 3 and day 7, while group PPADS did not.
Conclusion
Intrathecal TNP-ATP attenuated the morphine tolerance in rats, and suppressed spinal P2X4R、p-p38MAPK、BDNF expression and microglial activation, while PPADS could not. Therefore, the activation of spinal P2X4R/p38MAPK/BDNF pathway may be involved in the development of morphine tolerance.
引文
[1]Laul in JP, Celerier E, Larcher A, et al. Opiate tolerance to daily heroin administration:an apparent phenomenon associated with enhanced pain sensitivity. Neuroscience,1999,89:631-636.
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