激活第三组mGluRs抑制Formalin诱导的大鼠脊髓p38MAPK的活化
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摘要
目的:痛觉的产生起始于外周伤害性刺激作用于伤害性感受器而产生的疼痛信号。疼痛信号在经过脊髓上传至高级中枢的过程受到脊髓自身和脊髓上中枢的调控。大量资料表明,一系列神经化学物质参与了外周痛感受器的激活和痛信号在脊髓的传递,如谷氨酸通过激活离子型受体(iGluRs)和代谢型受体(mGluRs)在痛信号的产生和传递中发挥重要作用。我们以往的工作通过行为学观察和功能形态学的方法(Formalin引起脊髓背角Fos蛋白表达)证实了第三组mGluRs参与了外周及脊髓痛信号的产生和传递过程。本研究采用同一模型即Formalin痛模型,通过行为学观察和Western—blot方法(Formalin引起脊髓背角p38MAPK的活化),试图进一步证实第三组mGluRs在外周伤害性感受器的激活和外周痛信号产生中发挥的作用,同时也观察了这些受体在脊髓痛调制中的作用。
方法:实验在Wistar雄性大鼠(120-140g)进行。本实验分为两部分,第一部分是外周痛实验,分为行为学观察和大鼠脊髓p38MAPK活化的检测两个小部分。行为学观察分为对照组即生理盐水组和三个不同剂量的L-SOP实验组(100nmol,250nmol,500nmol)(每组6例)。在四组动物左后脚掌皮下注入Formalin(5%,50μl)前20分钟,生理盐水(NS)或L-SOP(100nmol,250nmol,500nmol)20μl被分别注入左后脚掌皮下,并立即进行行为学观察。p38MAPK活化的检测的分组和行为学一样,在Formalin注射后20分钟,处死动物,取脊髓腰膨大部分,用western-blot法进行p38MAPK检测。第二部分实验是脊髓痛实验,实验在鞘内置管成功的动物进行,分组和实验方法与外周痛相似,实验组动物通过鞘内注入L-SOP,对照组则在鞘内注入NS,20分钟后左后脚掌皮下注入Formalin(5%,50μl),然后进行行为学观察和p38MAPK活化的检测,并进行图象分析和统计学处理。
结果:1、在外周痛试验中,与对照组比较,注射L-SOP的三组大鼠第二时相的痛行为反应明显被抑制,250nmol组与500nmol组还观察到大鼠第一时相的痛行为反应亦受到抑制;此外,250nmol组与500nmol组脊髓p38MAPK的活化水平与对照组比较明显下降(P＜0.05)。2、在中枢痛实验中,与对照组比较,注射L-SOP的三组大鼠第二时相的痛行为反应明显被抑制,但对痛行为反应的第一时相无显著影响;此外,L-SOP的三组脊髓p38MAPK的活化水平与对照组比较明显下降(P＜0.05)。
结论:在大鼠Formalin炎性痛模型中,外周和鞘内注射L-SOP均能抑制痛行为反应及降低脊髓p38MAPK的活化水平,提示外周和脊髓组织中有功能性第三组代谢型谷氨酸受体的表达并分别参与外周和脊髓痛感受器对伤害性信息的处理。
Objective:It is generally accepted that central nociception is based on the initiation of centripetal signals from peripheral nociceptors by peripheral nociceptors are transmitted into the spinal dorsal horn.Evidence from the last decades indicates that glutamate plays a significant role in nociceptive processing by activation of both iGluRs and mGluRs.In previous study,we showed that activation of mGluRsⅢcan strengthen both processes of generation of nociceptive signals in peripheral nociceptors and transmission of nociceptive information in spinal dorsal horn by observating of nociceptive behavior combined with Fos expression examinations produced by peripherally injection Formalin.The aim of the present study is to further confirmed GroupⅢmGluRs are involved in the processing of noxious signals in peripheral nociceptors and nociceptive transmission in spinal cord by using the same model,by observating of nociceptive behavior combined with p38MAPK activated examinations produced by peripherally injection Formalin.
Methods:There were two parts of experiments.The first part of the experiment was designed for the examination of peripheral processing of noxious signals and fourty-eight male Wistar rats were divided randomly into four groups:control group or NS group and three different dose of L-SOP groups(100nmol,250nmol,500nmol).L-SOP group was experimental group with injection of selective GroupⅢmGluRs agonist L-SOP into the plantar aspect of the left hindpaw;and NS group was controlled with injection of normal saline.In all the four group,Formalin was injected 20 min after the pretreatment of agonist L-SOP or NS at the same site.For each group,6 rats used to observe flinching and licking time every as nociception behavior 3 minutes in 1 hour after formalin injected and the other 6 rots used to observe the activation of p38(P-p38) by western-blot.The second part of the experiment was carried out for the observations of spinal mechanisms of nociceptive processing.Fourty-eight male Wistar rats were divided randomly into four groups:control group or NS group and three different dose of L-SOP groups(100nmol,250nmol,500nmol).L-SOP group was experimental group with intrathecal injection of L-SOP;and NS group was controlled with intrathecal injection of normal saline.In all the four group,Formalin was injected at the site of the plantar aspect of the left hindpaw in the four group 20 min after the pretreatment of agonist L-SOP or NS.For each group,6 rats used to observe flinching and licking time every as nociception behavior 3 minutes in 1 hour after formalin injected and the other 6 rats used to observe the activation of p38 (P-p38) by western-blot.
Results:1.In the examination of peripheral processing of noxious signal,all the three different groups of L-SOP can inhibit noeiception behavior in the Tonic phase,and 250nmol and 500nmol groups can suppress not only in the tonic phase but also in the acute phase.250nmol and 500nmol groups can reduce activated or phosphorylated p38MAPK in spinal cord(P＜0.05). 2.In the examination of spinal mechanisms of noeiceptive processing,all the three different groups of L-SOP can inhibit nociception behavior in the Tonic phase but with no effects on the acute phase.All the three different groups of L-SOP can reduce activated or phosphorylated p38MAPK in spinal cord(P＜0.05).
Conclusion Periphery or intrathecal injection of L-SOP can reduce noeiceptive behavior and phosphorylated p38MAPK in the spinal cord in formalin-induced hyperalgia,it is suggested that there are functional expression of mGluRsⅢin the periphery and spinal and there are involved in the processing of peripheral noxious informations.
方法:实验在Wistar雄性大鼠(120-140g)进行。本实验分为两部分,第一部分是外周痛实验,分为行为学观察和大鼠脊髓p38MAPK活化的检测两个小部分。行为学观察分为对照组即生理盐水组和三个不同剂量的L-SOP实验组(100nmol,250nmol,500nmol)(每组6例)。在四组动物左后脚掌皮下注入Formalin(5%,50μl)前20分钟,生理盐水(NS)或L-SOP(100nmol,250nmol,500nmol)20μl被分别注入左后脚掌皮下,并立即进行行为学观察。p38MAPK活化的检测的分组和行为学一样,在Formalin注射后20分钟,处死动物,取脊髓腰膨大部分,用western-blot法进行p38MAPK检测。第二部分实验是脊髓痛实验,实验在鞘内置管成功的动物进行,分组和实验方法与外周痛相似,实验组动物通过鞘内注入L-SOP,对照组则在鞘内注入NS,20分钟后左后脚掌皮下注入Formalin(5%,50μl),然后进行行为学观察和p38MAPK活化的检测,并进行图象分析和统计学处理。
结果:1、在外周痛试验中,与对照组比较,注射L-SOP的三组大鼠第二时相的痛行为反应明显被抑制,250nmol组与500nmol组还观察到大鼠第一时相的痛行为反应亦受到抑制;此外,250nmol组与500nmol组脊髓p38MAPK的活化水平与对照组比较明显下降(P＜0.05)。2、在中枢痛实验中,与对照组比较,注射L-SOP的三组大鼠第二时相的痛行为反应明显被抑制,但对痛行为反应的第一时相无显著影响;此外,L-SOP的三组脊髓p38MAPK的活化水平与对照组比较明显下降(P＜0.05)。
结论:在大鼠Formalin炎性痛模型中,外周和鞘内注射L-SOP均能抑制痛行为反应及降低脊髓p38MAPK的活化水平,提示外周和脊髓组织中有功能性第三组代谢型谷氨酸受体的表达并分别参与外周和脊髓痛感受器对伤害性信息的处理。
Objective:It is generally accepted that central nociception is based on the initiation of centripetal signals from peripheral nociceptors by peripheral nociceptors are transmitted into the spinal dorsal horn.Evidence from the last decades indicates that glutamate plays a significant role in nociceptive processing by activation of both iGluRs and mGluRs.In previous study,we showed that activation of mGluRsⅢcan strengthen both processes of generation of nociceptive signals in peripheral nociceptors and transmission of nociceptive information in spinal dorsal horn by observating of nociceptive behavior combined with Fos expression examinations produced by peripherally injection Formalin.The aim of the present study is to further confirmed GroupⅢmGluRs are involved in the processing of noxious signals in peripheral nociceptors and nociceptive transmission in spinal cord by using the same model,by observating of nociceptive behavior combined with p38MAPK activated examinations produced by peripherally injection Formalin.
Methods:There were two parts of experiments.The first part of the experiment was designed for the examination of peripheral processing of noxious signals and fourty-eight male Wistar rats were divided randomly into four groups:control group or NS group and three different dose of L-SOP groups(100nmol,250nmol,500nmol).L-SOP group was experimental group with injection of selective GroupⅢmGluRs agonist L-SOP into the plantar aspect of the left hindpaw;and NS group was controlled with injection of normal saline.In all the four group,Formalin was injected 20 min after the pretreatment of agonist L-SOP or NS at the same site.For each group,6 rats used to observe flinching and licking time every as nociception behavior 3 minutes in 1 hour after formalin injected and the other 6 rots used to observe the activation of p38(P-p38) by western-blot.The second part of the experiment was carried out for the observations of spinal mechanisms of nociceptive processing.Fourty-eight male Wistar rats were divided randomly into four groups:control group or NS group and three different dose of L-SOP groups(100nmol,250nmol,500nmol).L-SOP group was experimental group with intrathecal injection of L-SOP;and NS group was controlled with intrathecal injection of normal saline.In all the four group,Formalin was injected at the site of the plantar aspect of the left hindpaw in the four group 20 min after the pretreatment of agonist L-SOP or NS.For each group,6 rats used to observe flinching and licking time every as nociception behavior 3 minutes in 1 hour after formalin injected and the other 6 rats used to observe the activation of p38 (P-p38) by western-blot.
Results:1.In the examination of peripheral processing of noxious signal,all the three different groups of L-SOP can inhibit noeiception behavior in the Tonic phase,and 250nmol and 500nmol groups can suppress not only in the tonic phase but also in the acute phase.250nmol and 500nmol groups can reduce activated or phosphorylated p38MAPK in spinal cord(P＜0.05). 2.In the examination of spinal mechanisms of noeiceptive processing,all the three different groups of L-SOP can inhibit nociception behavior in the Tonic phase but with no effects on the acute phase.All the three different groups of L-SOP can reduce activated or phosphorylated p38MAPK in spinal cord(P＜0.05).
Conclusion Periphery or intrathecal injection of L-SOP can reduce noeiceptive behavior and phosphorylated p38MAPK in the spinal cord in formalin-induced hyperalgia,it is suggested that there are functional expression of mGluRsⅢin the periphery and spinal and there are involved in the processing of peripheral noxious informations.
引文
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[2]Ozawa S,Kamiya H,Tauzuki K.Glutamate recepotors in the mammalian central nervous system.Prog Neurobiol,1998,54:581-618
[3]Nakanish S.Molecular diversity of glutamate receptors and implication for brain function.Science.1992,258:597-603
[4]Dingleding R,Borges K,Bowie D,et al.The glutamate receptors ion channels.Pharmacol Rew.1999,51:7-61
[5]Conn PJ.Pin JP.Pharmacology and functions of metabotropic glutamate receptors.Annu Rev Pharmacol Toxicol.1997,37:205-237
[6]Schoepp DD,Jane DE,Monn JA.Pharmacological agents acting at subtypes of metabotropic glutamate receptors.Neuropharmacol.1999,38:1431-1476
[7]Hollmann M,Heinemann S.Cloned glutamate recepters.Annu Rev Neurosci.1994,17:31-108
[8]Nakauishi S,Nakajima Y,Masu M,et al.Glutamate receptors:brain function and signal transducfion.Brain Res Rev.1998,26:230-235
[9]Pin JP,Duvoisin R.The metabotropic glutamate receptors:structure and function.Neuropharmacol,1995,34:1-26
[10]Svensson CI,.Marsala M,Westererlund A,et al.Activation of p38 mitogen-activated protein kinase in spinal microglia is a critical link in inflammation-induced spinal pain processing.JNeurochem,2003,86:1534-1544.
[11]Millan MJ.The induction of pain:an integrative review.Prog Neurobiol.1999,57:1-167
[12]Fundylus ME.Glutamate receptors and nocicepfion.CNS drugs.2001,15:29-58
[13]Li JL,Ohishi H,Kaueko T,et al.Immunohistochemical localization of a metabotropic glutamate receptor,mGluRs7,in ganglion neurons of the rat;with special reference to the presence in glutamatergic ganglion neurons.Neurosci Lett,1996,204:9-12.
[14]Li H,,Ohishi H,Kinoshita A,et al.Localization of a metabotropic glutamate receptor,mGluRs7,in axon terminals of presumed nociceptive,primary afferent fibers in the superficial layers of the spinal dorsal horn:an electron microscope study in the rat.Neurosci Lett.1997,223:153-156
[15]Azkue JJ,Murga M,Fernandez-Capetillo O,et al.Immunoreactivity for the group Ⅲmetabotropic glutamate receptor subtype mGluRs4a in the superficial laminae of the rat spinal dorsal horn.Comp Neurol.2001,430(4):448-457
[16]Thomas NK,Wright RA,Howson PA,et al.(S)-3,4-DCPG,apotent and selective mGlu8a receptor agonist,activates metabotropic glutamate receptors on primary afferent terminals in the neonatal rat spinal cord.Neuropharmacology.2001,40:311-318
[17]Xiao-Rong Yang,Yu Zhang,Ce Zhang.Group Ⅲ metabotropic glutamate recepters are involved in peripheral nociception.(in submission)
[18]Abbott FV,Frank lin KB,Westbrook RF.The formalin test:scoring properties of the first and second phases of the pain response in rats.Pain,1995;60(1):91.
[19]Fu KY,Light AR,Maixner W.Relationship between nocicepror activity,peripheral edema,spinal microglial activity and long-term hyperalgesia induced by formalin.Neuroscience.2000,101:1127-1135
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