吗啡对GRK2、GRK5和JNK3基因在大鼠脑内表达调控的研究
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摘要
长期使用阿片类药物会导致对药物的耐受、依赖和成瘾，但是其机制并未完全阐明。阿片受体的脱敏是耐受发生的重要分子机制之一，脑内基因表达的异常和神经元可塑性改变以及脑结构和功能的损害是产生和维持药物成瘾状态的重要神经和分子基础。
激动剂诱导的G蛋白偶联受体激酶(GRK)对G蛋白偶联受体(GPCR)的磷酸化是受体脱敏的关键步骤。GRK的表达水平可被GPCR的激动剂调节。GRK在体内的异常表达可以严重地影响器官和组织的功能。GRK2和GRK5是介导阿片受体磷酸化的主要亚型，在阿片受体的脱敏中起重要作用。但是，阿片类药物对GRK5的表达调节以及对GRK2在不同脑区内的表达调节还不清楚。c-Jun氨基末端蛋白激酶(JNK)是催化转录因子c-Jun磷酸化的主要蛋白激酶。JNK有3种亚型，其中JNK3特异性地分布在脑内，在脑内神经元的损伤和凋亡中发挥着极其重要的作用。吗啡通过JNK信号通路引起免疫细胞的凋亡。长期使用吗啡可引起脑内神经元结构损伤和可塑性发生改变。阿片类药物能否调节脑内JNK3表达，目前尚未见有报道。为此，我们采用原位杂交组织化学的方法，研究了急性、长期给予吗啡和吗啡戒断、纳络酮促戒断以及长时程戒断过程中，大鼠脑内多个脑区的GRK2、GRK5和JNK3三种蛋白激酶mRNA水平的变化。
结果显示，单次注射10mg／Kg吗啡能够上调GRK2和GRK5mRNA在皮层、海马以及GRK2 mRNA在丘脑的水平。每天2次，连续9天给予10mg／Kg吗啡引起吗啡耐受后，GRK2 mRNA水平在皮层、海马、五脑和蓝斑下降；GRK5mRNA水平与生理盐水对照组相比未见有显著变化。吗啡戒断显著升高GRK2和GRK5在多个脑区的mRNA水平。单次和长期给予吗啡，增加皮层的JNK3 mRNA水平，但海马、丘脑和蓝斑的JNK3 mRNA水平未见有明显变化。连续两周的长时程戒断，JNK3 mRNA水平在皮层、海马和丘脑显著升高。再次注射吗啡后，未见对这些脑区升高的JNK3 mRNA水平有明显的影响。此外，我们还比较了GRK2和GRK5mRNA在脑内的分布特征，发现在导水管周围灰质(PAG)两者的基因表达明显不同，表现为GRK5 mRNA在此区域内分布较GRK2 mRNA广泛，GRK5 mRNA阳性细胞灰度高于GRK2的mRNA阳性细胞。
我们的研究首次发现，阿片类药物能够在转录水平调控GRK的基因表达；单次和长期给予吗啡以及吗啡戒断对GRK mRNA水平的调节不同；GRK2和GRK5mRNA在PAG的分布不同；阿片类药物可以调节JNK3的基因表达；急性和长期
复旦大学博士论文 吗啡对 GRKZ。GRKS和 JNK3基因在大鼠脑内表达调控的研究
给予吗啡增加 JNK3 InRNA在皮层的水平，而未见海马、丘脑和蓝斑的 JNK3mRNA
水平发生改变，但长期吗啡戒断却引起海马和丘脑：17NH3 tYlxrvA水平迟发性升高。
我们的结果提示，阿片类药物对G见基因表达的调控，能够反过未影响阿片受体
的信号转导。吗啡增加 GIEUC的基因表达可能在急性吗啡耐受中起作用。长期给予
吗啡可以负性调节或抑制GRK的基因表达。吗啡戒断时GIUL基因超表达对于减弱
戒断过程中多种GPCR过度激活具有重要的意义。吗啡对WK3基因表达的上调在
吗啡成病和吗啡引起的脑内神经细胞损伤中起重要作用。在PAG，GRKS较G抓二
可能发挥重要的功能。
Prolonged exposure to opiate induces opioid tolerance, dependence and addiction, but the mechanisms responsible for these side-effects have not been well elucidated. Many studies have revealed that desensitization of opioid receptor is one of the molecular mechanisms of opioid tolerance. Abnormal regulation of gene expression, changes in plasticity of neuron and impairment of brain structure play important roles in the development of opioid addiction.
The phosphorylation of G protein-coupled receptor (GPCR) by G protein-coupled receptor kinases (GRKs) under the stimulation with their specific agonists is the critical step to desensitization of GPCR. Agonists for GPCR can regulate the expression level of GRK, and the abnormal expression of GRK in vivo can markedly influence physiological functions of organs and tissues. Both GRK2 and GRKS are the main isoforms of GRK in the phosphorylation of opioid receptors but the expression regulations of GRK2 and GRK5 in brain by opiates are unclear. JNKs are the primary kinases in the phosphorylation of c-Jun which isan important transcription factor in the regulation of gene expression. Three isoforms of JNKs have been cloned. JNK3 is characterized with its specific expression in brain and exerts pivotal roles in neuron apoptosis. Many research demonstrated that morphine could induce apoptosis of immunocytes and neuronal cells in vitro, and morphological impairment of neuron in brain as well as modification of neuro
nal plasticity in vivo. But whether these effects of morphine on neuronal cells are associated with the regulation of JNKs is not clarified. Using in situ hybridization in this study, we investigated the regulation of gene expression of GRK2, GRK5 and JNKS in rat brain after acute and chronic treatments with morphine, spontaneous morphine withdrawal, naloxone-precipitated withdrawal and long-term cessation of morphine.
The results showed that single injection of 10 mg/Kg morphine increased GRK2 mRNA level in cerebral cortex, hippocampus and thalamus, and GRKS mRNA level in cerebral cortex and hippocampus. Twice daily injection of 10 mg/Kg morphine for 9 days decreased GRK2 mRNA level in cerebral cortex, hippocampus, thalamus and locus coeruleus, but notGRK5 mRNA level in all the observed brain regions. Spontaneous withdrawal for 48 h and naloxone-precipitated withdrawal induced overshoot of both
GRK2 mRNA and GRK5 mRNA levels in most brain regions. Both acute and chronic morphine treatments enhanced JNK3 mRNA levels in frontal cortex, but not in hippocampus, thalamus and locus coeruleus. Long-term cessation of morphine for 2 weeks after chronic morphine treatment caused delayed increases in JNK3 mRNA levels in hippocampus and thalamus. A challenge injection of morphine could not modify the increased expression levels of JNK3 mRNA in these brain regions. The different distributions between GRK2 and GRK5 mRNA were also observed in periaqueductal gray (PAG) where GRK5 mRNA-positive cells are widely and uniformly distributed in the aqueduct with higher stain but GRK2 mRNA-positive cells only distribute around dorsal and ventral parts of the aqueduct with lower stain.
Our results first demonstrated that opiate could regulate the gene expression of GRK2, GRK5 in transcription level. Acute and chronic morphine treatments as well as morphine withdrawal could differently regulate both GRK mRNA levels in most brain regions. The expression patterns of GRK2 and GRK5 mRNA differ in PAG.. Opiate could regulate the gene expression of JNK3. Acute and chronic morphine treatments increase the gene expression of JNK3 in frontal cortex, but not in hippocampus, thalamus and locus coeruleus. Morphine abstinence could cause delayed up-regulation of JNK.3 gene expression in hippocampus and thalamus. Our results suggest that the up-regulation of GRK2 and GRK5 mRNA by acute morphine treatment may play important roles in acute opioid tolerance. Chronic morphine treatment may initiate inhibitory mechanism to down-regulate GRK2 gene expression and negatively regulate GRK5 gene
激动剂诱导的G蛋白偶联受体激酶(GRK)对G蛋白偶联受体(GPCR)的磷酸化是受体脱敏的关键步骤。GRK的表达水平可被GPCR的激动剂调节。GRK在体内的异常表达可以严重地影响器官和组织的功能。GRK2和GRK5是介导阿片受体磷酸化的主要亚型，在阿片受体的脱敏中起重要作用。但是，阿片类药物对GRK5的表达调节以及对GRK2在不同脑区内的表达调节还不清楚。c-Jun氨基末端蛋白激酶(JNK)是催化转录因子c-Jun磷酸化的主要蛋白激酶。JNK有3种亚型，其中JNK3特异性地分布在脑内，在脑内神经元的损伤和凋亡中发挥着极其重要的作用。吗啡通过JNK信号通路引起免疫细胞的凋亡。长期使用吗啡可引起脑内神经元结构损伤和可塑性发生改变。阿片类药物能否调节脑内JNK3表达，目前尚未见有报道。为此，我们采用原位杂交组织化学的方法，研究了急性、长期给予吗啡和吗啡戒断、纳络酮促戒断以及长时程戒断过程中，大鼠脑内多个脑区的GRK2、GRK5和JNK3三种蛋白激酶mRNA水平的变化。
结果显示，单次注射10mg／Kg吗啡能够上调GRK2和GRK5mRNA在皮层、海马以及GRK2 mRNA在丘脑的水平。每天2次，连续9天给予10mg／Kg吗啡引起吗啡耐受后，GRK2 mRNA水平在皮层、海马、五脑和蓝斑下降；GRK5mRNA水平与生理盐水对照组相比未见有显著变化。吗啡戒断显著升高GRK2和GRK5在多个脑区的mRNA水平。单次和长期给予吗啡，增加皮层的JNK3 mRNA水平，但海马、丘脑和蓝斑的JNK3 mRNA水平未见有明显变化。连续两周的长时程戒断，JNK3 mRNA水平在皮层、海马和丘脑显著升高。再次注射吗啡后，未见对这些脑区升高的JNK3 mRNA水平有明显的影响。此外，我们还比较了GRK2和GRK5mRNA在脑内的分布特征，发现在导水管周围灰质(PAG)两者的基因表达明显不同，表现为GRK5 mRNA在此区域内分布较GRK2 mRNA广泛，GRK5 mRNA阳性细胞灰度高于GRK2的mRNA阳性细胞。
我们的研究首次发现，阿片类药物能够在转录水平调控GRK的基因表达；单次和长期给予吗啡以及吗啡戒断对GRK mRNA水平的调节不同；GRK2和GRK5mRNA在PAG的分布不同；阿片类药物可以调节JNK3的基因表达；急性和长期
复旦大学博士论文 吗啡对 GRKZ。GRKS和 JNK3基因在大鼠脑内表达调控的研究
给予吗啡增加 JNK3 InRNA在皮层的水平，而未见海马、丘脑和蓝斑的 JNK3mRNA
水平发生改变，但长期吗啡戒断却引起海马和丘脑：17NH3 tYlxrvA水平迟发性升高。
我们的结果提示，阿片类药物对G见基因表达的调控，能够反过未影响阿片受体
的信号转导。吗啡增加 GIEUC的基因表达可能在急性吗啡耐受中起作用。长期给予
吗啡可以负性调节或抑制GRK的基因表达。吗啡戒断时GIUL基因超表达对于减弱
戒断过程中多种GPCR过度激活具有重要的意义。吗啡对WK3基因表达的上调在
吗啡成病和吗啡引起的脑内神经细胞损伤中起重要作用。在PAG，GRKS较G抓二
可能发挥重要的功能。
Prolonged exposure to opiate induces opioid tolerance, dependence and addiction, but the mechanisms responsible for these side-effects have not been well elucidated. Many studies have revealed that desensitization of opioid receptor is one of the molecular mechanisms of opioid tolerance. Abnormal regulation of gene expression, changes in plasticity of neuron and impairment of brain structure play important roles in the development of opioid addiction.
The phosphorylation of G protein-coupled receptor (GPCR) by G protein-coupled receptor kinases (GRKs) under the stimulation with their specific agonists is the critical step to desensitization of GPCR. Agonists for GPCR can regulate the expression level of GRK, and the abnormal expression of GRK in vivo can markedly influence physiological functions of organs and tissues. Both GRK2 and GRKS are the main isoforms of GRK in the phosphorylation of opioid receptors but the expression regulations of GRK2 and GRK5 in brain by opiates are unclear. JNKs are the primary kinases in the phosphorylation of c-Jun which isan important transcription factor in the regulation of gene expression. Three isoforms of JNKs have been cloned. JNK3 is characterized with its specific expression in brain and exerts pivotal roles in neuron apoptosis. Many research demonstrated that morphine could induce apoptosis of immunocytes and neuronal cells in vitro, and morphological impairment of neuron in brain as well as modification of neuro
nal plasticity in vivo. But whether these effects of morphine on neuronal cells are associated with the regulation of JNKs is not clarified. Using in situ hybridization in this study, we investigated the regulation of gene expression of GRK2, GRK5 and JNKS in rat brain after acute and chronic treatments with morphine, spontaneous morphine withdrawal, naloxone-precipitated withdrawal and long-term cessation of morphine.
The results showed that single injection of 10 mg/Kg morphine increased GRK2 mRNA level in cerebral cortex, hippocampus and thalamus, and GRKS mRNA level in cerebral cortex and hippocampus. Twice daily injection of 10 mg/Kg morphine for 9 days decreased GRK2 mRNA level in cerebral cortex, hippocampus, thalamus and locus coeruleus, but notGRK5 mRNA level in all the observed brain regions. Spontaneous withdrawal for 48 h and naloxone-precipitated withdrawal induced overshoot of both
GRK2 mRNA and GRK5 mRNA levels in most brain regions. Both acute and chronic morphine treatments enhanced JNK3 mRNA levels in frontal cortex, but not in hippocampus, thalamus and locus coeruleus. Long-term cessation of morphine for 2 weeks after chronic morphine treatment caused delayed increases in JNK3 mRNA levels in hippocampus and thalamus. A challenge injection of morphine could not modify the increased expression levels of JNK3 mRNA in these brain regions. The different distributions between GRK2 and GRK5 mRNA were also observed in periaqueductal gray (PAG) where GRK5 mRNA-positive cells are widely and uniformly distributed in the aqueduct with higher stain but GRK2 mRNA-positive cells only distribute around dorsal and ventral parts of the aqueduct with lower stain.
Our results first demonstrated that opiate could regulate the gene expression of GRK2, GRK5 in transcription level. Acute and chronic morphine treatments as well as morphine withdrawal could differently regulate both GRK mRNA levels in most brain regions. The expression patterns of GRK2 and GRK5 mRNA differ in PAG.. Opiate could regulate the gene expression of JNK3. Acute and chronic morphine treatments increase the gene expression of JNK3 in frontal cortex, but not in hippocampus, thalamus and locus coeruleus. Morphine abstinence could cause delayed up-regulation of JNK.3 gene expression in hippocampus and thalamus. Our results suggest that the up-regulation of GRK2 and GRK5 mRNA by acute morphine treatment may play important roles in acute opioid tolerance. Chronic morphine treatment may initiate inhibitory mechanism to down-regulate GRK2 gene expression and negatively regulate GRK5 gene
引文
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