CN108785676A - Trpv1对map成瘾调控作用 - Google Patents

Trpv1对map成瘾调控作用 Download PDF

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CN108785676A
CN108785676A CN201810662266.0A CN201810662266A CN108785676A CN 108785676 A CN108785676 A CN 108785676A CN 201810662266 A CN201810662266 A CN 201810662266A CN 108785676 A CN108785676 A CN 108785676A
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map
trpv1
habituation
regulating
controlling effects
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田玉花
郑劼
金景玉
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Qingdao University
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    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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Abstract

本发明公开了TRPV1对MAP成瘾调控作用，本发明揭示了TRPV1对MAP成瘾调控作用。TRPV1对MAP直接调控或者TRPV1通过改变关键脑区中突触前多巴胺DA释放实现对MAP调控。本发明的有益效果是能够指导治疗MAP的戒断、成瘾和复吸。

Description

TRPV1对MAP成瘾调控作用
技术领域
本发明属于医学技术领域，涉及TRPV1对MAP成瘾调控作用。
背景技术
甲基苯丙胺的滥用及成瘾已成为严重的公共卫生问题和社会问题20世纪90 年代以来，甲基苯丙胺(Methamphetamine，MAP；冰毒)已成为世界上流行最 快、滥用最为广泛的中枢兴奋剂。MAP不仅对人体中枢神经系统有严重的损害 作用，而且从社会学的角度对吸毒个人及其家庭均有广泛的危害性。《2015年中 国毒品形势报告》指出：截至2015年底，全国毒品滥用问题发生新变化，呈现 出滥用海洛因等阿片类毒品人员比例下降，而滥用合成毒品人员比例上升的特 点。在新发现的53.1万名吸毒人员中滥用合成毒品人员占80.5％，其中冰毒占 73.2％。MAP成瘾机制的研究对于指导临床治疗MAP等合成毒品的戒断、预防、成瘾和复吸具有重要意义。然而，由于目前对MAP成瘾机制研究相对较少，导 致成瘾治疗也面临巨大的困境。
辣椒素受体有望成为毒品成瘾研究的热点和新前沿。辣椒素受体(transientreceptorpotential vanilloid subtype 1channel，TRPV1)属于非特异性离子通道， 可被辣椒素(capsaicin)、内源性脂肪、有害热刺激、低pH值以及endovaniloids 等激活。TRPV1在体内的作用可以分为外周和中枢两部分：在外周，其作用主 要体现在神经末梢的感觉形成，是早期研究热点。而在中枢神经系统，TRPV1 的作用主要体现在知觉和行为的调节过程。TothA等人提出TRPV1蛋白表达神 经元存在于整个神经轴中，包括皮质区、纹状体以及海马。另外，有文献报导 TRPV1也分布在下丘脑、脑干和小脑等部位，参与突触可塑性的调节过程。而 近期的一些研究已证明TRPV1也分布在伏核(Nucleus accumbens,NAc)及背侧纹状体(Dorsal striatum,DSt)等脑区。众所周知这两个脑区均属于中枢神经系 统的“奖赏系统”，与毒品的成瘾有着密切的联系，成瘾性药物的滥用会导致正 常的奖赏系统相关神经回路和核团病理性改变，特别是增强中脑多巴胺神经元的 功能，尤以伏核更为显著。
发明内容
本发明的目的在于提供TRPV1对MAP成瘾调控作用，本发明的有益效果 是能够指导治疗MAP的戒断、成瘾和复吸。
本发明所采用的技术方案是TRPV1对MAP成瘾调控作用。
进一步，TRPV1对MAP直接调控。
进一步，TRPV1通过改变关键脑区中突触前多巴胺DA释放实现对MAP调 控。
附图说明
图1是CPP获得及恢复模型的给药方案；
图2是根据Mouse brain map确定伏核和背侧纹状体位置，进行脑内微注射。
具体实施方式
下面结合具体实施方式对本发明进行详细说明。
利用TRPV1拮抗剂和TRPV1敲除小鼠已充分证明TRPV1参与MAP成瘾 调控过程，并且是通过改变关键脑区中突触前多巴胺(dopamine,DA)释放而实 现的，改变DA释放的原因的途径是包括通过DA受体介导的MAPK信号传导 通路。另外，TRPV1对MAP也会直接调控。本发明利用已优化的动物和细胞模 型，采用电生理学技术以及多种分子生物学技术阐明其确切的分子机制，从而为 MAP的成瘾治疗研究提供可靠线索。
实验一、利用脑内微注射TRPV1拮抗剂确证其对MAP成瘾的调控作用具 有脑区特异性；
1.利用C57BL/6J雄性小鼠，采用在前期工作中已成功构建的MAP CPP获得及 恢复模型，观察TRPV1拮抗剂SB366791脑内微注射对MAP CPP获得及恢复的 抑制作用。我们将CPP获得和恢复模型的给药方案设计为如图1所示。
2.TRPV1拮抗剂SB366791将在腹腔注射MAP前30分钟进行伏核和背侧纹状 体内微注射，SB366791的剂量根据相关文献采用0.2ng/site(图2)。
3.C57BL/6J雄性小鼠适应性喂养一周后，随机分为4组即正常组、MAP单独给 药组(1mg/kg)、SB366791自身给药组(0.2ng/site)、SB366791与MAP同时 给药组，给药周期如图1所示。
4.CPP实验结束后处死小鼠，取相关脑区伏核与背侧纹状体，为下一步离体实验备用。
实验二、证明TRPV1是通过改变多巴胺转运蛋白、囊泡内单胺转运蛋白、 DA受体介导的MAPK信号通路以及在脑内与神经可塑性有关多种转录因子的 表达调控MAP成瘾；
1.利用SB366791+MAP给药组小鼠伏核与背侧纹状体组织，采用western blot、 放射自显影、免疫组化等方法，观察多巴胺转运蛋白、囊泡内单胺转运蛋白、 DA受体介导的MAPK信号通路以及在脑内与神经可塑性有关多种转录因子的 表达是否发生变化。
2.通过在体水平实验筛选可能参与的分子或通路后，利用质粒或慢病毒等工具，在HEK293细胞上分别进行TRPV1和其它目的分子如DA受体、MAPK等的共 转染后进行优化，利用western blot以及钙成像等技术证明共转染成功。
3.利用上述TRPV1与DA受体或TRPV1与MAPK共转染成功的细胞模型，采 用膜片钳技术和多种分子生物学技术，进一步阐明TRPV1通过DA而调控MAP 成瘾的确切机制。
实验三、确证MAP本身直接调控TRPV1；
1.取MAP单独给药组的小鼠伏核与背侧纹状体组织，进行real time RT-PCR、western blot和放射自显影法，在mRNA、蛋白及受体数目水平观察并分析TRPV1 对MAP成瘾的调控作用。
2.采用质粒在HEK293细胞上进行TRPV1过表达后，利用膜片钳技术，分别在 胞内或胞外给予MAP后测定细胞的电流反应，进一步明确MAP直接调控TRPV1 的可能性。
近年来由于麻黄素等MAP的制毒原料唾手可得，导致其非法制造和滥用现 象日益严重，而这种趋势必然会引发严重的社会问题。因此，MAP成瘾治疗及 药物研究，早已引起世界各国医药学界专家和政府部门的重视。本发明可以证明TRPV1在MAP成瘾过程中起到非常重要的作用。本发明首次提出TRPV1通过 影响脑内DA释放调控MAP成瘾，并且通过CPP实验和在体微透析得到了初步 的证实，而揭示TRPV1影响DA在脑内释放的确切分子机制对于指导临床治疗 MAP的戒断、成瘾和复吸具有重要意义。
以上所述仅是对本发明的较佳实施方式而已，并非对本发明作任何形式上的 限制，凡是依据本发明的技术实质对以上实施方式所做的任何简单修改，等同变 化与修饰，均属于本发明技术方案的范围内。

Claims (3)

1.TRPV1对MAP成瘾调控作用。
2.按照权利要求1所述TRPV1对MAP成瘾调控作用，其特征在于：所述TRPV1对MAP直接调控。
3.按照权利要求1所述TRPV1对MAP成瘾调控作用，其特征在于：所述TRPV1通过改变关键脑区中突触前多巴胺DA释放实现对MAP调控。
CN201810662266.0A 2018-06-25 2018-06-25 Trpv1对map成瘾调控作用 Pending CN108785676A (zh)

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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102428071A (zh) * 2009-05-07 2012-04-25 格吕伦塔尔有限公司 作为香草类化合物受体之配体的取代的苯基脲及苯基酰胺
CN103906734A (zh) * 2011-09-26 2014-07-02 格吕伦塔尔有限公司 被取代的甲磺酰胺衍生物作为类香草素受体配体

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102428071A (zh) * 2009-05-07 2012-04-25 格吕伦塔尔有限公司 作为香草类化合物受体之配体的取代的苯基脲及苯基酰胺
CN103906734A (zh) * 2011-09-26 2014-07-02 格吕伦塔尔有限公司 被取代的甲磺酰胺衍生物作为类香草素受体配体

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
YU-HUA TIAN等: "Blockade of TRPV1 Inhibits Methamphetamine-induced Rewarding Effects", 《SCIENTIFIC REPORTS》 *

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Inventor after: Tian Yuhua

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Application publication date: 20181113