Identification of factors in peripheral sensory neurons that contribute to the axonal targeting and functional coupling of G protein-coupled receptors such as opioid receptors

鉴定外周感觉神经元中有助于 G 蛋白偶联受体（如阿片受体）的轴突靶向和功能偶联的因素

• 批准号: 237095764
• 负责人: Professor Dr. Shaaban Mousa, Ph.D.
• 金额: --
• 依托单位: Klinik für Anästhesiologie mit Schwerpunkt operative Intensivmedizin
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2013
• 资助国家: 德国
• 起止时间: 2012-12-31 至 2016-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/237095764?language=en
• 关键词: Identification; factors; peripheral; sensory; neurons

It is well known that G protein-coupled receptors (GPCR) in peripheral sensory neurons contribute to the excitation and sensitization as well as to their inhibition. Since ion channels are distributed not only at the nerve terminals, but also along the axolemma of peripheral sensory neurons, the question arises whether it is conceivable that GPCRs are also located and functionally coupled to the axonal membrane? The demonstration of such GPCRs, e.g. opioid receptors, integrated into the axonal membrane is yet unknown and would encourage the clinical use of drugs for such receptors, e.g. opioids. First clinical trials seem to indicate a clinical benefit for patients suffering from nerve injury. Consistently, in animal models of sciatic nerve injury perineural application of opioids elicited potent antinociceptive effects, although they were not observed in animal models of inflammatory pain. Here we investigate the hypothesis that mechanisms of mu-opioi receptors (MOR) axonal transport, membrane targeting and functional coupling are different in peripheral nerve injury versus inflammatory pain. Our first goal will identify in animals with complete Freunds adjuvant hindpaw inflammation versus animals with chronic constriction nerve injury the distinct antinociceptive effects of perineural opioids in relation to their axonal presence and functional coupling of MOR. The second goal will identify whether MOR enter the axonal initial segment, a filter for axonally delivered proteins, they colocalize with vesicle-associated membrane proteins (VAMP), they are transported via motor proteins such as kinesins along intraaxonal microtubules, and they are finally delivered to their destination via myosin Va motor proteins along F-actin filaments. By interfering with these mechanisms we will assess the individual relevance of these components. The third goal will test local mechanisms such as enhanced production of lipid rafts, increased expression of G protein-regulated inducer of neurite outgrowth (GRIN1), or up-regulation of neural cell adhesion molecule L1 (L1-CAM) of being responsible for the integration of MOR into the axonal membrane and whether they depend on the local expression of growth factors (e.g. NGF). To understand the exact mechanisms that determine the targeting and functionally coupling of GPCRs such as opiod receptors to the axonal membrane may give novel incentives and tools to regulate this process towards a therapeutic advantage. This would be of great relevance particularly for patients suffering from severe pain due to nerve injury or to tumor infiltration.

众所周知，外周感觉神经元中的G蛋白偶联受体（GPCR）有助于兴奋和致敏，也有助于抑制它们。由于离子通道不仅分布在神经末梢，而且沿着外周感觉神经元的轴膜分布，因此产生了一个问题，即是否可以想象GPCR也位于轴突膜并在功能上与轴突膜偶联？此类GPCR（例如阿片样物质受体）整合到轴突膜中的证明尚不清楚，并且将鼓励用于此类受体（例如阿片样物质）的药物的临床使用。第一次临床试验似乎表明对神经损伤患者的临床益处。一致的是，在坐骨神经损伤的动物模型中，神经周围应用阿片类药物引起了有效的抗伤害性作用，尽管在炎性疼痛的动物模型中没有观察到。在这里，我们调查的假设，μ阿片受体（莫尔）轴突运输，膜靶向和功能耦合的机制是不同的周围神经损伤与炎症性疼痛。我们的第一个目标是在完全弗氏佐剂后爪炎症动物与慢性压迫性神经损伤动物中确定神经周围阿片类药物与其轴突存在和莫尔功能偶联相关的独特抗伤害作用。第二个目标是确定莫尔是否进入轴突起始段，轴突递送蛋白的过滤器，它们与囊泡相关膜蛋白（VAMP）共定位，它们通过马达蛋白如驱动蛋白沿着轴突内微管转运，并且它们最终通过肌球蛋白Va马达蛋白沿沿着F-肌动蛋白丝递送到它们的目的地。通过干预这些机制，我们将评估这些组件的个体相关性。第三个目标将测试局部机制，如脂筏的产生增强，G蛋白调节的神经突生长诱导物（GRIN 1）的表达增加，或负责将莫尔整合到轴突膜中的神经细胞粘附分子L1（L1-CAM）的上调，以及它们是否依赖于生长因子（例如NGF）的局部表达。为了理解确定GPCR如阿片受体与轴突膜的靶向和功能性偶联的确切机制，可以提供新的激励和工具来调节该过程以获得治疗优势。这对于由于神经损伤或肿瘤浸润而遭受严重疼痛的患者尤其具有重要意义。

项目成果

Accessibility of axonal G protein coupled mu‐opioid receptors requires conceptual changes of axonal membrane targeting for pain modulation

• DOI: 10.1016/j.jconrel.2017.10.016
• 发表时间: 2017-12
• 期刊: Journal of Controlled Release
• 影响因子: 10.8
• 作者: S. Mousa;M. Shaqura;Mohammed A Al-Madol;S. Tafelski;Baled I. Khalefa;M. Shakibaei;M. Schäfer

New insights into mechanisms of opioid inhibitory effects on capsaicin-induced TRPV1 activity during painful diabetic neuropathy

• DOI: 10.1016/j.neuropharm.2014.05.026
• 发表时间: 2014-10
• 期刊: Neuropharmacology
• 影响因子: 4.7
• 作者: M. Shaqura;Baled I. Khalefa;M. Shakibaei;C. Zöllner;M. Al-Khrasani;S. Fürst;M. Schäfer;S. Mousa

Protein kinase C-mediated mu-opioid receptor phosphorylation and desensitization in rats, and its prevention during early diabetes

• DOI: 10.1097/j.pain.0000000000000459
• 发表时间: 2016-04-01
• 期刊: PAIN
• 影响因子: 7.4
• 作者: Mousa, Shaaban A.;Shaqura, Mohammed;Schaefer, Michael
• 通讯作者: Schaefer, Michael

New Morphine Analogs Produce Peripheral Antinociception within a Certain Dose Range of Their Systemic Administration

• DOI: 10.1124/jpet.116.233551
• 发表时间: 2016-10-01
• 期刊: JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS
• 影响因子: 3.5
• 作者: Lacko, Erzsebet;Riba, Pal;Al-Khrasani, Mahmoud
• 通讯作者: Al-Khrasani, Mahmoud

Evidence for MOR on cell membrane, sarcoplasmatic reticulum and mitochondria in left ventricular myocardium in rats

MOR 对大鼠左心室心肌细胞膜、肌浆网和线粒体的影响的证据

• DOI: 10.1007/s00380-015-0784-8
• 发表时间: 2016
• 期刊: Heart and Vessels
• 影响因子: 1.5
• 作者: Treskatsch S;Shaqura M;Dehe L;Roepke TK;Shakibaei M;Schäfer M;Mousa SA
• 通讯作者: Mousa SA