Biasing Mu Opioid Receptor Signaling in vivo

体内 Mu 阿片受体信号传导偏向

• 批准号: 8838604
• 负责人: Laura M. Bohn
• 金额: $ 48万
• 依托单位: SCRIPPS FLORIDA
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-04-01 至 2020-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8838604
• 关键词: Absence of pain sensation; Adverse effects; Adverse reactions; Affect; Affinity; Agonist; Analgesics; Arr2; Arrestins; Attenuated; Bathing; Binding; Biological; Biological Assay; Brain Stem; Brain region; C57BL/6 Mouse; CREB1 gene; Cells; Chronic; Clinical Trials; Colon; Complement; Constipation; Corpus striatum structure; Dependence; Dose; Elements; Environment; Fentanyl; G-Protein Signaling Pathway; G-Protein-Coupled Receptors; GTP-Binding Proteins; Gastrointestinal Transit; Genetic; Genotype; Goals; Guanosine Triphosphate; Infusion procedures; Knockout Mice; Lead; Ligands; Loperamide; Measures; Mediating; Morphine; Morphine Dependence; Mus; Narcotics; Nature; Neurons; Opiates; Opioid; Organ; Oxycodone; Pain; Pain management; Pathway interactions; Pharmaceutical Preparations; Phosphorylation; Physical Dependence; Physiology; Play; Population; Process; Proteins; Publishing; Pump; Receptor Signaling; Recruitment Activity; Regulation; Reporting; Research; Rodent Model; Role; Scaffolding Protein; Severities; Signal Transduction; Signaling Protein; Site; System; Tail; Testing; Therapeutic; Time; Withdrawal; base; biological systems; body system; brain tissue; central pain; chemical property; desensitization; drug development; drug structure; ileum; improved; in vivo; mu opioid receptors; prescription opioid; prevent; public health relevance; receptor; receptor function; residence; response; therapeutic development; tool

DESCRIPTION (provided by applicant): Prescription opioid narcotics, such as morphine, oxycodone, and fentanyl, produce analgesia and side effects through activation of the mu opioid receptor (MOR), a G protein coupled receptor (GPCR). Our long-standing goal is to understand how MOR signals to produce distinct biological effects and to ultimately inform the development of therapeutics that will take advantage of "good" receptor signaling (pain relief) and avoid "bad" receptor signaling (tolerance, dependence, constipation and other side effects). It has become increasingly evident that different drug structures can elicit different receptor signaling cascade at a single receptor, likely by changing the affinities for association with intracellular binding partners. Further, the intracellular binding partner profile differs between neuronal populations. Therefore, the nature of a drug response can be determined not only by the chemical properties of the drug, but also by the complement of signaling proteins found in residence with the receptor; making it critical to study receptor signaling in physiologically relevant systems. One particular intracellular protein that influences MOR function is betaarrestin2. betaArrestin2 is a scaffolding protein that can act as desensitizing element or as a signal transduction facilitator. Our studies have shown that morphine-induced analgesia is enhanced while tolerance is attenuated in mice lacking betaarrestin2, which implicates betaarrestin2 as a desensitizing factor in pain regulating brain regions. Our collective body of work shows that the severity of certain side effects, including physical dependence and constipation, are significantly reduced in mice lacking betaarrestin2 suggesting that in some organ systems and brain regions, betaarrestin2 facilitates MOR signaling. Since receptor responsiveness to a drug in vivo is ultimately dependent upon the cellular environment that encompasses the receptor, we hypothesize that betaarrestin2 dampens morphine responsiveness in analgesia pathways while it mediates morphine-associated side effects such as physical dependence and constipation. To this end, we propose to elucidate the mechanisms by which betaarrestins regulate MOR in brain regions and tissues that mediate morphine-induced antinociception and tolerance (brainstem), physical dependence (striatum) and constipation (colon). We will utilize new MOR agonists that are functionally selective for activating G protein signaling pathways (we hypothesize this will promote antinociception) and against recruiting betaarrestin2 (we hypothesize that recruiting betaarrestin2 leads to tolerance, dependence and constipation). Published and preliminary evidence suggests that the G protein biased agonists promote antinociception with fewer side effects. We will use these tools to gain a greater understanding of MOR regulation in the endogenous setting as it pertains to in vivo physiologies. These studies should provide guidance for developing therapeutics that preferentially enhance desired effects such as improving pain therapy while preventing adverse reactions.

描述(申请人提供)：处方阿片类麻醉剂，如吗啡、羟考酮和芬太尼，通过激活Mu阿片受体(MOR)产生止痛和副作用，Mor是一种G蛋白偶联受体(GPCR)。我们的长期目标是了解MOR信号如何产生不同的生物效应，并最终为利用“好的”受体信号(疼痛缓解)和避免“坏的”治疗方法的发展提供信息。 受体信号(耐受性、依赖性、便秘和其他副作用)。越来越明显的是，不同的药物结构可以在单个受体上引发不同的受体信号级联，可能是通过改变与细胞内结合伙伴的亲和力。此外，不同神经元群体的细胞内结合伙伴谱也不同。因此，药物反应的性质不仅可以由药物的化学性质决定，还可以由与受体结合的信号蛋白的补体决定；这使得研究生理相关系统中的受体信号变得至关重要。一种影响MOR功能的特殊细胞内蛋白是Betaarrestin2。BetaArrest in2是一种支架蛋白，可以作为脱敏元件或信号转导促进剂。我们的研究表明，在缺乏Betaarrestin2的小鼠中，吗啡诱导的镇痛作用增强，而耐受性减弱，这意味着Betaarrestin2是疼痛调节脑区的脱敏因子。我们的集体工作表明，在缺乏Betaarrestin2的小鼠中，某些副作用的严重性，包括身体依赖和便秘，显著减轻。这表明在某些器官系统和大脑区域，Betaarrestin2促进了MOR信号的传递。由于受体在体内对药物的反应最终取决于围绕受体的细胞环境，我们假设Betaarrestin 2抑制了镇痛途径中的吗啡反应，同时它介导了吗啡相关的副作用，如身体依赖和便秘。为此，我们建议阐明Betaarrestins调节脑区和组织中MOR的机制，这些脑区和组织介导吗啡诱导的抗伤害感受和耐受(脑干)、身体依赖(纹状体)和便秘(结肠)。我们将利用新的MOR激动剂，这些激动剂在功能上具有选择性地激活G蛋白信号通路(我们假设这将促进抗伤害性)，并对抗招募β-抑制素2(我们假设招募β-抑制素2会导致耐受、依赖和便秘)。已发表的和初步的证据表明，偏向G蛋白的激动剂促进抗伤害作用，副作用较少。我们将使用这些工具来更好地了解内源性环境下的MOR调节，因为它与体内生理学有关。这些研究应该为开发优先增强预期效果的治疗方法提供指导，例如在预防不良反应的同时改善疼痛治疗。