Biasing Mu Opioid Receptor Signaling in vivo

体内 Mu 阿片受体信号传导偏向

• 批准号: 9452948
• 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/9452948
• 关键词: Absence of pain sensation; Acute; Adverse effects; Adverse reactions; Affect; Affinity; Agonist; 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 Protein alpha Subunits, Gs; GTP-Binding Proteins; Gastrointestinal Transit; Genetic; Genotype; Goals; Infusion procedures; Knock-out; Knockout Mice; Ligands; Loperamide; Measures; Mediating; Morphine; Morphine Dependence; Mus; Narcotics; Nature; Neurons; Opioid; Opioid Analgesics; Opioid agonist; Organ; Oxycodone; Pain; Pain management; Pathway interactions; Pharmaceutical Preparations; Pharmacology; Phosphorylation; Physical Dependence; Physiological; Physiology; Play; Population; Process; Proteins; Publishing; Pump; Receptor Signaling; 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; morphine tolerance; mu opioid receptors; pain processing; pain relief; prescription opioid; prevent; public health relevance; receptor; receptor function; recruit; 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 βarrestin2. 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 βarrestin2 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（由申请人提供）：处方阿片类麻醉药，例如吗啡、羟考酮和芬太尼，通过激活 mu 阿片受体 (MOR)（一种 G 蛋白偶联受体 (GPCR)）产生镇痛和副作用。我们的长期目标是了解 MOR 信号如何产生独特的生物效应，并最终为开发利用“好的”受体信号（缓解疼痛）并避免“坏的”受体信号的治疗方法提供信息 受体信号传导（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配偶体的亲和力来实现的。此外，神经元群体之间的细胞内结合配偶体谱也不同。因此，药物反应的性质不仅可以由药物的化学性质决定，还可以由与受体一起存在的信号蛋白的补体决定。因此研究生理相关系统中的受体信号传导至关重要。影响 MOR 功能的一种特殊细胞内蛋白是 βarrestin2。 betaArrestin2 是一种支架蛋白，可充当脱敏元件或信号转导促进剂。我们的研究表明，在缺乏βarrestin2的小鼠中，吗啡诱导的镇痛作用增强，而耐受性减弱，这表明βarrestin2是疼痛调节大脑区域的脱敏因子。我们的集体工作表明，在缺乏 betaarrestin2 的小鼠中，某些副作用（包括身体依赖性和便秘）的严重程度显着降低，这表明在某些器官系统和大脑区域中，betaarrestin2 促进了 MOR 信号传导。由于体内受体对药物的反应性最终取决于包围受体的细胞环境，因此我们假设 betaarrestin2 会抑制镇痛途径中的吗啡反应性，同时介导吗啡相关的副作用，例如身体依赖性和便秘。为此，我们建议阐明 betaarrestins 调节大脑区域和组织中 MOR 的机制，这些区域和组织介导吗啡诱导的镇痛和耐受（脑干）、身体依赖性（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选择性地激活 G 蛋白信号通路（我们假设这将促进镇痛）并阻止招募 βarrestin2（我们假设招募 βarrestin2 会导致耐受性、依赖性和便秘）。已发表的初步证据表明，G 蛋白偏向激动剂可促进镇痛作用，且副作用较少。我们将使用这些工具来更好地了解内源环境中的 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，例如改善疼痛治疗，同时预防不良反应。