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; 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（由申请人提供）：处方阿片类药物，例如吗啡，羟考酮和芬太尼，通过激活MU阿片受体（MOR），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如何产生不同的生物学作用，并最终告知将利用“良好”受体信号（缓解疼痛）并避免使用“不良”的治疗剂的发展。 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通过改变与细胞内结合伴侣的亲和力来引起不同的受体信号级联反应。此外，神经元种群之间的细胞内结合伴侣轮廓不同。因此，药物反应的性质不仅可以通过药物的化学特性来确定，还可以通过与受体居住的信号蛋白的补充来确定。在生理相关系统中研究受体信号传导至关重要。影响MOR功能的一种特定细胞内蛋白是betaarrestin2。 betaarrestin2是一种脚手架蛋白，可以充当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，耐受性降低了吗啡诱导的镇痛，这意味着betaarrestin2是调节疼痛调节大脑区域的脱敏因素。我们的集体工作表明，缺乏betaarrestin2的小鼠，某些副作用的严重程度大大减少，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。由于对体内药物的受体反应性最终取决于包含受体的细胞环境，因此我们假设betaarrestin2在镇痛途径中抑制了吗啡的反应性，同时它介导了吗啡相关的侧侧作用，例如物理依赖性和便秘。为此，我们建议阐明βarartin在介导吗啡诱导的抗伤害感受和耐受性（脑干），物理依赖（纹状体）和便秘（结肠）中调节脑区域和组织中MOR的机制。我们将利用具有功能选择性的新的MOR激动剂来激活G蛋白信号传导途径（我们假设这将促进抗伤害感受）并反对招募BetaArrestin2（我们假设募集betaarrestin2导致耐受性，依赖性和便携性）。发表的初步证据表明，G蛋白有偏的激动剂促进抗伤害感受，副作用较少。我们将使用这些工具对内源环境中的Mor调节有了更深入的了解，因为它与体内生理学有关。这些研究应为开发治疗剂提供指导，从而优先增强所需影响，例如改善疼痛疗法，同时预防不良反应。