Agonist-Directed MOR Desensitization in Opioid Analgesic Tolerance

激动剂导向的 MOR 脱敏治疗阿片类镇痛耐受

• 批准号: 7851235
• 负责人: Laura M. Bohn
• 金额: $ 9.73万
• 依托单位: SCRIPPS FLORIDA
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-06-01 至 2011-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7851235
• 关键词: Absence of pain sensation; Acute; Adverse effects; Agonist; Analgesics; Arrestins; Attenuated; Binding; Biochemical; Biological Assay; Brain region; CNS processing; Cells; Characteristics; Chronic; Constipation; Coupling; Development; Dose; Excision; G protein coupled receptor kinase; G-Protein-Coupled Receptors; GTP-Binding Proteins; Genetic; In Vitro; Knockout Mice; Lead; Ligands; Mediating; Minor; Modeling; Morphine; Mus; Nociception; Opiates; Opioid; Opioid Analgesics; Opioid Receptor; Pain; Perception; Pharmaceutical Preparations; Phosphorylation; Phosphotransferases; Physical Dependence; Property; Protein Kinase C; Rattus; Recruitment Activity; Regulation; Research Design; Role; Structure; Tail; Testing; base; desensitization; design; drug development; in vivo; kinase inhibitor; male; mu opioid receptors; novel; novel therapeutics; public health relevance; radioligand; receptor; receptor coupling; receptor internalization; respiratory; response; spinal reflex

DESCRIPTION (provided by applicant): We have previously described a novel opioid agonist, termed herkinorin, that activates mu opioid receptors without recruiting ?arrestin2. ?arrestins are involved in desensitizing and regulating opioid receptors and the removal ?arrestin2 in mice increases morphine's analgesic potency while attenuating morphine tolerance. Mice that lack ?arrestin2 also display significantly reduced morphine-associated side effects, such as constipation and respiratory suppression. Therefore, the development of a ligand that could activate the mu opioid receptor, but not invoke the ?arrestin2 interaction, may pharmacologically recapitulate the effects of morphine in ?arrestin2 knockout mice. Such compounds would ideally produce analgesia with very limited tolerance or side effects. Opioid tolerance has been associated with the desensitization of the mu opioid receptor. One would predict that in the absence of ?arrestins, the MOR would not be desensitized. However, chronic herkinorin treatment in cells leads to a desensitized MOR. This proposal has been developed to assess whether that desensitization is due to protein kinase C-dependent regulatory mechanisms as these kinases have been previously shown to regulate mu opioid receptor responsiveness. Further, we will directly test whether herkinorin will lead to analgesic tolerance in mice. Such studies are necessary to determine the feasibility of developing opioid agonists that do not recruit ?arrestins to promote analgesia in the absence of tolerance and side effects. The Public Health Relevance: Our studies are designed to explore the feasibility of designing new opioid analgesics that we predict will produce less analgesic tolerance and limited side effects such as constipation and respiratory suppression. We will base our studies on a lead compound that we have recently described; this compound has very promising biochemical properties that would lead us to predict it would possess these favorable characteristics.

描述（由申请人提供）：我们以前已经描述了一种新的阿片类激动剂，称为herkinorin，激活μ阿片受体，而不招募？逮捕2. ?抑制蛋白参与脱敏和调节阿片受体和清除？小鼠中的arrestin 2增加吗啡的镇痛效力，同时减弱吗啡耐受性。缺少的老鼠？抑制蛋白2还显示出显著降低的吗啡相关副作用，例如便秘和呼吸抑制。因此，开发一种配体，可以激活μ阿片受体，但不调用？arrestin 2的相互作用，可能会重演吗啡的影响？arrestin 2基因敲除小鼠。这样的化合物理想地产生具有非常有限的耐受性或副作用的镇痛。阿片耐受性与μ阿片受体的脱敏有关。有人会预测，在没有？抑制蛋白，则莫尔不会脱敏。然而，细胞中的慢性赫肯诺林治疗导致脱敏的莫尔。该提议已被开发以评估脱敏是否是由于蛋白激酶C依赖性调节机制，因为这些激酶先前已被证明可调节μ阿片受体反应性。此外，我们将直接测试赫肯诺林是否会导致小鼠的镇痛耐受性。这些研究是必要的，以确定开发阿片类激动剂，不招募？抑制素，以促进镇痛的耐受性和副作用的情况下。公共卫生相关性：我们的研究旨在探索设计新的阿片类镇痛药的可行性，我们预测这些镇痛药将产生更少的镇痛耐受性和有限的副作用，如便秘和呼吸抑制。我们将基于我们最近描述的一种先导化合物进行研究;这种化合物具有非常有前途的生化特性，这将使我们预测它将具有这些有利的特性。