Agonist-Directed MOR Desensitization in Opioid Analgesic Tolerance

描述（由申请人提供）：我们之前描述了一种新的阿片受体激动剂，称为herkinorin，可激活mu阿片受体而不招募？？抑制因子参与了阿片受体的脱敏和调节，以及阿片受体的移除。小鼠的Arrestin2增加吗啡的镇痛效力，同时减弱吗啡耐受性。缺乏的老鼠？Arrestin2也显示出明显减少吗啡相关的副作用，如便秘和呼吸抑制。因此，一种配体的开发可以激活mu阿片受体，但不会激活？Arrestin2相互作用，可能在药理学上概括吗啡在？Arrestin2敲除小鼠。理想情况下，这种化合物产生的镇痛药耐受性或副作用非常有限。阿片耐受性与mu阿片受体的脱敏有关。有人会预测，在没有？逮捕，铁道部不会脱敏。然而，细胞中的慢性herkinorin治疗导致MOR脱敏。该研究旨在评估这种脱敏是否与蛋白激酶c依赖的调节机制有关，因为这些激酶先前已被证明可调节mu阿片受体的反应性。进一步，我们将直接测试herkinorin是否会导致小鼠的镇痛耐受。这样的研究是必要的，以确定开发阿片类激动剂不招募？在无耐受性和副作用的情况下促进镇痛。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，我们预测这种镇痛药会产生更小的镇痛耐受性和有限的副作用，如便秘和呼吸抑制。我们将以我们最近描述的一种先导化合物为基础进行研究；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。

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.