Analgesic tolerance to mu-delta opioid bivalent ligands

描述(由申请人提供)： 阿片类药物是治疗中到重度疼痛的最佳镇痛剂，但长期使用会导致不良反应，如形成耐受性和身体依赖。我们的总体目标是开发一种不会产生这些无法忍受的副作用的新型止痛药。一个有希望的策略是靶向可能的Mu-Delta受体异源二聚体。体内研究表明，在慢性吗啡给药过程中，Delta受体的拮抗作用减少了耐受性和依赖性的形成。有研究表明，受体二聚化可能参与了这一效应。需要检验的假设是，对阿片激动剂-拮抗剂二价配体的耐受性和身体依赖性的发展依赖于两个药物载体之间的距离。为了验证这一假说，我们设计了以下具体目标：(1)评估急性给予不同间隔长度的阿片受体二价配体对热痛的影响。(2)观察不同间隔长度阿片受体二价配体急性给药对炎性疼痛的影响。(3)确定阿片受体二价配体慢性给药过程中是否形成耐受性和身体依赖。

DESCRIPTION (provided by applicant): Opioids are the best analgesics for moderate to severe pain, but their prolonged use leads to adverse effects such as the development of tolerance and physical dependence. Our overall goal is to develop a novel analgesic that does not produce these intolerable side effects. One promising strategy is to target the putative mu-delta receptor heterodimer. In vivo research indicates that antagonism of the delta receptor diminished the development of tolerance and dependence during chronic morphine administration. It has been suggested that receptor dimerization might be involved in this effect. The hypothesis to be tested is that the development of tolerance and physical dependence to opioid agonist-antagonist bivalent ligands is dependent on the distance between the two pharmacophores. The following specific aims are designed to test this hypothesis: (1) To evaluate the effects of acutely administered opioid receptor bivalent ligands with variable spacer lengths on thermal pain. (2) To evaluate the effects of acutely administered opioid receptor bivalent ligands with variable spacer lengths on inflammatory pain. (3) To determine whether tolerance and physical dependence develop during chronic administration of the opioid receptor bivalent ligands.