ROLE OF INTERNALIZATION IN THE FUNCTIONAL REGULATION OF OPIOID & ORL-1 RECEPTORS

研究MU、Delta和ORL-1受体及其受体的转运 受体激活后的配体。 a)。MU的细胞分布和/或囊泡定位是什么 不同急性和慢性损伤后的体外和体内受体 激动剂治疗。在体外，三角洲和ORL-1的运输 与Mu受体类似的受体？ B)随着荧光阿片肽配体的开发和使用，可以 我们研究了配体和受体的运输，并在现实中进行了观察 时间到了。 C)表面阿片和ORL-1受体恢复的动力学是什么 在体外和体内进行激动剂治疗后？什么是 在体外参与表面受体恢复的过程。 2.确定阿片类配体的结构特征 对于触发Mu、Delta和ORL-1受体的隔离和 确定配体的触发能力之间是否存在任何关联 内化及其对其他受体功能的效力或功效。 A)要求多肽和生物碱配体具有什么结构特征 在体外诱导MU、Delta和ORL-1受体的封存。 B)配体的触发能力之间有什么关系 内化及其结合亲和力或抑制效力 的cAMP蓄积和GTP-GammaS结合的刺激 ORL-1受体。 C)激动剂在体内引起内化的能力与 在体外对Mu、Delta和ORL-1受体？ 3.确定亩封存的功能意义 感受器。 A.MU的脱敏和复敏有区别吗？ 诱导隔离的激动剂之间的体外受体与那些 那不是吗？ 诱导内化的MU激动剂是否对 长时程增强(LTP)与哪些不同？ C.野生型和野生型之间的适应过程有何不同 内化缺陷突变体Mu受体？ D.行为表现和药理学后果是什么 阿片类药物治疗在表达内化缺陷小鼠中的作用 受体？ 4.确定MU、Delta或ORL-1受体内化是否可以 在诱导阿片类药物内源性释放的条件下观察 多肽。 A.应激后中枢神经系统能否观察到受体隔离- 使用游泳应激模型的诱导镇痛(SIA)？ 杏仁核点燃是否导致受体隔离？ C.刺激海马体的穿透通路是否会导致 受体隔离？

To study the trafficking of mu, delta and ORL-1 receptors and their ligands following receptor activation. a). What is the cellular distribution and/or vesicular localization of mu receptors both in vitro and in vivo following various acute and chronic agonist treatments. In vitro, is the trafficking of the delta and ORL-1 receptors similar to that of the mu receptor? b) With the development and use of fluorescent opioid peptide ligands, can we study the trafficking of ligands and receptors be observed in real time. C) What are the kinetics of recover of surface opioid and ORL-1 receptors following agonist treatment both in vitro and in vivo? What are the processes involved in the recovery of surface receptor in vitro. 2. To identify the structural features of opioid ligands which are critical for triggering mu, delta,, and ORL-1 receptor sequestration and determine if any correlation exists between a ligand's ability to trigger internalization and its potency or efficacy for other receptor functions. a) What structural features of peptide and alkaloid ligands are required to induce sequestration of mu, delta and ORL-1 receptors in vitro. b) What is the relationship between a ligand's ability to trigger internalization and its binding affinity potency or efficacy in inhibition of cAMP accumulation and stimulation of GTPgammaS binding in mu, delta and ORL-1 receptors. c) Is an agonist's capacity to cause internalization the same in vivo as in vitro for mu, delta and ORL-1 receptors? 3. To determine the functional significance of sequestration of mu receptors. a. Is there a difference in desensitization or resensitization of the mu receptor in vitro between agonists that induce sequestration verses those that do not? b. Do mu agonists that induce internalization have the same effects on long-term potentiation (LTP) as those which do not? c. How do adaptational processes differ between wild type and internalization-deficient mutant mu receptors? d. What are the behavioral manifestations and pharmacological consequences of opioid treatment in a mouse expressing an internalization-deficient mu receptor? 4. To determine whether mu, delta, or ORL-1 receptor internalization can be observed under conditions which induce the endogenous release of opioid peptides. a. Can receptor sequestration be observed in the CNS following stress- induced analgesia (SIA) using the swim stress model? b. Does amygdala kindling result in receptor sequestration? c. Does stimulation of the perforant pathway of the hippocampus result in receptor sequestration?