RGS9-2 Modulates Responses to Oxycodone in Pain-Free and Chronic Pain States
RGS9-2 Modulates Responses to Oxycodone in Pain-Free and Chronic Pain States
复制标题
DOI：
10.1038/npp.2017.4
复制
发表时间：
2017-06-01
影响因子：
7.6
通讯作者：
Zachariou, Venetia
中科院分区：
文献类型：
--
作者：
Gaspari, Sevasti;Cogliani, Valeria;Zachariou, Venetia
G蛋白信号调节因子9 - 2（RGS9 - 2）是一种在纹状体中富集的信号转导调节剂，已知在接触精神兴奋剂或阿片类药物后成瘾相关行为的发展中起关键作用。RGS9 - 2控制几种G蛋白偶联受体的功能，包括多巴胺受体和μ阿片受体（MOR）。我们先前表明，RGS9 - 2复合物负向控制吗啡镇痛，并促进吗啡耐受性的发展。相反，RGS9 - 2正向调节其他阿片类镇痛药的作用，如芬太尼和美沙酮。在此我们研究RGS9 - 2在调节对羟考酮反应中的作用，羟考酮是一种用于治疗严重疼痛病症的MOR激动剂，具有成瘾特性。利用缺失Rgs9基因的小鼠（RGS9KO），我们证明在无痛状态以及神经性疼痛模型中，RGS9 - 2正向调节羟考酮的奖赏效应。此外，尽管RGS9 - 2不影响羟考酮的镇痛效果或身体戒断的表现，但在急性疼痛和慢性神经性疼痛模型中，它都对抗羟考酮耐受性的发展。综上所述，这些数据为调节羟考酮的奖赏和镇痛作用的信号转导机制提供了新的信息。
Regulator of G-protein signaling 9-2 (RGS9-2) is a striatal-enriched signal-transduction modulator known to have a critical role in the development of addiction-related behaviors following exposure to psychostimulants or opioids. RGS9-2 controls the function of several G-protein-coupled receptors, including dopamine receptor and mu opioid receptor (MOR). We previously showed that RGS9-2 complexes negatively control morphine analgesia, and promote the development of morphine tolerance. In contrast, RGS9-2 positively modulates the actions of other opioid analgesics, such as fentanyl and methadone. Here we investigate the role of RGS9-2 in regulating responses to oxycodone, an MOR agonist prescribed for the treatment of severe pain conditions that has addictive properties. Using mice lacking the Rgs9 gene (RGS9KO), we demonstrate that RGS9-2 positively regulates the rewarding effects of oxycodone in pain-free states, and in a model of neuropathic pain. Furthermore, although RGS9-2 does not affect the analgesic efficacy of oxycodone or the expression of physical withdrawal, it opposes the development of oxycodone tolerance, in both acute pain and chronic neuropathic pain models. Taken together, these data provide new information on the signal-transduction mechanisms that modulate the rewarding and analgesic actions of oxycodone.