Department of Pharmacy and Biotechnology, Alma Mater Studiorum-University of Bologna, Irnerio 48, 40126 Bologna, Italy.
Int J Mol Sci. 2019 Mar 21;20(6):1441. doi: 10.3390/ijms20061441.
Intracellular signaling mechanisms underlying the opioid system regulation of nociception, neurotransmitters release, stress responses, depression, and the modulation of reward circuitry have been investigated from different points of view. The presence of the ubiquitin proteasome system (UPS) in the synaptic terminations suggest a potential role of ubiquitin-dependent mechanisms in the control of the membrane occupancy by G protein-coupled receptors (GPCRs), including those belonging to the opioid family. In this review, we focused our attention on the role played by the ubiquitination processes and by UPS in the modulation of opioid receptor signaling and in pathological conditions involving the endogenous opioid system. The collective evidence here reported highlights the potential usefulness of proteasome inhibitors in neuropathic pain, addictive behavior, and analgesia since these molecules can reduce pain behavioral signs, heroin self-administration, and the development of morphine analgesic tolerance. Moreover, the complex mechanisms involved in the effects induced by opioid agonists binding to their receptors include the ubiquitination process as a post-translational modification which plays a relevant role in receptor trafficking and degradation. Hence, UPS modulation may offer novel opportunities to control the balance between therapeutic versus adverse effects evoked by opioid receptor activation, thus, representing a promising druggable target.
从不同角度研究了阿片系统对伤害感受、神经递质释放、应激反应、抑郁和奖励回路调制的调节的细胞内信号机制。突触末端存在泛素蛋白酶体系统 (UPS) 表明泛素依赖性机制在控制 G 蛋白偶联受体 (GPCR) ，包括阿片类家族的 GPCR 对膜的占据中可能发挥作用。在这篇综述中，我们专注于泛素化过程和 UPS 在调节阿片受体信号和涉及内源性阿片系统的病理条件中的作用。这里报道的综合证据强调了蛋白酶体抑制剂在神经病理性疼痛、成瘾行为和镇痛中的潜在用途，因为这些分子可以减少疼痛行为迹象、海洛因自我给药和吗啡镇痛耐受的发展。此外，阿片受体激动剂与其受体结合所诱导的效应涉及泛素化过程作为一种翻译后修饰，它在受体运输和降解中发挥着重要作用。因此，UPS 调节可能为控制阿片受体激活引起的治疗与不良反应之间的平衡提供新的机会，因此，它代表了一个有前途的可药物靶标。
