Opioid crisis is a major threat of 21st century with a remarkable juxtaposition of use and abuse. Opioids are the most potent and efficacious class of analgesics but despite their proven therapeutic efficacy they have recently been degraded to third-line of therapy for the management of chronic pain in clinics. The reason behind is the development of potential side effects and tolerance after repeated dosing. Opioid tolerance is the major limiting factor leading to the treatment withdrawal, severe side effects due to dose escalation and sometimes even death of the patients. Every day more than 90 people die due to the overdose of opioids in America and similar trend has been seen across the globe. Researchers in past two decades are trying to dissect the neurobiological mechanism of opioid tolerance. Research on opioid tolerance shifted towards the CNS based adaptations because tolerance is much more than just being a cellular phenomenon. Thus, neurobiological adaptations associated with opioid tolerance are important to understand in order to set newer pain therapeutics. These adaptations are associated with the alterations in ascending and descending pain pathways, reward circuitry modulations, receptor desensitization and down-regulation, receptor internalization, heterodimerization and altered epigenetic regulation. The present review is focussed on novel circuitries in different brain areas such as periaqueductal gray (PAG), rostral ventromedial medulla (RVM), dorsal raphe nucleus (DRN), ventral tegmental area (VTA), and nucleus accumbens (NAc) associated with opioid tolerance. Understanding the neurobiological modulations associated with chronic opioid exposure and tolerance will pave the way for development of novel pharmacological tools for the safe and better management of chronic pain in patients.

中文翻译：

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支持与阿片耐受性相关的神经生物学复杂性。

阿片类药物危机是21世纪的主要威胁，其使用和滥用现象并存。阿片类药物是最有效和最有效的镇痛剂，但尽管已证明它们具有治疗作用，但它们最近已退化为临床上用于治疗慢性疼痛的第三线治疗药物。背后的原因是重复给药后潜在的副作用和耐受性的发展。阿片类药物耐受性是导致治疗停药，剂量增加导致严重副作用甚至患者死亡的主要限制因素。在美国，每天有超过90人死于阿片类药物过量，全球范围内也有类似的趋势。在过去的二十年中，研究人员试图剖析阿片耐受性的神经生物学机制。阿片类药物耐受性的研究转向了基于CNS的适应方法，因为耐受性远不只是细胞现象。因此，与阿片类药物耐受性相关的神经生物学适应性对于理解更新的止痛药非常重要。这些适应与疼痛的上升和下降途径的改变，奖励电路的调节，受体脱敏和下调，受体内在化，异二聚化和表观遗传调控的改变有关。目前的审查集中在不同脑区域的新电路，如导水管周围的灰色（PAG），延髓腹侧延髓（RVM），背缝核（DRN），腹侧被盖区（VTA）和与阿片类药物相关的伏隔核（NAc）公差。