Opioid receptors (ORs), μOR, δOR, κOR and ORL1 mediate numerous signalling cascades, most importantly, through the modulation of ion channels. Research demonstrates the role of OR mediated signal transduction in treating pain, cancer, neurodegenerative disorders and cardiac insults. Yet, the primary application of drugs that modulate ORs is analgesia. Current opioids like morphine that are mainly μOR orthosteric agonists attract many undesirable side-effects (constipation, urinary retention, respiratory depression and hypotension) and the existing modus operandi against these is the inclusion of a μOR antagonist (for example, naloxone) which itself produces side-effects. As such, there is a current thrust to delineate the anti-nociceptive pathways mediated by ORs from the pathways involved in their induction of debilitating side-effects, in order to develop enhanced lead molecules. This review discusses the effects of natural products on the OR-induced signalling cascades and compares these to current synthetic leads and drugs. Important to these discussions is the complexity of OR signalling which involves OR trafficking, de- and re-sensitization, homo- and hetero-dimerization, the type of ligand binding (agonist, antagonist, reverse antagonist, orthosteric and allosteric agonist and antagonist in the context of biased agonism) and reasons for dysregulation that primarily occur because of inter-individual variations. Our current understanding of the different forms of ORs has expanded, thus introducing the concept of allosterism, which is also discussed. The authors present possible combination therapies to be explored towards developing the ‘Holy Grail’ of analgesics, for example, ignavine, the natural μOR positive allosteric modulator (PAM) with codeine and the natural fascaplysin, a balanced agonist with fentanyl. There remain many gaps in natural products research on ORs, more so on ORL1 and δ- and κ receptors. Furthermore, additional exploration of ORs' modulation is needed for ameliorating other associated disease conditions of global concern.

阿片类药物受体（OR），μOR，δOR，κOR和ORL1介导众多信号级联，最重要的是通过离子通道的调节。研究表明OR介导的信号转导在治疗疼痛，癌症，神经退行性疾病和心脏损伤中的作用。但是，调节OR的药物的主要应用是镇痛。目前的吗啡类阿片类药物主要是μOR正构激动剂，它会引起许多不良副作用（便秘，尿retention留，呼吸抑制和低血压），而针对这些副作用的现有作案手法是加入了自身产生的μOR拮抗剂（例如纳洛酮）。副作用。因此，目前有一种方法来描述OR介导的抗伤害感受途径与诱导其使人衰弱的副作用的途径有关，为了开发增强的铅分子。这篇综述讨论了天然产物对OR诱导的信号级联反应的影响，并将其与当前的合成前导物和药物进行了比较。对这些讨论而言，重要的是OR信号传导的复杂性，涉及OR转运，脱敏和重新敏化，同源二聚和异源二聚化，配体结合的类型（激动剂，拮抗剂，反向拮抗剂，正构和变构激动剂和拮抗剂）。激动性的背景）以及失调的原因（主要是由于个体之间的差异而引起的）。我们对OR的不同形式的当前理解已经扩展，从而引入了变构主义的概念，对此也进行了讨论。作者提出了可能的组合疗法，以开发镇痛药的“圣杯”，例如，ignavine，具有可待因的天然μOR阳性变构调节剂（PAM）和天然fascaplysin（具有芬太尼的平衡激动剂）。天然产物对ORs的研究仍存在许多空白，尤其是ORL1和δ-和κ受体。此外，为了改善全球关注的其他相关疾病，还需要进一步研究OR的调节。