OPIATE RECEPTOR PHARMACOLOGY

阿片类药物对治疗疼痛很重要，但滥用阿片类药物会造成严重的健康问题。了解阿片类药物的作用对其临床合理使用和潜在滥用治疗的发展至关重要。阿片类药物和阿片肽通过一系列受体起作用，其中许多受体已被克隆。在组织培养中对这些受体的作用进行的研究为它们的生物化学提供了重要的信息。然而，这些进步现在需要被纳入行为系统。近年来利用反义方法的研究证实了克隆阿片受体在阿片药理研究中的重要性。反义技术可用于选择性地靶向单个外显子，允许检查剪接变异体。利用这种针对编码mu受体的莫尔-1克隆的反义定位方法，我们发现吗啡及其极有效的代谢物吗啡-6 -葡糖苷（M6G）的不同选择性谱，这意味着它们通过不同的受体起作用。这一点现已在mor1基因敲除小鼠中得到证实。这些动物对吗啡不敏感，但对M6G保持敏感性。这种M6G受体的重要性通过海洛因和几种强效临床镇痛药也通过M6G受体起作用的额外观察得到加强。尽管吗啡在基因敲除小鼠中没有活性，但海洛因仍保持其充分的镇痛活性。因此，M6G受体可能被认为是一种新的海洛因受体。这一概念为未来对mu阿片系统的研究提供了重要的见解。阿片受体家族的另一个成员也被证明非常有趣。孤儿阿片受体导致鉴定了一系列新的肽称为孤儿蛋白FQ或伤害肽。这些药物具有复杂的药理学，将进一步详细探讨。最后，先前的工作已经确定sigma受体激活中枢神经系统内一个有效的抗阿片系统。这一系统是造成某些物种镇痛敏感性变化的原因。我们最近克隆了小鼠sigma受体，并计划利用它通过反义和其他方法在分子水平上更好地了解该系统。

Opiates are important for the treatment of pain, but their abuse presents a major health proglem. Understanding opioid actions is crucial to their rational use clinically and the development of potential treatments for abuse. Opiates and the opioid peptides act through a family of receptors, of which a number have been cloned. Studies on the actions of these receptors carried out in tissue culture have provided important information regarding their biochemistry. However, these advances now need to be taken into behavioral systems. Recent work using antisense approaches has confirmed the importance of the cloned opioid receptors in opioid pharmacology. Antisense techniques can be used to selectively target individual exons, permitting the examination of splice variants. Using this antisense mapping approach against the MOR-1 clone, which encodes a mu receptor, we found different selectivity profiles for morphine and its extremely potent metabolite morphine-6beta-glucuronide (M6G), implying that they act through distinct receptors. This has now been confirmed in MOR-1 knockout mice. These animals are insensitive to morphine, but retain their sensitivity to M6G. The importance of this M6G receptor is enhanced by the additional observations that heroin and several highly potent clinical analgesics also act through the M6G receptor. Despite the inactivity of morphine in the knockout mice, heroin retains its full analgesic activity. Thus, the M6G receptor might be considered a new heroin receptor. This concept provides important insights into future studies of the mu opioid system. Another member of the opioid receptor family has also proven very interesting. The orphan opioid receptor has led to the identification of a new series of peptides termed orphanin FQ or nociceptin. These agents have a complex pharmacology which will be explored in further detail. Finally, prior work has established that the sigma receptor activates a potent anti-opioid system within the central nervous system. This system is responsible for variations in analgesic sensitivity among some species. We recently cloned the murine sigma receptor and plan to utilize it to gain a better understanding at the molecular level of this system through antisense and other approaches.