OPIATE RECEPTOR PHARMACOLOGY

阿片类药物对于治疗疼痛很重要，但它们的滥用会带来重大的健康问题。 了解阿片类药物的作用对于临床合理使用和开发潜在的滥用治疗方法至关重要。 阿片类药物和阿片肽通过一系列受体发挥作用，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提供了有关其生物化学的重要信息。 然而，这些进步现在需要纳入行为系统中。 最近使用反义方法的工作证实了克隆的阿片受体在阿片药理学中的重要性。 反义技术可用于选择性地靶向单个外显子，从而允许检查剪接变体。 使用这种针对编码 mu 受体的 MOR-1 克隆的反义作图方法，我们发现吗啡及其极强代谢物吗啡-6β-葡萄糖苷酸 (M6G) 具有不同的选择性特征，这意味着它们通过不同的受体发挥作用。 现在这一点已在 MOR-1 敲除小鼠中得到证实。 这些动物对吗啡不敏感，但保留对 M6G 的敏感性。 海洛因和几种高效临床镇痛药也通过 M6G 受体发挥作用的额外观察结果增强了这种 M6G 受体的重要性。 尽管吗啡在基因敲除小鼠中失去活性，但海洛因保留了其全部镇痛活性。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 mu 阿片类药物系统的未来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。 孤儿阿片受体导致了一系列新的肽的鉴定，称为孤儿素 FQ 或伤害感受肽。 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西格玛受体激活中枢神经系统内的有效抗阿片系统。 该系统是造成某些物种镇痛敏感性差异的原因。 我们最近克隆了小鼠西格玛受体，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.