Harrison L M, Kastin A J, Zadina J E
Tulane University School of Medicine and Veterans Affairs Medical Center, New Orleans, LA 70112-1262, USA.
Peptides. 1998;19(9):1603-30. doi: 10.1016/s0196-9781(98)00126-0.
Despite the existence of a large body of information on the subject, the mechanisms of opiate tolerance and dependence are not yet fully understood. Although the traditional mechanisms of receptor down-regulation and desensitization seem to play a role, they cannot entirely explain the phenomena of tolerance and dependence. Therefore, other mechanisms, such as the presence of antiopiate systems and the coupling of opiate receptors to alternative G-proteins, should be considered. A further complication of studies of opiate tolerance and dependence is the multiplicity of endogenous opiate receptors and peptides. This review will focus on the endogenous opioid system--peptides, receptors, and coupling of receptors to intracellular signaling via G-proteins--in the context of their roles in tolerance and dependence. Opioid peptides include the recently discovered endomorphins and those encoded by three known genes--pro-opiomelanocortin, pro-enkephalin, and pro-dynorphin. They bind to three types of receptors--mu, delta, and kappa. Each of the receptor types is further divided into multiple subtypes. These receptors are widely known to be coupled to G-proteins of the Gi and Go subtypes, but an increasing body of results suggests coupling to other G-proteins, such as Gs. The coupling of opiate receptors to Gs, in particular, has implications for tolerance and dependence. Alterations at the receptor and transduction level have been the focus of many studies of opiate tolerance and dependence. In these studies, both receptor down-regulation and desensitization have been demonstrated in vivo and in vitro. Receptor down-regulation has been more easily observed in vitro, especially in response to morphine, a phenomenon which suggests that some factor which is missing in vitro prevents receptors from down-regulating in vivo and may play a critical role in tolerance and dependence. We suggest that antiopiate peptides may operate in vivo in this capacity, and we outline the evidence for the antiopiate properties of three peptides: neuropeptide FF, orphanin FQ/nociceptin, and Tyr-W-MIF-1. In addition, we provide new results suggesting that Tyr-W-MIF-1 may act as an antiopiate at the cellular level by inhibiting basal G-protein activation, in contrast to the activation of G-proteins by opiate agonists.
尽管关于该主题已有大量信息，但阿片类药物耐受性和依赖性的机制尚未完全明确。虽然传统的受体下调和脱敏机制似乎发挥了作用，但它们无法完全解释耐受性和依赖性现象。因此，应考虑其他机制，如抗阿片系统的存在以及阿片受体与其他G蛋白的偶联。阿片类药物耐受性和依赖性研究的另一个复杂因素是内源性阿片受体和肽的多样性。本综述将聚焦于内源性阿片系统——肽、受体以及受体通过G蛋白与细胞内信号传导的偶联——在耐受性和依赖性中的作用。阿片肽包括最近发现的内吗啡肽以及由三个已知基因编码的肽——阿片促黑皮质素原、脑啡肽原和强啡肽原。它们与三种类型的受体——μ、δ和κ受体结合。每种受体类型又进一步分为多个亚型。众所周知，这些受体与Gi和Go亚型的G蛋白偶联，但越来越多的研究结果表明它们也与其他G蛋白，如Gs偶联。特别是阿片受体与Gs的偶联，对耐受性和依赖性具有重要意义。受体和转导水平的改变一直是阿片类药物耐受性和依赖性许多研究的重点。在这些研究中，体内和体外均已证实受体下调和脱敏现象。受体下调在体外更容易观察到，尤其是对吗啡的反应，这一现象表明体外缺乏的某些因素阻止了受体在体内下调，并且可能在耐受性和依赖性中起关键作用。我们认为抗阿片肽可能在体内发挥这种作用，并且我们概述了三种肽——神经肽FF、孤啡肽/痛敏肽和酪氨酸-色氨酸-巨噬细胞移动抑制因子-1——具有抗阿片特性的证据。此外，我们提供了新的研究结果，表明与阿片激动剂激活G蛋白相反，酪氨酸-色氨酸-巨噬细胞移动抑制因子-1可能通过抑制基础G蛋白激活在细胞水平上发挥抗阿片作用。
