药物成瘾是一个引人入胜的科学课题，因为对它的研究可以揭示出大脑运作是多么复杂。近日，一个国际研究小组获得了重大突破，他们发现了人体免疫系统放大对阿片类药物依赖性的关键机制，并证实可通过药物来阻断吗啡和海洛因成瘾，同时帮助缓解疼痛。临床试验预计将在未来18个月内进行。
澳大利亚阿德莱德大学和美国科罗拉多大学博尔德分校的科学家通过实验室研究发现，一种名为纳洛酮的药物可以选择性地阻断免疫成瘾反应。这项发表于《神经科学杂志》的新成果有望带来“二合一”型药物，既可缓解病人的剧烈疼痛症状，又能帮助海洛因成瘾者戒除药物依赖。
“我们的研究确凿地表明，我们可以通过大脑的免疫系统来阻止成瘾，而不针对大脑的神经系统。”研究论文的主要作者、阿德莱德大学医学院的马克·哈钦森说，“在成瘾过程中，中枢神经系统和免疫系统都发挥着重要作用，但我们的研究显示，只需阻止大脑中的免疫反应，就能阻断对阿片类药物的渴望。”
该团队将研究重点放在名为TLR4的免疫受体上。“阿片类药物，比如吗啡和海洛因，绑定TLR4受体的方式与免疫系统对细菌的正常反应相同，但问题是，TLR4随即变成了药物依赖性的放大器。”哈钦森说。
哈钦森表示，纳洛酮能够自动关闭对药物的依赖，它减少了对阿片类药物的需要以及与成瘾相关的行为，同时，大脑中的神经化学也在发生变化——大脑不再生产多巴胺了，这种重要的化学物质能够向大脑传递服用药物后的兴奋感。
研究论文的另一作者、科罗拉多大学博尔德分校神经科学中心教授琳达·沃特金斯说：“这项工作从根本上改变了我们对阿片类药物、奖励和上瘾机制的了解，多年来我们一直在怀疑TLR4可能是阻断阿片类药物成瘾的关键，现在我们掌握了证据。”
沃特金斯表示，用来阻止成瘾的药物纳洛酮是上世纪70年代发明的一种非阿片类镜像药物，他们相信可以将它与吗啡合用，进而开发出帮助患者缓解剧烈疼痛的同时又不至于让人上瘾的新止疼药物。或许有一天，在药物成瘾与戒断机理完全揭示之后，人类将告别毒品引发的生理痛苦。
Opioid Activation of Toll-Like Receptor 4 Contributes to Drug Reinforcement
M. R. Hutchinson, A. L. Northcutt, T. Hiranita, X. Wang, S. S. Lewis, J. Thomas, K. van Steeg, T. A. Kopajtic, L. C. Loram, C. Sfregola, E. Galer, N. E. Miles, S. T. Bland, J. Amat, R. R. Rozeske, T. Maslanik, T. R. Chapman, K. A. Strand, M. Fleshner, R. K. Bachtell, A. A. Somogyi, H. Yin, J. L. Katz, K. C. Rice, S. F. Maier, and L. R. Watkins
Opioid action was thought to exert reinforcing effects solely via the initial agonism of opioid receptors. Here, we present evidence for an additional novel contributor to opioid reward: the innate immune pattern-recognition receptor, toll-like receptor 4 (TLR4), and its MyD88-dependent signaling. Blockade of TLR4/MD2 by administration of the nonopioid, unnatural isomer of naloxone, (+)-naloxone (rats), or two independent genetic knock-outs of MyD88-TLR4-dependent signaling (mice), suppressed opioid-induced conditioned place preference. (+)-Naloxone also reduced opioid (remifentanil) self-administration (rats), another commonly used behavioral measure of drug reward. Moreover, pharmacological blockade of morphine-TLR4/MD2 activity potently reduced morphine-induced elevations of extracellular dopamine in rat nucleus accumbens, a region critical for opioid reinforcement. Importantly, opioid-TLR4 actions are not a unidirectional influence on opioid pharmacodynamics, since TLR4−/− mice had reduced oxycodone-induced p38 and JNK phosphorylation, while displaying potentiated analgesia. Similar to our recent reports of morphine-TLR4/MD2 binding, here we provide a combination of in silico and biophysical data to support (+)-naloxone and remifentanil binding to TLR4/MD2. Collectively, these data indicate that the actions of opioids at classical opioid receptors, together with their newly identified TLR4/MD2 actions, affect the mesolimbic dopamine system that amplifies opioid-induced elevations in extracellular dopamine levels, therefore possibly explaining altered opioid reward behaviors. Thus, the discovery of TLR4/MD2 recognition of opioids as foreign xenobiotic substances adds to the existing hypothesized neuronal reinforcement mechanisms, identifies a new drug target in TLR4/MD2 for the treatment of addictions, and provides further evidence supporting a role for central proinflammatory immune signaling in drug reward.
文献链接：Opioid Activation of Toll-Like Receptor 4 Contributes to Drug Reinforcement
