Placebo treatments are pharmacologically inert, but are known to alleviate symptoms across a variety of clinical conditions. Associative learning and cognitive expectations both play important roles in placebo responses, however we are just beginning to understand how interactions between these processes lead to powerful effects. Here, we review the psychological principles underlying placebo effects and our current understanding of their brain bases, focusing on studies demonstrating both the importance of cognitive expectations and those that demonstrate expectancy-independent associative learning. To account for both forms of placebo analgesia, we propose a dual-process model in which flexible, contextually driven cognitive schemas and attributions guide associative learning processes that produce stable, long-term placebo effects. According to this model, the placebo-induction paradigms with the most powerful effects are those that combine reinforcement (e.g., the experience of reduced pain after placebo treatment) with suggestions and context cues that disambiguate learning by attributing perceived benefit to the placebo. Using this model as a conceptual scaffold, we review and compare neurobiological systems identified in both human studies of placebo analgesia and behavioral pain modulation in rodents. We identify substantial overlap between the circuits involved in human placebo analgesia and those that mediate multiple forms of context-based modulation of pain behavior in rodents, including forebrain-brainstem pathways and opioid and cannabinoid systems in particular. This overlap suggests that placebo effects are part of a set of adaptive mechanisms for shaping nociceptive signaling based on its information value and anticipated optimal response in a given behavioral context.

安慰剂治疗在药理学上是惰性的，但已知可以缓解多种临床病症的症状。联想学习和认知期望在安慰剂反应中都发挥着重要作用，然而我们才刚刚开始了解这些过程之间的相互作用如何产生强大的影响。在这里，我们回顾了安慰剂效应背后的心理学原理以及我们目前对其大脑基础的理解，重点关注证明认知期望的重要性和那些证明与期望无关的联想学习的研究。为了解释这两种形式的安慰剂镇痛，我们提出了一个双过程模型，其中灵活的、情境驱动的认知模式和归因指导产生稳定、长期安慰剂效应的联想学习过程。根据该模型，具有最强大效果的安慰剂诱导范式是将强化（例如，安慰剂治疗后疼痛减轻的体验）与建议和情境线索相结合，通过将感知到的益处归因于安慰剂来消除学习歧义。使用该模型作为概念支架，我们回顾并比较了在啮齿动物安慰剂镇痛和行为疼痛调节的人体研究中确定的神经生物学系统。我们发现，人类安慰剂镇痛所涉及的回路与介导啮齿类动物基于情境的多种形式的疼痛行为调节的回路之间有很大的重叠，包括前脑-脑干通路，特别是阿片类药物和大麻素系统。 这种重叠表明安慰剂效应是一组自适应机制的一部分，用于根据给定行为环境中的信息价值和预期的最佳反应来塑造伤害性信号。