McGovern Institute for Brain Research, Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, 43 Vassar Street, Cambridge, MA 02139, USA.
Department of Neurobiology, Duke University Medical Center, 311 Research Drive, Durham, NC 27710, USA.
Curr Biol. 2024 Sep 23;34(18):4261-4271.e5. doi: 10.1016/j.cub.2024.08.004. Epub 2024 Sep 5.
Placebo analgesia is a widely observed clinical phenomenon. Establishing a robust mouse model of placebo analgesia is needed for careful dissection of the underpinning circuit mechanisms. However, previous studies failed to observe consistent placebo effects in rodent models of chronic pain. We wondered whether strong placebo analgesia can be reverse engineered using general-anesthesia-activated neurons in the central amygdala (CeA) that can potently suppress pain. Indeed, in both acute and chronic pain models, pairing a context with CeA-mediated pain relief produced robust context-dependent analgesia, exceeding that produced by morphine in the same paradigm. CeA neurons receive monosynaptic inputs from temporal lobe areas that could potentially relay contextual cues directly to CeA neurons. However, in vivo imaging showed that CeA neurons were not reactivated in the conditioned context, despite mice displaying a strong analgesic phenotype. This finding suggests that the placebo-context-induced pain relief engages circuits beyond CeA neurons and relies on plasticity in other analgesic and/or nociceptive circuits. Our results show that conditioning with the activation of a central pain-suppressing circuit is sufficient to engineer placebo analgesia and that purposefully linking a context with an active treatment could be a means to harness the power of placebo for pain relief.
安慰剂镇痛是一种广泛观察到的临床现象。为了仔细剖析潜在的电路机制，需要建立一个强大的、适用于安慰剂镇痛的小鼠模型。然而，之前的研究未能在慢性疼痛的啮齿动物模型中观察到一致的安慰剂效应。我们想知道，使用中脑杏仁核（CeA）中被全身麻醉激活的神经元是否可以对疼痛产生强大的抑制作用，从而反向设计出强烈的安慰剂镇痛效果。事实上，在急性和慢性疼痛模型中，将 CeA 介导的镇痛与一种环境联系起来，会产生强大的、与环境相关的镇痛作用，超过了在相同范式中使用吗啡产生的镇痛效果。CeA 神经元接受来自颞叶区域的单突触输入，这些区域可能直接将环境线索传递给 CeA 神经元。然而，体内成像显示，尽管小鼠表现出强烈的镇痛表型，但在条件化环境中，CeA 神经元并没有被重新激活。这一发现表明，安慰剂-环境引起的疼痛缓解涉及到 CeA 神经元以外的回路，并依赖于其他镇痛和/或痛觉回路的可塑性。我们的结果表明，通过激活中枢抑制疼痛的回路进行条件作用，足以设计出安慰剂镇痛效果，并且将环境与有效治疗联系起来，可能是利用安慰剂缓解疼痛的一种手段。
