Neuropathic pain can be a debilitating condition with both sensory and affective components, the underlying brain circuitry of which remains poorly understood. In the present study, a basolateral amygdala (BLA)–prefrontal cortex (PFC)–periaqueductal gray (PAG)–spinal cord pathway was identified that is critical for the development of mechanical and thermal hypersensitivity after peripheral nerve injury. It was shown that nerve injury strengthens synaptic input from the BLA onto inhibitory interneurons located in the prelimbic medial PFC, by virtue of reduced endocannabinoid modulation. These augmented synaptic connections mediate a feedforward inhibition of projections from the PFC to the ventrolateral PAG region and its downstream targets. Optogenetic approaches combined with in vivo pharmacology reveal that these BLA–PFC–PAG connections alter pain behaviors by reducing descending noradrenergic and serotoninergic modulation of spinal pain signals. Thus, a long-range brain circuit was identified that is crucial for pain processing and that can potentially be exploited toward targeting neuropathic pain.

神经性疼痛可能是具有感觉和情感成分的令人衰弱的疾病，其潜在的大脑电路仍知之甚少。在本研究中，确定了基底外侧杏仁核（BLA）–前额叶皮层（PFC）–导水管周围灰色（PAG）–脊髓通道，这对于周围神经损伤后机械和热超敏反应的发展至关重要。结果表明，神经损伤通过减少内源性大麻素调节，增强了从BLA向位于前缘内侧PFC的抑制性神经元的突触输入。这些增强的突触连接介导了从PFC到腹侧PAG区域及其下游靶点的投射的前馈抑制。光遗传学方法与体内药理学相结合揭示，这些BLA–PFC–PAG连接可通过减少降压的降压肾上腺素能和5-羟色胺能调节脊髓疼痛信号来改变疼痛行为。因此，确定了对于疼痛处理至关重要的远程大脑回路，并且可以潜在地用于靶向神经性疼痛。