Orofacial Neuropathic Pain Leads to a Hyporesponsive Barrel Cortex with Enhanced Structural Synaptic Plasticity

Chronic pain is a long-lasting debilitating condition that is particularly difficult to treat due to the lack of identified underlying mechanisms. Although several key contributing processes have been described at the level of the spinal cord, very few studies have investigated the supraspinal mechanisms underlying chronic pain. Using a combination of approaches (cortical intrinsic imaging, immunohistochemical and behavioural analysis), our study aimed to decipher the nature of functional and structural changes in a mouse model of orofacial neuropathic pain, focusing on cortical areas involved in various pain components. Our results show that chronic neuropathic orofacial pain is associated with decreased haemodynamic responsiveness to whisker stimulation in the barrel field cortex. This reduced functional activation is likely due to the increased basal neuronal activity (measured indirectly using cFos and phospho-ERK immunoreactivity) observed in several cortical areas, including the contralateral barrel field, motor and cingulate cortices. In the same animals, immunohistochemical analysis of markers for active pre- or postsynaptic elements (Piccolo and phospho-Cofilin, respectively) revealed an increased immunofluorescence in deep cortical layers of the contralateral barrel field, motor and cingulate cortices. These results suggest that long-lasting orofacial neuropathic pain is associated with exacerbated neuronal activity and synaptic plasticity at the cortical level.

慢性疼痛是一类长期致残性疾病，因尚未明确其潜在发病机制，临床治疗尤为棘手。尽管学界已在脊髓层面阐明了若干关键致病进程，但针对慢性疼痛潜在脊髓上（supraspinal）机制的研究仍寥寥无几。本研究结合皮层内源信号成像（cortical intrinsic imaging）、免疫组织化学分析与行为学检测等多种技术手段，旨在解析口面部神经病理性疼痛小鼠模型中大脑皮层的功能与结构变化本质，并聚焦于参与不同疼痛组分的皮层脑区。研究结果显示，慢性口面部神经病理性疼痛与小鼠桶状皮层（barrel field cortex）对胡须刺激的血流动力学反应性降低存在关联。这种功能激活的减弱，可能与多个皮层脑区（包括对侧桶状皮层、运动皮层与扣带回皮层）观察到的基础神经元活动增强有关——该神经元活动水平通过c-Fos与磷酸化ERK（phospho-ERK）免疫反应性间接测得。在同一批实验动物中，针对活性突触前（Piccolo）与突触后元件（磷酸化丝切蛋白，phospho-Cofilin）的标志物进行免疫组织化学分析后发现，对侧桶状皮层、运动皮层与扣带回皮层的皮层深层区域免疫荧光信号显著增强。上述结果表明，长期口面部神经病理性疼痛与皮层层面神经元活动亢进及突触可塑性（synaptic plasticity）改变密切相关。