周围神经损伤慢性疼痛中基因环境交互作用影响神经网络重塑机制及新靶点研究

Chronic pain has been extensively studied in clinic and basic neuroscience as a common commobidity after peripheral nerve injury(PNI), often refractory to currently established medications. The pathogenesis remains unknown but is believed to be related to both psycho-environmental and genetic factors such as ADRB2, COMT, OPRD,etc. Given such genetic substrates already known, numerous studies have also emphasized the importance of understanding how gene-environment interaction(GEI) affect individual’s phenotype in such disease. Along this line, Mogil et al. have recently, for the first time, manifested strong evidence of GEI of capsacin-induced pain in human and animal model. However, the mechanistic detail of GEI in chronic pain remains to be elucidated. Our preliminary findings suggest strong correlation of neuropathic phenotype with brain functional and structural changes in rodent model, with pain recovery and non-recovery rodent brain showing different pattern of brain functional and structural reorganization in limbic system, especially nucleus accumbens(NAc)-related brain circuit. Based on the knowledge that Nac and limbic system is both implicated in external input perception and modulated by genetic polymorphisms, we hypothesis that brain circuit- and network-scale changes serve as a pivotal mechanism for GEI to cause phenotypical variance in chronic pain. In this project, we aim to address this hypothesis using bench-to-bedside and back-to-bench paradigms. We would first investigate the brain network changes and its possible genetic substrates in PNI-induced chronic pain rodent model. We then study the chronic pain of amputation patients with imaging-genomic methodology to explore the critical single nucleus polymorphisms and associated brain network changes associated with GEI . We finally revalidated the proposed brain mechanism of GEI, back into rodent model , by intervening the associated functional/structural circuit and its pharmacological targets. Our project would tremendously improve current understanding of GEI in brain circuit- and network-scale level in chronic pain, and suggest potential therapeutic targets for treating chronic pain after PNI.

慢性疼痛是临床周围神经损伤后常见并发症，治疗困难，目前认为其发病与遗传因素及环境心理因素有关。近期研究表明，基因-环境间交互作是影响基因型表达和生物学功能的关键因素之一，但这种交互作用具体机制尚不明确。我们前期实验表明，周围神经损伤后，鼠脑边缘系统在功能、结构网络层面发生重塑，其中伏隔核相关回路变化与行为学表型高度一致。基于目前已知边缘系统参与外界感知并接受内源性基因多态性调节，我们推测基因-环境间交互作用可影响边缘系统神经网络而产生相应表型。本课题拟建立动物疼痛模型研究脑网络改变并筛选有潜在意义的单核苷酸多态性位点；其次通过临床研究探索这些基因多态与环境应激交互作用对于脑功能连接、白质结构及灰质形态三方面的影响;最后通过构建遗传、环境两因素下动物模型，验证临床发现，并对相应回路的传导、结构及药理学靶点进行干预实验。本研究旨在加深对于周围神经损伤慢性疼痛神经网络机制的理解，探索新治疗靶点。