SFB 1158: From nociception to chronic pain: Structure-function properties of neural pathways and their reorganisation

慢性病理性疼痛仍然是一个全球性的健康问题，也是对基础和临床科学的挑战。一个主要的障碍是，复杂的、多维的疼痛体验背后的神经回路的性质还没有被很好地理解，并且伴随着疼痛慢性化的各种不同的适应不良可塑性过程还没有从潜在的机制和功能相关性方面得到破译。重要的是，慢性疼痛与焦虑、恐惧和抑郁的相互关系仍不清楚，而焦虑、恐惧和抑郁会恶化预后。该联盟的主要目标是了解赋予疼痛感知特异性的细胞、电路和网络的结构-功能特性，并解决这些特性在从急性疼痛向慢性疼痛的转变过程中如何改变。重要的是，该联盟包括慢性疼痛的动物模型以及慢性疼痛患者，并努力实施翻译措施，将获得的知识用于得出新的治疗原则。我们在第一个筹资阶段进行的结构-功能分析阐明了特定区域、途径和特定活动节律对慢性疼痛的产生和维持的不同贡献。我们在第二个资助期进行了详细的机制分析，揭示了从急性疼痛到慢性疼痛过渡过程中神经元和胶质细胞可塑性的细胞决定因素、分子机制和遗传/表观遗传调控，并揭示了心理、社会和环境对疼痛感知的影响基础。有了到目前为止所获得的这些深刻的机制见解，我们现在建议通过阐明潜在的治疗效果的神经回路和机制以及识别与疼痛缓解相关的预测性生物标记物来特别关注优化现有的慢性疼痛治疗方法。此外，我们的目标是为慢性疼痛的新治疗干预开发创新战略。我们的分析将涵盖药理学和基因治疗方法、不同类型的神经调节/神经刺激和感觉-运动范例、虚拟现实应用、认知行为和社会干预以及数字诊断和干预。面向翻译的支助项目，包括体外人体细胞模型系统、活体干预平台和中央数据基础设施项目，将协助啮齿动物、人类和人类啮齿动物串联项目。通过这一战略，儿童权利委员会寻求产生机械性和独一无二的知识以及战胜慢性痛苦和相关痛苦的具体战略。

Chronic, pathological pain remains a global health problem and a challenge to basic and clinical sciences. A major obstacle has been that the nature of neural circuits underlying the complex, multidimensional experience of pain is not well understood and the diverse maladaptive plasticity processes that accompany pain chronicity have not been decoded in terms of underlying mechanisms and functional relevance. Importantly, interrelationship of chronic pain with anxiety, fear and depression, which worsen prognosis is still not understood. The primary goal of this consortium is to understand structure-function properties of cells, circuits and networks that impart specificity to the perception of pain and to address how these are altered during the transition from acute to chronic pain. Importantly, the consortium encompasses animal models of chronic pain as well as chronic pain patients and strives to implement translational measures to use the knowledge gained towards deriving new therapeutic principles. Our structure-function analyses conducted over the first funding period elucidated the differential contributions of specific regions, pathways and particular activity rhythms to the generation and maintenance of chronic pain. Our detailed mechanism-oriented analyses in the second funding period uncovered cellular determinants, molecular mechanisms and genetic/epigenetic regulation in plasticity of neurons and glia in the transition from acute to chronic pain, and revealed the basis of psychological, social and environmental influences on pain perception. With these deep mechanistic insights gained thus far, we now propose to place a particular focus on optimizing existing therapies for chronic pain by elucidating neural circuits and mechanisms underlying therapeutic effects and identifying predictive biomarkers associated with pain relief. Moreover, we aim to develop innovative strategies for new therapeutic interventions in chronic pain. Our analyses will span pharmacological and gene therapy approaches, different types of neuromodulation/neurostimulation and sensory-motor paradigms, virtual reality applications, cognitive behavioural and social interventions as well as digital diagnostics and interventions. Translationally-oriented supporting projects, including in vitro human cellular model systems, an in vivo interventional platform and a central data infrastructure project, will assist rodent-, human- and human-rodent tandem projects. Via this strategy, the CRC seeks to generate mechanistic and unique knowledge as well as concrete strategies for defeating chronic pain and associated suffering.