痛觉神经元Fc-gamma-I型受体在慢性痛发生中的作用

Chronic pain often accompanies antigen-specific immune diseases such as rheumatoid arthritis. However, the mechanisms underlying chronic pain in these conditions are not clear, and currently there is a lack of satisfying treatment. Our previous studies demonstrated that some nociceptive afferent neurons may express Fc-gamma-Receptor type I (FcγRI), the high-affinity receptor for immunoglobulin G (IgG), and could be directly activated by IgG immune complex evoking an increase in the intracellular calcium level and neuronal excitability, and sometimes even inducing ectopic action potential discharges. This novel mechanism may involve in the development of chronic pain especially in immune disorders involving an elevated level of IgG and immune complex. In the proposed project, we will elucidate this mechanism of chronic pain in antigen-specific immune diseases represented by rheumatoid arthritis (RA) using two approaches: first, we will study the in vitroresponses of acutely dissociated mouse dorsal root ganglion (DRG) neurons to IgG immune complex; secondly, using a mouse model of RA, we will study the mechanisms of in vivo activation of nociceptive DRG neurons by IgG immune complex which may lead to neurogenic inflammation and chronic pain. The effects of blocking the FcγRI to neuronal excitability, pain and inflammation will also be investigated. This study will reveal a previously unknown mechanism for chronic pain related to antigen-specific immune diseases, and may provide novelstrategies and targets for the treatment of chronic pain.

慢性痛常伴发于各种抗原特异性的免疫相关疾病，如类风湿关节炎等。目前对于这些疾病中慢性痛与炎症的关系及其发生机制尚不明确，导致缺乏针对性的治疗措施，是一个世界性难题。我们的前期工作提示，部分外周痛觉传入神经元表达免疫球蛋白G（IgG）的高亲和力受体FcγRI，并可特异性的被IgG免疫复合物激活，引起细胞内钙离子浓度和膜兴奋性升高甚至异常放电，从而参与慢性痛的发生。本项目将从两个方面进一步阐明这一机制及其在以类风湿关节炎为代表的抗原特异性免疫相关疾病上的作用。首先，我们将研究离体的小鼠背根节神经元细胞体对于IgG免疫复合物的反应；另一方面，将在小鼠的类风湿关节炎模型上研究免疫复合物在体直接激活痛觉神经元而引起神经源性炎症和疼痛的机制，并探讨阻断FcγRI对于神经元兴奋性、疼痛行为和炎症的影响。本项研究将阐明一个抗原特异性免疫相关的慢性痛机制，为慢性痛的治疗提供新的指导策略和药物靶点。

本项目综合运用了动物行为、电生理、免疫组化和分子生物学等手段研究了Fc受体在免疫相关疾病导致的抗原特异性疼痛和瘙痒动物模型中的作用。研究结果发现外周痛觉神经元表达的IgG高亲和力受体FcγRI可直接被IgG免疫复合物激活，引起神经元兴奋性增高甚至放电，并导致病理条件下的抗原特异性疼痛；在抗原诱导的类风湿关节炎动物模型中，外周痛觉神经元中的FcγRI显著上调并参与了IgG免疫复合物导致的慢性疼痛。这一发现表明痛觉神经元的FcγRI可能在免疫相关疾病导致的抗原特异性疼痛中起到了重要作用。此外，利用同一研究平台发现痒觉神经元表达的IgE受体FcεRI可被IgE免疫复合物特异性的激活，并参与了小鼠过敏性结膜炎的眼部瘙痒，说明了FcεRI受体可能在免疫相关的瘙痒中有重要作用。以上研究成果为免疫相关疾病导致的慢性痛和瘙痒症提供了新的研究思路与潜在靶点。