青藤碱调控脊髓背角CB1R-HCN通路发挥抗神经病理性疼痛作用的机制研究

神经病理性疼痛（NP）发病率高且发病机制复杂，临床治疗现状差强人意。近年研究报道，青藤碱（中药青风藤单体碱）具有良好抗NP作用，机制可能与改变痛觉传递通路中神经元兴奋性有关。超极化激活环核苷酸门控（HCN）通道参与影响神经元兴奋性，其表达和功能受I型大麻素受体（CB1R）调控；HCN通道及其介导的电流Ih异常是NP形成的关键机制。课题组前期研究发现：青藤碱可下调NP导致的脊髓背角HCN通道（HCN2亚型）的表达增加，并减小脊髓背角胶状质（SG）神经元的Ih。因此我们推测：青藤碱可能通过作用于脊髓背角CB1R、改变HCN通道表达及功能、影响SG神经元兴奋性发挥抗NP效应。为证实该假说，我们将建立NP小鼠模型，应用电生理学、分子生物学、组织学等技术，从离体-在体双水平揭示脊髓背角“CB1R-HCN”通路在青藤碱抗NP过程中的作用机制，为青藤碱临床应用奠定坚实的理论基础。

Neuropathic pain (NP) is a chronic, complex condition with high prevalence and can seriously impact patients’ physiological and psychosocial function. Current treatment of NP is often unsatisfactory. Recent studies suggest that sinomenine, a principal ingredient of traditional Chinese medicine, is able to alleviate NP. Although, the central mechanisms of its antinociceptive effect is not fully elucidated, it may related with the alteration of neuronal excitability along the nociceptive pathway. Hyperpolarization-activated cyclic nucleotide-gated cation (HCN) channels, which expression and function affected by cannabinoid receptor 1 (CB1R), contribute to regulate neuronal excitability in the central nervous system. As reported previously, HCN channelopathy and hyperpolarization-activated current (Ih) abnormality plays a critical role in the development and maintenance of NP. Our preliminary studies found that the expression levels of HCN2 protein, a subtype of HCN channels, were significantly upregulated in the condition of NP, and sinomenine could decrease the abnormal expression and inhibit Ih in substantia gelatinosa (SG) neurons. Therefore, we hypothesize that sinomenine may exert antinociceptive effect via affecting CB1R in the spinal dorsal horn, which would further result in alterations of HCN channels’ expression and function, and influence the excitability of SG neurons. Here, by using electrophysiological, molecular biological together with immunohistochemistrical methods, we will elucidate the role of “CB1R-HCN” pathway in the anti-NP effect of sinomenine in both in vivo and in vitro aspects, and thus provide novel theoretical foundation for its clinical application.