背根神经元向TRPV1/TRPA1双阳性神经元表型转换介导慢性痛发生

外周神经病变介导多种慢性痛，折磨亿万患者，但其机制尚未明确。辣椒素受体TRPV1和大蒜素受体TRPA1是介导痛激活外周神经元的关键离子通道，我们前期发现，炎性痛时根据是否表达受体V1、A1划分的4类背根神经元中，仅有V1/A1双阳性神经元比例明显升高且兴奋性增强最多（可被镇痛逆转）；通过3种转基因小鼠实现特异标记双阳性神经元，发现光遗传激活双阳性神经元可直接诱发痛反应；单细胞测序等分析提示慢性痛时A1单阳性神经元可能转化为双阳性。据此提出：外周V1/A1双阳性神经元可能是编码痛信息的关键；组织炎症或神经损伤时，A1单阳性神经元内出现V1过表达、上膜，并与A1形成复合体，导致双阳性比例升高及兴奋性增强，向中枢持续发放痛信号产生慢性痛。阐明外周双阳性神经元在痛编码中的关键作用及病理时特定类型神经元表型迁变、兴奋性增高机制，将在细胞层面厘清慢性痛发生过程，助力更精准临床镇痛治疗实现。

Peripheral neuropathy mediates a variety of chronic pain and afflicts hundreds of millions of patients, but its mechanism has not been clarified. Capsaicin receptor TRPV1 and allicin receptor TRPA1 are the key ion channels that mediate pain-activated peripheral neurons. We found that among the four types of dorsal root ganglia neurons divided according to the expression of V1 and A1 during inflammatory pain, only the proportion of V1/A1 double-positive neurons increased significantly and the excitability increased the most (which can be reversed by analgesia). Moreover, After the double positive neurons were specifically labeled by mating with three transgenic mice, it was found that the photogenetic activation of double positive neurons could directly induce the pain response. Single cell sequencing and other analysis suggested that there was a phenotypic switching of A1 single-positive neurons to double-positive neurons in chronic pain. It is suggested that peripheral V1/A1 double positive neurons may be the key to encoding pain information. While tissue inflammation or nerve injury occurs, V1 receptors overexpress, transfer to membrane and form complexes with A1 receptors in A1 single-positive neurons, which leads to the increase of double positive ratio and excitability, continuously sending pain signals to the central nervous system and resulting in chronic pain. To elucidate the key role of peripheral double positive neurons in pain coding and the mechanism of phenotypic migration and increased excitability of specific types of neurons during pathology will clarify the process of chronic pain at the cellular level and help to achieve more accurate clinical analgesia.