PV中间神经元介导的“赢家通吃”机制在神经病理性疼痛与抑郁共病中的作用

The neuropathic pain and depression comorbidity has definitely clinical evidence, however, the neuropathological mechanisms underlying this coexisted excitation and inhibition status, hyperalgesia and depression, remain unknown. “Winner-take-all” mechanism is that the fired pyramidal cells promptly provide inhibition singal for the discharging of the remaining inactive pyramidal cells by activating PV interneurons, resulting in that only the fired pyramidal cells excite and the other pyramidal cells are inhibited. Considering that ① PV interneurons act as key cells in the “winner-take-all” mechanism; and ② our previous studies suggest that the disinhibition of pyramidal cells by down-regulating the inhibitory function of PV interneurons efficiently improves the depression, and the expression levels of PV are increased in the pain and depression comorbidity. Therefore, we hypothesized that the “winner-take-all” mechanism may underlie the neuropathology of excitation and inhibition imbalance in the neuropathic pain and depression comorbidity. We will establish the neuropathic pain and depression comorbidity animal models and apply microarray electrode analysis, patch clamp, transgenic, and immunofluorescence techniques to determine the excitability and function of PV interneurons and pyramidal cells, and then to demonstrate: ① the role of “winner-take-all” mechanism in the neuropathic pain and depression comorbidity; and ② PV interneurons might serve as the critical target cells for treatment of the neuropathic pain and depression comorbidity. This study will provide a new avenue for the prevention and treatment of neuropathic pain and depression comorbidity.

临床上神经病理性疼痛与抑郁共病有确切依据，但痛觉敏化与情绪低落这种兴奋与抑制状态共存的神经病理学机制还很不清楚。“赢家通吃”机制指：兴奋的锥体细胞通过激活PV中间神经元快速侧向抑制其它锥体细胞，从而表现为仅已兴奋的锥体细胞兴奋，其它锥体细胞无法兴奋。鉴于①PV中间神经元是“赢家通吃”机制的关键细胞；②我们研究表明，PV中间神经元的抑制功能下调使锥体细胞去抑制可有效治疗抑郁；疼痛与抑郁共病中PV表达增加。因此我们推测：“赢家通吃”机制是神经病理性疼痛与抑郁共病的神经病理学基础。本课题拟采用神经病理性疼痛与抑郁共病动物模型，通过微阵列电极记录、脑片膜片钳、转基因、免疫荧光等技术测定PV中间神经元及周围锥体细胞的兴奋性及功能，说明①“赢家通吃”机制在神经病理性疼痛与抑郁共病中的作用；②PV中间神经元是治疗神经病理性疼痛与抑郁共病的关键靶细胞。本研究可为神经病理性疼痛与抑郁共病的防治提供新思路。

临床上神经病理性疼痛与抑郁共病有确切依据，但痛觉敏化与情绪低落这种兴奋与抑制状态共存的神经病理学机制还很不清楚。“赢家通吃”机制指：兴奋的锥体细胞通过激活PV中间神经元快速侧向抑制其它锥体细胞，从而表现为仅已兴奋的锥体细胞兴奋，其它锥体细胞无法兴奋。鉴于①PV中间神经元是“赢家通吃”机制的关键细胞；②我们研究表明，PV中间神经元的抑制功能下调使锥体细胞去抑制可有效治疗抑郁；疼痛与抑郁共病中PV表达增加。因此我们推测：“赢家通吃”机制是神经病理性疼痛与抑郁共病的神经病理学基础。本课题拟采用神经病理性疼痛与抑郁共病动物模型，通过微阵列电极记录、脑片膜片钳、转基因、免疫荧光等技术测定PV中间神经元及周围锥体细胞的兴奋性及功能，说明①“赢家通吃”机制在神经病理性疼痛与抑郁共病中的作用；②PV中间神经元是治疗神经病理性疼痛与抑郁共病的关键靶细胞。本研究可为神经病理性疼痛与抑郁共病的防治提供新思路。