阿片类药物对PVT神经元兴奋性的影响和机制研究

Opioids are often used as analgesics for chronic or severe pain, but they are addictive. Morphine is one of opioids, which can increase the neuronal excitability of the paraventricular nucleus of the thalamus (PVT). PVT has been implicated in drug addiction and withdrawal in recent years, but the neural mechanism remains unclear. We recorded the electrical activity of PVT neurons in brain slices of normal mice, and found that the excitability of cells was decreased after direct application of morphine. Opioid receptors in the brain can be activated by morphine, and their effect is inhibitory. Therefore, direct application of morphine in brain slices can inhibit the activity of PVT neurons. But in vivo injection of morphine did increase the excitability of PVT, suggesting that the role of neural circuits may be more important. How does morphine affect the activities of PVT neurons? We speculate that morphine does not directly act on the PVT nucleus, but may target the opioid receptors of the inhibitory neurons in the upstream nucleus. The activation of upstream opioid receptors may reduce the release of presynaptic inhibitory neurotransmitters, thereby improving the neuronal excitability of PVT. To test this hypothesis, this project will focus on the neural mechanism of morphine addiction in the perspective of neural circuits, with techniques of optogenetics, patch clamp recording and retrograde tract-tracing, and so on.

阿片类药物常被用于慢性疼痛或剧烈疼痛的镇痛药物，但其具有成瘾性。吗啡是阿片类药物的一种，吗啡可以提高丘脑室旁核（PVT）的兴奋性，而PVT在近几年被发现参与药物成瘾和中断药物后的戒断反应，但其中的神经环路机制尚不清楚。我们发现，在离体脑片上记录正常小鼠PVT神经元的电活动，直接给予吗啡后细胞的兴奋性降低；而在体研究发现，急性注射吗啡提高了PVT神经元的兴奋性。吗啡是怎样影响PVT神经元的电活动？我们推测吗啡并不直接作用于PVT核团，其可能主要作用于PVT上游抑制性神经元的阿片类受体，这些受体被激活后降低了突触前抑制性神经递质的释放，从而提高了PVT的兴奋性。为了验证这个假设，本项目将利用光遗传学、膜片钳记录和逆向示踪等实验技术和方法，探究吗啡作用于PVT的神经环路机制。

丘脑室旁核（PVT）参与阿片类药物相关的成瘾行为，且具有阿片受体的广泛表达。吗啡是阿片类药物的一种，临床上主要应用于缓解剧痛，但其具有成瘾性和耐受性。吗啡主要通过阿片受体起作用，目前为止PVT中的阿片受体功能尚不完全清楚。我们利用离体电生理记录技术，研究小鼠PVT神经元的动作电位发放和突触传递，发现阿片受体可以调控PVT神经元的发放活动和抑制性突触传递。在离体脑片上，阿片受体主要发挥抑制性作用，可以抑制PVT神经元的动作电位发放，也可以降低抑制性突触输入。另外，慢性吗啡处理降低了阿片受体的调控作用，阿片受体激动剂不再显著抑制PVT神经元的动作电位发放，也不再显著降低抑制性突触传递，这可能是由于长期使用吗啡引起阿片受体的失敏和内吞。总之，阿片受体对PVT神经元的活动具有重要的调控作用。