脊髓神经肽Y阳性抑制性中间神经元在阿片镇痛中的作用及机制研究

病理性疼痛给患者带来非常严重的身体和心理折磨，显著地降低患者的生活质量。阿片类药物是临床上广泛使用的镇痛药物。但是阿片类药物的副作用导致了阿片类药物的使用存在很大的局限性。因此，研究阿片类药物产生镇痛及其副作用的产生机制对临床上阿片类镇痛药物的应用以及研发新型低副作用的阿片类镇痛药物具有广泛的指导意义。我们前期的研究报道在脊髓背角中，µ阿片受体不仅表达在兴奋性中间神经元上，在抑制性中间神经元中也具有很高的表达量。我们的结果表明选择性敲除抑制性中间神经元上的µ阿片受体能够增强吗啡在热板实验中的镇痛作用。同时，我们发现抑制性中间神经元上的µ阿片受体主要与神经肽Y共表达。本项目将利用基因编辑小鼠、组织学染色、药理学、膜片钳电生理等多种手段全面评价脊髓神经肽Y阳性抑制性中间神经元上的µ阿片受体在阿片镇痛、耐受以及阿片诱发痛敏中的调控作用。本研究将为阿片类药物的镇痛药理学机制提供新的理论依据。

Pathological pain brings both physiological and psychological burden to the patients, can also significantly impact patients’ quality of life. Opioids are mainstay treatments for clinical pain conditions. However, the clinical usage of opioids is restricted by their side effects. This makes the investigation of underlying mechanism for opioid analgesia and other opioid related side effects especially important for the clinic usage of opioids and development of novel opioid analgesics. Our recent study reported that µ-opioid receptor is not only expressed on the excitatory interneurons, but also highly expressed on the inhibitory interneurons in the spinal cord dorsal horn. Conditional knockout of µ-opioid receptor on the inhibitory interneurons significantly enhanced morphine analgesia in the hot-plate test. Furthermore, µ-opioid receptor on inhibitory interneurons is highly co-expressed with neuropeptide Y (NPY). In this study, we will use tansgenetic mice, behavioral, histological, pharmacological, patch clamp electrophysiological approaches to study the critical roles of µ-opioid receptor on NPY positive inhibitory interneurons in opioid analgesia, tolerance, and opioid induced hyperalgesia (OIH). This study will provide new insights in understanding the underlying mechanism of opioid analgesia.