脊髓背角内GRPR阳性神经元参与痒觉信息传递的机制研究

Itch, especially chronic itch, is a long-period troublesome symptom of human disease, and lack of effective treatment method up to now. The main reason is due to the transmission mechanisms of itch information is still obscure. In 2007, Zhou-Feng Chen's lab in USA found the first itch-specific sensation molecular-GRPR (gastrin-releasing peptide receptors), which was the milestone of itch research.It provides necessary condition for clarify the transmission mechanisms of itch. We had produced high specific GRPR antibody through cooperation with Prof. Chen's lab, and have carried out some pre-experiments on the mechanisms of spinal dorsal horn GRPR positive neurons participating itch tansmission,and found that GRPR positive neurons in the spinal dorsal horn were all excitatory interneurons instead of projection neurons.These pre-experiment results define the direction for elucidating the mechanisms of GRPR positive neuron participating itch transmission. Therefore, the present project is intended to select GRPR as the key molecular, import and use GRPR-eGFP mouse, and integrated application of morphology, behavior, imaging,and functional research methods to reveal the pripheraal and central mechanisms of spinal dorsal horn GRPR positive neurons involving in the transmission of itch information, preliminary clarify the relationship between itch and pain transmission pathway,and reveal the plasticity changes of GRPRergic neurons and the itch transmission pathway it involved in chronic itch state. We hope this study may provide experimental evidence and drug targets for itch therapy.

瘙痒，尤其是慢性瘙痒是长期困扰人类的顽疾，至今缺乏有效的治疗手段，其主要原因是由于痒觉的传递机制尚不清楚。2007年，美国陈宙峰实验室发现了第一个特异性痒觉介导分子-胃泌素释放肽受体（GRPR），为阐明痒觉的传递机制提供了必要条件。本项目组与该实验室合作筛选出了特异性高的GRPR抗体，并开展了脊髓背角内GRPR阳性神经元参与痒觉传递的预实验，发现脊髓背角的GRPR阳性神经元均为兴奋性中间神经元，并非投射神经元，为阐明其参与痒觉信息传递的机制找到了方向。因此，本项目拟以GRPR为关键分子，引进并利用GRPR-eGFP小鼠，综合应用形态学、行为学、影像学、机能学等研究手段，初步揭示脊髓背角内GRPR 阳性神经元参与痒觉传递的外周和中枢机制，阐明痒觉与痛觉传递通路的关系，并揭示在慢性痒状态下GRPR阳性神经元及其参与构成的痒觉传递通路的可塑性变化，为深入研究瘙痒症的治疗提供理论依据和药物靶点。

痒觉的传递与调控机制不清楚，慢性痒的产生及维持机制不明，导致了瘙痒治疗的困难。本研究以特异性痒觉介导分子—胃泌素释放肽受体（GRPR）为主要研究目标。综合应用形态学、行为学、影像学、机能学等研究手段，揭示脊髓背角内GRPR 阳性神经元参与痒觉传递的外周和中枢机制，探索痒觉与痛觉传递通路的关系，并观察在慢性痒状态下GRPR阳性神经元及其参与构成的痒觉传递通路的可塑性变化，拓展性的研究瘙痒与负性情绪间的关系及可能机制。结果显示：（1）正常情况下脊髓背角浅层GRPR阳性神经元均为中间神经元，并且与投射神经元之间存在突触联系；（2）脊髓背角浅层GRPR阳性神经元大多（约75%）为兴奋性神经元，且易发生可塑性变化；（3）脊髓背角浅层GRPR阳性神经元可参与构成多种痒觉信息传递与调控局部环路，并通过臂旁核向中枢传递痒觉信息；（4）瘙痒与抑郁存在交互恶化现象，促糖皮质激素释放激素（CRH）可能参与了该过程。上述研究结果为深入阐明痒的传递与调控机制奠定了坚实的基础，也为瘙痒症的治疗提供了理论依据。