脊髓神经元ArrB1-GRPR脱敏异常介导放射性痒中枢敏化机能研究

放疗毒性诱发难治性痒症限制肿瘤患者治疗依从性，降低患者生存期。我们建立放疗范式辐照能诱发野生型小鼠异常痒行为，可模拟人的放射性痒这一高级神经功能，但是放射性痒的机制尚无定论。已证实，外周痒觉信号肽GRP受表达其受体的脊髓背角神经突触的敏感性门控，ArrB家族依赖性肽类受体脱敏是感觉功能自稳态机制的重要发现。我们前期在人源神经母细胞系中发现，辐照直接下调ArrB1表达；在arrb1基因敲除小鼠模型中，GRP诱发的脊髓神经元兴奋性突触电流显著增强，导致神经元兴奋性异常增高，但是辐照是如何兴奋脊髓痒觉特异环路尚不明确。本研究拟在放射性痒动物模型研究基础上，进一步阐明辐照诱发脊髓痒觉环路敏化机制，揭示ArrB1-GRPR脱敏异常是放射性痒觉信号的起源，拓展辐照后痒相关高级脑功能紊乱的认识，为缓解放疗后放射性痒症候提供中枢治疗靶点。

Radiotherapy toxicity induces refractory itching to limit treatment compliance and reduce patient survival in cancer patients. We established that radiation paradigm can induce abnormal itching behavior in wild-type mice, which can mimic the higher neural function of human radiation itching, but the mechanism of radiation itching is inconclusive. It has been demonstrated that the peripheral itch signal peptide GRP is gated by the sensitivity of spinal dorsal horn synapses expressing GRP receptor(GRPR), and ArrB-dependent desensitization of peptide receptors is an important finding in the homeostatic mechanism of sensory function. We previously found that irradiation directly down-regulates ArrB1 expression in a human-derived neuroblast cell line; GRP-evoked synaptic currents in spinal neurons were significantly enhanced in the arrb1 knockout mouse model, resulting in abnormally high neuronal excitability, but how irradiation excites spinal item-specific circuits is not clear. This study intends to further elucidate the mechanism of irradiation-induced sensitization of spinal cord itching circuits on the basis of animal models of radiation itching, reveal that ArrB1-GRPR desensitization abnormalities are the origin of abnormal itching signals, expand the understanding of itching related higher brain dysfunction after irradiation, and provide a central therapeutic target for relieving radiation itching symptoms after radiotherapy.