Buhidma Yazead, Hobbs Carl, Malcangio Marzia, Duty Susan
King's College London, Institute of Psychiatry, Psychology & Neuroscience, Wolfson Centre for Age-Related Diseases, Guy's Campus, London, SE1 1UL, UK.
NPJ Parkinsons Dis. 2023 Apr 26;9(1):69. doi: 10.1038/s41531-023-00510-3.
Pain is a key non-motor feature of Parkinson's disease (PD) that significantly impacts on life quality. The mechanisms underlying chronic pain in PD are poorly understood, hence the lack of effective treatments. Using the 6-hydroxydopamine (6-OHDA) lesioned rat model of PD, we identified reductions in dopaminergic neurons in the periaqueductal grey (PAG) and Met-enkephalin in the dorsal horn of the spinal cord that were validated in human PD tissue samples. Pharmacological activation of D-like receptors in the PAG, identified as the DRD5 phenotype located on glutamatergic neurons, alleviated the mechanical hypersensitivity seen in the Parkinsonian model. Downstream activity in serotonergic neurons in the Raphé magnus (RMg) was also reduced in 6-OHDA lesioned rats, as detected by diminished c-FOS positivity. Furthermore, we identified increased pre-aggregate α-synuclein, coupled with elevated activated microglia in the dorsal horn of the spinal cord in those people that experienced PD-related pain in life. Our findings have outlined pathological pathways involved in the manifestation of pain in PD that may present targets for improved analgesia in people with PD.
疼痛是帕金森病（PD）的一个关键非运动特征，对生活质量有显著影响。PD 慢性疼痛的潜在机制尚不清楚，因此缺乏有效的治疗方法。利用 6-羟基多巴胺（6-OHDA）损伤的 PD 大鼠模型，我们发现中脑导水管周围灰质（PAG）中的多巴胺能神经元和脊髓背角中的甲硫氨酸脑啡肽减少，这在人类 PD 组织样本中得到了验证。PAG 中 D 样受体的药理学激活，被确定为位于谷氨酸能神经元上的 DRD5 表型，减轻了帕金森病模型中出现的机械性超敏反应。通过减少 c-FOS 阳性检测发现，6-OHDA 损伤大鼠中缝大核（RMg）中血清素能神经元的下游活性也降低。此外，我们发现，在生活中经历过 PD 相关疼痛的人群中，脊髓背角中预聚集的α-突触核蛋白增加，同时活化的小胶质细胞增多。我们的研究结果概述了 PD 疼痛表现所涉及的病理途径，这可能为改善 PD 患者的镇痛提供靶点。
