背景:疼痛是一种影响帕金森病患者生活质量的非运动症状。患者的病理性伤害性超敏反应可能是由于基底神经节水平的体感信息处理的变化,包括丘脑底核(STN),但是潜在的机制还没有定义。这里,我们调查了STN和脊髓背角(DHSC)之间的相互作用,通过首先检查对外周伤害性刺激作出反应的STN神经元的性质以及它们在正常和病理条件下的反应性质。接下来,我们研究了STN的深部脑刺激(DBS)对DHSC神经元电活动的影响。然后,我们研究了STN-DBS的治疗作用是否由涉及延髓头端腹内侧段(RVM)的脑干下降途径介导.最后,为了更好地理解STN如何调节异常性疼痛,我们使用了在STN中表达的专门由设计药物激活的设计受体(DREADDs)。
方法:这项研究是在帕金森病的6-OHDA啮齿动物模型上进行的,通过将神经毒素立体定向注射到大鼠和小鼠的内侧前脑束中获得。在这些动物中,我们使用了运动和伤害性行为测试,STN和宽动态范围(WDR)DHSC神经元响应周围刺激的体内电生理学,STN的深部脑刺激和选择性DREADD方法。Vglut2-ires-cre小鼠用于特异性靶向和抑制STN谷氨酸能神经元。
结果:STN神经元能够检测伤害性刺激,对它们的强度进行编码并产生类似弯曲的可塑性,比如DHSC中的WDR神经元.这些现象在多巴胺耗尽的动物中受损,因为脊髓和丘脑下神经元的强度反应都发生了变化。此外,和左旋多巴一样,STN-DBS在大鼠中改善6-OHDA诱导的异常性疼痛,这种效应是由脑干投射下降介导的,导致DHSC神经元伤害性整合正常化。此外,通过选择性抑制Vglut2-ires-cre小鼠中的STN谷氨酸能神经元来再现这种治疗作用。
结论:我们的研究强调了STN在伤害性回路中的中心地位,它与DHSC的相互作用及其在帕金森病疼痛感觉中的关键参与。此外,我们的结果首次提供证据表明,丘脑下DBS通过下行脑干通路使脊髓WDR神经元的反应正常化,从而产生镇痛作用.这些影响是由于直接抑制,而不是激活STN或通道纤维中的谷氨酸能神经元,如DREADDs实验所示。
BACKGROUND: Pain is a non-motor symptom that impairs quality of life in Parkinson\'s patients. Pathological nociceptive hypersensitivity in patients could be due to changes in the processing of somatosensory information at the level of the basal ganglia, including the subthalamic nucleus (STN), but the underlying mechanisms are not yet defined. Here, we investigated the interaction between the STN and the dorsal horn of the spinal cord (DHSC), by first examining the nature of STN neurons that respond to peripheral nociceptive stimulation and the nature of their responses under normal and pathological conditions. Next, we studied the consequences of deep brain stimulation (DBS) of the STN on the electrical activity of DHSC neurons. Then, we investigated whether the therapeutic effect of STN-DBS would be mediated by the brainstem descending pathway involving the rostral ventromedial medulla (RVM). Finally, to better understand how the STN modulates allodynia, we used Designer Receptors Exclusively Activated by Designer Drugs (
DREADDs) expressed in the STN.
METHODS: The study was carried out on the 6-OHDA rodent model of Parkinson\'s disease, obtained by stereotactic injection of the neurotoxin into the medial forebrain bundle of rats and mice. In these animals, we used motor and nociceptive behavioral tests, in vivo electrophysiology of STN and wide dynamic range (WDR) DHSC neurons in response to peripheral stimulation, deep brain stimulation of the STN and the selective DREADD approach. Vglut2-ires-cre mice were used to specifically target and inhibit STN glutamatergic neurons.
RESULTS: STN neurons are able to detect nociceptive stimuli, encode their intensity and generate windup-like plasticity, like WDR neurons in the DHSC. These phenomena are impaired in dopamine-depleted animals, as the intensity response is altered in both spinal and subthalamic neurons. Furthermore, As with L-Dopa, STN-DBS in rats ameliorated 6-OHDA-induced allodynia, and this effect is mediated by descending brainstem projections leading to normalization of nociceptive integration in DHSC neurons. Furthermore, this therapeutic effect was reproduced by selective inhibition of STN glutamatergic neurons in Vglut2-ires-cre mice.
CONCLUSIONS: Our study highlights the centrality of the STN in nociceptive circuits, its interaction with the DHSC and its key involvement in pain sensation in Parkinson\'s disease. Furthermore, our results provide for the first-time evidence that subthalamic DBS produces analgesia by normalizing the responses of spinal WDR neurons via descending brainstem pathways. These effects are due to direct inhibition, rather than activation of glutamatergic neurons in the STN or passage fibers, as shown in the
DREADDs experiment.