Pain is a common non-motor symptom of Parkinson's disease (PD), which often occurs in the early disease stages. Despite the high prevalence, it remains inadequately treated. In a hemi-parkinsonian rat model, we aimed to investigate the neurochemical factors involved in orofacial pain development, with a specific focus on pain-related peptides and cannabinoid receptors. We also evaluated whether treadmill exercise could improve orofacial pain and modulate these mechanisms. Rats were unilaterally injected in the striatum with either 6-hydroxydopamine (6-OHDA) or saline. Fifteen days after stereotactic surgery, the animals were submitted to treadmill exercise (EX), or remained sedentary (SED). Pain assessment was performed before the surgical procedure and prior to each training session. Pain-related peptides, substance P (SP), calcitonin gene-related peptide (CGRP), and transient receptor potential vanilloid type 1 (TRPV1) activation and cannabinoid receptor type 1 (CB1) and type 2 (CB2) were evaluated in the trigeminal nucleus. In order to confirm the possible involvement of cannabinoid receptors, we also injected antagonists of CB1 and CB2 receptors. We confirmed the presence of orofacial pain after unilateral 6-OHDA-injection, which improved after aerobic exercise training. We also observed increased pain-related expression of SP, CGRP and TRPV1 and decreased CB1 and CB2 in the trigeminal ganglion and caudal spinal trigeminal nucleus in animals with PD, which was reversed after aerobic exercise training. In addition, we confirm the involvement of cannabinoid receptors since both antagonists decreased the nociceptive threshold of PD animals. These data suggest that aerobic exercise effectively improved the orofacial pain associated with the PD model, and may be mediated by pain-related neuropeptides and cannabinoid receptors in the trigeminal system.

Graphical Abstract

中文翻译：

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运动可改善帕金森病大鼠模型的口面部疼痛并改变神经肽表达

疼痛是帕金森病（PD）常见的非运动症状，常发生在疾病早期。尽管患病率很高，但治疗仍然不充分。在偏侧帕金森病大鼠模型中，我们旨在研究与口面部疼痛发展有关的神经化学因素，特别关注与疼痛相关的肽和大麻素受体。我们还评估了跑步机运动是否可以改善口面部疼痛并调节这些机制。向大鼠纹状体单侧注射 6-羟基多巴胺 (6-OHDA) 或盐水。立体定向手术后十五天，对动物进行跑步机锻炼（EX），或保持静坐（SED）。在手术之前和每次训练之前进行疼痛评估。在三叉神经中评估疼痛相关肽、P 物质 (SP)、降钙素基因相关肽 (CGRP)、瞬时受体电位香草酸 1 型 (TRPV1) 激活以及大麻素受体 1 型 (CB1) 和 2 型 (CB2)核。为了证实大麻素受体的可能参与，我们还注射了CB1和CB2受体的拮抗剂。我们证实单侧注射 6-OHDA 后出现口面部疼痛，经过有氧运动训练后有所改善。我们还观察到PD动物的三叉神经节和三叉神经尾部脊髓核中SP、CGRP和TRPV1与疼痛相关的表达增加，CB1和CB2减少，而有氧运动训练后这种情况得到逆转。此外，我们确认了大麻素受体的参与，因为两种拮抗剂均降低了 PD 动物的伤害性阈值。这些数据表明，有氧运动有效改善了与PD模型相关的口面部疼痛，并且可能是由三叉神经系统中与疼痛相关的神经肽和大麻素受体介导的。

图形概要