Department of Pharmacology, School of Pharmacy, Fujian Medical University, Fuzhou, 350122, Fujian China.
Fujian Center for Safety Evaluation of New Drug, Fujian Medical University, Fuzhou, 350122, Fujian China.
J Neurosci. 2022 Oct 26;42(43):8184-8199. doi: 10.1523/JNEUROSCI.0920-22.2022. Epub 2022 Sep 15.
Diabetic neuropathic pain (DNP) is a diabetes complication experienced by many patients. Ventrolateral periaqueductal gray (vlPAG) neurons are essential mediators of the descending pain modulation system, yet the role of vlPAG astrocytes in DNP remains unclear. The present study applied a multidimensional approach to elucidate the role of these astrocytes in DNP. We verified the activation of astrocytes in different regions of the PAG in male DNP-model rats. We found that only astrocytes in the vlPAG exhibited increased growth. Furthermore, we described differences in vlPAG astrocyte activity at different time points during DNP progression. After the 14th day of modeling, vlPAG astrocytes exhibited obvious activation and morphologic changes. Furthermore, activation of Gq-designer receptors exclusively activated by a designer drug (Gq-DREADDs) in vlPAG astrocytes in naive male rats induced neuropathic pain-like symptoms and pain-related aversion, whereas activation of Gi-DREADDs in vlPAG astrocytes in male DNP-model rats alleviated sensations of pain and promoted pain-related preference behavior. Thus, bidirectional manipulation of vlPAG astrocytes revealed their potential to regulate pain. Surprisingly, activation of Gi-DREADDs in vlPAG astrocytes also mitigated anxiety-like behavior induced by DNP. Thus, our results provide direct support for the hypothesis that vlPAG astrocytes regulate diabetes-associated neuropathic pain and concomitant anxiety-like behavior. Many studies examined the association between the ventrolateral periaqueductal gray (vlPAG) and neuropathic pain. However, few studies have focused on the role of vlPAG astrocytes in diabetic neuropathic pain (DNP) and DNP-related emotional changes. This work confirmed the role of vlPAG astrocytes in DNP by applying a more direct and robust approach. We used chemogenetics to bidirectionally manipulate the activity of vlPAG astrocytes and revealed that vlPAG astrocytes regulate DNP and pain-related behavior. In addition, we discovered that activation of Gi-designer receptors exclusively activated by a designer drug in vlPAG astrocytes alleviated anxiety-like behavior induced by DNP. Together, these findings provide new insights into DNP and concomitant anxiety-like behavior and supply new therapeutic targets for treating DNP.
糖尿病性神经病理性疼痛（DNP）是许多患者经历的一种糖尿病并发症。腹外侧导水管周围灰质（vlPAG）神经元是下行疼痛调节系统的重要介导者，但 vlPAG 星形胶质细胞在 DNP 中的作用尚不清楚。本研究采用多维方法阐明这些星形胶质细胞在 DNP 中的作用。我们验证了 DNP 模型大鼠 PAG 不同区域星形胶质细胞的激活。我们发现只有 vlPAG 中的星形胶质细胞表现出生长增加。此外，我们描述了 DNP 进展过程中不同时间点 vlPAG 星形胶质细胞活性的差异。建模后第 14 天，vlPAG 星形胶质细胞表现出明显的激活和形态变化。此外，在雄性 DNP 模型大鼠的 vlPAG 星形胶质细胞中激活 Gq- Designer Receptors 特异性激活 Designer Drug（Gq-DREADDs）会引起类似神经病理性疼痛的症状和疼痛相关的厌恶，而在 DNP 模型大鼠的 vlPAG 星形胶质细胞中激活 Gi-DREADDs 可减轻疼痛感觉并促进疼痛相关的偏好行为。因此，双向操纵 vlPAG 星形胶质细胞揭示了它们调节疼痛的潜力。令人惊讶的是，在 DNP 诱导的焦虑样行为中，vlPAG 星形胶质细胞中 Gi-DREADDs 的激活也减轻了焦虑样行为。因此，我们的研究结果直接支持了 vlPAG 星形胶质细胞调节糖尿病相关神经病理性疼痛和伴随的焦虑样行为的假说。许多研究检查了腹外侧导水管周围灰质（vlPAG）与神经病理性疼痛之间的关联。然而，很少有研究关注 vlPAG 星形胶质细胞在糖尿病性神经病理性疼痛（DNP）和 DNP 相关情绪变化中的作用。本工作通过应用更直接和强大的方法证实了 vlPAG 星形胶质细胞在 DNP 中的作用。我们使用化学遗传学方法双向操纵 vlPAG 星形胶质细胞的活性，揭示了 vlPAG 星形胶质细胞调节 DNP 和与疼痛相关的行为。此外，我们发现，在 vlPAG 星形胶质细胞中激活 Gi-Designer Receptors 特异性激活 Designer Drug 可减轻 DNP 诱导的焦虑样行为。总之，这些发现为 DNP 和伴随的焦虑样行为提供了新的见解，并为治疗 DNP 提供了新的治疗靶点。
