Department of Anesthesiology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China.
Department of Anesthesiology and Pain Clinic, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China.
FASEB J. 2024 Nov 15;38(21):e70152. doi: 10.1096/fj.202401481R.
Approximately 50% of patients with chronic neuropathic pain experience cognitive impairment, which negatively impacts their quality of life. The cannabinoid type 2 receptor (CB2R) may be involved in hippocampal cognitive processes. However, its role in chronic neuropathic pain-induced cognitive impairment remains elusive. Spared nerve injury (SNI) was used to induce chronic neuropathic pain in rats, while the novel-object recognition test and the Y-maze test were employed to assess cognitive function. Immunofluorescence, western blotting, and stereotaxic hippocampal microinjection were utilized to elucidate the potential mechanisms. We observed a reduction in mechanical pain threshold and cognitive impairment in SNI rats. This was accompanied by a tendency for hippocampal microglia to adopt pro-inflammatory functions. Notably, no changes were detected in CB2R expression. However, downregulation of the endogenous ligands AEA and 2-AG was evident. Hippocampal microinjection of a CB2R agonist mitigated cognitive impairment in SNI rats, which correlated with a tendency for microglia to adopt anti-inflammatory functions. Additionally, SNI-induced activation of the p-ERK/NFκB pathway in the hippocampus. Activation of CB2R reversed this process by upregulating DUSP6 expression in microglia. The effects elicited by CB2R activation could be inhibited through the downregulation of microglial DUSP6 via hippocampal adeno-associated virus (AAV) microinjection. Conversely, overexpression of hippocampal DUSP6 using AAV ameliorated the cognitive deficits observed in SNI rats, which remained unaffected by the administration of a CB2R antagonist. Our findings demonstrate that activation of hippocampal CB2R can mitigate chronic neuropathic pain-induced cognitive impairment through the modulation of the DUSP6/ERK/NFκB pathway.
大约 50%的慢性神经性疼痛患者存在认知功能障碍，这会对他们的生活质量产生负面影响。大麻素受体 2（CB2R）可能参与海马认知过程。然而，其在慢性神经性疼痛引起的认知功能障碍中的作用仍不清楚。采用 spared nerve injury（SNI）诱导大鼠慢性神经性疼痛，利用 novel-object recognition test 和 Y-maze test 评估认知功能。利用免疫荧光、western blot 和立体定向海马微量注射来阐明潜在机制。我们观察到 SNI 大鼠的机械痛阈降低和认知功能障碍。这伴随着海马小胶质细胞向促炎功能的转变趋势。值得注意的是，CB2R 的表达没有变化。然而，内源性配体 AEA 和 2-AG 的表达下调。CB2R 激动剂海马微量注射减轻了 SNI 大鼠的认知功能障碍，这与小胶质细胞向抗炎功能转变趋势相关。此外，SNI 诱导的海马 p-ERK/NFκB 通路激活。CB2R 的激活通过上调小胶质细胞中的 DUSP6 逆转了这一过程。通过海马腺相关病毒（AAV）微量注射下调小胶质细胞的 DUSP6，可以抑制 CB2R 激活引起的作用。相反，使用 AAV 过表达海马 DUSP6 可改善 SNI 大鼠的认知缺陷，而 CB2R 拮抗剂的给药对其没有影响。我们的研究结果表明，激活海马 CB2R 可以通过调节 DUSP6/ERK/NFκB 通路来减轻慢性神经性疼痛引起的认知功能障碍。
