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CB1-cannabinoid-, TRPV1-vanilloid- and NMDA-glutamatergic-receptor-signalling systems interact in the prelimbic cerebral cortex to control neuropathic pain symptoms
Brain Research Bulletin ( IF 3.8 ) Pub Date : 2020-10-07 , DOI: 10.1016/j.brainresbull.2020.09.013
Priscila Medeiros 1 , Mariana Oliveira-Silva 2 , Sylmara Esther Negrini-Ferrari 2 , Ana Carolina Medeiros 1 , Daoud Hibraim Elias-Filho 3 , Norberto Cysne Coimbra 4 , Renato Leonardo de Freitas 5
Affiliation  

Neuropathic pain (NP) is a challenge due to our limited understanding of the mechanisms that initiate and maintain chronic pain. The prelimbic division (PrL) of the medial prefrontal cortex (mPFC) is an important area of the emotional and cognitive components of pain and pharmacological systems can interact into the neocortex to elaborate the chronic pain. This work aimed to investigate the pharmacological cross-talk between synaptic neurotransmission, neuroanatomical approaches and NP conditions. A bidirectional neural tract tracer, the 3000-molecular-weight biodextran (BDA) was microinjected into the PrL cortex. The mechanical withdrawal threshold (MWT) was recorded by a von Frey test, and the effect of prelimbic cortex CB1, NMDA, and TRPV1 receptor modulation was evaluated 21 days after chronic constriction injury (CCI) of the sciatic nerve in male Wistar rats. Microinjection of a bidirectional neurotracer in the PrL cortex showed connections with the lateral division of the mediodorsal thalamic nucleus (MDL), central division of the mediodorsal thalamic nucleus (MDC), centrolateral thalamic nucleus (CL), ventromedial thalamic nucleus (VM), and the paracentral thalamic nucleus (PC). In detail, AM251, a CB1 receptor antagonist (at 50, 100 and 200 pmol) microinjections intra-PrL cortex decreased the MWT. Administrations of 6-iodonordihydrocapsaicin (6-I-CPS), a transient receptor potential vanilloid type 1 (TRPV1) antagonist, at 3 nmol and the endocannabinoid anandamide (AEA) at 50 and 100 pmol increased the MWT. AEA at 200 pmol injected in the PrL cortex decreased the MWT, and this hyperalgesic effect was blocked by 6-I-CPS at 3 nmol. The AEA (at 100 pmol) anti-allodynic effect was attenuated by AM251 (at 5 pmol). The TRPV1 selective agonist N-oleoyldopamine (OLDA) at 10 μM decreased the MWT. The blockade of the NMDA receptor with LY235959 (at 8 nmol) and 6-I-CPS (at 3 nmol) reversed the OLDA (at 10 μM) hyperalgesic effect. These findings showed that the PrL cortex sends pathways to thalamic nuclei that can mediate the nociception. We also suggest that the PrL cortex is involved in the potentiation and maintenance of mechanical allodynia by NMDA and TRPV1 receptor activation and that attenuation of this allodynia depends on CB1 receptor activation during NP.



中文翻译:

CB1-大麻素-、TRPV1-香草素-和 NMDA-谷氨酸能-受体-信号系统在前脑皮层相互作用以控制神经性疼痛症状

由于我们对引发和维持慢性疼痛的机制的了解有限,因此神经性疼痛 (NP) 是一项挑战。内侧前额叶皮层 (mPFC) 的前缘分裂 (PrL) 是疼痛的情绪和认知成分的重要区域,药理系统可以与新皮层相互作用以阐述慢性疼痛。这项工作旨在研究突触神经传递、神经解剖学方法和 NP 条件之间的药理学串扰。双向神经束示踪剂,3000 分子量的生物葡聚糖 (BDA) 被显微注射到 PrL 皮层。机械戒断阈值 (MWT) 通过 von Frey 检验记录,以及前边缘皮质 CB 1、NMDA 和 TRPV 1 的影响在雄性 Wistar 大鼠坐骨神经慢性收缩损伤 (CCI) 后 21 天评估受体调节。PrL 皮层中双向神经示踪剂的显微注射显示与丘脑内侧核 (MDL) 的外侧分裂、丘脑内侧核 (MDC) 的中央分裂、中央外侧丘脑核 (CL)、腹内侧丘脑核 (VM) 和旁中央丘脑核(PC)。详细地说,AM251,一种CB 1受体拮抗剂(50、100 和200 pmol)显微注射PrL 皮层内降低了MWT。施用 6-碘或二氢辣椒素 (6-I-CPS),一种瞬时受体电位香草素 1 型 (TRPV 1)) 拮抗剂,3 nmol 和内源性大麻素 anandamide (AEA) 在 50 和 100 pmol 增加 MWT。在 PrL 皮质中注射 200 pmol 的 AEA 降低了 MWT,并且这种痛觉过敏作用被 3 nmol 的 6-I-CPS 阻断。AEA(100 pmol)抗异常性疼痛作用被AM251(5 pmol)减弱。10 μM的 TRPV 1选择性激动剂 N-油酰多巴胺 (OLDA) 降低了 MWT。用 LY235959(8 nmol)和 6-I-CPS(3 nmol)阻断 NMDA 受体逆转了 OLDA(10 μM)的痛觉过敏作用。这些发现表明,PrL 皮层向丘脑核发送通路,可以介导伤害感受。我们还建议 PrL 皮层参与 NMDA 和 TRPV 1对机械性异常性疼痛的增强和维持受体激活,并且这种异常性疼痛的减弱取决于NP 期间CB 1受体的激活。

更新日期:2020-10-16
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