Department of Neurobiology and Collaborative Innovation Center for Brain Science, School of Basic Medicine, Fourth Military Medical University, Xi'an 710032, P.R. China.
Cadet Brigade, Fourth Military Medical University, Xi'an 710032, P.R. China.
Cereb Cortex. 2018 Jun 1;28(6):2118-2130. doi: 10.1093/cercor/bhx117.
The anterior cingulate cortex (ACC) is a critical hub for nociceptive perception and pain-related anxiety. Long-term synaptic plasticity in ACC was found to be important for chronic inflammatory pain and pain-related anxiety. As short-term synaptic plasticity, depolarization-induced suppression of excitation (DSE) is involved in several conditions, such as chronic stress, epilepsy, and autism. However, it is still unknown whether DSE in the ACC is involved in the central sensitization of pain and anxiety. Using a whole-cell patch clamp, calcium imaging, western blot, and behavioral testing, we found that DSE was induced by a 2 s depolarization in postsynaptic pyramidal cells in ACC. DSE was mediated by endocannabinoid signaling and modulated by metabotropic glutamate receptor 5 (mGluR5). DSE was impaired by decreasing expression and dysfunction of mGluR5 in a mouse model of inflammatory pain induced by complete Freund's adjuvant. CDPPB, an mGluR5-positive allosteric modulator, could rescue hypersensitivity and anxiety-like behavior in this pain model. Our results demonstrated that mGluR5-mediated short-term plasticity in ACC may be a critical mechanism for chronic pain, and mGluR5 may potentially serve as a target of pain therapy, including treatments for hyperalgesia and anxiety.
扣带前皮质（ACC）是痛觉感知和与疼痛相关焦虑的关键枢纽。研究发现，ACC 中的长时程突触可塑性对于慢性炎症性疼痛和与疼痛相关的焦虑很重要。作为短时程突触可塑性，去极化诱导的兴奋性抑制（DSE）涉及多种情况，如慢性应激、癫痫和自闭症。然而，目前尚不清楚 ACC 中的 DSE 是否参与疼痛和焦虑的中枢敏化。通过全细胞膜片钳、钙成像、western blot 和行为测试，我们发现，在 ACC 的突触后锥体神经元中，2 秒的去极化可诱导 DSE。DSE 由内源性大麻素信号转导介导，并受代谢型谷氨酸受体 5（mGluR5）调节。在完全弗氏佐剂诱导的炎症性疼痛小鼠模型中，通过降低 mGluR5 的表达和功能，DSE 受到损害。mGluR5 的正变构调节剂 CDPPB 可挽救该疼痛模型中的过敏和焦虑样行为。我们的研究结果表明，ACC 中 mGluR5 介导的短时程可塑性可能是慢性疼痛的一个关键机制，mGluR5 可能作为疼痛治疗的靶点，包括治疗痛觉过敏和焦虑。
