Liu Shui-bing, Tian Zhen, Guo Yan-yan, Zhang Nan, Feng Bin, Zhao Ming-gao
Department of Pharmacology, School of Pharmacy, The Fourth Military Medical University, Xi'an 710032, China.
Department of Pharmacology, School of Pharmacy, The Fourth Military Medical University, Xi'an 710032, China.
Psychoneuroendocrinology. 2015 Mar;53:94-107. doi: 10.1016/j.psyneuen.2014.12.021. Epub 2015 Jan 6.
Estrogen regulates neuroendocrine and inflammatory processes that play critical roles in neuroinflammation, anxiety, and chronic pain. Patients suffering from chronic pain often complain of anxiety. However, limited information is available regarding the neural circuitry of chronic pain-related anxiety and the related function of estrogen. Hindpaw injection of complete Freund's adjuvant (CFA) and chronic constriction injury (CCI) of the sciatic nerve induced notable pain sensitization and anxiety-like behavior in ovariectomized (OVX) mice. We found that the level of G-protein-coupled receptor 30 (GPR30), a membrane estrogen receptor, was significantly increased in the basolateral amygdala (BLA) of ovariectomized (OVX) mice suffering from chronic inflammatory and neuropathic pain. Subcutaneous injection or BLA local infusion of the GPR30 agonist G1 significantly reduced anxiety-like behavior in CFA-injected and CCI-OVX mice; however, this treatment did not alter the nociceptive threshold. GPR30 knock down by shRNA in the BLA of OVX mice inhibited the anxiolytic effects of GPR30 activation. G1 administration reversed the upregulation of GluR1 subunit in AMPA and NR2A-containing NMDA receptors and the downregulation of GABAA receptors in the BLA of CFA-injected and CCI-OVX mice. Electrophysiological recording revealed that GPR30 activation could prevent imbalance between excitatory and inhibitory transmissions in the BLA synapses of CFA-injected OVX mice. In conclusion, GPR30 activation induced anxiolytic effects but did not affect the nociceptive threshold of mice under chronic pain. The anxiolytic effects of GPR30 were partially due to maintaining the balance between excitatory and inhibitory transmissions in the BLA.
雌激素调节神经内分泌和炎症过程，这些过程在神经炎症、焦虑和慢性疼痛中起关键作用。患有慢性疼痛的患者常伴有焦虑症状。然而，关于慢性疼痛相关焦虑的神经回路以及雌激素的相关功能，目前可用信息有限。后爪注射完全弗氏佐剂（CFA）和坐骨神经慢性缩窄损伤（CCI）可诱导去卵巢（OVX）小鼠出现明显的疼痛敏化和焦虑样行为。我们发现，在患有慢性炎症和神经病理性疼痛的去卵巢（OVX）小鼠的基底外侧杏仁核（BLA）中，膜雌激素受体G蛋白偶联受体30（GPR30）的水平显著升高。皮下注射或BLA局部注入GPR30激动剂G1可显著降低CFA注射和CCI-OVX小鼠的焦虑样行为；然而，这种治疗并未改变痛觉阈值。在OVX小鼠的BLA中，通过shRNA敲低GPR30可抑制GPR30激活的抗焦虑作用。给予G1可逆转CFA注射和CCI-OVX小鼠BLA中AMPA的GluR1亚基和含NR2A的NMDA受体的上调以及GABAA受体的下调。电生理记录显示，GPR30激活可防止CFA注射的OVX小鼠BLA突触中兴奋性和抑制性传递之间的失衡。总之，GPR30激活可诱导抗焦虑作用，但不影响慢性疼痛小鼠的痛觉阈值。GPR30的抗焦虑作用部分归因于维持BLA中兴奋性和抑制性传递之间的平衡。
