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.

中文翻译：

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GPR30 的激活减轻了去卵巢小鼠的慢性疼痛相关焦虑

雌激素调节在神经炎症、焦虑和慢性疼痛中起关键作用的神经内分泌和炎症过程。患有慢性疼痛的患者经常抱怨焦虑。然而，关于慢性疼痛相关焦虑的神经回路和雌激素的相关功能的信息有限。后爪注射完全弗氏佐剂 (CFA) 和坐骨神经慢性收缩性损伤 (CCI) 可在切除卵巢 (OVX) 的小鼠中引起显着的疼痛敏化和焦虑样行为。我们发现 G 蛋白偶联受体 30 (GPR30)，一种膜雌激素受体，在患有慢性炎症和神经性疼痛的卵巢切除 (OVX) 小鼠的基底外侧杏仁核 (BLA) 中显着增加。GPR30 激动剂 G1 的皮下注射或 BLA 局部输注显着降低了注射 CFA 和 CCI-OVX 小鼠的焦虑样行为；然而，这种治疗并没有改变伤害感受阈值。GPR30 在 OVX 小鼠的 BLA 中被 shRNA 击倒抑制了 GPR30 激活的抗焦虑作用。G1 给药逆转了含有 AMPA 和 NR2A 的 NMDA 受体中 GluR1 亚基的上调以及注射 CFA 和 CCI-OVX 小鼠的 BLA 中 GABAA 受体的下调。电生理记录显示 GPR30 激活可以防止注射 CFA 的 OVX 小鼠的 BLA 突触中兴奋性和抑制性传递之间的失衡。总之，GPR30 激活诱导了抗焦虑作用，但不影响慢性疼痛下小鼠的伤害感受阈值。