title: Activation of GPR30 attenuates chronic pain-related anxiety in ovariectomized mice.
abstract: 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.
authors.affiliation: Department of Pharmacology, School of Pharmacy, The Fourth Military Medical University, Xi'an 710032, China.
authors.forename: Shui-bing
authors.initials: SB
authors.lastname: Liu
authors.affiliation: Department of Pharmacology, School of Pharmacy, The Fourth Military Medical University, Xi'an 710032, China.
authors.forename: Zhen
authors.initials: Z
authors.lastname: Tian
authors.affiliation: Department of Pharmacology, School of Pharmacy, The Fourth Military Medical University, Xi'an 710032, China.
authors.forename: Yan-yan
authors.initials: YY
authors.lastname: Guo
authors.affiliation: Department of Pharmacology, School of Pharmacy, The Fourth Military Medical University, Xi'an 710032, China.
authors.forename: Nan
authors.initials: N
authors.lastname: Zhang
authors.affiliation: Department of Pharmacology, School of Pharmacy, The Fourth Military Medical University, Xi'an 710032, China.
authors.forename: Bin
authors.initials: B
authors.lastname: Feng
authors.affiliation: Department of Pharmacology, School of Pharmacy, The Fourth Military Medical University, Xi'an 710032, China. Electronic address: minggao@fmmu.edu.cn.
authors.forename: Ming-gao
authors.initials: MG
authors.lastname: Zhao
mesh_terms: D000679:Amygdala / Q000378:metabolism*; D000818:Animals; D001007:Anxiety; D059350:Chronic Pain; D015536:Down-Regulation; D005260:Female; D005620:Freund's Adjuvant / Q000633:toxicity; D055785:Gene Knockdown Techniques; D051379:Mice; D010052:Ovariectomy; D017288:Pain Threshold; D034741:RNA, Small Interfering; D018091:Receptors, AMPA / Q000378:metabolism; D011960:Receptors, Estrogen; D043562:Receptors, G-Protein-Coupled / Q000819:agonists / Q000378:metabolism*; D011963:Receptors, GABA-A / Q000378:metabolism; D012584:Sciatic Nerve / Q000293:injuries; D020426:Sciatic Neuropathy / Q000139:chemically induced / Q000209:etiology; D015854:Up-Regulation
chemical_list: D005620:Freund's Adjuvant; D034741:RNA, Small Interfering; D018091:Receptors, AMPA; D011960:Receptors, Estrogen; D043562:Receptors, G-Protein-Coupled; D011963:Receptors, GABA-A; C532507:GPER1 protein, mouse
keywords: Amygdala; Anxiety; Chronic pain; Estrogen; Synaptic transmission