Research Papers:

GPR30 disrupts the balance of GABAergic and glutamatergic transmission in the spinal cord driving to the development of bone cancer pain

Jie Luo, Xiaoxia Huang, Yali Li, Yang Li, Xueqin Xu, Yan Gao, Ruoshi Shi, Wanjun Yao, Juying Liu and Changbin Ke _

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Oncotarget. 2016; 7:73462-73472. https://doi.org/10.18632/oncotarget.11867

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Jie Luo1,*, Xiaoxia Huang2,*, Yali Li1, Yang Li1, Xueqin Xu1, Yan Gao1, Ruoshi Shi1, Wanjun Yao1, Juying Liu1, Changbin Ke1

1Institute of Anesthesiology & Pain (IAP), PET-CT, Institute of Anesthesiology and Department of Anesthesiology, Taihe Hospital, Hubei University of Medicine, Shiyan City, 442000, Hubei Province, China

2Department of Nephrology, Taihe Hospital, Hubei University of Medicine, Shiyan City, 442000, Hubei Province, China

*These authors have contributed equally to this work

Correspondence to:

Changbin Ke, email: [email protected]

Keywords: bone cancer pain, spinal cord, GPR30, excitatory transmission, inhibitory transmission

Received: June 13, 2016     Accepted: August 26, 2016     Published: September 06, 2016


Cancer induced bone pain is a very complicated clinical pain states that has proven difficult to be treated effectively due to poorly understand of underlying mechanism, but bone cancer pain (BCP) seems to be enhanced by a state of spinal sensitization. In the present study, we showed that carcinoma tibia implantation induced notable pain sensitization and up-regulation of G-protein-coupled estrogen receptor (GPR30) in the spinal cord of rats which was reversed by GPR30 knockdown. Further studies indicated that upregulation of GPR30 induced by cancer implantation resulted in a select loss of γ-aminobutyric acid-ergic (GABAergic) neurons and functionally diminished the inhibitory transmission due to reduce expression of the vesicular GABA transporter (VGAT). GPR30 contributed to spinal cord disinhibition by diminishing the inhibitory transmission via upregulation of α1 subunit and downregulation of γ2 subunits. GPR30 also facilitated excitatory transmission by promoting functional up-regulation of the calcium/calmodulin-dependent protein kinase II α (CaMKII α) in glutamatergic neurons and increasing the clustering of the glutamate receptor subunit 1 (GluR1) subunit to excitatory synapse.

Taken together, GPR30 contributed to the development of BCP by both facilitating excitatory transmission and inhibiting inhibitory transmission in the spinal cord. Our findings provide the new spinal disinhibition and sensitivity mechanisms underlying the development of bone cancer pain.

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