GPR30 disrupts the balance of GABAergic and glutamatergic transmission in the spinal cord driving to the development of bone cancer pain.
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.
Institute 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.
Jie
J
Luo
Department of Nephrology, Taihe Hospital, Hubei University of Medicine, Shiyan City, 442000, Hubei Province, China.
Xiaoxia
X
Huang
Institute 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.
Yali
Y
Li
Institute 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.
Yang
Y
Li
Institute 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.
Xueqin
X
Xu
Institute 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.
Yan
Y
Gao
Institute 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.
Ruoshi
R
Shi
Institute 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.
Wanjun
W
Yao
Institute 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.
Juying
J
Liu
Institute 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.
Changbin
C
Ke
D000818:Animals; D001859:Bone Neoplasms / Q000150:complications*; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000378:metabolism; D000072716:Cancer Pain / Q000209:etiology* / Q000378:metabolism*; D004195:Disease Models, Animal; D005260:Female; D059330:GABAergic Neurons / Q000378:metabolism*; D005786:Gene Expression Regulation; D018698:Glutamic Acid / Q000378:metabolism; D020671:Posterior Horn Cells / Q000378:metabolism; D051381:Rats; D043562:Receptors, G-Protein-Coupled / Q000235:genetics* / Q000378:metabolism; D018079:Receptors, GABA / Q000378:metabolism; D013116:Spinal Cord / Q000378:metabolism*; D009435:Synaptic Transmission / Q000235:genetics
C520305:Gper1 protein, rat; D043562:Receptors, G-Protein-Coupled; D018079:Receptors, GABA; D018698:Glutamic Acid; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2
GPR30; bone cancer pain; excitatory transmission; inhibitory transmission; spinal cord