Blockade of spinal dopamine D1/D2 receptor heteromers by <i>levo</i>-Corydalmine suppressed calcium signaling cascade in spinal neurons to alleviate bone cancer pain in rats

Ma, Xiao-Nan; Yao, Chang-Heng; Yang, Yu-Jie; Li, Xue; Zhou, Meng-Yuan; Yang, Jin; Zhang, Shen; Yu, Bo-Yang; Dai, Wen-Ling; Liu, Ji-Hua

doi:10.7150/jca.91129

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J Cancer 2024; 15(4):1041-1052. doi:10.7150/jca.91129 This issue Cite

Research Paper

Blockade of spinal dopamine D1/D2 receptor heteromers by levo-Corydalmine suppressed calcium signaling cascade in spinal neurons to alleviate bone cancer pain in rats

Xiao-Nan Ma^1,2#, Chang-Heng Yao^2#, Yu-Jie Yang^2#, Xue Li^2#, Meng-Yuan Zhou², Jin Yang², Shen Zhang², Bo-Yang Yu^2,3, Wen-Ling Dai^2✉, Ji-Hua Liu^2,3✉

1. The Public Laboratory Platform, China Pharmaceutical University, Nanjing, Jiangsu 211198, China.
2. Jiangsu Key Laboratory of TCM Evaluation and Translational Research, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing, Jiangsu 211198, China.
3. State Key Laboratory of Natural Medicines, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing, Jiangsu 210009, China.
# These authors contributed equally to the work.

Citation:

Ma XN, Yao CH, Yang YJ, Li X, Zhou MY, Yang J, Zhang S, Yu BY, Dai WL, Liu JH. Blockade of spinal dopamine D1/D2 receptor heteromers by levo-Corydalmine suppressed calcium signaling cascade in spinal neurons to alleviate bone cancer pain in rats. J Cancer 2024; 15(4):1041-1052. doi:10.7150/jca.91129. https://www.jcancer.org/v15p1041.htm

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Abstract

Background: Dopamine receptors have been reported to be involved in pain, while the exact effects and mechanism in bone cancer pain have not been fully explored.

Methods: Bone cancer pain model was created by implanting walker 256 mammary gland carcinoma into right tibia bone cavity. Primary cultured spinal neurons were used for in vitro evaluation. FLIPR, western-blot, immunofluorescence, and Co-IP were used to detect cell signaling pathway.

Results: Our results indicated that spinal dopamine D1 receptor (D1DR) and spinal dopamine D2 receptor (D2DR) could form heteromers in TCI rats, and antagonizing spinal D1DR and D2DR reduced heteromers formation and alleviated TCI-induced bone cancer pain. Further results indicated that D1DR or D2DR antagonist induced antinociception in TCI rats could be reversed by D1DR, D2DR, and D1/D2DR heteromer agonists. And Gq, IP3, and PLC inhibitors also attenuated TCI-induced bone cancer pain. In vitro results indicated that D1DR or D2DR antagonist decreased the Ca²⁺ oscillations upregulated by D1DR, D2DR, and D1/D2DR heteromer agonists in activated primary cultured spinal neurons. Moreover, inhibition of D1/D2DR heteromers induced antinociception in TCI rats was partially mediated by the CaMKII and MAPKs pathway. In addition, a natural compound levo-Corydalmine (l-CDL), could inhibit D1/D2DR heteromers and attenuate bone cancer pain.

Results: Inhibition of spinal D1/D2DR heteromers via l-CDL decreases excitability in spinal neurons, which might present new therapeutic strategy for bone cancer pain.

Keywords: Dopamine D1 receptors, Dopamine D2 receptors, D1/D2DR heteromers, calcium signaling cascade, bone cancer pain, levo-Corydalmine

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APA

Ma, X.N., Yao, C.H., Yang, Y.J., Li, X., Zhou, M.Y., Yang, J., Zhang, S., Yu, B.Y., Dai, W.L., Liu, J.H. (2024). Blockade of spinal dopamine D1/D2 receptor heteromers by levo-Corydalmine suppressed calcium signaling cascade in spinal neurons to alleviate bone cancer pain in rats. Journal of Cancer, 15(4), 1041-1052. https://doi.org/10.7150/jca.91129.

ACS

Ma, X.N.; Yao, C.H.; Yang, Y.J.; Li, X.; Zhou, M.Y.; Yang, J.; Zhang, S.; Yu, B.Y.; Dai, W.L.; Liu, J.H. Blockade of spinal dopamine D1/D2 receptor heteromers by levo-Corydalmine suppressed calcium signaling cascade in spinal neurons to alleviate bone cancer pain in rats. J. Cancer 2024, 15 (4), 1041-1052. DOI: 10.7150/jca.91129.

NLM

CSE

Ma XN, Yao CH, Yang YJ, Li X, Zhou MY, Yang J, Zhang S, Yu BY, Dai WL, Liu JH. 2024. Blockade of spinal dopamine D1/D2 receptor heteromers by levo-Corydalmine suppressed calcium signaling cascade in spinal neurons to alleviate bone cancer pain in rats. J Cancer. 15(4):1041-1052.

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