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Activation of Dopamine D2 Receptors Alleviates Neuronal Hyperexcitability in the Lateral Entorhinal Cortex via Inhibition of HCN Current in a Rat Model of Chronic Inflammatory Pain

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Abstract

Functional changes in synaptic transmission from the lateral entorhinal cortex to the dentate gyrus (LEC-DG) are considered responsible for the chronification of pain. However, the underlying alterations in fan cells, which are the predominant neurons in the LEC that project to the DG, remain elusive. Here, we investigated possible mechanisms using a rat model of complete Freund’s adjuvant (CFA)-induced inflammatory pain. We found a substantial increase in hyperpolarization-activated/cyclic nucleotide-gated currents (Ih), which led to the hyperexcitability of LEC fan cells of CFA slices. This phenomenon was attenuated in CFA slices by activating dopamine D2, but not D1, receptors. Chemogenetic activation of the ventral tegmental area -LEC projection had a D2 receptor-dependent analgesic effect. Intra-LEC microinjection of a D2 receptor agonist also suppressed CFA-induced behavioral hypersensitivity, and this effect was attenuated by pre-activation of the Ih. Our findings suggest that down-regulating the excitability of LEC fan cells through activation of the dopamine D2 receptor may be a strategy for treating chronic inflammatory pain.

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Acknowledgements

This work was supported by the National Natural Science Foundation of China (81901119 and 81901142), Special Project on Innovation and Generation of Medical Support Capacity, and the Natural Science Foundation of Tibet (XZ2019ZRG-119), China.

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Authors and Affiliations

  1. Department of Rehabilitation, Daping Hospital, Army Medical University, Chongqing, 400042, China

    Shi-Hao Gao, Yong Tao, Yang Zhu, Hao Huang & Chang-Yue Gao

  2. Department of Respiratory and Critical Care Medicine, Xinqiao Hospital, Army Medical University, Chongqing, 400037, China

    Lin-Lin Shen

  3. Army 953 Hospital, Army Medical University, Shigatse, 857000, China

    Shi-Hao Gao

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  1. Shi-Hao Gao
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  2. Yong Tao
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Correspondence to Lin-Lin Shen or Chang-Yue Gao.

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Shi-Hao Gao and Yong Tao contributed equally to this work.

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Gao, SH., Tao, Y., Zhu, Y. et al. Activation of Dopamine D2 Receptors Alleviates Neuronal Hyperexcitability in the Lateral Entorhinal Cortex via Inhibition of HCN Current in a Rat Model of Chronic Inflammatory Pain. Neurosci. Bull. 38, 1041–1056 (2022). https://doi.org/10.1007/s12264-022-00892-z

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