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HCN-Channel-Dependent Hyperexcitability of the Layer V Pyramidal Neurons in IL-mPFC Contributes to Fentanyl-Induced Hyperalgesia in Male Rats

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Abstract

Opioids are often first-line analgesics in pain therapy. However, prolonged use of opioids causes paradoxical pain, termed “opioid-induced hyperalgesia (OIH).” The infralimbic medial prefrontal cortex (IL-mPFC) has been suggested to be critical in inflammatory and neuropathic pain processing through its dynamic output from layer V pyramidal neurons. Whether OIH condition induces excitability changes of these output neurons and what mechanisms underlie these changes remains elusive. Here, with combination of patch-clamp recording, immunohistochemistry, as well as optogenetics, we revealed that IL-mPFC layer V pyramidal neurons exhibited hyperexcitability together with higher input resistance. In line with this, optogenetic and chemogenetic activation of these neurons aggravates behavioral hyperalgesia in male OIH rats. Inhibition of these neurons alleviates hyperalgesia in male OIH rats but exerts an opposite effect in male control rats. Electrophysiological analysis of hyperpolarization-activated cation current (Ih) demonstrated that decreased Ih is a prerequisite for the hyperexcitability of IL-mPFC output neurons. This decreased Ih was accompanied by a decrease in HCN1, but not HCN2, immunolabeling, in these neurons. In contrast, the application of HCN channel blocker increased the hyperalgesia threshold of male OIH rats. Consequently, we identified an HCN-channel-dependent hyperexcitability of IL-mPFC output neurons, which governs the development and maintenance of OIH in male rats.

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Acknowledgements

We sincerely appreciate the electrophysiological platform provided by the South-Central University for Nationalities.

Funding

This study was supported by grants from the National Natural Science Foundation of China (grant number: 81974165).

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  1. Xixi Wang and Sifei Gan contributed equally to this work.

Authors and Affiliations

  1. Department of Anesthesiology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China

    Xixi Wang, Sifei Gan, Zeru Zhang, Pengfei Zhu & Fang Luo

  2. The Laboratory of Membrane Ion Channels and Medicine, Key Laboratory of Cognitive Science, State Ethnic Affairs Commission, College of Biomedical Engineering, South-Central University for Nationalities, Wuhan, Hubei, China

    Chen Hong Li

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Contributions

Designed experiments: Xixi Wang and Fang Luo; performed experiments: Xixi Wang and Sifei Gan; analyzed data: Xixi Wang and Sifei Gan; assisted in writing manuscript: Xixi Wang, Sifei Gan, Fang Luo, Zeru Zhang, Pengfei Zhu, and Chen Hong Li.

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Correspondence to Fang Luo.

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Wang, X., Gan, S., Zhang, Z. et al. HCN-Channel-Dependent Hyperexcitability of the Layer V Pyramidal Neurons in IL-mPFC Contributes to Fentanyl-Induced Hyperalgesia in Male Rats. Mol Neurobiol 60, 2553–2571 (2023). https://doi.org/10.1007/s12035-023-03218-w

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