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α4 nicotinic receptors on GABAergic neurons mediate a cholinergic analgesic circuit in the substantia nigra pars reticulata

Acta Pharmacologica Sinica (2024)Cite this article

Summary

Nicotinic acetylcholine receptors (nAChRs) regulate pain pathways with various outcomes depending on receptor subtypes, neuron types, and locations. But it remains unknown whether α4β2 nAChRs abundantly expressed in the substantia nigra pars reticulata (SNr) have potential to mitigate hyperalgesia in pain states. We observed that injection of nAChR antagonists into the SNr reduced pain thresholds in naïve mice, whereas injection of nAChR agonists into the SNr relieved hyperalgesia in mice, subjected to capsaicin injection into the lower hind leg, spinal nerve injury, chronic constriction injury, or chronic nicotine exposure. The analgesic effects of nAChR agonists were mimicked by optogenetic stimulation of cholinergic inputs from the pedunculopontine nucleus (PPN) to the SNr, but attenuated upon downregulation of α4 nAChRs on SNr GABAergic neurons and injection of dihydro-β-erythroidine into the SNr. Chronic nicotine-induced hyperalgesia depended on α4 nAChRs in SNr GABAergic neurons and was associated with the reduction of ACh release in the SNr. Either activation of α4 nAChRs in the SNr or optogenetic stimulation of the PPN-SNr cholinergic projection mitigated chronic nicotine-induced hyperalgesia. Interestingly, mechanical stimulation-induced ACh release was significantly attenuated in mice subjected to either capsaicin injection into the lower hind leg or SNI. These results suggest that α4 nAChRs on GABAergic neurons mediate a cholinergic analgesic circuit in the SNr, and these receptors may be effective therapeutic targets to relieve hyperalgesia in acute and chronic pain, and chronic nicotine exposure.

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Fig. 1: Inhibition of nAChRs in the SNr reduces pain threshold in mice.
Fig. 2: Nicotine in the SNr mitigates hyperalgesia in acute and chronic pain mouse models.
Fig. 3: Activation of α4β2 nAChRs mitigates hyperalgesia in acute and chronic pain.
Fig. 4: α4 nAChRs in SNr GABAergic neurons modulate pain states in mice.
Fig. 5: Stimulating the PPN-SNr projection mitigates hyperalgesia in acute pain.
Fig. 6: The role of α4 nAChRs on SNr GABAergic neurons in chronic nicotine-induced hyperalgesia in mice.
Fig. 7: Chronic nicotine reduces ACh release in the SNr.
Fig. 8: Pain stimulation-induced ACh release in the SNr is reduced in capsaicin nociceptive pain and neuropathic pain.

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Acknowledgements

This work was supported by the National Natural Science Foundation of China (82071231 (CX), 81971038 (CYZ), 82171235 (CYZ), 82271293 (CX), 82371242 (CYZ)), the Fund for Jiangsu Province Specially Appointed Professor (CX, CYZ), the Natural Science Foundation of Jiangsu Province (BK20211349, CYZ), the Natural Science Foundation of the Jiangsu Higher Education Institutions of China (23KJA320006 (CYZ), 23KJA320007, (CX)), and the Leadership Program in Xuzhou Medical University (JBGS202203, CX). We thank Terrence Z.Y. Xiao for data organization and grammar check for the manuscript.

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  1. These authors contributed equally: Yu Han, Jia-qi Zhang

Authors and Affiliations

  1. Jiangsu Province Key Laboratory of Anesthesiology, School of Anesthesiology, Xuzhou Medical University, Xuzhou, 221004, China

    Yu Han, Jia-qi Zhang, Ya-wei Ji, Yi-wen Luan, Shu-yi Li, Hui-zhen Geng, Ying Ji, Cui Yin, Su Liu, Chun-yi Zhou & Cheng Xiao

  2. Jiangsu Province Key Laboratory of Anesthesia and Analgesia Application Technology, Xuzhou Medical University, Xuzhou, 221004, China

    Yu Han, Jia-qi Zhang, Ya-wei Ji, Shu-yi Li, Cui Yin, Su Liu, Chun-yi Zhou & Cheng Xiao

  3. NMPA Key Laboratory for Research and Evaluation of Narcotic and Psychotropic Drugs, School of Anesthesiology, Xuzhou Medical University, Xuzhou, 221004, China

    Yu Han, Jia-qi Zhang, Ya-wei Ji, Shu-yi Li, Cui Yin, Su Liu, Chun-yi Zhou & Cheng Xiao

  4. Department of Anesthesiology, Yiwu Central Hospital, Yiwu, 322099, China

    Yu Han

  5. Wuxi People’s Hospital, Wuxi, 214023, China

    Yi-wen Luan

  6. Department of Anesthesiology, Affiliated Hospital of Xuzhou Medical University, Xuzhou, 221002, China

    Su Liu

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Contributions

CX, CYZ and SL designed the experiments. CX and CYZ supervised this research. YH, JQZ, YWL and YJ performed mouse survival surgeries and morphological experiments. YH, JQZ, SYL, YWL, CY and YJ performed behavioral tests and managed the mouse colony. YWJ and HZG collected and analyzed electrophysiological data. CX, CYZ and YH wrote the manuscript. All authors read and approved the manuscript.

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Correspondence to Chun-yi Zhou or Cheng Xiao.

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Han, Y., Zhang, Jq., Ji, Yw. et al. α4 nicotinic receptors on GABAergic neurons mediate a cholinergic analgesic circuit in the substantia nigra pars reticulata. Acta Pharmacol Sin (2024). https://doi.org/10.1038/s41401-024-01234-7

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