2. Academic Validation
  3. α4 nicotinic receptors on GABAergic neurons mediate a cholinergic analgesic circuit in the substantia nigra pars reticulata

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

  • Acta Pharmacol Sin. 2024 Mar 4. doi: 10.1038/s41401-024-01234-7.
Yu Han # 1 2 3 4,  Jia-Qi Zhang # 1 2 3,  Ya-Wei Ji 1 2 3,  Yi-Wen Luan 1 5,  Shu-Yi Li 1 2 3,  Hui-Zhen Geng 1,  Ying Ji 1,  Cui Yin 1 2 3,  Su Liu 1 2 3 6,  Chun-Yi Zhou 7 8 9,  Cheng Xiao 10 11 12
Affiliations

Affiliations

  • 1 Jiangsu Province Key Laboratory of Anesthesiology, School of Anesthesiology, Xuzhou Medical University, Xuzhou, 221004, China.
  • 2 Jiangsu Province Key Laboratory of Anesthesia and Analgesia Application Technology, Xuzhou Medical University, Xuzhou, 221004, China.
  • 3 NMPA Key Laboratory for Research and Evaluation of Narcotic and Psychotropic Drugs, School of Anesthesiology, Xuzhou Medical University, Xuzhou, 221004, China.
  • 4 Department of Anesthesiology, Yiwu Central Hospital, Yiwu, 322099, China.
  • 5 Wuxi People's Hospital, Wuxi, 214023, China.
  • 6 Department of Anesthesiology, Affiliated Hospital of Xuzhou Medical University, Xuzhou, 221002, China.
  • 7 Jiangsu Province Key Laboratory of Anesthesiology, School of Anesthesiology, Xuzhou Medical University, Xuzhou, 221004, China. chunyi.zhou@xzhmu.edu.cn.
  • 8 Jiangsu Province Key Laboratory of Anesthesia and Analgesia Application Technology, Xuzhou Medical University, Xuzhou, 221004, China. chunyi.zhou@xzhmu.edu.cn.
  • 9 NMPA Key Laboratory for Research and Evaluation of Narcotic and Psychotropic Drugs, School of Anesthesiology, Xuzhou Medical University, Xuzhou, 221004, China. chunyi.zhou@xzhmu.edu.cn.
  • 10 Jiangsu Province Key Laboratory of Anesthesiology, School of Anesthesiology, Xuzhou Medical University, Xuzhou, 221004, China. xchengxj@xzhmu.edu.cn.
  • 11 Jiangsu Province Key Laboratory of Anesthesia and Analgesia Application Technology, Xuzhou Medical University, Xuzhou, 221004, China. xchengxj@xzhmu.edu.cn.
  • 12 NMPA Key Laboratory for Research and Evaluation of Narcotic and Psychotropic Drugs, School of Anesthesiology, Xuzhou Medical University, Xuzhou, 221004, China. xchengxj@xzhmu.edu.cn.
  • # Contributed equally.
PMID: 38438581 DOI: 10.1038/s41401-024-01234-7
Abstract

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.

Keywords

cholinergic system; chronic nicotine; nicotinic acetylcholine receptor; pain; pedunculopontine nucleus; substantia nigra pars reticulata.

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