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Original research
Inhibition of the glutamatergic PVT-NAc projections attenuates local anesthetic-induced neurotoxic behaviors
  1. Yu Zou1,
  2. Xin He1,
  3. Zhiwen Ye2,3,
  4. Zhengyiqi Li1,
  5. Qulian Guo1,
  6. Wangyuan Zou1 and
  7. Qianyi Peng2,3
  1. 1Department of Anesthesia, Xiangya Hospital Central South University, Changsha, Hunan Province, China
  2. 2Department of Critical Care Medicine, Xiangya Hospital Central South University, Changsha, Hunan Province, China
  3. 3Xiangya Hospital Central South University National Clinical Research Center for Geriatric Disorders, Changsha, Hunan Province, China
  1. Correspondence to Dr Qianyi Peng, Department of Critical Care Medicine, Central South University, Changsha, Hunan Province, China; 405905{at}csu.edu.cn; Professor Wangyuan Zou, Department of Anesthesia, Xiangya Hospital Central South University, Changsha, Hunan Province, China; wangyuanzou{at}csu.edu.cn

Abstract

Introduction Local anesthetic-induced neurotoxicity contributes to perioperative nerve damage; however, the underlying mechanisms remain unclear. Here, we investigated the role of the paraventricular thalamus (PVT)-nucleus accumbens (NAc) projections in neurotoxicity induced by ropivacaine, a local anesthetic agent.

Methods Ropivacaine (58 mg/kg, intraperitoneal administration) was used to construct the local anesthetic systemic toxicity (LAST) mice model. We first identified neural projections from the PVT to the NAc through the expression of a retrograde tracer and virus. The inhibitory viruses (rAAV-EF1α-DIO-hm4D(Gi)-mCherry-WPREs: AAV2/retro and rAAV-CaMKII-CRE-WPRE-hGh: AAV2/9) were injected into the mice model to assess the effects of the specific inhibition of the PVT-NAc pathway on neurological behaviors in the presence of clozapine-N-oxide. The inhibition of the PVT-NAc pathway was evaluated by immunofluorescence staining of c-Fos-positive neurons and Ca2+ signals in CaMKIIa neurons.

Results We successfully identified a circuit connecting the PVT and NAc in C57BL/6 mice. Ropivacaine administration induced the activation of the PVT-NAc pathway and seizures. Specific inhibition of NAc-projecting CaMKII neurons in the PVT was sufficient to inhibit the neuronal activity in the NAc, which subsequently decreased ropivacaine-induced neurotoxicity.

Conclusion These results reveal the presence of a dedicated PVT-NAc circuit that regulates local anesthetic-induced neurotoxicity and provide a potential mechanistic explanation for the treatment and prevention of LAST.

  • Neurotoxicity Syndromes
  • Anesthesia, Local
  • Animal Experimentation

Data availability statement

Data are available in a public, open access repository. Data are available upon reasonable request. All processed data used in this study can be obtained from the corresponding author on reasonable request.

https://doi.org/10.1136/rapm-2023-104964

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    Data availability statement

    Data are available in a public, open access repository. Data are available upon reasonable request. All processed data used in this study can be obtained from the corresponding author on reasonable request.

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    Footnotes

    • YZ and XH contributed equally.

    • WZ and QP contributed equally.

    • Contributors YZ performed the experiments and wrote the manuscript. QP designed the research. XH and ZL collected the data. ZY performed the data analysis. WZ and QG reviewed the manuscript. All the authors reviewed and approved the manuscript. YZ is the author responsible for the overall content as the guarantor.

    • Funding The present research study received funding from the National Natural Science Foundation of China (grant numbers: 82372199 and 81901264).

    • Competing interests None declared.

    • Provenance and peer review Not commissioned; externally peer reviewed.

    • Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.