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Quantitative Electrophysiological Evaluation of the Analgesic Efficacy of Two Lappaconitine Derivatives: A Window into Antinociceptive Drug Mechanisms

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Abstract

Quantitative evaluation of analgesic efficacy improves understanding of the antinociceptive mechanisms of new analgesics and provides important guidance for their development. Lappaconitine (LA), a potent analgesic drug extracted from the root of natural Aconitum species, has been clinically used for years because of its effective analgesic and non-addictive properties. However, being limited to ethological experiments, previous studies have mainly investigated the analgesic effect of LA at the behavioral level, and the associated antinociceptive mechanisms are still unclear. In this study, electrocorticogram (ECoG) technology was used to investigate the analgesic effects of two homologous derivatives of LA, Lappaconitine hydrobromide (LAH) and Lappaconitine trifluoroacetate (LAF), on Sprague-Dawley rats subjected to nociceptive laser stimuli, and to further explore their antinociceptive mechanisms. We found that both LAH and LAF were effective in reducing pain, as manifested in the remarkable reduction of nocifensive behaviors and laser-evoked potentials (LEPs) amplitudes (N2 and P2 waves, and gamma-band oscillations), and significantly prolonged latencies of the LEP-N2/P2. These changes in LEPs reflect the similar antinociceptive mechanism of LAF and LAH, i.e., inhibition of the fast signaling pathways. In addition, there were no changes in the auditory-evoked potential (AEP-N1 component) before and after LAF or LAH treatment, suggesting that neither drug had a central anesthetic effect. Importantly, compared with LAH, LAF was superior in its effects on the magnitudes of gamma-band oscillations and the resting-state spectra, which may be associated with their differences in the octanol/water partition coefficient, degree of dissociation, toxicity, and glycine receptor regulation. Altogether, jointly applying nociceptive laser stimuli and ECoG recordings in rats, we provide solid neural evidence for the analgesic efficacy and antinociceptive mechanisms of derivatives of LA.

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Acknowledgements

This work was supported by the National Natural Science Foundation of China (51873175) and the Special Fund of Guiding Scientific and Technological Innovation and Development in Gansu Province, China (2019ZX-05).

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  1. Guixiang Teng and Fengrui Zhang contributed equally to this work.

Authors and Affiliations

  1. College of Life Science, Northwest Normal University, Lanzhou, 730070, China

    Guixiang Teng, Lele Chen, Tao Zhou & Ji Zhang

  2. The Rural Development Academy, Northwest Normal University, Lanzhou, 730070, China

    Guixiang Teng, Lele Chen, Tao Zhou & Ji Zhang

  3. CAS Key Laboratory of Mental Health, Institute of Psychology, Chinese Academy of Sciences, Beijing, 100101, China

    Fengrui Zhang, Libo Zhang & Lupeng Yue

  4. Department of Psychology, University of the Chinese Academy of Sciences, Beijing, 100049, China

    Fengrui Zhang, Libo Zhang & Lupeng Yue

  5. School of Psychology, Jiangxi Normal University, Nanchang, 330022, China

    Zhenjiang Li

  6. School of Chemical and Biological Engineering, Lanzhou Jiaotong University, Lanzhou, 730070, China

    Chun Zhang

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  1. Guixiang Teng
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Teng, G., Zhang, F., Li, Z. et al. Quantitative Electrophysiological Evaluation of the Analgesic Efficacy of Two Lappaconitine Derivatives: A Window into Antinociceptive Drug Mechanisms. Neurosci. Bull. 37, 1555–1569 (2021). https://doi.org/10.1007/s12264-021-00774-w

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