Quantitative Electrophysiological Evaluation of the Analgesic Efficacy of Two Lappaconitine Derivatives: A Window into Antinociceptive Drug Mechanisms
Guixiang Teng1,2 • Fengrui Zhang3,4 • Zhenjiang Li5 • Chun Zhang6 • Libo Zhang3,4 • Lele Chen1,2 • Tao Zhou1,2 • Lupeng Yue3,4 • Ji Zhang1,2
1 College of Life Science, Northwest Normal University, Lanzhou 730070, China 2 The Rural Development Academy, Northwest Normal University, Lanzhou 730070, China 3 CAS Key Laboratory of Mental Health, Institute of Psychology, Chinese Academy of Sciences, Beijing 100101, China 4 Department of Psychology, University of the Chinese Academy of Sciences, Beijing 100049, China 5 School of Psychology, Jiangxi Normal University, Nanchang 330022, China 6 School of Chemical and Biological Engineering, Lanzhou Jiaotong University, Lanzhou 730070, China
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 laserevoked 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 gammaband 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.
Keywords
Electrocorticogram; Analgesic effect; Lappaconitine derivatives; Antinociceptive mechanisms;Laser-evoked potentials
