Background and objective Long-acting nociceptive-selective regional anesthesia has remained an elusive clinical goal. We aspired to identify a novel compound that would produce nociceptive-selective regional anesthesia through the transient receptor potential vanilloid 1 (TRPV1) channels.
Methods We designed and synthesized a novel compound (LL-a) that penetrates the cell membrane through TRPV1 channels and binds to voltage-gated sodium channels. The regional anesthetic effect of LL-a was evaluated in a rodent sciatic nerve block model. Electrophysiological recording was applied to test the inhibition of LL-a on voltage-gated sodium channel currents.
Results LL-a inhibited sodium channel currents on the dorsal root ganglion neurons of mice and this action was diminished by TRPV1 channel knockout. In a sciatic nerve block model of a rat, 0.2% and 0.4% (w/v) LL-a produced selective sensory block with median (IQR) durations of 42.0 (24.0, 48.0) and 72.0 (69.0, 78.0) hours, respectively. No motor block was found for 0.2% LL-a. 0.4% LL-a produced a motor block with a median (IQR) duration of 3.0 (0.0, 6.0) hours. This selective sensory block was not observed on TRPV1 knockout mice. As a positive control, 0.5% and 0.75% levobupivacaine produced a non-selective sciatic nerve block with median (IQR) durations of 2.8 (2.6, 2.8) and 3.8 (3.8, 4.8) hours, respectively. No systemic or local irritation was observed during injection of LL-a and sensory and motor function completely recovered for all the animals.
Conclusions LL-a is a potential novel local anesthetic for long-lasting nociceptive-selective analgesia.
- pain medicine
- animal studies
- pharmacology: local anesthetics
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CZ, LT and QY contributed equally.
Contributors CZ: Conception and design, conduct, acquisition of data, analysis and interpretation of data and manuscript writing. LT: Conception and design, acquisition of data, analysis and interpretation of data. QY: Conduct, acquisition of data, analysis and interpretation of data and manuscript writing. LY, DG, YK, HC, JF, YZ, DQ, QZ: Acquisition of data. BK: Analysis and interpretation of data. JL: Discuss the planning, conduct, analysis and interpretation of data. WZ: Discuss the planning, analysis and interpretation of data and manuscript writing. JY: Discuss the planning, conduct, acquisition of data analysis, interpretation of data and manuscript writing.
Funding This study was supported by grant 2019YFS0093 (to JY) from Key Research & Development Projects of Department of Science & Technology of Sichuan Province.
Competing interests None declared.
Patient consent for publication Not required.
Ethics approval The Institutional Animal Experimental Ethics Committee of Sichuan University (Chengdu, China) reviewed and approved all the protocols.
Provenance and peer review Not commissioned; externally peer reviewed.
Data availability statement All data relevant to the study are included in the article or uploaded as supplementary information.
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