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Front. Neurosci. | doi: 10.3389/fnins.2018.00494

An in vivo mouse model to investigate the effect of local anaesthetic nanomedicines on axonal conduction and excitability

 Mihai Moldovan1, 2*,  Susana Alvarez1, Christian Rothe3,  Thomas L. Andresen4, Andrew Urquhart4,  Kai H. Lange3 and  Christian Krarup1, 2
  • 1Department of Neuroscience, University of Copenhagen, Denmark
  • 2Department of Clinical Neurophysiology, Rigshospitalet, Denmark
  • 3Department of Anesthesia, Nordsjællands Hospital, Denmark
  • 4Department for Micro- and Nanotechnology, Technical University of Denmark, Denmark

Peripheral nerve blocks (PNBs) using local anaesthetic (LA) are superior to systemic analgesia for management of post-operative pain. An insufficiently short PNB duration following single-shot LA can be optimized by development of extended release formulations among which liposomes have been shown to be the least toxic. In vivo rodent models for PNB have focused primarily on assessing behavioural responses following LA. In a previous study in human volunteers we found that it is feasible to monitor the effect of LA in vivo by combining conventional conduction studies with nerve excitability studies. Here we aimed to develop a mouse model where the same neurophysiological techniques can be used to investigate liposomal formulations of LA in vivo. To challenge the validity of the model, we tested the motor PNB following an unilamellar liposomal formulation, filled with the intermediate-duration LA lidocaine. Experiments were carried out in adult transgenic mice with fluorescent axons and with fluorescent tagged liposomes to allow in vivo imaging by probe-based confocal laser endomicroscopy. Recovery of conduction following LA injection at the ankle was monitored by stimulation of the tibial nerve fibres at the sciatic notch and recording of the plantar compound motor action potential (CMAP). We detected a delayed recovery in CMAP amplitude following liposomal lidocaine, without detrimental systemic effects. Furthermore, CMAP threshold-tracking studies of the distal tibial nerve showed that the increased rheobase was associated with a sequence of excitability changes similar to those found following non-encapsulated lidocaine PNB in humans, further supporting the translational value of the model.

Keywords: Liposomes, peripheral nerve block, threshold-tracking, in vivo imaging, Lidocaine

Received: 20 Apr 2018; Accepted: 02 Jul 2018.

Edited by:

Ioan Opris, University of Miami, United States

Reviewed by:

Angelika Lampert, Uniklinik RWTH Aachen, Germany
Mario Valentino, University of Malta, Malta  

Copyright: © 2018 Moldovan, Alvarez, Rothe, Andresen, Urquhart, Lange and Krarup. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

* Correspondence: MD, PhD. Mihai Moldovan, University of Copenhagen, Department of Neuroscience, Copenhagen, Denmark, moldovan@sund.ku.dk