An in Vivo Mouse Model to Investigate the Effect of Local Anesthetic Nanomedicines on Axonal Conduction and Excitability

Mihai Moldovan*, Susana Alvarez, Christian Rothe, Thomas L. Andresen, Andrew Urquhart, Kai H. W. Lange, Christian Krarup

*Corresponding author for this work

    Research output: Contribution to journalJournal articleResearchpeer-review

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    Abstract

    Peripheral nerve blocks (PNBs) using local anesthetic (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 behavioral 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 fibers 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.
    Original languageEnglish
    Article number494
    JournalFrontiers in Neuroscience
    Volume12
    Number of pages9
    ISSN1662-4548
    DOIs
    Publication statusPublished - 2018

    Keywords

    • Liposomes
    • Peripheral nerve block
    • Threshold-tracking
    • In vivo imaging
    • Lidocaine

    Cite this

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    title = "An in Vivo Mouse Model to Investigate the Effect of Local Anesthetic Nanomedicines on Axonal Conduction and Excitability",
    abstract = "Peripheral nerve blocks (PNBs) using local anesthetic (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 behavioral 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 fibers 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",
    author = "Mihai Moldovan and Susana Alvarez and Christian Rothe and Andresen, {Thomas L.} and Andrew Urquhart and Lange, {Kai H. W.} and Christian Krarup",
    year = "2018",
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    language = "English",
    volume = "12",
    journal = "Frontiers in Neuroscience",
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    An in Vivo Mouse Model to Investigate the Effect of Local Anesthetic Nanomedicines on Axonal Conduction and Excitability. / Moldovan, Mihai; Alvarez, Susana; Rothe, Christian; Andresen, Thomas L.; Urquhart, Andrew; Lange, Kai H. W.; Krarup, Christian.

    In: Frontiers in Neuroscience, Vol. 12, 494, 2018.

    Research output: Contribution to journalJournal articleResearchpeer-review

    TY - JOUR

    T1 - An in Vivo Mouse Model to Investigate the Effect of Local Anesthetic Nanomedicines on Axonal Conduction and Excitability

    AU - Moldovan, Mihai

    AU - Alvarez, Susana

    AU - Rothe, Christian

    AU - Andresen, Thomas L.

    AU - Urquhart, Andrew

    AU - Lange, Kai H. W.

    AU - Krarup, Christian

    PY - 2018

    Y1 - 2018

    N2 - Peripheral nerve blocks (PNBs) using local anesthetic (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 behavioral 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 fibers 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.

    AB - Peripheral nerve blocks (PNBs) using local anesthetic (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 behavioral 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 fibers 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.

    KW - Liposomes

    KW - Peripheral nerve block

    KW - Threshold-tracking

    KW - In vivo imaging

    KW - Lidocaine

    U2 - 10.3389/fnins.2018.00494

    DO - 10.3389/fnins.2018.00494

    M3 - Journal article

    C2 - 30093852

    VL - 12

    JO - Frontiers in Neuroscience

    JF - Frontiers in Neuroscience

    SN - 1662-4548

    M1 - 494

    ER -