Functional magnetic resonance imaging in wild-type and CB1 receptor knockout mice revealed that lidocaine at low doses induces hyperalgesia, predominantly mediated by CB1 receptors located on nociceptors.
Lidocaine is clinically widely used as a local anesthetic inhibiting propagation of action potentials in peripheral nerve fibers. Correspondingly, the functional magnetic resonance imaging (fMRI) response in mouse brain to peripheral noxious input is largely suppressed by local lidocaine administered at doses used in a clinical setting. We observed, however, that local administration of lidocaine at doses 100× lower than that used clinically led to a significantly increased sensitivity of mice to noxious forepaw stimulation as revealed by fMRI. This hyperalgesic response could be confirmed by behavioral readouts using the von Frey filament test. The increased sensitivity was found to involve a type 1 cannabinoid (CB1) receptor-dependent pathway as global CB1 knockout mice, as well as wild-type mice pretreated systemically with the CB1 receptor blocker rimonabant, did not display any hyperalgesic effects after low-dose lidocaine. Additional experiments with nociceptor-specific CB1 receptor knockout mice indicated an involvement of the CB1 receptors located on the nociceptors. We conclude that low concentrations of lidocaine leads to a sensitization of the nociceptors through a CB1 receptor-dependent process. This lidocaine-induced sensitization might contribute to postoperative hyperalgesia.
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a Institute for Biomedical Engineering, University and ETH Zurich, Zürich 8093, Switzerland
b Neuroscience Center, University and ETH Zurich, Switzerland, Zürich 8057, Switzerland
c Institute of Pharmacology and Toxicology, University of Zurich, Zürich 8057, Switzerland
d Institute of Pharmaceutical Sciences, ETH Zurich, Zürich 8093, Switzerland
*Corresponding author. Address: Institute for Biomedical Engineering, Animal Imaging Center, Wolfgang-Pauli-Str. 27, Zurich 8093, Switzerland. Tel.: +41 44 633 76 04; fax: +41 44 633 11 87.
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Article history: Received 21 June 2011; Received in revised form 29 March 2012; Accepted 2 April 2012.