Methadone is a local anaesthetic-like inhibitor of neuronal Na+ channels and blocks excitability of mouse peripheral nerves
Stoetzer C, Kistner K, Stüber T, Wirths M, Schulze V, Doll T, Foadi N, Wegner F, Ahrens J, Leffler A (2015)
Publication Type: Journal article
Publication year: 2015
Journal
Publisher: Oxford University Press (OUP): Policy B - Oxford Open Option B
Book Volume: 114
Pages Range: 110-20
Journal Issue: 1
DOI: 10.1093/bja/aeu206
Abstract
Opioids enhance and prolong analgesia when applied as adjuvants to local anaesthetics (LAs). A possible molecular mechanism for this property is a direct inhibition of voltage-gated Na(+) channels which was reported for some opioids. Methadone is an effective adjuvant to LA and was recently reported to inhibit cardiac Na(+) channels. Here, we explore and compare LA properties of methadone and bupivacaine on neuronal Na(+) channels, excitability of peripheral nerves, and cell viability.Effects of methadone were explored on compound action potentials (CAP) of isolated mouse saphenous nerves. Patch clamp recordings were performed on Na(+) channels in ND7/23 cells, the ?-subunits Nav1.2, Nav1.3, Nav1.7, and Nav1.8, and the hyperpolarization-activated cyclic nucleotide-gated channel 2 (HCN2). Cytotoxicity was determined using flow cytometry.Methadone (IC50 86-119 µM) is a state-dependent and unselective blocker on Nav1.2, Nav1.3, Nav1.7, and Nav1.8 with a potency comparable with that of bupivacaine (IC50 177 µM). Both bupivacaine and methadone also inhibit C- and A-fibre CAPs in saphenous nerves in a concentration-dependent manner. Tonic block of Nav1.7 revealed a discrete stereo-selectivity with a higher potency for levomethadone than for dextromethadone. Methadone is also a weak blocker of HCN2 channels. Both methadone and bupivacaine induce a pronounced cytotoxicity at concentrations required for LA effects.Methadone induces typical LA effects by inhibiting Na(+) channels with a potency similar to that of bupivacaine. This hitherto unknown property of methadone might contribute to its high efficacy when applied as an adjuvant to LA.
Authors with CRIS profile
Involved external institutions
Germany (DE)How to cite
APA:
Stoetzer, C., Kistner, K., Stüber, T., Wirths, M., Schulze, V., Doll, T.,... Leffler, A. (2015). Methadone is a local anaesthetic-like inhibitor of neuronal Na+ channels and blocks excitability of mouse peripheral nerves. British Journal of Anaesthesia, 114(1), 110-20. https://doi.org/10.1093/bja/aeu206
MLA:
Stoetzer, C., et al. "Methadone is a local anaesthetic-like inhibitor of neuronal Na+ channels and blocks excitability of mouse peripheral nerves." British Journal of Anaesthesia 114.1 (2015): 110-20.
BibTeX: Download