Mechanisms of (local) anaesthetics on voltage-gated sodium and other ion channels  A Scholz  British Journal of Anaesthesia  Volume 89, Issue 1, Pages 52-61 (July 2002) DOI: 10.1093/bja/aef163 Copyright © 2002 British Journal of Anaesthesia Terms and Conditions

Fig 1 Structure of a Na+ channel α-subunit. (a) Schematic diagram of the four domains DI–DIV. Each domain consists of six segments, which span the membrane. Part of the ‘pore’ loops, the amino acid links between the S5 and the S6 segments are symbolized as red triangles. These four amino acid links ‘DEKA’ form the selectivity filter in the outer pore mouth (for more details see section Structure of Na+ channel). (b) 3D sketches of a Na+ channel with top and bottom views and large cross-section as derived from data of cryo-electron microscopy and single particle analysis.60 On the left side of the large cross-section the cut is through the S4 segment (the function of the cavity marked in red is unclear) and on the right side the cross-section is through the S6 segment overlaid with the amino acid sequence of rat brain Na+ channel (Nav 1.2). Residues that are coloured and numbered (60 for amino acid 1760 etc.) are important for the affinity of local anaesthetics. (Adapted with permission from Nature18 and Mosby Saunders.63) British Journal of Anaesthesia 2002 89, 52-61DOI: (10.1093/bja/aef163) Copyright © 2002 British Journal of Anaesthesia Terms and Conditions

Fig 2 Tetrodotoxin (TTX)-resistant and TTX-sensitive Na+ currents in rat dorsal root ganglion neurones blocked by lidocaine. (a) TTX-resistant Na+ currents. Fitting to the decaying parts (dotted lines) showed time constants of 3.6 ms in Ringer-TTX solution and 3.2 ms in the presence of lidocaine 300 μmol litre−1. (b) The TTX-sensitive Na+ currents decayed faster, with time constants of 0.4 ms in Ringer solution and 0.5 ms in the presence of lidocaine 50 μmol litre−1. Less than 2% of the current remained in the presence of TTX 200 nmol litre−1. (Adapted with permission of J. Neurophysiol.66) British Journal of Anaesthesia 2002 89, 52-61DOI: (10.1093/bja/aef163) Copyright © 2002 British Journal of Anaesthesia Terms and Conditions

Fig 3 Local anaesthetics reduce firing frequency in small dorsal root ganglia neurones. (a) Trains of tetrodotoxin (TTX)-resistant action potentials elicited by a 750 ms 400 pA current stimulus are reduced in firing frequency by increasing concentrations of lidocaine. (b) Similar effects as in (a) seen with bupivacaine in another neurone. Extracellular solution in bath containing TTX 200 nM; high KI in pipette; 22–23°C. (Modified with permission from International Association of Pain.67) British Journal of Anaesthesia 2002 89, 52-61DOI: (10.1093/bja/aef163) Copyright © 2002 British Journal of Anaesthesia Terms and Conditions

Fig 4 Different sensitivities to local anaesthetics of firing frequency, action potential (AP) amplitude and tetrodotoxin (TTX)-resistant Na+ current. (a) The number of TTX-resistant (TTXr) AP (left ordinate) during 750 ms current injections depended on the concentration of lidocaine. A Hill equation was fitted to the data, revealing IC50 values of 24, 27 and 23 μM for 300, 400 and 500 pA current stimuli, respectively, from a single small dorsal root ganglion neurone. Blockade of active amplitudes of TTXr AP (right ordinate) revealed an IC50 of 730 μM lidocaine. For comparison, the reduction of TTXr Na+ current (dotted line66) is given, with an IC50 of 210 μM lidocaine. (b) The reduction in the number of AP from another neurone revealed IC50 values of 7, 9 and 7 μM bupivacaine for 200, 300 and 400 pA stimuli, respectively. The IC50 of reduction of active TTXr action potential amplitudes (open circles, same neurone) was 110 μM bupivacaine. The IC50 of reduction of TTXr Na+ current (dotted line66) was 32 μM bupivacaine. (Modified with permission from International Association of Pain.67) British Journal of Anaesthesia 2002 89, 52-61DOI: (10.1093/bja/aef163) Copyright © 2002 British Journal of Anaesthesia Terms and Conditions