Lidocaine acts as local anaesthetic by blocking sodium channels, but also has inhibitory effects on nicotinic acetylcholine (ACh) receptors (nAChRs). This work was aimed to determine the mechanisms underlying lidocaine actions on purified Torpedo nAChRs transplanted to Xenopus oocytes. For this purpose, we recorded the membrane currents elicited by ACh (IACh) either alone or co-applied with lidocaine.

IACh was reversibly blocked by lidocaine, in a concentration-dependent way (IC50 = 70 mM; Hill coefficient, 1). The mechanism of IACh blockade was markedly dependent on lidocaine dosage. So, at low lidocaine concentrations (lower than IC50), IACh inhibition was only present at negative potentials and showed a non-competitive behaviour, suggesting an open-channel block as the main mechanism of blockade. At higher lidocaine concentrations, nAChRs were blocked both at positive and negative potentials, IACh desensitisation increased and the ACh concentration-IACh amplitude curve shifted to the right, indicating an additional mechanism of inhibition, apparently competitive. To determine whether lidocaine binds within the ion channel at the same loci that edrophonium or BW284c51, which are nAChR inhibitors with charged ammonium groups (alike to a fraction of lidocaine molecules at physiological pH), ACh was co-applied with both lidocaine (20 mM) and either edrophonium (3 mM) or BW284c51 (0.5 mM). Co-application of lidocaine with any of them resulted in synergic inhibitory effects on IACh, indicating that these molecules have different binding sites within the ion channel.

This work was partially supported by DGICYT grant BFU2006-04781 (Spain).