Tramadol, but not its major metabolite (mono‐O‐demethyl tramadol) depresses compound action potentials in frog sciatic nerves

Abstract

Background and purpose: Although tramadol is known to exhibit a local anaesthetic effect, how tramadol exerts this effect is not understood fully. Experimental approach: The effects of tramadol and its metabolite mono‐O‐demethyl‐tramadol (M1) on compound action potentials (CAPs) were examined by applying the air‐gap method to frog sciatic nerves, and the results were compared with those of other local anaesthetics, lidocaine and ropivacaine. Key results: Tramadol reduced the peak amplitude of the CAP in a dose‐dependent manner (IC₅₀=2.3 mM). On the other hand, M1 (1–2 mM), which exhibits a higher affinity for μ‐opioid receptors than tramadol, did not affect CAPs. These effects of tramadol were resistant to the non‐selective opioid receptor antagonist naloxone and the μ‐opioid receptor agonist, DAMGO, did not affect CAPs. This tramadol action was not affected by a combination of the noradrenaline uptake inhibitor, desipramine, and the 5‐hydroxytryptamine uptake inhibitor, fluoxetine. Lidocaine and ropivacaine also concentration‐dependently reduced CAP peak amplitudes with IC₅₀ values of 0.74 and 0.34 mM, respectively. Conclusions and implications: These results indicate that tramadol reduces the peak amplitude of CAP in peripheral nerve fibres with a potency which is less than those of lidocaine and ropivacaine, whereas M1 has much less effect on CAPs. This action of tramadol was not produced by activation of μ‐opioid receptors nor by inhibition of noradrenaline and 5‐hydroxytryptamine uptake. It is suggested that the methyl group present in tramadol but not in M1 may play an important role in producing nerve conduction block. British Journal of Pharmacology (2006) 149, 319–327. doi:10.1038/sj.bjp.0706868