The methyl group present in tramadol but not mono-O-demethyl-tramadol (M1), both of which exhibit a high affinity for μ-opioid receptors, is suggested to play an important role in producing nerve conduction block. To address further this issue, we examined the effects of opioids (morphine, codeine and ethylmorphine) on compound action potentials (CAPs) by applying the air-gap method to frog sciatic nerves. All of the drugs at concentrations less than 10 mM depressed the peak amplitude of CAP in a reversible manner. When compared in efficacy among the opioids, codeine more effectively reduced CAP peak amplitudes than morphine (30 and 15%, respectively, at 5 mM) did, where their chemical structures are distinct in only a substituent in the benzene ring in such that codeine and morphine have -OCH3 and -OH, respectively, in the ring. This structure-activity relationship was the same as that for tramadol and M1. Ethylmorphine having -O-CH2-CH3 in the benzene ring was more effective in reducing CAP amplitudes (61% at 5 mM; IC50 = 3.7 mM) than morphine and codeine. All of the opioid actions were resistant to an opioid-receptor antagonist naloxone (10 μM). It is concluded that opioids reduce CAP peak amplitudes in a manner which is independent of opioid receptor activation. It is suggested that the substituted groups of -OH bound to the benzene ring of codeine, morphine and ethylmorphine may play an important role in producing nerve conduction block. [J Physiol Sci. 2007;57 Suppl:S226]
