Membrane toxicity of opioids measured by protozoan motility

The acute toxicity of some opioid drugs cannot solely be explained by a specific interaction with the opioid receptor. The anaesthetic-like membrane effect of 10 opioid agents and the antagonist naloxone was determined and correlated with their hydrophobicity. The inhibitory effect of drugs on protozoan motility was used as a measure of their membrane toxicity, measured by the reduction in swimming speed of Tetrahymena pyriformis using an image analysis system. Hydrophobicity was determined as the n-octanol/water partition coefficient, at pH 7.4, 37 degrees C. Opioid agents dose-dependently reduced the swimming speed of Tetrahymena pyriformis with a wide range of IC50 values. Some weak opioid agents were shown to have high protozoan immobilising potency comparable to quinidine, an agent with known membrane stabilising activity. Norpropoxyphene, the metabolite of dextropropoxyphene, with little affinity for the opioid receptor, also had a high potency. The inhibition of protozoan motility by these opioid agents was not antagonised by the opioid receptor antagonist naloxone; moreover an additive inhibitory action was demonstrated when opioid agents were combined with naloxone. The effect of opioid agents on protozoan motility was closely correlated with their partition coefficient but not with their known affinity for opioid receptors. These results suggest that opioid agents possess differing degrees of membrane depressant action independent from their interaction with the opioid receptor, and have a potential for causing depressant effects on excitable tissues.