Naloxone Counteracts the Fast Development of Tolerance to Morphine in Guinea‐Pig Ileum

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Abstract
The ability of naloxone to inhibit the fast development of tolerance to morphine was examined in the guinea‐pig ileum preparation. Dose‐response curves were obtained either non‐cumulatively with morphine alone or cumulatively with morphine alone and in combination with different concentrations of naloxone. We present some theoretical considerations concerning the competitive interaction between agonist and antagonist on a receptor. According to these theories, it is possible to perform dose‐response experiments for an agonist in combination with different concentrations of antagonist and extrapolate to the dose‐response curve for agonist alone and to the dissociation constant for the antagonist. EC50values for morphine alone obtained either non‐cumulatively or by extrapolation are almost identical and are significantly lower than those obtained cumulatively. The results indicate that tolerance developes very quickly when dose‐response curves are obtained cumulatively with morphine alone and that low concentrations of naloxone counteract the development of tolerance.