MODEL OF OPIATE DEPENDENCE IN THE GUINEA‐PIG ISOLATED ILEUM

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Abstract
Segments of ileum, incubated for 2–24 h at 22°C with normorphine (0.01‐1.0 μm), in the presence of hexamethonium, contracted when challenged with naloxone (0.03 μm). No response to this dose of naloxone was induced either by incubation in control solution without opiate for 2–24 h or by exposure of the preparation to opiate for 30 min at 37°C. When segments were incubated for 24 h, the size of the response to naloxone was directly related both to the normorphine concentration in the incubation fluid (0.01 to 0.1 μm), and to the concentration of naloxone applied (0.03 to 0.1 μm). A spontaneous withdrawal contracture was elicited in ilea that had been incubated with normorphine (1.0 μm), when the normorphine‐containing bathing fluid was exchanged for one without opiate. Normorphine restored to resting level the tension of the withdrawal contracture, whether it had been elicited spontaneously or by naloxone challenge. Addition of naloxone (1.0 μm) to normorphine (1.0 μm) in the incubation fluid abolished the withdrawal contracture to subsequent challenge with naloxone. Naloxone elicited a contracture from segments incubated for 24 h at 22°C with levorphanol (0.1 μm) but not from those incubated with dextrorphan. Application of (+)‐naloxone (0.03 μm) to segments previously incubated with normorphine (0.1 μm) did not elicit a contracture. The contracture elicited by naloxone in preparations incubated with morphine (10 μm) was associated with a reduction in sensitivity to the acute inhibitory effect of morphine on the electrically‐evoked response. Addition of hyoscine (0.5 μm) immediately after challenge with naloxone restored the tension of the withdrawal contracture to resting level. Tetrodotoxin (3.0 μm) given before challenge, prevented naloxone from eliciting a withdrawal contracture. The inclusion of 5‐hydroxytryptamine (10 μm) with morphine (10 μm) inhibited the induction of tolerance to morphine. These experiments, together with those described earlier, indicate that incubation with opiate induces a dependence in the final cholinergic motor neurones of the myenteric plexus, manifested as a contracture of the longitudinal muscle on removal of opiate or administration of an antagonist. This dependence is associated with tolerance, expressed as a decrease in sensitivity to inhibition by morphine of the electrically‐evoked contracture. Tolerance and dependence are induced and withdrawal precipitated through specific and stereospecific opiate receptors.