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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.

1 BAY u3405 (3(R)- [[(4-fluorophenyl) sulphonyl]amino]-1,2,3,4-tetrahydro-9H-carbazole-9-propanoic acid) has been evaluated on airway smooth muscle, from a number of species including man, for its thromboxane A2 (TXA2) antagonist activity. 2 BAY u3405 was a potent, and competitive, antagonist of the TXA2-mimetic U46619-induced contractions of human, guinea-pig, rat and ferret airway smooth muscle with pA2 values between 8.0 and 8.9 and with no inherent contractile activity (10 -IO-M). 3 The TXA2 antagonist activity of BAY u3405 was stereoselective. Its (S)-enantiomer, BAY u3406, was approximately 50 fold less effective against U46619 on guinea-pig and human airway smooth muscle. 4 BAY u3405 also competitively antagonized contractions of guinea-pig airway smooth muscle induced by prostaglandin D2 (PGD2) or its metabolite 9a, 1 lfl-PGF2. On human and ferret airway smooth muscle it abolished contractions induced by PGD2, PGF2. and 16, 5 A high concentration (10-6 M) of BAY u3405 had no effect on the contraction, or relaxation, of airway smooth muscle induced by a range of other agonists, nor did BAY u3405 have any effect on other prostanoid receptor types (DP, EP1, EP2, FP or IP). 6 BAY u3405, in contrast to some other TXA2 antagonists, is a potent and selective antagonist on a wide range of airways including human. This high affinity, and the oral activity of the compound described elsewhere, suggest it may be an appropriate tool to investigate the role of prostanoids in airway diseases such as asthma.

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The contribution of receptor-operated Ca2+ channels (ROCs), voltage-operated Ca2+ channels (VOCs), and intracellular Ca2+ release to contractions induced by a range of stimuli in the guinea pig isolated trachea has been evaluated. In the presence of physiological Ca2+ (1.3 x 10(-3) M), tissue pretreatment with ethylene glycol-bis(beta-aminoethyl ether)-N,N,N',N'-tetraacetic acid (EGTA) (4 x 10(-3) M for 5 min) markedly inhibited (> 90%) the contractile responses to a range of agonists. Therefore, under physiological Ca2+ concentration, Ca2+ mobilization from internal stores appeared to make little contribution to maximum contractions. Nifedipine (10(-7) M) or verapamil (10(-5) M) abolished KCl-induced contractions but produced variable inhibition of contractions induced by other agonists. The ROC (and VOC) blocker, SK&F 96365 (10(-5)-10(-4) M), inhibited both KCl-induced contractions and the nifedipine-insensitive component of contractions induced by acetylcholine (ACh), U46619, or leukotriene D4 [half maximal inhibitory concentration (IC50) values 1.7-3.8 x 10(-5) M]. Ni2+, which has ROC- and VOC-blocking actions, also abolished nifedipine-insensitive contractions induced by ACh. When Ca2+ was replaced with Ba2+, the contraction induced by ACh was blocked by nifedipine. Also, under these conditions, ACh did not increase the KCl maximum contraction. These data are consistent with there being distinct ROC and VOC influx pathways in guinea pig trachea and with ROCs playing a significant role in smooth muscle contraction.