1. The actions on the taenia of 4-(m-chlorophenylcarbamoyloxy)-2-butynyl-trimethylammonium chloride (McN-A-343), N-benzyl-3-pyrrolidyl acetate methobromide (AHR-602), tetramethylammonium (TMA) and choline phenyl ether have been examined and compared with the actions of acetylcholine, nicotine and 1,1-dimethyl-4-phenylpiperazinium (DMPP).2. Responses of the taenia to these agonists are quantitatively and often qualitatively dependent on the tone of the preparation. A method is described which makes allowance for the effect of tone on heights of contractions.3. Acetylcholine, McN-A-343 and AHR-602 produced only contractions; TMA produced contractions or biphasic responses; and choline phenyl ether, nicotine and DMPP produced contractions, relaxations or biphasic responses.4. The mode of action of these compounds has been analysed by means of hyoscine, ganglion-blocking drugs, tetrodotoxin and local anaesthetics.5. It is concluded that acetylcholine, McN-A-343, AHR-602, TMA and choline phenyl ether act on muscarinic receptors in the smooth muscle. Choline phenyl ether has an additional action on nicotinic receptors of cholinergic neurones. Nicotine and DMPP act on nicotinic receptors of cholinergic neurones and of inhibitory neurones. An action on the latter is sometimes also seen with TMA and choline phenyl ether.6. With nicotine or DMPP, and TMA or choline phenyl ether in the presence of hyoscine, part of the contraction phase of biphasic responses (in which a contraction follows relaxation) is best explained as being triggered by the initial relaxation-that is, as a "rebound contraction".7. None of the compounds tested appeared to exert an atropine-sensitive action on neurones.8. In the presence of hyoscine high concentrations of agonists can act on sites not involved with lower concentrations.

Acetylcholine↗

PubMed1969

Comparison of effect of morphine-like analgesics on transmurally stimulated guinea-pig ileum.

1. Morphine-like analgesic drugs caused depression of twitches of the isolated guinea-pig ileum in response to transmural electrical stimulation. The drugs tested were the narcotic analgesics codeine, diamorphine, fentanyl, morphine, morphine-N-oxide, normorphine, oxymorphone, pethidine, phenazocine and phenoperidine and the analgesic narcotic antagonists nalorphine and pentazocine.2. With the first application of one of these drugs the extent of depression of twitches was proportional to concentration. Except in the case of pethidine, there was no further depression when additional drug was added to the organ bath. With the second application of a drug after washing out the first dose, the depressant effect was less; that is, tolerance developed. With pethidine, the depression of twitches was proportional to concentration and tolerance could not be observed.3. When tolerance had been produced by cumulative addition of these drugs, a concentration was reached at which further addition resulted in increased activity of the ileum.4. With codeine, morphine and normorphine, the twitches were increased in height and regular.5. With diamorphine, fentanyl, oxymorphone, pentazocine, phenazocine and phenoperidine there were increased but irregular responses to transmural stimulation.6. Having reached the concentration at which these effects were observed, washout of the drug resulted in reduction of activity; the twitches became smaller or the irregular responses ceased.7. Readministration of a drug after activity of the ileum had been depressed by withdrawal of that drug resulted in restoration of activity, the ileum being dependent on the presence of the drug for its activity.8. Codeine and nalorphine did not produce as great an increase in activity on readministration to a dependent ileum as did morphine: they seem to act as partial agonists in producing this effect.9. In similar experiments with the isolated urinary bladder of the rat and guinea-pig, morphine was less active in depressing responses to stimulation than it was on the ileum, and tolerance to the drug and dependence on it did not occur.10. These observations have been discussed in relation to analgesic activity, tolerance and dependence in man.

Analgesics↗

PubMed1969