The action of morphine and related substances on contraction and on acetylcholine output of coaxially stimulated guinea-pig ileum / by W.D.M. Paton.

  • Paton, William D. M.
Date:
[1957?]
Catalogue details

Licence: In copyright

Credit: The action of morphine and related substances on contraction and on acetylcholine output of coaxially stimulated guinea-pig ileum / by W.D.M. Paton. Source: Wellcome Collection.

    10/14 (page 126)
    separately determined, from the total output observed. It will be seen here, as will be discussed more fully in another paper, that the normal out¬ put of acetylcholine decreases as the repetition frequency of the stimulus increases. But the effect of morphine is such as to reduce the acetylcholine output to an approximately constant low amount. Thus the proportionate reduction of acetylcholine output is greater on the slow rates of stimulation than on the rapid. It appears as though there were a morphine-susceptible quantum of acetyl¬ choline output, together with an irreducible quan¬ tum which morphine cannot touch. Morphine reduces the resting output by 20 to 40% ; thus in three experiments the output fell from 2.7 to 1.5, 1.7 to 1.4, and 1.2 to 0.8 ng./min. respectively, in the presence of morphine in concentrations from 1CT6 to 4 x 10-6. It was also found, however, that some¬ times the resting output increased above its initial level after the morphine was washed out ; in the most striking case, the resting output, after stimu¬ lation for 20 min. at 5/sec. in the presence of morphine 2 x 10~6, rose to 3.2 ng./min., from a control value of 1.1 ng./min. It may be questioned whether the reduction of output of acetylcholine achieved by morphine is sufficient to produce failure of neuromuscular transmission in the intestine. It has already been stated that the output of acetylcholine/shock can be reduced in another way, by stimulating the intestine more rapidly. If this is done in the un- eserinized preparation the twitch height begins to fall below its normal level at rates of about 20/ min., and falls further as faster rates are applied. Combining this result with those of Table II, it may be estimated that failure of transmission will begin when the output falls below about a value of the order of 0.2 ng./shock. It is clear from the same table that morphine can reduce the output far below these levels. It appears, therefore, that the action of morphine can be satisfactorily explained by a depression of acetylcholine output by it. But if acetylcholine output is depressed in this way one might expect that a similar depression of output could be obtained at other cholinergic synapses, such as the junction of motor nerves with striated muscle, or in autonomic ganglia. Accordingly the effect of morphine on acetylcholine output from the perfused ganglion was examined. It was found, however, as Hebb and Konzett (1949) reported, that morphine does not depress ganglionic trans¬ mission except in very large doses ; indeed its first action is to potentiate the effects of preganglionic stimulation. In addition, a dose of 1 mg. injected into the arterial perfusion cannula had no effect on acetylcholine output. Similarly a test of mor¬ phine on the neuromuscular junction showed that it has singularly little neuromuscular effect ; it required 5 mg. morphine given by close-arterial injection into the tibialis muscle of the cat to pro¬ duce a very transient reduction of the twitch to sciatic nerve stimulation. It is clear, therefore, that the action of morphine is not exerted at all cholinergic synapses ; the experiment on the ganglion serves to show, however, that when acetylcholine output is not depressed, transmission is not impaired. Discussion These experiments show that morphine, in low concentrations, has a depressant action on the post¬ ganglionic cholinergic nerve fibres of the guinea- pig intestine, reducing both the resting output of acetylcholine and the output from the nerve- endings when they are stimulated. In these con¬ centrations, morphine did not stimulate the gut, nor interfered with its contractile power, nor lessened its sensitivity to acetylcholine. On this preparation, therefore, the action of morphine was exerted only on the nervous tissue and not on the smooth muscle. The work reported by Schaumann et al. (1952) and Schaumann (1955), using a different method, points to the same con¬ clusion. Schaumann et al. showed that a number of strong analgesics could depress the peristaltic reflex of the guinea-pig ileum ; and this was fol¬ lowed by the demonstration (Schaumann, 1955) that morphine could paralyse the preparatory phase of the peristaltic reflex ; this phase of the reflex resists ganglion-blocking agents, but is sen¬ sitive to atropine, and so presumably involves post¬ ganglionic cholinergic nerve fibres. Kosterlitz and Robinson (1955) have confirmed these observa¬ tions, and found in addition that morphine has an inhibiting effect on the action of 5-hydroxytrypt- amine, whose action on the ileum is now believed to involve a nervous pathway (Robertson, 1953 ; Rocha e Silva, Valle and Picarelli, 1953 ; Gaddum and Hameed, 1954). No obvious reason can yet be advanced why this action of morphine is exerted on cholinergic nerve fibres in the intestine, but not on those of the autonomic ganglion or neuromuscular junc¬ tion of striated muscle. It may be, indeed, that the action concerned is not one specifically on acetyl¬ choline output, but that morphine has some other effect at the terminations of postganglionic nerves, which results in a failure of normal nerve terminal activity. Kosterlitz and Robinson (1955) suggest