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.

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    THE ACTION OF MORPHINE AND RELATED SUBSTANCES ON CONTRACTION AND ON ACETYLCHOLINE OUTPUT OF COAXIALLY STIMULATED GUINEA-PIG ILEUM BY W. D. M. PATON From the Department of Pharmacology, Royal College of Surgeons of England, London (RECEIVED DECEMBER 21, 1956) Morphine depresses the twitch and tetanus of stimulated guinea-pig ileum by reducing acetylcholine released from cholinergic nerve endings. Acetylcholine output per shock falls to roughly the same residual amount at varying stimulation rates. Since normal output per shock declines with increasing stimulus frequency, the proportionate effect of morphine diminishes as stimulus frequency rises. Acute “ tolerance ” to morphine and a state of “ morphine- dependence ” can be produced. Phenadoxone, heroin are more active, codeine and pethidine depresses the twitch and can desensitize the gut Despite the widespread use of morphine there is still no agreement as to the mode of action, either when used as an analgesic or for depressing the activity of the intestine. It has been suggested that its anticholinesterase activity causes the cen¬ tral actions ; but it is a relatively feeble inhibitor of cholinesterase, and much more active inhibitors do not reproduce its effects. On the intestine, attention has focused on morphine’s ability either to depress propulsion, or to increase the tone of the gut. An investigation of the action of opiates on intestinal loops in the dog by Vaughan Williams and Streeten (1950, 1951) has clarified some apparent contradictions in previous experi¬ mental results, and shown how the stimulant action of morphine could lead to a failure of transport of intestinal contents. Recent work by the Schaumanns (Schaumann, Giovannini and Jochum, 1952 ; Schaumann, 1955) and by Kosterlitz and Robinson (1955) has indicated, however, that the action of morphine may be through a depression of nervous mechanisms involved in peristalsis. The method recently developed for exciting the nervous tissue in the wall of the small intestine (Paton, 1955) offered a suitable means for analysing the activity of morphine further. If electrodes are placed within and without the lumen of a strip of guinea-pig ileum immersed in Krebs solution and current is passed between them, vigorous twitch¬ like contractions can be obtained to single shocks, which are due to excitation of postganglionic dihydromorphinone, metopon, methadone, and less active, than morphine. Nalorphine also both to itself and to morphine. cholinergic nerves. The contractions are repro¬ ducible, are antagonized by small doses of atropine, are potentiated by anticholinesterases, and resist ganglion-blocking agents. Further, it has proved possible to measure the output of acetylcholine in response to the excitation of nervous tissue in the wall of the gut. In this paper the effect of morphine (and related drugs) on the twitch of the intestine and on its acetylcholine output is described. A short account of some of the results obtained with morphine was given elsewhere (Paton, 1956). Methods The experiments were all made on strips of guinea- pig ileum suspended in Krebs solution, bubbled with 95% O2 and 5% CO2. Rectangular current pulses usually of 1 msec, duration, and of sufficient strength to produce a maximal response to a single shock, were applied to the electrodes ; the intraluminal electrode was made the anode. When necessary, repetitive stimulation was used to produce a partially or com¬ pletely fused tetanus for a period of a few seconds or a minute. The contractions of the gut were re¬ corded either on a smoked drum or by a light ink- recorder. The bath was kept at 35 to 37° C. The capacity of the bath in which the gut and electrodes were immersed was normally 50 ml. The assay of acetylcholine output was conducted on another strip of guinea-pig ileum treated with 5 /Ag./l. of neostigmine and 10 mg./I. of morphine. As soon as the first observation was made that mor¬ phine reduced the output of acetylcholine by the gut.