The responses of the isolated guinea-pig ileum to coaxial stimulation of its nerves, to
histamine,
acetylcholine,
bradykinin,
nicotine,
tetramethylammonium, 1,1-dimethyl-4-phenyl-piperazinium
iodide and
5-hydroxytryptamine were studied, before and during
anoxia, cooling, or exposure to
hyoscine,
phenoxybenzamine hydrochloride,
morphine or
hexamethonium. Dose ratios were used to determine the amount of block induced by these procedures. With the response to coaxial nerve stimulation as an indication of the excitability of the nervous tissue, it was found that
anoxia or cooling abolished the response to single shocks. Under these conditions the response of the ileum to
histamine,
acetylcholine and
bradykinin was hardly affected, indicating a direct action of these substances on the muscle fibres. The effects of
nicotine,
tetramethylammonium,
dimethylphenylpiperazinium and
5-hydroxytryptamine were reduced to various degrees, and we have concluded that their main actions are indirect, through stimulation of
cholinergic nerve fibres. When these indirect actions were prevented, increasing the dose revealed a direct action, a larger increase in dose being required for
5-hydroxytryptamine and
dimethylphenylpiperazinium than for
tetramethylammonium and
nicotine. Exposure of the ileum to
hyoscine and
phenoxybenzamine showed that these direct actions of
nicotine and
tetramethylammonium were not only on
acetylcholine receptors but also on receptors insensitive to
hyoscine but sensitive to
phenoxybenzamine. The main action of
5-hydroxytryptamine was on nervous elements, yet treatment of the ileum with
phenoxybenzamine gave a higher dose ratio for
5-hydroxytryptamine than did treatment with
morphine. The meaning of this result is discussed in relation to the general belief that receptors sensitive to
morphine are in nervous tissue and receptors sensitive to
phenoxybenzamine are in smooth muscle. We have concluded that
morphine is only a partial antagonist of
5-hydroxytryptamine receptors in nervous tissue and that
phenoxybenzamine antagonizes more
5-hydroxytryptamine receptors than those in smooth muscle.