The mechanism of action of narcotic analgesics in the guinea-pig ileum.

1. Intracellular recordings were made from neurones in the myenteric plexus of the guinea-pig ileum. Single myenteric ganglia were maintained in vitro and drugs were applied by adding them to the perfusing solution. 2. Narcotic analgesics hyperpolarized the membrane of a proportion of neurones in the myenteric plexus. 3. The membrane hyperpolarization was sometimes associated with a decrease in input resistance. These effects reduced the excitability of myenteric neurones. 4. The effects of narcotics occurred at low concentrations (10 nM to 1 micrometer), were stereospecific and were reversed by naloxone. 5. It is proposed that the morphine-sensitive neurones may be the cholinergic efferents to the muscle layers. By hyperpolarizing these neurones, morphine may prevent their excitation by electric field stimulation. This may explain why narcotic analgesics reduce the output of acetylcholine and the contractile response of this preparation when it is excited by field stimulation.