The influence of opiates on ion transport across rabbit ileal mucosa in vitro
Endogenous opiates, the enkephalins, have been identified in the brain and intestine. Their physiological role in the gut has yet to be determined, but since opiates have anti-diarrhoeal actions it was thought possible that they might be involved in the control of mucosal ion transport in addition to their known effects on motility. This possibility was studied using the lq'in vitro' technique of Ussing and Zerahn. Morphine (10-6 to 10-4M) induced a significant fall in potential difference (PD) and short-circuit current (Isc) across stripped rabbit ileal mucosa, with no change in tissue resistance. A maximal electrical response was dependent on the presence of Na, Cl and HCO3 in the bathing medium. A significant increase in Cl absorption due to a decrease in serosa to mucosa flux was provoked in response to morphine (2 x 10-5M), accompanied by an increase in residual ion flux (JR/net), possibly due to HCO3 secretion. Na transport was unaffected. Dextromoramide (10-5M) mimicked the response to morphine, but the inactive isomer laevomoramide (10-5M) had no effect. Naloxone (10-6M) inhibited the response to morphine (2 x 10-5M) and this inhibition was competitive in nature supporting the existence of mucosal opiate receptors. The enkephalin analogue Me-Tyr-D-Met-Gly-Phe-Pro-NH2 also decreased the PD and Isc and produced a similar increase in Cl absorption and JR/net. This analogue had a more rapid action and provoked a response at a lower dose (10-8M) than morphine. Tetrodotoxin (10-7M) inhibited the response to morphine (10-4M) but blockade of cholinergic, α and β adrenergic and dopaminergic mechanisms had no effect. Morphine (10-4M) inhibited the secretion produced by three secretagogues, prostaglandin E2 (10-5M), acetylcholine (10-4M) and cholera toxin (1 μg/ml). Adenyl cyclase and cyclic AMP levels were unaffected by morphine, but the electrical response to morphine was increased by omitting Ca^+ + from the medium. Thus these studies provide evidence for the presence of mucosal opiate receptors which may have a physiological role, and demonstrate that opiates enhance Cl absorption and inhibit secretion provoked by three secretagogues. The mechanism of action may be related to an antagonism to intracellular calcium.