The possibility that the endogenous opioid system could be involved in the central nervous system (CNS)-mediated gastroprotective effect of clonidine was investigated. Intracerebroventricularly (i.c.v.) injected clonidine (470 pmol/rat) inhibited the gastric mucosal lesions induced by (orally administered) acidified ethanol in a significant manner in the rat. The gastroprotective effect of the centrally administered clonidine was antagonised by i.c.v. or intracisternally (i.c.) administered presynaptic alpha-2 adrenoceptor antagonist, yohimbine; the non-selective opioid receptor antagonist, naloxone; and the delta opioid receptor antagonist naltrindole. These results suggest that an interaction between central alpha-2 adrenoceptors and endogenous opioid systems is involved in mediating the mucosal protective effect. beta-endorphin antiserum (i.c.) also antagonised the gastroprotection induced by intracerebroventricularly injected clonidine indicating that beta-endorphin release is likely to be a key factor in the gastroprotective effect of clonidine. Furthermore, the i.c.v. or i.c. injection of beta-endorphin produced a potent gastroprotection in the picomolar range. The mucosal protective effect of clonidine was abolished after vagotomy indicating that the central effect may be conveyed to the periphery by vagal efferents. Since atropine (1 mg/kg i.v.) failed to modify, but hexamethonium (10 mg/kg i.v.) antagonised the gastroprotective effect of clonidine, it would appear that in the periphery nicotinic, but not muscarinic, cholinergic receptors are likely to be involved in the mucosal protective effect of clonidine. In conclusion, clonidine (i.c.v.) induces gastroprotective action by releasing an endogenous opioid substance - most likely beta-endorphin - in the rat. The clonidine-induced central gastroprotection requires the integrity of vagal pathway; cholinergic nicotinic - but not muscarinic - receptors might mediate the effect in the periphery.