Pharmacological analysis of the receptors mediating the gastroprotective effect of agmatine in the rat

Introduction: Our previous results suggested that centrally injected agmatine (an endogenous ligand of the imidazoline receptors) induces gastric mucosal protection in the rat, and both central I1 receptors and α2-adrenoceptors are involved in it. It is also well established that the endogenous opioid system has an important role in the regulation of different gastrointestinal functions and several lines of evidence suggest an interaction between agmatine and the opioid system. Aims: 1. To analyse, which α2-adrenoceptor subtypes mediate the effect of agmatine. 2. To investigate, whether the endogenous opioid system is involved in the agmatine-induced mucosal protection. Methods: The ethanol-ulcer model was used. After 24h starvation, male Wistar rats were given 0.5ml acidified ethanol orally. The mucosal lesions were evaluated 1h later. Agmatine was given intracerebroventricularly (i.c.v.) 10min before the ethanol challenge. The α2-, and opioid-receptor antagonists were injected either peripherally (s.c.) or centrally (i.c.v.) before the administration of agmatine. Results: 1. Agmatine (0.044–1.76 nmol/rat i.c.v.) induced a dose-dependent gastroprotection. 2. Both the selective α2A-adrenoceptor subtype antagonist BRL-44408 (15 nmol/rat i.c.v) and α2B-adrenoceptor subtype antagonist prazosin (4.8 nmol/rat i.c.v.) inhibited the agmatine-induced mucosal protection. 3. Similarly, pretreatment with the non-selective opioid-receptor antagonist naloxone (2.75µmol/kg s.c.) and the selective δ-opioid receptor antagonist naltrindole (0.5 nmol/rat i.c.v.) abolished the effect, while β-FNA (20 nmol/rat i.c.v.) and norBNI (14 nmol/rat i.c.v.), the respective µ- and κ-opioid receptor selective antagonists failed to reduce the agmatine-induced protection. Conclusions: Our results demonstrate that both central α2A- and α2B-adrenoceptor subtypes may be involved in the agmatine induced mucosal protection. Moreover, the endogenous opioid system – by central δ-opioid receptors – also takes part in the agmatine-induced gastroprotection.