Effects of a new sigma ligand, JO 1784, on cysteamine ulcers and duodenal alkaline secretion in rats.
BACKGROUND
The ulceroprotective effects of JO 1784 [(+)-N-cyclopropyl-methyl-N-methyl-1,4-diphenyl-1-ethyl-but-3-en-1-yl amine, hydrochloride], a new specific and highly selective sigma ligand, were examined in rats.


METHODS
Different models of gastric ulcers (4-hour restraint stress, aspirin, ethanol, and taurocholate) and cysteamine-induced duodenal ulcers were used. The gastric acid secretion (4-hour Shay rat preparation) and the duodenal bicarbonate secretion were also studied.


RESULTS
JO 1784 elicited a potent protection against duodenal ulcers but had a weaker protective effect on any of the gastric ulceration models tested. It displayed no gastric antisecretory activity but induced a dose-dependent stimulation of duodenal bicarbonate secretion. Haloperidol, hexamethonium, tetrodotoxin, bivagotomy (but not atropine), and the intravenous but not intracerebroventricular administration of devazepide, a cholecystokinin A antagonist, inhibited the stimulatory effect of JO 1784.


CONCLUSIONS
These results show that JO 1784, a selective sigma ligand, is a potent protector of the duodenal mucosa. This activity may be related to its stimulating effect on bicarbonate secretion, which is driven through a complex nervous mechanism involving muscarinic synapses, vagal afferent fibers, and peripheral cholecystokinin receptors. This drug might open a new specific way in the treatment of duodenal ulcers.
Pascaud
X B
XB
Institut de Recherche Jouveinal, Fresnes, France.
Chovet
M
M
Soulard
P
P
Chevalier
E
E
Roze
C
C
Junien
J L
JL
D000818:Animals; D001639:Bicarbonates / Q000378:metabolism*; D002934:Cinnamates / Q000494:pharmacology*; D003521:Cyclopropanes / Q000494:pharmacology*; D003543:Cysteamine; D004381:Duodenal Ulcer / Q000517:prevention & control*; D004386:Duodenum / Q000187:drug effects* / Q000378:metabolism*; D005744:Gastric Acid / Q000378:metabolism; D006146:Guanidines / Q000494:pharmacology; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D017480:Receptors, sigma / Q000187:drug effects*; D013276:Stomach Ulcer / Q000517:prevention & control*
D001639:Bicarbonates; D002934:Cinnamates; D003521:Cyclopropanes; D006146:Guanidines; D017480:Receptors, sigma; D003543:Cysteamine; C050232:1,3-ditolylguanidine; C065310:igmesine