Involvement of cannabinoid CB1- and CB2-receptors in the modulation of exocrine pancreatic secretion.
The role of the cannabinoid system in the regulation of exocrine pancreatic secretion was investigated by studying the effects of the synthetic CB1- and CB2-receptors agonist, WIN55,212, on amylase secretion in isolated lobules and acini of guinea pig and rat, and the expression of CB-receptors in rat pancreatic tissue by immuno-chemistry and Western-blot analysis in both basal and cerulein (CK)-induced pancreatitis condition. In pancreatic lobules of guinea pig and rat, WIN55,212 significantly inhibited amylase release stimulated by KCl depolarization through inhibition of presynaptic acetylcholine release, but did not modify basal, carbachol- or CK-stimulated amylase secretion. The effect of WIN55,212 was significantly reduced by pre-treatment with selective CB1- and CB2-receptor antagonists. The antagonists, when given alone, did not affect the KCl-evoked response. Conversely, WIN55,212 was unable to affect basal and CK- or carbachol-stimulated amylase release from pancreatic acini of guinea pig and rat. Immunofluorescent staining of rat pancreatic tissues showed that CB1- and CB2-receptors are expressed in lobules and in acinar cells and their presence in acinar cells was also shown by Western-blot analysis. After CK-induced pancreatitis, the expression of CB1-receptors in acinar cells was not changed, whilst a down-regulation of CB2-receptors was observed. In conclusion, the present study shows that WIN55,212 inhibits amylase release from guinea pig and rat pancreatic lobules and, for the first time, that cannabinoid receptors are expressed in lobules of the rat pancreas, suggesting an inhibitory presynaptic role of this receptor system. Finally, in rat pancreatic acinar cells, CB1- and CB2-receptors, expressed both in basal conditions and after CK-induced pancreatitis but inactive on amylase secretion, have an unknown role both in physiological and pathological conditions.
Linari
G
G
Department of Physiology and Pharmacology "V.Erspamer", University "Sapienza", Rome, Italy. giorgio.linari@uniroma1.it
Agostini
S
S
Amadoro
G
G
Ciotti
M T
MT
Florenzano
F
F
Improta
G
G
Petrella
C
C
Severini
C
C
Broccardo
M
M
D000681:Amylases / Q000378:metabolism; D000818:Animals; D048588:Benzoxazines / Q000494:pharmacology; D015153:Blotting, Western; D006168:Guinea Pigs; D008297:Male; D009025:Morpholines / Q000494:pharmacology; D009281:Naphthalenes / Q000494:pharmacology; D046790:Pancreas, Exocrine / Q000737:chemistry / Q000378:metabolism*; D010195:Pancreatitis / Q000378:metabolism / Q000473:pathology; D051381:Rats; D043884:Receptor, Cannabinoid, CB1 / Q000032:analysis / Q000502:physiology*; D043885:Receptor, Cannabinoid, CB2 / Q000032:analysis / Q000502:physiology*
D048588:Benzoxazines; D009025:Morpholines; D009281:Naphthalenes; D043884:Receptor, Cannabinoid, CB1; D043885:Receptor, Cannabinoid, CB2; C070417:(3R)-((2,3-dihydro-5-methyl-3-((4-morpholinyl)methyl)pyrrolo-(1,2,3-de)-1,4-benzoxazin-6-yl)(1-naphthalenyl))methanone; D000681:Amylases