Differential distribution of functional cannabinoid CB1 receptors in the mouse gastroenteric tract

Recently, the gastrointestinal pharmacology of cannabinoid CB1 receptors has been extensively explored. We employed western blotting and immunohistochemistry techniques to study the distribution of the cannabinoid CB1 receptor protein in the mouse gastroenteric tract. The cannabinoid CB1 receptor peptide was detected by western blotting only in its glycosylated form (63 kDa) with a significant differential distribution. The highest levels of expression were detected in the stomach and in the colon, while the pyloric valve was devoid of any cannabinoid CB1 receptor protein. The immunohistochemical study showed intense cannabinoid CB1 receptor immunoreactivity in ganglia subadjacent to the gastric epithelium and in the smooth muscle layers of both the small and large intestine. Only the small intestine showed (-)-3[2-hydroxyl-4-(1,1-dimethylheptyl)-phenyl]-4-(3-hydroxylpropyl) cyclohexan-1-ol) ([H-3]CP 55,940) specific binding (27%). These receptors mediated pharmacologically significant effects since the cannabinoid CB1 receptor agonist R(-)-7-hydroxy-delta-6-tetra-hydrocannabinol-dimethylheptyl (HU 2 10) dose dependently inhibited gastrointestinal transit up to 70%, while the cannabinoid CB1 receptor antagonist N-piperidino-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methylpyrazole-3-carboxamide (SR 141716A) increased gastrointestinal transit. Moreover, the dose of 0.3 mug/kg of HU 2 10, devoid per se of any activity on mouse intestinal propulsion, blocked the increased gastroenteric transit induced by the cannabinoid CB1 antagonist SR 141716A. (C) 2002 Elsevier Science B.V. All rights reserved.