Endocannabinoids modulate non-adrenergic, non-cholinergic inhibitory neurotransmission in strips from the mouse gastric fundus.

Aim: To investigate the effects of endocannabinoids on non-adrenergic, non-cholinergic (NANC) relaxant responses in gastric strips from mice. Methods: Gastric longitudinal strips from the fundus region were mounted in organ baths for isometric recording. Results: In carbachol-precontracted strips, electrical field stimulation (EFS) elicited tetrodotoxin (TTX)-sensitive fast nitrergic relaxant responses that were followed, at the highest stimulation frequency, by sustained relaxations. The latter were abolished by a-chymotrypsin. Anandamide caused a TTX-sensitive relaxation that was abolished by a-chymotrypsin but unaffected by the nitric oxide (NO) synthesis inhibitor, Nx-nitro-Larginine (L-NNA). Anandamide reduced the amplitude of EFS-induced fast relaxations, whereas increased that of sustained ones. Relaxation to the nicotinic receptor agonist dimethylphenyl piperazinium iodide (DMPP) was decreased in amplitude by either anandamide or L-NNA, whereas, surprisingly, it was increased by a-chymotrypsin and abolished by L-NNA plus a-chymotrypsin. Relaxation to vasoactive intestinal polypeptide (VIP) was not influenced by anandamide or L-NNA and was abolished by a-chymotrypsin. Following VIP desensitization, fast relaxant responses to EFS were reduced and the sustained ones abolished. The CB1 receptor antagonist AM251 increased, only at the highest stimulation frequency, the amplitude of the EFS-induced fast relaxation and reduced the sustained one. AM251 increased the response to DMPP and abolished that to anandamide. The CB2 receptor antagonist AM630 had no effects. Conclusion: These results indicate that endocannabinoids modulate, via prejunctional CB1 receptors, the NANC peptidergic neurotransmission that, in turn, affects the nitrergic one.