McNa-343

The crosstalk between the M1 muscarinic acetylcholine receptor and the endocannabinoid system was investigated during acetic acid-induced experimental colitis. In this research, male mice were treated with the agonist M1 receptor McN-A-343 (1.5 mg/kg; intraperitoneal) or dexamethasone (2.0 mg/kg; subcutaneous) 17 h or 17 h 30 min after the induction of acetic acid colitis, respectively. The cannabinoid receptor antagonists, CB1 (AM251, 3.0 mg/kg, intraperitoneal) and CB2 (AM630, 1.0 mg/kg, intraperitoneal), were administered 30 min before McN-A-343 and dimethyl sulfoxide (DMSO, 4 %, intraperitoneal) at the same time as the antagonists. After 18 h of colitis induction, 5 cm of the distal part of the colon was collected for analysis of macroscopic and microscopic lesion scores, intestinal wet weight, biochemical measurements: concentration of myeloperoxidase, tumor necrosis fator alpha (TNF-α), interleukin-1β (IL-1β), malondialdehyde, reduced glutathione, nitrate/nitrite and protein expression of Nf-κB (Nuclear Factor-κBp65), inducible nitric oxide (iNOs) and cyclooxygenases 2 (Cox-2) by Western Blotting. Administration of AM251 or AM630 before treatment with McN-A-343 significantly altered the anti-inflammatory response of the agonist M1 receptor, evidenced by the accentuation of intestinal damage, increased wet weight, myeloperoxidase levels, pro-inflammatory cytokines, oxidative stress markers and protein expression of NF-κB, iNOs and Cox-2. These results suggest that CB1 and CB2 receptors are involved in the anti-inflammatory action of McN-A-343 in experimentally induced colitis. Therefore, the crosstalk between these systems may present promising potential for treatment of intestinal inflammatory conditions.