Melanocortin peptides are endowed with anti-inflammatory properties; their actions are mediated by a subgroup of G-protein coupled receptors: out of the five receptors identified so far, MC1 and MC3 have been indicated, in distinct experimental settings, for bringing about the anti-inflammatory effects of melanocortins. Here we have used null mice to determine the counter-regulatory role of MC3 and MC1 in vascular inflammation monitoring leukocyte-endothelial dynamics after mesenteric ischaemia reperfusion (I/R). C57Bl/6 (WT), MC3-/- or MC1 mutant (recessive yellow e/e colony) (~15-20 g body weight) were anaesthetised and surgically prepared; ischaemia was produced by the occlusion of the superior mesenteric artery (SMA) by a small clamp for 35 min; after clamp removal, reperfusion was allowed for 90 min [1] or 4 h. Leukocyte-endothelial interactions were monitored by intravital microscopy, quantifying by off-line analysis the extent of cell rolling, adhesion and emigration. Sham-operated animals underwent the same surgical procedure without clamping. In some animals, the MC3 agonist dTrp⁸-γ-MSH was given i.v. before SMA clamping, at the dose of 10µg [2]. The IR procedure provoked significant and time-dependent increases in the parameters measured, with maximal responses already at 90 min, when compared to sham operated mice. At 90 min post-reperfusion, MC3-/- mice displayed marked augmentation of cell adhesion and emigration (two-fold increase vs. WT mice, P<0.05, n=6), whereas no changes in cell rolling were evident. By the 4 h time-point, MC3-/- mice still had higher extent of cell adhesion in the inflamed microcirculation (n=6, P<0.05). Of interest, even the modest response observed in sham-operated mice was increased in the absence of MC3. Experiments in the MC1 mutant (inactive) colony yielded different results: no difference from WT was obtained at 90 min post-reperfusion on any of the parameters under analysis (n=6) and the same was true at the 4 h time-point. Using the 35/90 min protocol, we could observe that single treatment of WT mice with dTrp⁸-γ-MSH (10µg/mouse) inhibited (>60%) both cell adhesion and emigration (P<0.05; n=6), with no effect on cell rolling. Collectively these data indicate the existence of an endogenous counter-regulatory circuit centred on MC3 and rapidly activated after vascular injury as obtained with an IR procedure. Therefore, therapeutic targeting of MC3 may be beneficial for the treatment of acute IR-related injured, such as in aorta aneurisma, coronary disease and stroke.