The differential influences of melanocortins on nociception in the formalin and tail flick tests

Melanocortins exert multiple physiological effects that include the modulation of immune responses, inflammation processes, and pain transmission. In the present study we investigated the peripheral activity of natural melanocortins - α-, β-, γ1- and γ2-melanocyte stimulating hormone (MSH) - and melanocortin receptor subtypes 3 and 4 (MC3/4 receptor) antagonist HS014 in pain (formalin and tail flick) tests after peptide subcutaneous administration in mice. In the formalin test, among all substances tested only α-MSH (1 μmol/kg) statistically significantly inhibited the formalin-induced first phase pain response, however, all tested peptides (except γ1-MSH) at the dose of 1 μmol/kg produced a pronounced inhibitory effect on nociceptive behavior in the second phase and this activity was comparable with that of indomethacin (reference drug, 5 mg/kg intraperitoneally); β-MSH was also active at a dose 0.1 μmol/kg. In the tail flick test, α-MSH (1 μmol/kg) showed algesic, whereas HS014 (0.5 μmol/kg) and indomethacin (10 mg/kg) exerted analgesic activity. Other peptides did not exert any activity in the tail flick test. These data indicate that peripherally administered melanocortin receptor agonists α-MSH, β-MSH and γ2-MSH, as well as MC3/4 receptor antagonist HS014 induced antinociception on pain/inflammatory events caused by formalin suggesting a predominant anti-inflammatory role of these peptides.