Antiinflammatory influences of α-MSH molecules: Central neurogenic and peripheral actions

α-Melanocyte-stimulating hormone (α-MSH_1-13) and its COOH-terminal tripeptide α-MSH_11-13 (Lys Pro Val) inhibit inflammation when administered systemically. Recent evidence indicates that α-MSH_1-13 can likewise inhibit inflammation in the skin solely via an action within the brain. Because of the potential importance of this discovery to understanding the control of inflammation and because α-MSH molecules might be useful for treatment of inflammation, experiments were performed to learn more about the mechanisms of action of these peptides. In tests on inflammation induced in the mouse ear by intradermal injections of recombinant human interleukin- 1β, α-MSH_1-13 administered intracerebroventricularly effectively reduced inflammation. This effect of centrally administered α-MSH_1-13 was inhibited by systemic injection of the nonspecific β-adrenergic receptor blocker propranolol and by administration of a specific β₂-adrenergic receptor antagonist; the effect was not altered by blockade of cholinergic, α-adrenergic, or β₁-adrenergic receptors. In mice with inflammation induced in a hind paw and with the spinal cord transected, the antiinflammatory effect of centrally administered α-MSH_1-13 was prevented, indicating that intact descending neuronal pathways are required for the antiinflammatory influence of the central peptide. Systemic injection of α-MSH_1-13 in animals with spinal cord transection had a smaller and later antiinflammatory effect, which suggests that the molecule also has an action, albeit lesser, in the periphery. However, α-MSH_11-13 injected intraperitoneally had marked antiinflammatory activity in animals with spinal cord transection. The combined evidence indicates that α-MSH_1-13 has both central and peripheral sites of action in modulation of inflammation; the central effects of α-MSH_1-13 are mediated by pathways that involve peripheral β₂-adrenergic receptors; the antiinflammatory/antipyretic message sequence of α-MSH_1-13, α-MSH_11-13, has potent antiinflammatory activity when given systemically, activity that does not require intact spinal cord pathways.