ANTIINFLAMMATORY INFLUENCES OF ALPHA-MSH MOLECULES - CENTRAL NEUROGENIC AND PERIPHERAL ACTIONS

alpha-Melanocyte-stimulating hormone (alpha-MSH(1-13)) and its COOH-te rminal tripeptide alpha-MSH(11-13) (Lys Pro Val) inhibit inflammation when administered systemically. Recent evidence indicates that alpha-M SH(1-13) can likewise inhibit inflammation in the skin solely via an a ction within the brain. Because of the potential importance of this di scovery to understanding the control of inflammation and because alpha -MSH molecules might be useful for treatment of inflammation, experime nts were performed to learn more about the mechanisms of action of the se peptides. In tests on inflammation induced in the mouse ear by intr adermal injections of recombinant human interleukin-1 beta, alpha-MSH( 1-13) administered intracerebroventricularly effectively reduced infla mmation. This effect of centrally administered alpha-MSH(1-13) was inh ibited by systemic injection of the nonspecific beta-adrenergic recept or blocker propranolol and by administration of a specific beta(2)-adr energic receptor antagonist; the effect was not altered by blockade of cholinergic, alpha-adrenergic, or beta(1)-adrenergic receptors. In mi ce with inflammation induced in a hind paw and with the spinal cord tr ansected, the antiinflammatory effect of centrally administered alpha- MSH(1-13) was prevented, indicating that intact descending neuronal pa thways are required for the antiinflammatory influence of the central peptide. Systemic injection of alpha-MSH(1-13) in animals with spinal cord transection had a smaller and later antiinflammatory effect, whic h suggests that the molecule also has an action, albeit lesser, in the periphery. However, alpha-MSH(11-13) injected intraperitoneally had m arked antiinflammatory activity in animals with spinal cord transectio n. The combined evidence indicates that alpha-MSH(1-13) has both centr al and peripheral sites of action in modulation of inflammation; the c entral effects of alpha-MSH(1-13) are mediated by pathways that involv e peripheral beta(2)-adrenergic receptors; the antiinflammatory/antipy retic message sequence of alpha-MSH(1-13), alpha-MSH(11-13), has poten t antiinflammatory activity when given systemically, activity that doe s not require intact spinal cord pathways.