With the rise in the field of neuroimmunomodulation research, there is increased recognition of the influence of the nervous system and neuropeptides in peripheral disease. The neuropeptide alpha-melanocyte-stimulating hormone (alpha-MSH) is a neuroimmunomodulatory agent that modulates production of proinflammatory cytokines and inhibits peripheral inflammation via actions on CNS receptors. We examined whether central alpha-MSH operates by inhibiting activation of the nuclear factor kappa B (NF-kappaB) that is essential to the expression of proinflammatory cytokines and development of inflammation in the periphery. Electrophoretic mobility shift assays of nuclear extracts from the murine foot pad injected with TNF-alpha demonstrated that centrally administered alpha-MSH does inhibit NF-kappaB activation. Western blot analysis revealed that this inhibition was linked to central alpha-MSH-induced preservation of expression of IkappaBalpha protein in the peripheral tissue. The NF-kappaB and IkappaBalpha effects were inhibited in mice with spinal cord transection. Intraperitoneal (i.p.) injection of the nonspecific beta-adrenergic receptor blocker propranolol, and of a specific beta2-adrenergic receptor antagonist, likewise prevented these effects of central alpha-MSH; blockade of cholinergic, alpha-adrenergic, or beta1-adrenergic receptors did not. Centrally administered alpha-MSH inhibited peripheral NF-kappaB activation and IkappaBalpha degradation even in mice with nonfunctional melanocortin 1 receptors (MC1R). These findings indicate that alpha-MSH can act centrally to inhibit NF-kappaB activation in peripheral acute inflammation via a descending neural pathway. The pathway involves beta2-adrenergic receptors, but does not require activation of MC1R within the brain.