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 α-melanocyte-stimulating hormone (α-MSH) is a neuroimmunomodulatory agent that modulates production of proinflammatory cytokines and inhibits peripheral inflammation via actions on CNS receptors. We examined whether central α-MSH operates by inhibiting activation of the nuclear factor kappa B (NF-κB) 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-α demonstrated that centrally administered α-MSH does inhibit NF-κB activation. Western blot analysis revealed that this inhibition was linked to central α-MSH-induced preservation of expression of IκBα protein in the peripheral tissue. The NF-κB and IκBα effects were inhibited in mice with spinal cord transection. Intraperitoneal (ip) injection of the nonspecific β-adrenergic receptor blocker propranolol, and of a specific β 2-adrenergic receptor antagonist, likewise prevented these effects of central α-MSH; blockade of cholinergic, α-adrenergic, or β 1-adrenergic receptors did not. Centrally administered α-MSH inhibited peripheral NF-κB activation and IκBα degradation even in mice with nonfunctional melanocortin 1 receptors (MC1R). These findings indicate that α-MSH can act centrally to inhibit NF-κB activation in peripheral acute inflammation via a descending neural pathway. The pathway involves β 2-adrenergic receptors, but does not require activation of MC1R within the brain.