INHIBITION OF LIPOPOLYSACCHARIDE-INDUCED NITRIC-OXIDE AND CYTOKINE PRODUCTION BY ULTRALOW CONCENTRATIONS OF DYNORPHINS IN MIXED GLIA CULTURES

Dynorphins (dyn) are a major class of endogenous opioid peptides that modulate the functions of immune cells. However, the effects of dyn on the immune functions of glial cells in the central nervous system (CN S) have not been well characterized. Because nitric oxide (NO) and the proinflammatory cytokine tumor necrosis factor-alpha (TNF-alpha) prod uced by glial cells are involved in various physiopathological conditi ons in the CNS, this study examined the effects of dyn on the producti on of NO and TNF-alpha from mouse glial cells treated with lipopolysac charide (LPS). LPS induced a concentration-dependent increase in the p roduction of NO or TNF-alpha from the mouse primary mixed glia culture s. Ultralow concentrations (10(-16)-10(-12) M) of dynorphin (dyn) A-(1 -8) significantly inhibited the LPS-induced production of NO or TNF-al pha. The inhibitory effects of dyn A-(1-8) were not blocked by nor-bin altorphimine, a selective kappa opioid receptor antagonist. U50-488H, a selective kappa opioid receptor agonist, did not affect the LPS-indu ced production of NO or TNF-alpha. Ultralow concentrations (10(-16)-10 (-12) M) of des[Tyr(1)]-dyn A-(2-17), a nonopioid analog that does not bind to kappa opioid receptors, exhibited the same inhibitory effects as dyn A-(1-17) and dyn A-(1-8). These results suggest that dyn modul ate the immune functions of microglia and/or astrocytes in the brain a nd these modulatory effects of dyn are not mediated by classical kappa opioid receptors.