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 (CNS) have not been well characterized. Because nitric oxide (NO) and the proinflammatory cytokine tumor necrosis factor-alpha (TNF-alpha) produced by glial cells are involved in various physiopathological conditions in the CNS, this study examined the effects of dyn on the production of NO and TNF-alpha from mouse glial cells treated with lipopolysaccharide (LPS). LPS induced a concentration-dependent increase in the production of NO or TNF-alpha from the mouse primary mixed glia cultures. Ultralow concentrations (10(-16)-10(-12) M) of dynorphin (dyn) A-(1-8) significantly inhibited the LPS-induced production of NO or TNF-alpha. The inhibitory effects of dyn A-(1-8) were not blocked by nor-binaltorphimine, a selective kappa opioid receptor antagonist. U50-488H, a selective kappa opioid receptor agonist, did not affect the LPS-induced production of NO or TNF-alpha. Ultralow concentrations (10(-16)-10(-12) M) of des-[Tyr1]-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 modulate the immune functions of microglia and/or astrocytes in the brain and these modulatory effects of dyn are not mediated by classical kappa opioid receptors.