The central effect of opioid peptide on natural killer (NK) cell activity in BALB/c mice was investigated. Injection of methionine-enkephalin (Met-Enk), 0.02 μg/mouse or 1 μg/kg, directly into the cisterna magna (CM) of the brain, resulted in a significant enhancement of NK cell activity. This enhancement was blocked by opiate antagonists, naltrexone and quaternary naltrexone. The same dose of Met-Enk had no effect on NK cell activity when given to the mouse intraperitoneally or intraveneously. Moreover, des-tyrosine-methionine-enkephalin injected into the CM at 1 μg/kg, had no effect on NK cell activity. The results indicate that activation of an opioid-mediated pathway in the central nervous system is capable of activating the pathways that stimulate the NK cell response in the periphery. © 1992.