In the present work, the effect of intrahippocampal microinjection of opioid receptor antagonist naloxone on the enhancement of cellular immune responses induced by enkephalin was studied in rat. The results showed that (1) the proliferation activity of splenic lymphocytes stimulated by Con A and natural killer (NK) cell activity were decreased with microinjection of 1 microl lipopolysaccharide (LPS,50 ng/microl) into bilateral hippocampus; (2) the decrease of cellular immune responses induced by LPS could be inhibited by a preceding intrahippocampal injection of 1 microl met-enkephalin (10 microg/1 microl); (3) the enhancement of cellular immune responses induced by met-enkephalin could be blocked by an opioid receptor antagonist naloxon (10 microg/microl); and (4) cellular immune responses were also inhibited when naloxon was injected intrahippocampally alone. The above results suggest that the enhancement of cellular immune responses induced by enkephalin was mediated by opioid receptors in hippocampus.