NEUROPEPTIDE Y (NPY) and endogenous opioids (EOPs) such as methionine-enkephalin (Met-enk) regulate similar physiological responses, but it is not known whether nociceptive and immune responses also show analogy after intracerebroventricular (i.c.v.) application. Dose–response studies show that Met-enk stimulates the blood granulocyte and splenic natural killer (NK) cell function of Lewis rats at a low dose (102ng/kg, i.c.v.), whereas a high dose (105ng/kg) causes suppression of innate immune functions associated with analgesia in the hot-plate test. At 15 min, 1 h and 24 h after i.c.v. application, both Met-enk (102ng/kg) and NPY (1 ng/kg) produced similar effects: An initial suppression of innate immune function was followed by a long lasting stimulatory action on cell functions and serum inter-leukin-6 (sIL-6) levels. Thus, central NPY application resembles Met-enk-induced immunostimulation at doses not affecting nociception, suggesting an involvement of both peptides in shaping stress-induced immunomodulation of the non-analgetic form, possibly via activation of a common immunomodulatory effector mechanism.