The antianalgesic effect of dynorphin A (1-17) (dyn A) was demonstrated by i.c.v. administration of agonists (morphine, Tyr-D-Ala2-Gly-N-MePhe4-Gly-ol5, D-Pen2-D-Pen5-enkephalin, beta-endorphin, U50,488H and physostigmine) at 10 min and intrathecal administration of dyn A at 5 min before the tail-flick test in mice. This antianalgesic effect of dyn A was eliminated by 3 or 5.5 hr pretreatment s.c. with 10 or 100 mg/kg of morphine, respectively. This desensitization lasted for about 18 hr. Three-hour pretreatment intrathecally with dyn A also desensitized the mice to dyn A. Previously we had shown that i.c.v. administration of morphine simultaneously activates analgesic and antianalgesic systems and the latter is mediated spinally by dyn A, an endogenous antianalgesic opioid. Present results are consistent with that concept and systemic pretreatment with morphine may release dyn A in the spinal cord to produce the desensitization to the subsequently elicited antianalgesic action of dyn A.