TRIMU-5 (Tyr-D-Ala-Gly-NHC2H4CH(CH3)2) is a potent mu 2-opioid agonist/mu 1-opioid antagonist. A supraspinal dose (0.5 micrograms i.c.v.) of TRIMU-5 which is not analgesic when given alone antagonizes the analgesia produced by intracerebroventricular (i.c.v.) morphine, a mu 1 action. In contrast, in a synergy model consisting of the simultaneous administration of intrathecal morphine (0.1 micrograms) with multiple doses of i.c.v. morphine, the same supraspinal TRIMU-5 dose (0.5 micrograms i.c.v.) enhances analgesia. Supraspinal TRIMU-5 also potentiates spinal morphine directly, shifting its dose-response to the left. These results imply that within the brainstem mu 1 receptors mediate supraspinal analgesia while mu 2 receptors mediate the synergy with spinal mu systems.