Morphine is a potent analgesic when microinjected into the periaqueductal gray (PAG), the rostral ventral medulla (RVM) which contains the nuclei raphe magnus and reticularis gigantocellularis and the dorsolateral pons (DLP) which includes the locus coeruleus. Coadministration of low morphine doses which are inactive alone into combinations of these three regions elicits dramatic analgesic responses, implying the existence of synergy. The most effective combination is the PAG/RVM, whereas the PAG/DLP and RVM/DLP combinations are much less efficacious. In addition to fixed combinations, inclusion of a low morphine dose in one region shifts the analgesic dose-response curves in the others. The marked synergy between the PAG and the RVM is sensitive to naloxonazine, implying a role for mu 1 receptors. Thus, these studies indicate the presence of intrinsic brainstem mu 1 receptor systems with synergistic interactions which can be pharmacologically distinguished from the brainstem mu 2 receptors mediating supraspinal/spinal synergy.