The clinical effectiveness of morphine is limited by several side effects, including the development of tolerance and dependence. Most of these side effects are believed to be mediated by central opioid receptors therefore, hydrophilic opioids, which dont cross the blood-brain barrier, may have advantages over morphine in some clinical applications. We recently synthesized several analogues of DALDA (Tyr-D-Arg-Phe-Lys-NH2), a highly hydrophilic peptide derived from the endogenous opioid peptide dermorphin; all of them, particularly [Dmt¹] DALDA (Dmt - 2,6-dimethyl tyrosine), had high potency and selectivity at μ receptors, the target of morphine, in activity assays. Here we report the pharmacological characterization of [Dmt¹] DALDA in the whole animal. [Dmt¹]DALDA was 40 times more potent than morphine in inducing antinociception in mice when both drugs were given s.c., and 6-14 times more potent than DAMGO, a selective μ agonist, when both drugs were given it. However, [Dmt¹]DALDA showed poor cross-tolerance to morphine; thus chronic morphine treatment of animals increased the antinociceptive AD50 of systemic [Dmt1]DALDA two fold or less, as compared to an 8-9-fold increase for morphine and a 4-5-fold increase for DAMGO. The antinociceptive activity of [Dmt¹]DALDA (i.t) was blocked by CTAP, a selective μ antagonist, but not by TIPPΨ, a selectiveδ antagonist, nor by nor-BNI, a selective κ antagonist. [Dmt¹]DALDA-induced antinociception was also blocked by naloxone methiodide, an antagonist that does not cross the blood-brain barrier, when agonist and antagonist were given i.t. or i.c.v., but not when they were given s.c. We conclude that [Dmt¹] DALDA is a highly potent analgesic acting at μ receptors. Though it appears to penetrate the blood-brain barrier, it exhibits low cross-tolerance to morphine, suggesting that it may have advantages over the latter in certain clinical applications.