The antinociceptive effects of synthetic dermorphin and its analogues containing D-Arg in position 2 injected into the lateral cerebroventricle were examined in conscious mice. Intracerebroventricular (i.c.v.) administration of dermorphin and [D-Arg2] dermorphin produced potent and long-lasting antinociceptive activity as assayed by the tail-pressure test. Dermorphin and [D-Arg2] dermorphin were 210 and 52 times more potent than morphine, respectively. The antinociceptive effects produced by these heptapeptides were antagonized by a low dose (0.5 mg kg-1, i.p.) of the opioid antagonist naloxone. The ED50 values for [D-Arg2] dermorphin (1-6), (1-5) and (1-4) were not significantly different from that for [D-Arg2] dermorphin. The potency of the shortest fragment, [D-Arg2] dermorphin (1-2) was found to possess a severely reduced activity, whilst [D-Arg2] dermorphin (1-3) maintained activity and was 10 times more potent than morphine. [D-Arg2] dermorphin analogues showed almost identical effects when tested on the electrically-induced contractions of the guinea-pig isolated ileum. These results led us to conclude that the presence of the N-terminal tripeptide in the structure of [D-Arg2] dermorphin is of crucial importance for the manifestation of the full intrinsic opioid-like antinociceptive activity of [D-Arg2] dermorphin, which is presumably mediated through opioid receptors in the brain.