Dynorphins, such as dynorphin A(1-13) (Dyn A(1-13)), have been shown to enhance analgesia in morphine-tolerant animals, despite their very short half-life after intravenous administration. The potential use of dynorphins in humans is therefore of interest. This laboratory has recently evaluated the metabolic fate of stabilized dynorphin derivatives. This study was conducted to evaluate whether such stabilized derivatives, ie, [N-Met-Tyr1]-Dynorphin A(1-13) (N-MT Dyn A, stabilized at the N-terminal end) and [N-Met-Tyr1]-Dynorphin A(1-13) amide (N-MT Dyn A amide, stabilized at the C- and N-terminal ends), would enhance the antinociceptive activity of morphine not only after intravenous administration but also after subcutaneous and pulmonary delivery. Intravenous administration of N-MT Dyn A (5 micromol/kg) and N-MT Dyn A amide (5 micromol/kg) to morphine-tolerant rats resulted in significantly higher tail-flick latencies than those observed for the saline group. These effects could be observed for up to 2.0 +/- 0.1 hours after intravenous administration of N-MT Dyn A and for up to 3.4 +/- 1.4 hours for N-MT Dyn A amide. The time-averaged effects of both peptides were similar. After pulmonary delivery of the same dose, derivatives remained active. The duration of the effects after pulmonary administration of the amide was 4.4 +/- 2.5 hours while that of N-MT Dyn A was slightly shorter (2.8 +/- 0.9 hours). No effect was observed after subcutaneous administration of N-MT Dyn A. These results suggest that pulmonary delivery of stabilized dynorphin derivatives represents a possible alternative to intravenous administration.