Neurotensin is a neurotransmitter/modulator with a wide range of actions. Using a series of 10 stable analogs, we have examined neurotensin antinociception in mice. By incorporating (2S)-2-amino-3-(1H-4-indoyl)propanoic acid (l-neoTrp), a series of neurotensin analogs have been synthesized that are stable in serum and are systemically active in vivo. When administered in mice, they all were antinociceptive in the radiant heat tail-flick assay. Time-action curves revealed a peak effect at 30 min and a duration of action ranging from 2 to 4 h. Dose-response curves revealed that two compounds were partial agonists with maximal responses below 75%, whereas all of the remaining compounds displayed a full response. Overall, the compounds were quite potent, with ED(50) values similar to those of opioids. At peak effect, the ED(50) values ranged from 0.91 to 9.7 mg/kg s.c. Two of the analogs were active topically. Together, these studies support the potential of neurotensin analogs as analgesics. They are active systemically and by using them topically, it may be possible to avoid problematic side effects, such as hypothermia and hypotension.