Neurotensin (NT), administered intracisternally to mice, produced significant dose-dependent antinociception in three analgesic tests: tail immersion, hot-plate and acetic acid writhing. Naloxone (1-5 mg/kg), an opiate antagonist administered i.p. 20 min before NT administration, did not significantly alter NT-induced antinociception in any of these tests; naloxone did significantly reverse beta-endorphin-induced antinociception. However, centrally and peripherally administered thyrotropin-releasing hormone antagonized NT-induced (but not beta-endorphin-induced) antinociception. Equimolar doses of another tripeptide (Pro-Leu-Gly-NH2; melanostatin) did not alter the effects of NT. The data obtained in this study confirm NT-induced antinociception, provide further evidence that NT does not activate naloxone-sensitive opiate receptors and demonstrate that this brain effect of NT is antagonized by thyrotropin-releasing hormone. These findings therefore support the hypothesis that NT and thyrotropin-releasing hormone are functional antagonists in the central nervous system.