Initial reports suggest that naltrindole hydrochloride (NTI), a recently developed opioid, acts as a selective delta (delta) antagonist in vivo. Three experiments were conducted in rats to test NTI for its ability to dose-dependently and selectively block the analgesia produced by a delta-selective opioid agonist without affecting analgesia produced by mu (mu) receptor opioid agonists. Intracerebroventricular (ICV) administration of the delta-selective agonist, DPDPE (30 micrograms/rat), and the mu-selective agonist, DAGO (0.3 micrograms/rat), increased paw-lick latency (2-fold relative to baseline) in the hot-plate assay. NTI (0.01-1.0 micrograms/rat, ICV) dose-dependently attenuated DPDPE-induced analgesia (1.0 micrograms reduced paw-lick latency to baseline), but failed to affect DAGO-induced analgesia at any dose tested. A third experiment determined whether the ICV administration of NTI (1.0 micrograms/rat) would attenuate restraint stress-induced potentiation of morphine analgesia as indexed by the tail-flick assay. Rats that underwent 5 days of 1 h restraint stress and nonstressed rats were injected subcutaneously with morphine (1.0-8.0 mg/kg). The magnitude (greater than 2-fold) and duration of morphine-induced analgesia in restrained rats were significantly potentiated compared to nonstressed rats. NTI (1 microgram, ICV) failed to affect the magnitude and duration of morphine-induced analgesia regardless of restraint treatment. Thus, NTI failed to attenuate the analgesia produced by DAGO or morphine (in two assays of antinociception), whereas NTI (0.01-1.0 micrograms, ICV) antagonized dose-dependently DPDPE-induced analgesia. These results support the view that NTI is a selective delta-receptor antagonist in vivo.