The effects of two endogenous mammalian FMRFamide (Phe-Met-Arg-Phe-NH2)-related peptides, an octapeptide F8Fa (Phe-Leu-Phe-Gln-Pro-Gln-Arg-Phe-NH2) and an octadecapeptide A18Fa (Ala-Gly-Glu-Gly-Leu-Ser-Ser-Pro-Phe-Trp-Ser-Leu-Ala-Ala-Pro-Gln-Arg-Phe -NH2) on morphine- and restraint stress-induced analgesia and basal nociceptive sensitivity, as measured by the latency of a foot-lifting response to a warmed surface, were examined in male mice. Intracerebroventricular (i.c.v.) administrations of F8Fa and A18Fa (0.10-10 micrograms) during the day-time significantly reduced morphine (10 mg/kg) and restraint-induced analgesia at 30 min after administration, with F8Fa having a greater inhibitory effect than A18Fa. At night during the dark period i.c.v. F8Fa also significantly reduced the elevated nocturnal thermal response latency, while not affecting the shorter day-time nociceptive responses. Peripheral administrations of the prototypic opiate antagonist, naloxone (1.0 mg/kg), had similar inhibitory effects on morphine- and stress-induced analgesia, and the day-night rhythm of nociceptive sensitivity. These results indicate that F8Fa and A18Fa are involved in the modulation of opioid analgesia and suggest that these endogenous FMRFamide-related peptides may be associated with the expression of the day-night rhythm of opioid-mediated nociceptive sensitivity.