Despite much study since its discovery in 1995, the effects of orphanin FQ/nociceptin (OFQ/N), the endogenous ligand of the 'orphan' opioid receptor, on nociceptive sensitivity remain unclear. Different laboratories have variously reported hyperalgesic, analgesic, anti-analgesic or no effect of the peptide on thermal assays following supraspinal injection in rodents. We and others have argued previously that methodological inconsistencies and experimental parameters may explain some of the contradictions in the literature, especially in mice where intracerebroventricular (i.c.v.) injections proceed directly through the skull. We report presently that both the magnitude of stress-induced analgesia (SIA) produced by such i.c.v. injections, and the ability of OFQ/N to antagonize this opioid-mediated SIA, are strain-dependent. Specifically, significant injection-related SIA was observed in four of six strains studied (outbred: CD-1, SW; inbred: AKR/J, BALB/cJ, C3H/HeJ, CBA/J) on the 47.5 degrees C tail-withdrawal assay, and OFQ/N blocked this SIA in two strains. These data suggest that genetic variability among subject populations may underlie the inconsistent findings among researchers, and may in addition provide a promising avenue for future study of this novel neuromodulator.