Intrathecally (i.t.) administered corticotropin-releasing factor (CRF) has been shown to produce antinociception in the mouse abdominal stretching (writhing) assay. It also has been demonstrated that spinal kappa opioid receptors as well as CRF receptors are involved in the antinociception induced by CRF. In the present study, the role of CRF i.t. in modulating nociception was assessed further using the mouse tail-flick test. In addition, the modulatory effect of i.t. administered CRF on the antinociceptive activity of morphine was studied. Despite its potent and long-lasting antinociceptive effect in the writhing assay, CRF injected i.t. produced no consistent antinociception in the tail-flick test at doses up to 20 times the antinociceptive ED50 of CRF in the writhing test. In contrast, i.t. injection of CRF significantly attenuated the antinociceptive action of s.c. administered morphine. CRF at doses of 0.1 and 0.2 nmol/mouse i.t. increased the antinociceptive ED50 of s.c. morphine by 2- and 4-fold, respectively. The antagonistic action of CRF peaked between 15 min and 1 hr after i.t. injection and was still observable 4 hr after injection, demonstrating a time course similar to that of the antinociceptive effect of CRF in the writhing test. Intrathecal injection of alpha-helical CRF(9-41), a competitive CRF receptor antagonist, was able to inhibit, in a dose-dependent manner, the antagonistic activity of CRF. The antagonistic action of CRF also was attenuated dose-dependently by i.t. injection of nor-binaltorphimine (nor-BNI), a highly selective kappa opioid receptor antagonist. However, intrathecal injection of (+)-1-nor-BNI, an inactive enantiomer of nor-BNI, did not affect the antagonistic action of CRF. These data suggest that spinal kappa opioid receptors as well as CRF receptors are involved in the antagonistic effect of CRF against morphine antinociception.