Orphanin FQ (OFQ), the endogenous ligand for the orphan opioid receptor, LC132, was recently isolated and characterized. The anti-opioid role of OFQ in supraspinal pain modulation was demonstrated by our previous observations that intracerebroventricular (i.c.v.) OFQ administration dose-dependently reverses systemic morphine antinociception and opioid-mediated stress-induced antinociception. The present study was designed to evaluate whether OFQ also modulates the antinociceptive actions of morphine in the spinal cord. Immediately after assessment of baseline nociceptive sensitivity on the 49 degrees C tail-withdrawal assay, mice of both sexes were given i.c.v. or intrathecal (i.t.) cocktails of morphine (0, 1, 10 or 50 micrograms [0-135 nmol]) and OFQ (0 or 10 nmol), and re-tested 15, 30 and 60 min later. OFQ alone did not affect nociceptive sensitivity when administered by either route. Following i.c.v. administration, the antinociception produced by 10 micrograms morphine was completely reversed by 10 nmol OFQ; antinociception induced by 50 micrograms morphine was significantly antagonized. In contrast, OFQ was completely ineffective against antinociception induced by i.t. morphine. These findings indicate that the anti-opioid actions of OFQ are restricted to supraspinal central nervous system sites.