We assessed whether tolerance develops to the antinociceptive effect of intrathecal (i.t.) orphanin FQ, the endogenous ligand of the orphan opioid-like receptor, and whether there is a cross-tolerance between the antinociceptive effect of i.t. orphanin FQ and the mu opioid receptor agonist morphine. Orphanin FQ administered i.t. at 10 micrograms induced strong thermal antinociception as assessed with the tail flick test without inducing motor impairment or sedation. Tolerance developed in 4 days to the antinociceptive effect of orphanin FQ upon twice daily injections. However, rats rendered tolerant to orphanin FQ did not exhibit cross-tolerance to morphine. Moreover, in rats made tolerant to morphine, orphanin FQ induced similar antinociceptive effect as in morphine naive rats. The present results are the first to show that there is no cross-tolerance between orphanin FQ and morphine in eliciting spinal antinociception, supporting the notion that orphanin FQ produced spinal antinociception through a site which is different from classical opioid receptors.