Orphanin FQ, also known as nociceptin, is a heptadecapeptide with very high affinity for a novel member of the cloned opioid receptor family which produces hyperalgesia in mice. In addition to hyperalgesia, which is observed soon after administration of orphanin FQ, we now describe a delayed analgesic response. Unlike orphanin FQ-induced hyperalgesia, orphanin FQ-induced analgesia is readily reversed by the opioid antagonist naloxone, implying an opioid mechanism of action. In view of the very poor affinity of orphanin FQ for all the known traditional opioid receptors and the low affinity of opioids for the 125I[Tyr14]orphanin FQ binding site, orphanin FQ-induced analgesia is probably mediated through a novel orphanin FQ receptor subtype.