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In the last decade a number of selective and potent non-peptidic agents became available to explore the usefulness of the delta-opioid receptor in modulation of pain of different origins. As a continuing effort in this field, potent and selective delta-opioid agonists based on the pyrrolomorphinan framework have been designed, synthesised and characterised biologically in our laboratories. In animal models, a selected compound of interest, SB 235863, has proved the concept that selective delta-opioid agonists may have great potential as pain relief agents in inflammatory and neuropathic pain conditions. Importantly, such a compound was free of the unwanted side effects usually associated with narcotic analgesics such as morphine.

Anew sequence, which encoded a novel G protein-coupled receptor, was disclosed by two different groups, using the nucleic acid probes based on the delta opioid receptor, first cloned in 1992. The new receptor, which Meunier called opioid-receptor-like 1 (ORL-1), was shown to share high homology with the opioid receptors and therefore thought to be a potential target for new analgesics. In this respect, the present review reports on the literature referring to ORL-1, to its natural ligand (nociceptin or orphanin FQ) and to several synthetic analogues recently described, both as agonists or antagonists at the receptor.