The G protein coupled nociceptin receptor known as ORL1 has been shown to be involved in the modulation of pain in animal models. It bears high homology to the classic opioid receptors (μ, k, δ), but has little cross reactivity with their native ligands. Current opioid analgesics target these classic opioid receptors, but have limiting side effect profiles (e.g. tolerance, physical dependence, respiratory depression and decrease of gastrointestinal function). ORL1 receptors are colocalized in regions of the CNS similar to the opiod receptors, as well as in the periphery.
Nociceptin, the endogenous ligand to ORL1, was discovered in 1995 and shown to be a peptide ligand that activates the ORL1 receptor, but not the classic opioid receptors. Initial reports have suggested that nociceptin and the ORL1 receptor are involved in a newly discovered pathway involved in the perception of pain. Further reports have shown nociceptin to be analgesic when administered intrathecally to rodents. The in vivo efficacy of nociceptin in animal models of pain is similar to that of the endogenous opioids. Nociceptin is also reported to act as an anxiolytic agent when administered into the brains of rodents. The in vivo efficacy in rodent anxiety models is similar to classic benzodiazepine anxiolytics. In addition, nociceptin has been recently reported to inhibit capsaicin induced bronchoconstriction in isolated guinea pig lung tissue, suggesting a role for ORL1 agonists in the treatment of cough. Together, these data suggest that nociceptin receptor agonists may have significant analgesic, anxiolytic, or antitussive properties.