Pharmacology of Mixed NOP/Mu Ligands

Activation of NOP receptors produces a complex pharmacology leading to either antinociceptive activity or inhibition of opiate antinociception, depending upon the route of administration. Systemic administration of NOP receptor agonists does not induce antinociception in most acute pain models in rodents. However, activation of NOP receptors does block opiate-mediated reward and reduces opiate tolerance development. Compounds have been synthesized to test the hypothesis that mixed NOP/mu ligands could have antinociceptive activity, with reduced addiction liability and reduced tolerance development. We discuss the background and rationale for developing mixed NOP/mu compounds and review the pharmacology of compounds with varying affinity and efficacy at NOP and mu opioid receptors. Among these novel compounds are those that have potent antinociceptive activity with reduced reward and other compounds that are devoid of antinociceptive activity, but attenuate morphine CPP. These results suggest that mixed NOP/mu compounds have potential clinical value as analgesics and/or as treatments for drug abuse.