Pharmacological Investigation of NOP-Related Ligands as Analgesics without Abuse Liability

Most widely used analgesic drugs for the treatment of moderate to severe pain are mu-opioid receptor agonists such as morphine. However, analgesic value of these drugs is compromised due to unwanted side effects including respiratory depression, abuse liability, itch, and tolerance to analgesia. Nociceptin/orphanin FQ receptor (NOP) is emerging as a potential analgesic target without abuse liability. Analgesic properties of NOP-related agonists have been investigated in rodents and monkeys. In rodents, spinal injection of NOP agonists produces antinociception against diverse pain modalities and also potentiates morphine-induced antinociception. In monkeys, both spinal and systemic administration of NOP agonists produce morphine-comparable antinociceptive effects against acute nociception, capsaicin-induced allodynia, and carrageenan-induced hyperalgesia. More importantly, NOP agonists do not produce respiratory depression, itch scratching, and reinforcing effects at the antinociceptive doses. Interestingly, spinal or systemic administration of NOP agonists can potentiate mu-opioid receptor mediated antinociception and widen the therapeutic window in monkeys. Therefore, NOP agonists have a promising analgesic value when injected alone or in combination with mu opioid analgesics. These studies further support the therapeutic potential of NOP-related ligands including selective NOP agonists and bifunctional NOP/MOP agonists as effective analgesics in order to achieve strong pain relief without concerns over abuse and safety.