The NOP (Nociceptin/Orphanin FQ peptide) receptor, the fourth opioid receptor subtype, mediates distinctive actions in non-human primates that suggest the possibility that activity at this receptor may result in strong analgesia in the absenc of virtually all of the side effects that are found in mu opioid receptor (MOP) agonists. NOP agonists, either peptidic or non-peptidic, produce full analgesia in each of the three assays that we use in rhesus monkeys, when delivered locally, systemically, or intrathecally. Yet small molecule NOP agonists do not serve as reinforcers and may produce anti- reinforcing effects in rodent models. Furthermore, we have found that combinations of MOP partial agonists and NOP agonists have synergistic antinociceptive effects in our monkey models. These exciting results prompt this application to evaluate a novel buprenorphine analog, BU08028, that has been developed and synthesized by Dr. Husbands in side-by-side comparisons with the MOP agonist, buprenorphine, in a number of assays in rhesus monkeys. BU08028 has binding affinities on both MOP and NOP receptors and displays partial agonist actions on both receptors. These monkey assays have been designed specifically to reflect the therapeutic (analgesia) and side effect (abuse liability, physiological changes and physical dependence) profile of opioid analgesics. Many of these assays were developed in this laboratory and have been validated over the course of a decade or more. In the first aim of this application, effects o BU08028 following acute and repeated administration will be evaluated and compared. In the second aim, the receptor mechanisms of BU08028 will be elucidated by selective MOP and NOP antagonists. The possibility that drugs with agonist actions at both receptors will be potent and effective analgesics with reduced side effects encourages our pharmacological studies of BU08028. Our unique set of assays in rhesus monkeys, our extensive history of research on these models in these animals, in combination with the availability of a novel bifunctional MOP/NOP agonist, sets the stage for the identification of a breakthrough in the treatment of pain and drug abuse in the clinical population.
The proposed research is relevant to public health because it could result in the identification of strong analgesics with promising therapeutic profiles. Identification of a superior analgesic with fewer side effects has long been a goal of pain management, and such drugs could profoundly impact human suffering as well as reducing the risks of drug abuse that are posed by the currently available strong mu opioid analgesics.
