Millions of people are prescribed mu opioid receptor (MOR) agonists such as oxycodone, fentanyl, and morphine for the treatment of malignant and non-malignant moderate to severe pain. Although these drugs are highly effective, they also cause significant side effects such as constipation, sedation, itch, physical dependence, and have the potential for abuse (Ko et al., 2009). Thus, there is a clinical need to identify novel receptor targets for pain relief. In the early 1990's a fourth member of the opioid receptor famil was identified and named the nociceptin/orphanin FQ (NOP), formerly known as the opioid-like receptor 1 (ORL1) (Lambert, 2008). Agonists that bind NOP are capable of producing profound analgesia in non-human primates without the potential for abuse, respiratory depression, or itch. Although the preclinical data supporting the development of these drugs is promising, several important pharmacodynamic characteristics that have limited traditional opioid therapy have not been evaluated. In order to test if the favorable profile of NOP agonist may include other important behavioral effects, this study will investigate the discriminative stimulus, sedating, an constipating effects of NOP agonists in comparison to the current standard of treatment, MOR agonists. To better understand how these drugs produce their effects in the brain, NOP will be imaged in vivo using Positron Emission Tomography (PET). The doses of NOP agonist that produce analgesia, discriminative stimulus effects, sedation, and changes in gastrointestinal transit time, will be correlated with receptor occupancy data to determine: 1) if different behavioral effects are produced with different levels of receptor occupancy and 2) which brain regions display the highest level of receptor binding for a given effect. These studies will lead t a better understanding of the neuroanatomy of pain control as well as provide information on the different brain structures that are involved in producing the behavioral effects of opioids. Finaly, although NOP agonists produce pain relief in preclinical models, their mechanism of action is poorly understood. It is known that classic opioid peptides (e.g. enkephalin) are released in response to pain, and it has been proposed that this serves to feedback on the intensity of painful stimuli (Bencherif et al., 2002). Clinical and preclinical studies have found elevated leves of nociceptin, the endogenous ligand for NOP, in various pain states (Ko et al., 2002 and Rosen et al., 2000). Therefore, using PET we will test if nociceptin is endogenously released in brain regions known to regulate the sensory and affective dimensions of pain in response to noxious stimuli. Understanding the relationship between pain and the endogenous nociceptin system would provide a strong rationale for developing NOP agonists as novel therapeutic agents for analgesia.
This research proposal will evaluate the NOP receptor, a novel opioid target for the treatment of malignant and non-malignant moderate to severe pain. In contrast to mu opioid receptor (MOR) agonists such as morphine and oxycodone, drugs that activate the NOP receptor produce potent analgesia in non-human primates without the potential for abuse, respiratory depression, or itch. The goals of this project are: 1) to evaluate other clinically relevant pharmacodynamic properties of NOP agonists 2) provide insight into their analgesic mechanism of action. The purpose of this research is to establish a novel drug target for pain control that will have more tolerable side effects, and lead to better patient outcomes.