Undertreatment of pain is a serious problem in the United States. The economic and social costs of chronic pain are substantial, estimates ranging in the tens of billions of dollars annually. For many patients, opioid analgesics when used as recommended by established pain management guidelines are the most effective way to treat their pain, and often the only treatment option that provides significant relief. However, opioids are one of several types of controlled substances that have potential for abuse; they are carefully regulated by the Drug Enforcement Administration (DEA). Impediments to the use of opioids include concerns about addiction, fear of inducing physiological dependence following chronic treatment. Research to identify potential analgesics with reduced abuse liability and fewer side effects is pivotal to advances in health care of the general public.

Scientists have discovered orphanin FQ/Nociceptin (OFQ/N), which is an endogenous peptide for the NOP receptors, the fourth member within the opioid receptor family. The sequence of the NOP receptor is closely related to each of the classical, well-characterized mu, delta, and kappa opioid receptors. Although inhibitory actions of OFQ/N have much in common with those of opioid peptides at the cellular level, behavioral effects of NOP receptor agonists have not been studied in primates. Humans and monkeys have similar thresholds for detecting noxious stimuli, and the neural systems responsible for these sensations in the two species are fundamentally similar. Scientific studies have shown that the functional and behavioral effects of opioid analgesics are more appropriately reflected in monkeys than in rodents. The monkey model may be able to clarify many issues in terms of functions and behavioral effects of NOP receptors in primates.

Our preliminary studies have found that intrathecal administration of OFQ/N produces uncomplicated, strong antinociception in monkeys. We also discovered that a newly developed non-peptidic NOP receptor agonist, Ro 64-6198, produces strong antinociception without the classical side effects associated with mu opioids in monkeys. These novel, important findings require further studies of NOP receptor functions in primates. The studies proposed in this project will test the hypotheses that in the nonhuman primates (1) the functions and behavioral effects of NOP receptors are independent from classical opioid receptors, (2) activation of NOP receptors produces strong antinociception without abuse liability, and (3) NOP agonists possess a promising therapeutic profile as analgesics compared to morphine following chronic administration. In our proposed studies, the antinociceptive effectiveness of NOP receptor agonists and mu opioids will be evaluated and compared by using different pain models in monkeys. Receptor-selective agonists and antagonists will be used to confirm the function of NOP receptors. In particular, different routes of administration will be conducted to clarify the central versus peripheral sites of actions of NOP receptor agonists. In conjunction with these state-of-the-art studies of analgesia in nonhuman primates, careful evaluation will be made of the reinforcing effects and abuse liability of these drugs when they are made available intravenously for lever-press responding in this same species. This will be done in a facility that the DEA has depended on for primate abuse liability evaluation of drugs they have confiscated. Furthermore, other side effects, particularly development of tolerance and physical dependence following chronic administration, will also be evaluated and compared with effects produced by a commonly used analgesic, morphine.

We anticipate that (1) intrathecal or intravenous/subcutaneous administration of NOP receptor agonists produces strong antinociceptive effects comparable to morphine in three experimental pain models in monkeys, (2) actions of the NOP receptors are independent of classical opioid receptors demonstrated by both behavioral and G protein activation studies, (3) the site of antinociceptive actions of systemic administration of NOP receptor agonists is mainly located in the central nervouc system, (4) NOP receptor agonists do not produce reinforcing/abuse liability, respiratory depressant, and pruritic side effects like mu opioid analgesics, and (5) NOP receptor agonists possess a wider safety margin and a less potential for development of tolerance and physical dependence following chronic administration in primates.

This project will help understand the NOP receptors characteristics in primates, leading directly to Phase I clinical trials. Behavioral effects of NOP receptor agonists can be systematically compared with those of mu, kappa, and delta opioid receptor agonists across different well-established in vivo functional assays in monkeys under acute and chronic administrations. In particular, the therapeutic margin of safety of NOP receptor agonists will be evaluated and compared with morphine in our monkey models. These basic pharmacological studies will establish a valuable foundation for research and development of NOP receptor agonists as a new generation of analgesics in humans. More important, the development of analgesics without respiratory depression, and with potentially reduced physiological dependence capability and abuse liability, should be of considerable interest and benefit to the general public. This project will make a notable advance and support for public health-related research in the field of chronic pain and analgesia.