Strategies to Improve Opioid Analgesia: Nociceptin Receptor Agonists and Intranasal Delivery in Monkeys.

Abstract

There are two general approaches for improving pain control with opioids: identifying novel analgesics without μ-opioid receptor side effects, and developing strategies to optimize clinically used opioids. This thesis investigates a novel target for pain control (the nociceptin/orphanin FQ (NOPr) receptor), as well as the potential for improving current and future opioid medications by utilizing the intranasal (IN) route of delivery. In rhesus monkeys, NOPr agonists have been shown to produce analgesia in the absence of unwanted μ-receptor mediated effects. Other behaviors produced through NOP receptors have not been characterized. This thesis established for the first time in monkeys that the NOPr agonist Ro 64-6198 produced discriminative stimulus effects that were behaviorally and pharmacologically distinct from other opioid receptors, but were similar to the benzodiazepine, diazepam. In contrast to previous work, Ro 64-6198 did not produce antinociception in the monkey tail withdrawal assay, suggesting that this effect may be more variable than previously thought. IN drug administration offers several benefits for developing and administering therapeutics. Despite the favorable profile, IN delivery is employed less frequently than other parenteral routes, and functional animal models for IN delivery are not well established. This thesis reports the first model to measure the analgesic effects of intranasally administered opioids in rhesus monkeys. The effects of IN fentanyl and buprenorphine were found to be dose-dependent; a comparison to intramuscular (IM) administration suggested that IN delivery may result in a faster onset of action, and produce greater analgesia at lower doses. The translational aspects of this model were further explored by studying the actions of IN naloxone (NLX), a drug that is routinely used to reverse opioid toxicity, and where some questions remain about its potency and effectiveness relative to other routes. IN and IV NLX were found to be equipotent in reversing fentanyl-induced antinociception, however there was a trend for IV administration to produce larger decreases. Data obtained from PET images showed a similar trend for receptor occupancy. Overall, this thesis expanded the behavioral profile of NOPr agonists in monkeys, and provided a framework to investigate the IN delivery of novel and clinically used opioids.