SUMMARY (Project B): Opiates are medically appropriate for the treatment of acute (nociceptive) or cancer pain. It is not known, however, whether these drugs provide long-term benefit in chronic non-malignant (e.g., neuropathic) pain. Some studies suggest an overall decrease in quality of life of patients receiving opiates for chronic pain. Additionally, opiates can produce physical dependence, and promote addiction, drug abuse and death due to overdose. Eric Holder, Attorney General of the United States, recently stated ?right now, few substances are more lethal than prescription opiates and heroin? (NY Times, March 10, 2014). There is a high unmet medical need for the discovery of treatments that allow management of chronic non-malignant pain, that sustain efficacy for extended periods while maintaining quality of life and that diminish the possibility of addiction and abuse. In this sub-project (Project B), and consistent with the overall aims of the Program Project grant, we consider the adaptive changes that occur in the brain as a consequence of chronic pain, and from the opiates themselves, in the design of novel therapies. Preclinical research has demonstrated that experimental neuropathic pain, or sustained exposure to opiates such as morphine, produces upregulation of cholecystokinin (CCK) in descending pain modulation circuits as well as in reward/motivation circuits. CCK elicits both pro-nociceptive and anti-opioid actions. Together these neural adaptations diminish the analgesic actions of opiates so that more drug is needed to elicit the same effect on pain (i.e., tolerance). Higher doses of drugs are associated with increased side-effects and increased likelihood of addiction and abuse. CCK produces hyperalgesia in animals and is associated with the nocebo response in humans. Blockade of CCK receptors (a) enhances opiate potency and promotes sustained efficacy in experimental chronic non-malignant pain; (b) diminishes opiate-induced sedation and gastrointestinal slowing, common side- effects that decrease quality of life with chronic use; (c) decreases the naloxone-precipitated withdrawal syndrome in morphine-dependent rats; and (d) decreases morphine-induced dopamine release in the reward pathway. Thus, blockade of CCK receptors could allow for improved opiate-mediated control of chronic non- malignant pain while maintaining quality of life. Additionally, CCK receptor blockade could diminish opiate dependence, as well as addiction and possibly drug craving providing benefits both to individuals and society. We hypothesize that we can discover a single small molecular weight, non-peptidic molecule with high affinity CCK antagonist and mu opioid agonist activity. We additionally hypothesize that such orally availability and CNS penetrant molecules will show enhanced and sustained activity in chronic pain, as well as reduced liability for dependence, addiction and craving. Such compounds with dual functionality may achieve pain-related efficacy at decreased mu opioid receptor engagement resulting in decreased side-effects, improved quality of life and diminished dependence and addiction liability. We will build on strong preliminary lead compounds with dual functionality to optimize desired interactions of a single molecule with opiate and CCK receptors, ADME and pharmacokinetics (Aim 1); characterize these molecules for effects on experimental chronic (e.g., neuropathic) non-malignant pain (Aim 2); evaluate the effects of sustained administration of these new molecules alone, or with new delivery methods, for overall liabilities that may impact quality of life from side- effects (Aim 3); and evaluate the liability of these molecules for physical dependence, addictive liability, and craving (Aim 4). This proposal is based on the optimization of novel chemical entities that have been specifically designed to address the established neural consequences that result from opiate use for chronic pain, i.e., drug design for disease.