Chemical Countermeasures Research Program (CCRP) Initiative: Basic Research on The Deleterious Effects of Acute Exposure to Ultra-Potent Synthetic (UPS) Opioids (R01 Clinical Trial Not Allowed)

Funding Opportunity Description Background The Chemical Countermeasures Research Program (CCRP) is a trans-NIH initiative to support the research and early development of medical countermeasures (MCMs) and to advance national medical and public health preparedness for response to, and recovery from, chemical emergencies. Ultra-potent synthetic (UPS) opioids (e.g., fentanyl, carfentanil) have been designated as high consequence chemicals of concern (CoC) by United States Government agencies, including the Department of Homeland Security (DHS). Concerns stem from multiple factors that include their highly toxic and addictive properties, ease of synthesis, and wide availability, resulting in enormous economic and social harm. Consequently, owing to their high in vivo potency, rapid onset, and toxicity, UPS opioids are not only considered public health risks under the ongoing opioid epidemic, but also deemed as chemical threats by both military and civilian agencies when there is accidental exposure or when used intentionally, in weaponized form on a large-scale (e.g., aerosolized), either as a single agent or as a mixture of agents, such as during the Moscow theater hostage crisis in 2002. Along with the CCRP, the National Institute on Drug Abuse (NIDA) aims to support research on understanding, treating and/or preventing injuries and deaths that may result from exposure to UPS opioids. The UPS opioid fentanyl exhibits a unique pharmacology while behaving as a -opioid receptor ( OR) agonist. The dissociation kinetics of fentanyl and congeners differ significantly when compared to that of classical OR agonists such as morphine. The immediate effects after acute UPS opioid exposure primarily include Opioid-Induced Respiratory Depression (OIRD), Opioid-Induced Persistent Apnea (OIPA), Wooden Chest Syndrome (WCS), decreased brain and nerve function, muscle rigidity, bradycardia, and decreased tidal volume and airway compromise, which are often associated with lethality. The short-acting OR antagonist naloxone, despite its limitations to counter re-narcotization, was approved as a high-dose formulation to protect against potential exposure to weaponized UPS opioids. This product was also meant to protect military personnel and chemical incident responders entering an area contaminated with such agents. Assuming its intended benefits outweigh some of the documented risks, the reformulated long acting OR antagonist nalmefene is also being considered as an emergency treatment option in similar community settings. However, evidence suggests that non- OR mechanisms, pathways, and secondary targets contribute to the severity of overdose symptoms. Such non- OR effects may not be fully reversed by OR antagonists alone especially since a plethora of targets and signaling pathways may be involved in regulating key physiological processes whose function may be disrupted upon acute exposure to UPS opioids. As with other CoCs, acute exposure to UPS opioids may also lead to long-lasting and delayed health sequelae as a function of direct toxic effects of such agents wherein survivors might experience unknown intermediate, persistent and debilitating non-lethal effects (e.g., hypoxic brain injury caused by OIRD and/or OIPA). There is currently a significant knowledge gap on how acute exposure to UPS opioids potentially impacts persistent or delayed morbidities with lasting molecular, cellular, and behavioral changes that might develop following such exposure. There is an urgent need to understand such outcomes, especially in vulnerable populations. Overall, the information obtained on the mechanisms underlying the effects of acute UPS opioid exposure will facilitate development of new standalone or concurrent/adjunctive overdose therapies that are rapidly effective, scalable, and easily field deployable during mass casualty public emergencies. Scientific Research Objectives and Scope The overarching goal of this NIDA-CCRP FOA is to reveal, elucidate and validate mechanisms (e.g., molecular, cellular, genetic, circuitry, structural) and biological pathways (e.g., gene expression, signal transduction, neural, developmental) for identifying actionable therapeutic targets that can help mitigate the observed toxicities underlying: 1) the deleterious effects and lethal consequences of acute exposure to UPS opioids and/or 2) non-lethal, delayed, or persistent pathophysiological effects after acute exposure to UPS opioids. When developing proposals on the topics listed, applications must be clear in dissociating potential direct toxic effects from long-term effects caused by acute exposure to UPS opioids. Additionally, mechanisms secondary to acute effects must be dissociated from direct pharmaco-toxicological effects of the UPS opioid at the end-organ. Applicants are encouraged to contact the Scientific/Research Contact(s) prior to submission as they may choose to develop their research projects in one or more areas based on their expertise and feasibility. It is anticipated that compelling projects will utilize well-defined, integrated, and multidisciplinary approaches requiring collaborations between individuals with diverse expertise. Applicants are encouraged to establish such collaborations if necessitated. Representative topics of programmatic interest include: Research on elucidating the mechanisms and pathways underlying the effects of acute UPS opioid exposure and overdose. Proposed studies may include mechanisms by which deleterious effects (e.g., OIRD, OIPA, WCS, CNS depression) and sudden death occur, and target identification and validation for facilitating development of centrally and/or peripherally focused reversal/mitigation strategies Research on the candidate genes, and pathway-specific cell and neuronal types/states and remodeling; studies elucidating the molecular signatures and signaling pathways, their functional consequences, neural forms and their activity and function, and interactions between the pathways and circuits in the context of acute UPS opioid exposure and toxicity Research on the transcriptional alterations upon acute exposure to UPS opioids Omics studies and other precision approaches to inform our understanding on the mechanisms of UPS opioid-induced overdose and toxicity Research on identifying signaling molecules and their biological targets and deciphering their functional relationships and physiological roles to understand acute UPS opioid exposure and toxicity Fundamental research on the etiology and pathophysiology of non-lethal, persistent, or delayed effects of acute UPS opioid exposure, and long-term effects following apparent recovery from acute effects, e.g., OIRD, OIPA or WCS, on CNS function, including cognition, plasticity and/or motor function. Studies on elucidating the mechanisms and markers associated with other key physiological processes whose function may be disrupted upon acute exposure to UPS opioids (e.g., cardiovascular, hepatic, gastrointestinal, endocrine, immune), including pregnancy and birth outcomes