In vivo imaging modalities such as positron emission tomography (PET) and functional magnetic resonance imaging (fMRI) are powerful translational tools for studying molecular interactions and neural activation in the living brain. This K01 Award will provide protected time for the candidate to enhance his existing knowledge base by acquiring new training necessary for establishing research independence. The candidate?s long term career goal is to become an innovative translational neuroimaging scientist with a strong foundation in neurochemistry and neuropharmacology to answer the complex and key underlying mechanisms of opioid addiction in the living brain. Guided by mentors with excellent track records in neuroimaging, animal behavior, addiction research, and mentorship, the candidate will obtain necessary training to solidify a knowledgebase leading to independent research in addiction. A major strength of this proposal is the integrative training at two leading research centers, Massachusetts General Hospital and McLean Hospital, and will integrate training through coursework, seminars, meetings, discussions with mentors, and hands-on supervised research. Mu opioid receptor (MOR) targeting pain killers, e.g., oxycodone, hydrocodone, morphine, are powerful analgesics but suffer from euphoria, respiratory depression, dependence, and high abuse liability. Unfortunately, there has been limited success on the development of new painkillers, void of the addicting properties of conventional opiates. The kappa opioid receptor (KOR) is the most abundant OR in the human brain, and KOR agonists produce potent analgesic efficacy. Unfortunately, first generation KOR agonists are aversive, dysphoric and dissociative in humans, limiting their therapeutic potential. Recently, an exciting new class of KOR agonists has been reported across several research groups and it was shown in rodents that these drugs provide effective analgesia with reduced side effects. These novel KOR agonists termed, G protein-biased agonists, display functional selectivity upon ligand binding and preferentially activate signaling that primarily leads to analgesic efficacy. Although these preliminary results are promising, quantitative translational methods assessing their ?bias? in vivo have been lacking. Therefore, it is imperative that translational tools are developed for understanding brain activation/circuitry of KOR agonists in the living brain. The candidate will examine KOR agonist-mediated effects in the living rat brain with simultaneous PET- MR to measure cerebral blood volume changes (CBV, fMRI) and occupancy at KORs (BPND, PET) following KOR agonist administration. This work will result in tools for quantifying the functional and molecular signatures of current and future KOR biased agonists. These signatures will be correlated with previous in vitro data and also with trusted animal behavior paradigms. Understanding KOR-mediated signatures in the living brain with translational imaging will undoubtedly accelerate development of this class of non-addictive analgesics.

Public Health Relevance

Opiates that target the mu opioid receptor remain the most effective medications for treating pain, but they suffer from side effects such as euphoria and respiratory depression, and addiction to these drugs has created a national epidemic. Alternatively, analgesics that target the kappa opioid receptor are non-addictive and effective for treating pain, but they are also aversive and depressive in humans. We will use cutting edge neuroimaging methods to characterize these drugs and determine what makes them aversive, the key to unlocking this class of non-addictive opioids for treating pain.

National Institute of Health (NIH)
National Institute on Drug Abuse (NIDA)
Research Scientist Development Award - Research & Training (K01)
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Molecular Neuropharmacology and Signaling Study Section (MNPS)
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Wenzel, Jennifer Millicent
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Massachusetts General Hospital
United States
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