Sunday, May 11, 2025
5/11/2025
Behavioral Pharmacology of Injury Restricted Fentanyl Analogues. - PROJECT SUMMARY Mu-opioid receptor (MOR) agonists (e.g., fentanyl, oxycodone) are highly efficacious for the treatment of pain. However, their therapeutic benefits are coupled with unwanted side effects like tolerance, respiratory depression, and addiction, indicating the need for improved therapeutic options. Recently, fluorinated fentanyl analogues (FFAs) have been produced which possessed a decreased pKa relative to fentanyl. This property allows these novel MOR agonists to become selectively activated by the low pH microenvironment associated with injured tissues while remining relatively inert systemically. Therefore, they should produce antinociception with efficacy and potency like fentanyl while avoiding the unwanted effects of traditional MOR agonists (addiction, respiratory depression.) However, literature regarding the abuse liability and respiratory depressing effects of these pH- restricted ligands is limited. This fellowship proposes to rigorously compare FFAs to fentanyl in models of antinociception, abuse potential, and respiratory depression in rats. Specifically, Aim 1 will determine the anti- nociceptive potency and efficacy of the test ligands across highly varied pain modalities. Aim 2 will evaluate the potency and efficacy of the test ligands to produce abuse-related effects in self-administration. Finally, Aim 3 will measure the potency and efficacy of the test ligands to produce respiratory depression using whole-body plethysmography. Sex effects will also be investigated. Ultimately, the proposed research will provide critical information regarding the safety margins of a new class of candidate opioid therapeutics. The results of this investigation will contribute greatly to the search for safer, non-reinforcing, treatments for pain. This fellowship training plan will encompass scientific training and professional development. To ensure proper preparation for a career as a physician-scientist, special attention will be paid to integration of academic research with continued exposure to clinical medicine. All aspects of this fellowship will be carried out at the Jackson campus of the University of Mississippi Medical Center. The applicant will receive scientific training and professional development from the Sponsor and Co-Sponsor, their collaborators, the Program In Neuroscience, and the School of Graduate Studies in the Health Sciences.
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