Pain affects more Americans than does diabetes, heart disease and cancer combined. Opioids are a key drug class for pain treatment, however, there are significant drawbacks (e.g. CNS adverse effects, social and legal issues) that limit their use for effective management of pain. Consequently, development of novel approaches for improved pain control is a critically important research objective. To eliminate adverse CNS- derived effects, attention has turned to targeting peripherally located opioid receptors expressed on the pain- sensing neurons themselves. Importantly, the regulatory mechanisms of opioid receptor systems in peripheral sensory neurons are unique, and results obtained from studies in other systems (CNS, heterologous expression systems, etc.) do not always translate to peripheral sensory neurons. Thus, to understand opioid receptor function in peripheral sensory neurons, experiments must be done with peripheral sensory neurons. The goal of this project is to study the regulation of kappa opioid receptor (KOR) signaling systems in peripheral sensory neurons, using primary cultures of adult rat sensory neurons and a behavioral model of nociception.
Our specific aims are 1) To delineate the role of ERK in regulation of KOR function in peripheral sensory neurons;2) To delineate the role of JNK in regulation of KOR function in peripheral sensory neurons; and 3) To delineate the role of acute desensitization in regulating KOR agonist efficacy in peripheral sensory neurons. Our overall goal is to increase the reliability and therapeutic efficacy of peripherally-restricted kappa opioid analgesic drugs. By understanding the cellular mechanisms that are involved in regulating the responsiveness of kappa opioid receptor systems on peripheral sensory neurons, improved approaches to treat pain can be developed that have improved therapeutic efficacy and are devoid of debilitaing CNS-mediated adverse effects. The combination of rigorous mechanistic studies using primary sensory neurons in culture with the translational value of behavioral studies provides a powerful approach to understanding the regulation kappa opioid receptor agonist efficacy in a physiologically relevant system and may lead to new approaches for improved pharmacotherapy for pain.

Public Health Relevance

Pain affects millions of people in the United States and is poorly managed. Peripheral kappa opioid receptors may provide a novel and improved target for treatment of pain that is devoid of debilitating, dose-limiting, CNS-mediated adverse effects. In this application, we propose to identify cellular mechanisms which regulate kappa opioid receptor-mediated analgesia in peripheral sensory neurons with the ultimate goal of producing effective relief of pain.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Research Project (R01)
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Molecular Neuropharmacology and Signaling Study Section (MNPS)
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Dunsmore, Sarah
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University of Texas Health Science Center San Antonio
Schools of Medicine
San Antonio
United States
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Berg, Kelly A; Clarke, William P (2018) Making Sense of Pharmacology: Inverse Agonism and Functional Selectivity. Int J Neuropsychopharmacol 21:962-977
Jacobs, Blaine A; Pando, Miryam M; Jennings, Elaine et al. (2018) Allosterism within ? Opioid-? Opioid Receptor Heteromers in Peripheral Sensory Neurons: Regulation of ? Opioid Agonist Efficacy. Mol Pharmacol 93:376-386
Jamshidi, Raehannah J; Sullivan, Laura C; Jacobs, Blaine A et al. (2016) Long-Term Reduction of Kappa Opioid Receptor Function by the Biased Ligand, Norbinaltorphimine, Requires c-Jun N-Terminal Kinase Activity and New Protein Synthesis in Peripheral Sensory Neurons. J Pharmacol Exp Ther 359:319-328
Sullivan, Laura C; Chavera, Teresa S; Jamshidi, Raehannah J et al. (2016) Constitutive Desensitization of Opioid Receptors in Peripheral Sensory Neurons. J Pharmacol Exp Ther 359:411-419
Jamshidi, Raehannah J; Jacobs, Blaine A; Sullivan, Laura C et al. (2015) Functional selectivity of kappa opioid receptor agonists in peripheral sensory neurons. J Pharmacol Exp Ther 355:174-82