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Department

Pharmacology

Kelly Berg, Ph.D.

Professor/Research

Personal Statement:

Our work centers on questions concerning the molecular nature of drug efficacy and the mechanisms by which the efficacy of drugs can be regulated. Our current projects include studies on the regulation of opioid receptor agonist efficacy in primary sensory neurons, determination of the role of opioid receptor heteromers in peripheral mechanisms of analgesia and measurement of functional selectivity profiles of kappa opioid receptor ligands.
The management of pain represents a major medical and scientific challenge. Pain affects more Americans than diabetes, heart disease and cancer combined, yet it is one of the most poorly treated conditions in primary care and accounts for less than 1% of total NIH funding. Opioids represent a major drug class for the treatment of pain, however there are major drawbacks to their systemic use. In addition to serious adverse effects (e.g., dependence, tolerance, sedation), there are social and legal issues that limit their use. Consequently, there has been considerable interest in the peripheral analgesic effects of opioids since this approach may offer improved therapeutic outcomes. Currently we study mechanisms involved in the regulation of agonist efficacy at all three major opioid receptors, mu (MOR), delta (DOR) and kappa (KOR) receptor systems expressed on primary (peripheral) sensory neurons. We utilize primary cultures of adult rat sensory neurons as well as rat behavioral models of peripheral nociception for these studies. The results of this work will lead to a better understanding of the cellular factors involved in regulating opioid agonist efficacy and may lead to novel approaches for the management of pain.
Originally thought to function only as receptor monomers, it is now known that G protein coupled receptors (GPCRs) also function as homo- and heterodimeric complexes (between different receptor subtypes) and perhaps even as higher order oligomers. Receptor heteromers are attractive targets for pharmacotherapy as allosteric interactions that can occur between protomers of a given heteromer may be exploited to regulate drug efficacy. Currently we study the function of opioid receptor heteromers in peripheral sensory neurons in culture and in rat behavioral models of peripheral nociception with the ultimate goal of identifying new pharmacological targets for improved pain therapy.
Ligand functional selectivity is a term used to describe the ability of drugs to differentially activate signaling cascades coupled to a single receptor subtype. The mechanism underlying functional selectivity is based upon the capacity of ligands with different chemical structures to promote different spectra of receptor protein conformations. Since these receptor conformations can interact differently with cellular signal transduction molecules (e.g. G proteins, ß-arrestins, etc.), the profile of cellular signaling produced is differs for different ligands. Importantly, differences in the functional selectivity profile between drugs acting at the same receptor subtype may underlie differences in therapeutic efficacy and/or adverse effect liability. We were among the first to describe ligand functional selectivity for both agonists and inverse agonists that target serotonin receptors. Currently we are determining functional selectivity profiles for ligands that target kappa opioid receptors in primary sensory neurons.


Research

• G protein coupled receptors • signal transduction
• ligand functional selectivity • constitutive receptor activity
• opioids • serotonin
• pain

Lab Members

Teresa Chavera, M.S. (Research Associate- Senior, Lab Manager)
Dr. Elaine Jennings (Postdoctoral Fellow)
Joshua Zamora (Research Assistant)
Miryam Pando (Graduate Student- Neuroscience Discipline)
Hudson Smith (Graduate Student- Neuroscience Discipline)
Emily Debner (Graduate Student- Neuroscience Discipline)

Publications

Jacobs BA, Pando MM, Jennings EM, Jamshidi RJ, Zamora JC, Chavera TS, Clarke WP, Berg KA. (2019) Signaling characteristics and functional regulation of delta opioid-kappa opioid receptor (DOP-KOP) heteromers in peripheral sensory neurons. Neuropharmacology. 2019 Feb 15. pii: S0028-3908(18)30877-3. [Epub ahead of print]
Berg KA, Clarke WP. (2018) Making Sense of Pharmacology: Inverse Agonism and Functional Selectivity. Int J Neuropsychopharmacol. Oct 1;21(10):962-977.
Jacobs BA, Pando MM, Jennings E, Chavera TA, Clarke WP, Berg KA. (2018) Allosterism within δ Opioid-κ Opioid Receptor Heteromers in Peripheral Sensory Neurons: Regulation of κ Opioid Agonist Efficacy. Mol Pharmacol. Apr;93(4):376-386
Sullivan LC, Chavera TA, Gao X, Pando MM, Berg KA. (2017) Regulation of δ Opioid Receptor-Mediated Signaling and Antinociception in Peripheral Sensory Neurons by Arachidonic Acid-Dependent 12/15-Lipoxygenase Metabolites. J Pharmacol Exp Ther. Jul;362(1):200-209.
Sullivan LC, Chavera TS, Jamshidi RJ, Berg KA, Clarke WP. (2016) Constitutive Desensitization of Opioid Receptors in Peripheral Sensory Neurons. J Pharmacol Exp Ther. 2016 Dec;359(3):411-419.
Jamshidi RJ, Sullivan LC, Jacobs BA, Chavera TA, Berg KA, Clarke WP. (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. 2016 Nov;359(2):319-328
Jamshidi RJ, Jacobs BA, Sullivan LC, Chavera TA, Saylor RM, Prisinzano TE, Clarke WP, Berg KA.(2015) Functional selectivity of kappa opioid receptor agonists in peripheral sensory neurons. J Pharmacol Exp Ther. 2015 Nov;355(2):174-82.
Sullivan LC, Clarke WP, Berg KA. (2015) Atypical antipsychotics and inverse agonism at 5-HT2 receptors. Curr Pharm Des. 21(26):3732-8
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