Departments & Divisions
Our work centers on questions concerning the molecular nature of drug efficacy and the mechanisms by which the efficacy of drugs can be regulated. We employ a combination of in vitro and in vivo pharmacological approaches designed to enhance our understanding of the fundamental mechanisms of peripheral opioid receptor function and analgesia with the ultimate goal of establishing new strategies for treatment of pain. 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 development of a novel opioid receptor antagonist for the treatment of opioid overdose.
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, the profile of cellular signaling produced is expected to differ 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. Currently, we are determining functional selectivity profiles for ligands that target kappa opioid receptors and serotonin type 1 receptors in primary sensory neurons.
Related diseases: pain, aging, opioid overdose and abuse
Techniques: Cell Culture, radioligand binding, signal transduction assays, Western blot/immunocytochemistry, pain behavioral assays
Our work centers on the molecular nature of drug efficacy and mechanisms by which drug efficacy can be regulated. We use a combination of in vitro and in vivo pharmacological approaches to 1) probe regulation of opioid receptor agonist efficacy in peripheral sensory neurons, 2) the role of opioid receptor heteromers in peripheral analgesia, and 3) the development of novel opioid receptor ligands for treatment of opioid overdose and abuse.
Pain, opioid overdose/ abuse
Cell Culture, signaling assays, Western blot, IHC, pain behavioral assays
Funding Agency NIH/NIDA Title KOR agonist functional selectivity in peripheral sensory neurons Status Active Period 9/2015 - 7/2020 Role Principal Investigator Grant Detail The major goal of this project is to examine structure-functional selectivity relationships of KOR agonists, using U50488 and Salvinorin-A as scaffolds measuring a variety of cellular signaling pathways in peripheral sensory neurons that have relevance for antinociception. Funding Agency NIH/NIA Title Aging, peripheral pain and analgesia Status Active Period 2/2015 - 1/2018 Role Co-Investigator Grant Detail We propose to evaluate the effect of aging on the function and regulation of peripheral, pain-sensing neurons and opioid receptor systems expressed by these neurons. Our ultimate goal is to develop analgesics with improved efficacy and safety for use in the elderly population Funding Agency NIH/NGMS Title Regulation of Kappa opioid receptor-mediated signaling and peripheral analgesia Status Active Period 1/2014 - 11/2017 Role Co-Investigator Grant Detail The major goal of this project is to study the regulation of kappa opioid receptor (KOR) signaling systems by the MAPKinases, ERK and JNK, as well as acute desensitization of KOR agonist signaling in peripheral sensory neurons, using primary cultures of adult rat sensory neurons and a behavioral model of nociception Funding Agency NIH/NIDA Title Regulation of DOR-KOR heteromer formation in pain-sensing neurons Status Active Period 9/2014 - 8/2017 Role Co-Investigator Grant Detail We propose to validate approaches to disrupt the formation or function of delta-kappa opioid receptor heteromers expressed by pain-sensing neurons in vivo and ex vivo.
Smith HR, Zamora JC, Chavera TS, Jennings EM, Winger GD, Woods JH, Clarke WP, and Berg KA. Agonst-dependent modulation by the long-acting mu opioid receptor antagonist, methoinnamox (MCAM). 2020 (Experimental Biology/ASPET; The FASEB Journal Vol 34, Issue S1)
Pando MM, Jennings EM, Chavera TS, Clarke WP, and Berg KA. A Role for Keratinocytes in Peripheral Kappa Opioid Receptor-Mediated Antinociception; 2020 (Experimental Biology/ASPET; The FASEB Journal Vol 34, Issue S1)
Pando MM, Jennings EM, Jacobs BA, Jamshidi RJ, Clarke WP and Berg KA . Peripheral Kappa Opioid Receptor-Mediated Antinociception Requires G Protein-Gated Inward Rectifying Potassium (Girk) Channels; 2019 (Experimental Biology/ASPET; The FASEB Journal Volume 33, Supplement 1)
Zamora JC, Kotipalli V, Jennings EM, Disney A, Husbands S, Winger G, Clarke WP, Woods JH, and Berg KA. Methocinnamox (MCAM) is a selective, long acting antagonist at mu opioid receptors in vitro; 2019 (Experimental Biology/ASPET; The FASEB Journal Volume 33, Supplement 1)
Debner EK, Jennings EM, Chavera TS, Clarke WP and Berg KA. Prolonged sumatriptan treatment differentially alters 5-HT1 receptor-mediated signlaing in rat trigeminal ganglion; 2019 (Experimental Biology/ASPET; The FASEB Journal Volume 33, Supplement 1)
Zamora JC, Chavera T, Jennings EM, Johnson SN, Prisinzano TE, Berg KA, Clarke WP. Functional selectivity of U50, 488 analogues at kappa opioid receptors (KOR) expressed in peripheral pain-sensing neurons; 2017. (Kappa Therapeutics Conference).
Pando M, Chavera TA, Clarke WP, Berg KA. 12- and 15-HETE block antinociceptive signaling of delta opioid (DOR) and kappa opioid (KOR) receptors, but not of DOR-KOR heteromers, in peripheral nociceptors; 2017. (Behavior, Biology and Chemistry: Translational Research in Addiction).
Pando, M, Chavera T, Clarke WP, Berg KA. DOR-KOR heteromers, expressed in peripheral nociceptors, maintain functional competency under prolonged inflammatory conditions; 2017. (Kappa Therapeutics Conference).
Smith HR, LoCoco PM, Chavera TA, Berg KA, Clarke WP. The neuroprotective agent, P7C3-A20, prevents paclitaxel-induced peripheral neuropathy; 2017. (Behavior, Biology and Chemistry: Translational Research in Addiction).
Zamora JC, Chavera TA, Jennings EM, Johnson SN, Prisinzano TE, Clarke WP, Berg KA. Evaluation of the functional selectivity profiles of U50,488 analogues at peripheral kappa opioid receptors (KOR); 2017. (Behavior, Biology and Chemistry: Translational Research in Addiction).
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. 151:208-218.
Berg KA and Clarke WP (2018) Making sense of pharmacology: Inverse agonism an functional selectivity. Int J Neuropsychopharmacol. 21(10): 962–977
Jacobs, BA, Pando MM, Jennings E, Chavera TS, Clarke WP, Berg KA (2018) Allosterism within delta opioid-kappaopioid receptor heteromers in peripheral nociceptors: regulation of opioid agonist efficacy. Mol Pharmacol. 93:376-386.
Higgins GA, Silenieks LB, Patrick A, Delannoy IAM, Fletcher PJ, Parker LA, MacLusky NJ, Sullivan LC, Chavera TA, Berg KA (2017) Studies to examine potential tolerability differences between the 5-HT2C receptor selective agonists lorcarserin and CP-809101 ACS Chem Neuro. 8(5):1074-1084.
Sullivan LC, Chavera, TA, Gao X, Pando M, Berg KA. (2017) Regulation of delta opioid receptor-mediated signaling and antinociception in peripheral sensory neurons by arachidonic acid-dependent 12/15-lipoxygenase metabolites. J Pharmacol Exp Ther. 362: 200-209.
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 359(2):319-328.
Sullivan LC, Clarke WP, Berg KA. (2015) Atypical antipsychotics and inverse agonism at 5-HT2 receptors Curr Pharm Des. Vol 21(26):3732-3738.
Jamshidi RJ, Jacobs BA, Sullivan LC, Chavera TA, Saylor RM, Prisinzano TE, Clarke WP, Berg KA. (2015) Functional selectivity of kappa opioid receptor (KOR) agonists in peripheral sensory neurons. J Pharmacol Exp Ther. Vol 355:174-182.