Laurie P Sutton1, Olga Ostrovskaya1, Maria Dao2, Keqiang Xie1, Cesare Orlandi1, Roy Smith3, Sunmee Wee4, Kirill A Martemyanov5. 1. Departments of Neuroscience, The Scripps Research Institute, Jupiter, Florida. 2. Department of Molecular Therapeutics, The Scripps Research Institute, Jupiter, Florida; Department of Metabolism and Aging, The Scripps Research Institute, Jupiter, Florida. 3. Department of Metabolism and Aging, The Scripps Research Institute, Jupiter, Florida. 4. Department of Molecular Therapeutics, The Scripps Research Institute, Jupiter, Florida. 5. Departments of Neuroscience, The Scripps Research Institute, Jupiter, Florida. Electronic address: kirill@scripps.edu.
Abstract
BACKGROUND: Morphine mediates its euphoric and analgesic effects by acting on the μ-opioid receptor (MOR). MOR belongs to the family of G-protein coupled receptors whose signaling efficiency is controlled by the regulator of G-protein signaling (RGS) proteins. Our understanding of the molecular diversity of RGS proteins that control MOR signaling, their circuit specific actions, and underlying cellular mechanisms is very limited. METHODS: We used genetic approaches to ablate regulator of G-protein signaling 7 (RGS7) both globally and in specific neuronal populations. We used conditioned place preference and self-administration paradigms to examine reward-related behavior and a battery of tests to assess analgesia, tolerance, and physical dependence to morphine. Electrophysiology approaches were applied to investigate the impact of RGS7 on morphine-induced alterations in neuronal excitability and plasticity of glutamatergic synapses. At least three animals were used for each assessment. RESULTS: Elimination of RGS7 enhanced reward, increased analgesia, delayed tolerance, and heightened withdrawal in response to morphine administration. RGS7 in striatal neurons was selectively responsible for determining the sensitivity of rewarding and reinforcing behaviors to morphine without affecting analgesia, tolerance, and withdrawal. In contrast, deletion of RGS7 in dopaminergic neurons did not influence morphine reward. RGS7 exerted its effects by controlling morphine-induced changes in excitability of medium spiny neurons in nucleus accumbens and gating the compositional plasticity of α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid and N-methyl-D-aspartate receptors. CONCLUSIONS: This study identifies RGS7 as a novel regulator of MOR signaling by dissecting its circuit specific actions and pinpointing its role in regulating morphine reward by controlling the activity of nucleus accumbens neurons.
BACKGROUND:Morphine mediates its euphoric and analgesic effects by acting on the μ-opioid receptor (MOR). MOR belongs to the family of G-protein coupled receptors whose signaling efficiency is controlled by the regulator of G-protein signaling (RGS) proteins. Our understanding of the molecular diversity of RGS proteins that control MOR signaling, their circuit specific actions, and underlying cellular mechanisms is very limited. METHODS: We used genetic approaches to ablate regulator of G-protein signaling 7 (RGS7) both globally and in specific neuronal populations. We used conditioned place preference and self-administration paradigms to examine reward-related behavior and a battery of tests to assess analgesia, tolerance, and physical dependence to morphine. Electrophysiology approaches were applied to investigate the impact of RGS7 on morphine-induced alterations in neuronal excitability and plasticity of glutamatergic synapses. At least three animals were used for each assessment. RESULTS: Elimination of RGS7 enhanced reward, increased analgesia, delayed tolerance, and heightened withdrawal in response to morphine administration. RGS7 in striatal neurons was selectively responsible for determining the sensitivity of rewarding and reinforcing behaviors to morphine without affecting analgesia, tolerance, and withdrawal. In contrast, deletion of RGS7 in dopaminergic neurons did not influence morphine reward. RGS7 exerted its effects by controlling morphine-induced changes in excitability of medium spiny neurons in nucleus accumbens and gating the compositional plasticity of α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid and N-methyl-D-aspartate receptors. CONCLUSIONS: This study identifies RGS7 as a novel regulator of MOR signaling by dissecting its circuit specific actions and pinpointing its role in regulating morphine reward by controlling the activity of nucleus accumbens neurons.
Authors: Sevasti Gaspari; Maria M Papachatzaki; Ja Wook Koo; Fiona B Carr; Maria-Efstratia Tsimpanouli; Eugenia Stergiou; Rosemary C Bagot; Deveroux Ferguson; Ezekiell Mouzon; Sumana Chakravarty; Karl Deisseroth; Mary Kay Lobo; Venetia Zachariou Journal: Neuropsychopharmacology Date: 2014-02-24 Impact factor: 7.853
Authors: Brian S Muntean; Dipak N Patil; Franck Madoux; James Fossetta; Louis Scampavia; Timothy P Spicer; Kirill A Martemyanov Journal: Assay Drug Dev Technol Date: 2018-04 Impact factor: 1.738
Authors: Kylie B McPherson; Emily R Leff; Ming-Hua Li; Claire Meurice; Sherrica Tai; John R Traynor; Susan L Ingram Journal: J Neurosci Date: 2018-08-27 Impact factor: 6.167
Authors: Katherine E Squires; Carolina Montañez-Miranda; Rushika R Pandya; Matthew P Torres; John R Hepler Journal: Pharmacol Rev Date: 2018-07 Impact factor: 25.468
Authors: Sevasti Gaspari; Immanuel Purushothaman; Valeria Cogliani; Farhana Sakloth; Rachael L Neve; David Howland; Robert H Ring; Elliott M Ross; Li Shen; Venetia Zachariou Journal: Proc Natl Acad Sci U S A Date: 2018-02-12 Impact factor: 11.205
Authors: Navatha Alugubelly; Afzaal N Mohammad; Mariola J Edelmann; Bindu Nanduri; Mohammed Sayed; Juw Won Park; Russell L Carr Journal: Behav Brain Res Date: 2019-09-04 Impact factor: 3.332