title: RGS9-2--controlled adaptations in the striatum determine the onset of action and efficacy of antidepressants in neuropathic pain states.
abstract: The striatal protein Regulator of G-protein signaling 9-2 (RGS9-2) plays a key modulatory role in opioid, monoamine, and other G-protein-coupled receptor responses. Here, we use the murine spared-nerve injury model of neuropathic pain to investigate the mechanism by which RGS9-2 in the nucleus accumbens (NAc), a brain region involved in mood, reward, and motivation, modulates the actions of tricyclic antidepressants (TCAs). Prevention of RGS9-2 action in the NAc increases the efficacy of the TCA desipramine and dramatically accelerates its onset of action. By controlling the activation of effector molecules by G protein α and βγ subunits, RGS9-2 affects several protein interactions, phosphoprotein levels, and the function of the epigenetic modifier histone deacetylase 5, which are important for TCA responsiveness. Furthermore, information from RNA-sequencing analysis reveals that RGS9-2 in the NAc affects the expression of many genes known to be involved in nociception, analgesia, and antidepressant drug actions. Our findings provide novel information on NAc-specific cellular mechanisms that mediate the actions of TCAs in neuropathic pain states.
authors: Department of Basic Sciences, Faculty of Medicine, University of Crete, Heraklion, Crete, Greece, 71003; Fishberg Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY 10029;
authors: Vasiliki
authors: V
authors: Mitsi
authors: Department of Basic Sciences, Faculty of Medicine, University of Crete, Heraklion, Crete, Greece, 71003;
authors: Dimitra
authors: D
authors: Terzi
authors: Fishberg Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY 10029;
authors: Immanuel
authors: I
authors: Purushothaman
authors: Department of Basic Sciences, Faculty of Medicine, University of Crete, Heraklion, Crete, Greece, 71003;
authors: Lefteris
authors: L
authors: Manouras
authors: Department of Basic Sciences, Faculty of Medicine, University of Crete, Heraklion, Crete, Greece, 71003; Fishberg Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY 10029;
authors: Sevasti
authors: S
authors: Gaspari
authors: Department of Brain and Cognitive Sciences, McGovern Institute of Brain Research at MIT, Cambridge, MA 02139.
authors: Rachael L
authors: RL
authors: Neve
authors: Department of Basic Sciences, Faculty of Medicine, University of Crete, Heraklion, Crete, Greece, 71003;
authors: Maria
authors: M
authors: Stratinaki
authors: Fishberg Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY 10029;
authors: Jian
authors: J
authors: Feng
authors: Fishberg Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY 10029;
authors: Li
authors: L
authors: Shen
authors: Department of Basic Sciences, Faculty of Medicine, University of Crete, Heraklion, Crete, Greece, 71003; Fishberg Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY 10029; venetia.zachariou@mssm.edu.
authors: Venetia
authors: V
authors: Zachariou
mesh_terms: D000222:Adaptation, Physiological / Q000187:drug effects / Q000235:genetics; D000818:Animals; D000928:Antidepressive Agents / Q000494:pharmacology*; D015153:Blotting, Western; D003342:Corpus Striatum / Q000378:metabolism* / Q000503:physiopathology; D005260:Female; D015870:Gene Expression / Q000187:drug effects; D063990:Gene Ontology; D053263:Gene Regulatory Networks / Q000187:drug effects; D006930:Hyperalgesia / Q000503:physiopathology / Q000517:prevention & control; D008297:Male; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009437:Neuralgia / Q000235:genetics / Q000503:physiopathology / Q000517:prevention & control*; D009714:Nucleus Accumbens / Q000378:metabolism / Q000503:physiopathology; D020710:RGS Proteins / Q000235:genetics / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D016896:Treatment Outcome
chemical_list: D000928:Antidepressive Agents; D020710:RGS Proteins; C116925:regulator of g-protein signaling 9
keywords: HDAC5; desipramine; duloxetine; gene expression; spared nerve injury