• Vasiliki Mitsi, Dimitra Terzi, Immanuel Purushothaman, Lefteris Manouras, Sevasti Gaspari, Rachael L Neve, Maria Stratinaki, Jian Feng, Li Shen, and Venetia Zachariou.
• 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;
• Proc. Natl. Acad. Sci. U.S.A. 2015 Sep 8; 112 (36): E5088-97.

AbstractThe 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.

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