This project will elucidate antidepressant-induced changes on signal transduction in sensory and affective brain circuitry mediating neuropathic pain. Neuropathic pain is a chronic condition characterized by both sensory deficits (mechanical and cold allodynia, thermal hyperalgesia) and mood disorders (anxiety and depression). Most drugs used to treat the pain-like symptoms of this disorder have low efficacy, carry major side-effects and in the case of opioids may lead to debilitating physical addiction. Thus, there is a pressing need for the development of more efficacious and better tolerated medications for treating chronic neuropathic pain. Tricyclic antidepressants and the selective, serotonin/norepinephrine reuptake inhibitors contain both antiallodynic and antidepressant properties. However, their chronic use is also accompanied by severe adverse effects. Understanding the cellular mechanisms mediating the actions of TCAs and SNRIs will facilitate the development of novel and more efficacious medications for the treatment of neuropathic pain. Preliminary findings from our laboratory indicate that RGS9-2, a potent regulator of striatal GPCR signaling amplitude and desensitization, plays a potent, modulatory role in the antiallodynic and antidepressant actions of TCAs. We will use genetic mouse models and gene transfer approaches to test our hypothesis that RGS9-2 in the NAc negatively regulates the actions of TCAs and SNRIs in neuropathic pain models. In addition, we will use biochemical and molecular biological approaches to test our hypotheses on both the critical RGS9-2 protein-protein interactions modulating the effects of TCA and SNRI and the long-term epigenetic changes downstream of RGS9-2 in response to TCA and SNRI treatment. Finally, we will characterize antidepressant-induced and RGS9-2 modulated global gene regulation using RNA-sequencing in models of neuropathic pain. Our findings will clarify the mechanism by which GPCR signaling machinery in NAc modulates the effects of antidepressant drugs on the sensory and affective symptoms of neuropathic pain.

Public Health Relevance

Neuropathic pain is a major challenge in therapeutics as the available treatments show poor efficacy and most of the patients need additional medications for the co- morbid depression. The proposal aims to understand the signal transduction mechanisms via which tricyclic antidepressants and serotonin/norepinephrine reuptake inhibitors alleviate sensory symptoms and stress/anxiety behaviours. In order to provide information for the development of new treatments for neuropathic pain conditions

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project (R01)
Project #
Application #
Study Section
Special Emphasis Panel (ZRG1-MDCN-P (57))
Program Officer
Chen, Daofen
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Icahn School of Medicine at Mount Sinai
Schools of Medicine
New York
United States
Zip Code
Gaspari, Sevasti; Purushothaman, Immanuel; Cogliani, Valeria et al. (2018) Suppression of RGSz1 function optimizes the actions of opioid analgesics by mechanisms that involve the Wnt/?-catenin pathway. Proc Natl Acad Sci U S A 115:E2085-E2094
Chen, Yunjia; Booth, Christopher; Wang, Hongxia et al. (2017) Effective Attenuation of Adenosine A1R Signaling by Neurabin Requires Oligomerization of Neurabin. Mol Pharmacol 92:630-639
Descalzi, Giannina; Mitsi, Vasiliki; Purushothaman, Immanuel et al. (2017) Neuropathic pain promotes adaptive changes in gene expression in brain networks involved in stress and depression. Sci Signal 10:
Gaspari, Sevasti; Cogliani, Valeria; Manouras, Lefteris et al. (2017) RGS9-2 Modulates Responses to Oxycodone in Pain-Free and Chronic Pain States. Neuropsychopharmacology 42:1548-1556
Gacias, Mar; Gaspari, Sevasti; Santos, Patricia-Mae G et al. (2016) Microbiota-driven transcriptional changes in prefrontal cortex override genetic differences in social behavior. Elife 5:
Mitsi, Vasiliki; Zachariou, Venetia (2016) Modulation of pain, nociception, and analgesia by the brain reward center. Neuroscience 338:81-92
Caldarone, Barbara J; Zachariou, Venetia; King, Sarah L (2015) Rodent models of treatment-resistant depression. Eur J Pharmacol 753:51-65
Descalzi, Giannina; Ikegami, Daigo; Ushijima, Toshikazu et al. (2015) Epigenetic mechanisms of chronic pain. Trends Neurosci 38:237-46
Mitsi, Vasiliki; Terzi, Dimitra; Purushothaman, Immanuel et al. (2015) RGS9-2--controlled adaptations in the striatum determine the onset of action and efficacy of antidepressants in neuropathic pain states. Proc Natl Acad Sci U S A 112:E5088-97
Terzi, Dimitra; Gaspari, Sevasti; Manouras, Lefteris et al. (2014) RGS9-2 modulates sensory and mood related symptoms of neuropathic pain. Neurobiol Learn Mem 115:43-8