RGS9-2–controlled adaptations in the striatum determine the onset of action and efficacy of antidepressants in neuropathic pain states
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 accum...
| Main Authors: | , , , , , , , , , |
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| Format: | Article |
| Language: | en_US |
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National Academy of Sciences (U.S.)
2016
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| Online Access: | http://hdl.handle.net/1721.1/101408 https://orcid.org/0000-0002-3854-5968 |
| _version_ | 1826207412486406144 |
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| author | Mitsi, Vasiliki Terzi, Dimitra Purushothaman, Immanuel Manouras, Lefteris Gaspari, Sevasti Neve, Rachael L. Stratinaki, Maria Feng, Jian Shen, Li Zachariou, Venetia |
| author2 | Massachusetts Institute of Technology. Department of Brain and Cognitive Sciences |
| author_facet | Massachusetts Institute of Technology. Department of Brain and Cognitive Sciences Mitsi, Vasiliki Terzi, Dimitra Purushothaman, Immanuel Manouras, Lefteris Gaspari, Sevasti Neve, Rachael L. Stratinaki, Maria Feng, Jian Shen, Li Zachariou, Venetia |
| author_sort | Mitsi, Vasiliki |
| collection | MIT |
| description | 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. |
| first_indexed | 2024-09-23T13:49:16Z |
| format | Article |
| id | mit-1721.1/101408 |
| institution | Massachusetts Institute of Technology |
| language | en_US |
| last_indexed | 2024-09-23T13:49:16Z |
| publishDate | 2016 |
| publisher | National Academy of Sciences (U.S.) |
| record_format | dspace |
| spelling | mit-1721.1/1014082022-09-28T16:26:02Z RGS9-2–controlled adaptations in the striatum determine the onset of action and efficacy of antidepressants in neuropathic pain states Mitsi, Vasiliki Terzi, Dimitra Purushothaman, Immanuel Manouras, Lefteris Gaspari, Sevasti Neve, Rachael L. Stratinaki, Maria Feng, Jian Shen, Li Zachariou, Venetia Massachusetts Institute of Technology. Department of Brain and Cognitive Sciences McGovern Institute for Brain Research at MIT Neve, Rachael L. 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. 2016-03-02T17:37:26Z 2016-03-02T17:37:26Z 2015-09 2015-03 Article http://purl.org/eprint/type/JournalArticle 0027-8424 1091-6490 http://hdl.handle.net/1721.1/101408 Mitsi, Vasiliki, Dimitra Terzi, Immanuel Purushothaman, Lefteris Manouras, Sevasti Gaspari, Rachael L. Neve, Maria Stratinaki, Jian Feng, Li Shen, and Venetia Zachariou. “RGS9-2–controlled Adaptations in the Striatum Determine the Onset of Action and Efficacy of Antidepressants in Neuropathic Pain States.” Proc Natl Acad Sci USA 112, no. 36 (August 24, 2015): E5088–E5097. https://orcid.org/0000-0002-3854-5968 en_US http://dx.doi.org/10.1073/pnas.1504283112 Proceedings of the National Academy of Sciences Article is made available in accordance with the publisher's policy and may be subject to US copyright law. Please refer to the publisher's site for terms of use. application/pdf National Academy of Sciences (U.S.) National Academy of Sciences (U.S.) |
| spellingShingle | Mitsi, Vasiliki Terzi, Dimitra Purushothaman, Immanuel Manouras, Lefteris Gaspari, Sevasti Neve, Rachael L. Stratinaki, Maria Feng, Jian Shen, Li Zachariou, Venetia RGS9-2–controlled adaptations in the striatum determine the onset of action and efficacy of antidepressants in neuropathic pain states |
| title | RGS9-2–controlled adaptations in the striatum determine the onset of action and efficacy of antidepressants in neuropathic pain states |
| title_full | RGS9-2–controlled adaptations in the striatum determine the onset of action and efficacy of antidepressants in neuropathic pain states |
| title_fullStr | RGS9-2–controlled adaptations in the striatum determine the onset of action and efficacy of antidepressants in neuropathic pain states |
| title_full_unstemmed | RGS9-2–controlled adaptations in the striatum determine the onset of action and efficacy of antidepressants in neuropathic pain states |
| title_short | RGS9-2–controlled adaptations in the striatum determine the onset of action and efficacy of antidepressants in neuropathic pain states |
| title_sort | rgs9 2 controlled adaptations in the striatum determine the onset of action and efficacy of antidepressants in neuropathic pain states |
| url | http://hdl.handle.net/1721.1/101408 https://orcid.org/0000-0002-3854-5968 |
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