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Edited by Robert C. Malenka, Stanford University School of Medicine, Stanford, CA, and approved July 24, 2015 (received for review March 3, 2015)
Significance
Neuropathic pain is a complex disorder, characterized by affective and sensory symptoms. Efficient treatment of this condition should target both pain-modulating pathways and mood/affect networks. We show that tricyclic antidepressants (TCAs), which modulate spinal pain processing, also act in the brain reward center to alleviate allodynia and depression-like behaviors. We reveal how one key protein of nucleus accumbens (NAc)-specific signaling affects several molecules/pathways with emerging roles in antinociceptive and antidepressant mechanisms. Our study provides information about the cellular adaptations induced by TCAs in the NAc and novel targets for pain treatment.
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.
Footnotes
↵1V.M. and D.T. contributed equally to this work.
- ↵2To whom correspondence should be addressed. Email: venetia.zachariou{at}mssm.edu.
Author contributions: V.M., D.T., and V.Z. designed research; V.M., D.T., I.P., L.M., S.G., M.S., J.F., and V.Z. performed research; R.L.N. and V.Z. contributed new reagents/analytic tools; V.M., D.T., I.P., L.M., S.G., M.S., J.F., L.S., and V.Z. analyzed data; and V.M., D.T., and V.Z. wrote the paper.
The authors declare no conflict of interest.
This article is a PNAS Direct Submission.
Data deposition: The data reported in this paper have been deposited in the Gene Expression Omnibus (GEO) database, www.ncbi.nlm.nih.gov/geo (accession no. GSE71527).
This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1504283112/-/DCSupplemental.
RGS9-2 modulates antidepressant drug actions
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