Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

Tianeptine promotes lasting antiallodynic effects in a mouse model of neuropathic pain

Neuropsychopharmacology volume 48, pages 1680–1689 (2023)Cite this article

Subjects

Abstract

Tricyclic antidepressants (TCAs), such as desipramine (DMI), are effective at managing neuropathic pain symptoms but often take several weeks to become effective and also lead to considerable side effects. Tianeptine (TIAN) is an atypical antidepressant that activates the mu-opioid receptor but does not produce analgesic tolerance or withdrawal in mice, nor euphoria in humans, at clinically-relevant doses. Here, we evaluate the efficacy of TIAN at persistently alleviating mechanical allodynia in the spared nerve injury (SNI) model of neuropathic pain, even well after drug clearance. After finding an accelerated onset of antiallodynic action compared to DMI, we used genetically modified mice to gain insight into RGS protein-associated pathways that modulate the efficacy of TIAN relative to DMI in models of neuropathic pain. Because we observed similar behavioral responses to both TIAN and DMI treatment in RGS4, RGSz1, and RGS9 knockout mice, we performed RNA sequencing on the NAc of TIAN- and DMI-treated mice after prolonged SNI to further clarify potential mechanisms underlying TIANs faster therapeutic actions. Our bioinformatic analysis revealed distinct transcriptomic signatures between the two drugs, with TIAN more directly reversing SNI-induced differentially expressed genes, and further predicted several upstream regulators that may be implicated in onset of action. This new understanding of the molecular pathways underlying TIAN action may enable the development of novel and more efficacious pharmacological approaches for the management of neuropathic pain.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: TIAN induces antiallodynic effects more rapidly than DMI.
Fig. 2: RGSz1 negatively modulates acute antinociceptive effects of TIAN without affecting sustained antiallodynic properties.
Fig. 3: RGS4 is necessary for sustained antiallodynic effects of TIAN.
Fig. 4: RGS9-2 delays the onset of antiallodynic action following TIAN treatment.
Fig. 5: TIAN treatment more directly counteracts SNI-specific gene expression changes in the NAc.

Similar content being viewed by others

References

  1. Dahlhamer J, Lucas J, Zelaya C, Nahin R, Mackey S, DeBar L, et al. Prevalence of chronic pain and high-impact chronic pain among adults—United States, 2016. Morb Mortal Wkly Rep. 2018;67:1001–6.

    Article  Google Scholar 

  2. Latremoliere A, Woolf CJ. Central sensitization: a generator of pain hypersensitivity by central neural plasticity. J Pain. 2009;10:895–926.

    Article  PubMed  PubMed Central  Google Scholar 

  3. Serafini RA, Pryce KD, Zachariou V. The mesolimbic dopamine system in chronic pain and associated affective comorbidities. Biol Psychiatry. 2020;87:64–73.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Kelly K, Posternak M, Alpert JE. Toward achieving optimal response: understanding and managing antidepressant side effects. Dialogues Clin Neurosci. 2008;10:409–18.

    Article  PubMed  PubMed Central  Google Scholar 

  5. Swann AC. Major system toxicities and side effects of anticonvulsants. J Clin Psychiatry. 2001;62:16–21.

    CAS  PubMed  Google Scholar 

  6. Benyamin R, Trescot AM, Datta S, Buenaventura R, Adlaka R, Sehgal N, et al. Opioid complications and side effects. Pain Physician. 2008;11:S105–20.

    Article  PubMed  Google Scholar 

  7. Kasper S, Olié JP. A meta-analysis of randomized controlled trials of tianeptine versus SSRI in the short-term treatment of depression. Eur Psychiatry. 2002;17:331–40.

    Article  PubMed  Google Scholar 

  8. Nickel T, Sonntag A, Schill J, Zobel AW, Ackl N, Brunnauer A, et al. Clinical and neurobiological effects of tianeptine and paroxetine in major depression. J Clin Psychopharmacol. 2003;23:155–68.

    Article  CAS  PubMed  Google Scholar 

  9. Bilge SS, Bozkurt A, Ilkaya F, Çiftcioǧlu E, Kesim Y, Uzbay TI. The antinociceptive effects of intravenous tianeptine in colorectal distension-induced visceral pain in rats: the role of 5-HT 3 receptors. Eur J Pharm. 2012;681:44–9.

    Article  CAS  Google Scholar 

  10. Heo BH, Shin JY, Park KS, Lee HG, Choi JI, Yoon MH, et al. Effects of tianeptine on the development and maintenance of mechanical allodynia in a rat model of neuropathic pain. Neurosci Lett. 2016;633:82–6.

    Article  CAS  PubMed  Google Scholar 

  11. Kim WM, Lee SH, Jeong HJ, Lee HG, Choi JI, Yoon MH. The analgesic activity of intrathecal tianeptine, an atypical antidepressant, in a rat model of inflammatory pain. Anesth Analg. 2012;114:683–9.

    Article  CAS  PubMed  Google Scholar 

  12. Kole MHP, Swan L, Fuchs E. The antidepressant tianeptine persistently modulates glutamate receptor currents of the hippocampal CA3 commissural associational synapse in chronically stressed rats. Eur J Neurosci. 2002;16:807–16.

    Article  PubMed  Google Scholar 

  13. Svenningsson P, Bateup H, Qi H, Takamiya K, Huganir RL, Spedding M, et al. Involvement of AMPA receptor phosphorylation in antidepressant actions with special reference to tianeptine. Eur J Neurosci. 2007;26:509–17.

    Article  Google Scholar 

  14. McEwen BS, Chattarji S, Diamond DM, Jay TM, Reagan LP, Svenningsson P, et al. The neurobiological properties of tianeptine (Stablon): from monoamine hypothesis to glutamatergic modulation. Mol Psychiatry. 2010;15:237–49.

    Article  CAS  PubMed  Google Scholar 

  15. Shields SD, Eckert WA, Basbaum AI. Spared nerve injury model of neuropathic pain in the mouse: a behavioral and anatomic analysis. J Pain. 2003;4:465–70.

    Article  PubMed  Google Scholar 

  16. Backonja MM, Serra J. Pharmacologic management part 1: better-studied neuropathic pain diseases. Pain Med. 2004;5:S28–47.

    Article  PubMed  Google Scholar 

  17. Luttrell LM, Maudsley S, Bohn LM. Fulfilling the promise of ‘biased’ G protein-coupled receptor agonism. Mol Pharm. 2015;88:579–88.

    Article  CAS  Google Scholar 

  18. Sakloth F, Polizu C, Bertherat F, Zachariou V. Regulators of G protein signaling in analgesia and addiction. Mol Pharm. 2020;119:119206.

    Google Scholar 

  19. Senese NB, Kandasamy R, Kochan KE, Traynor JR. Regulator of G-protein signaling (RGS) protein modulation of opioid receptor signaling as a potential target for pain management. Front Mol Neurosci. 2020;13:5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. von Zastrow M. Proteomic approaches to investigate regulated trafficking and signaling of G protein–coupled receptors. Mol Pharmacol 2021;99:392–8.

    Article  Google Scholar 

  21. Gaspari S, Purushothaman I, Cogliani V, Sakloth F, Neve RL. Suppression of RGSz1 function optimizes the actions of opioid analgesics by mechanisms that involve the Wnt/β-catenin pathway. Proc Natl Acad Sci USA. 2018; 115:E2085–94.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Han MH, Renthal W, Ring RH, Rahman Z, Psifogeorgou K, Howland D, et al. Brain region specific actions of regulator of G protein signaling 4 oppose morphine reward and dependence but promote analgesia. Biol Psychiatry. 2010. https://doi.org/10.1016/j.biopsych.2009.08.041.

  23. Mitsi V, Terzi D, Purushothaman I, Manouras L, Gaspari S, Neve RL. 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. 2015;112:E5088–97.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Terzi D, Gaspari S, Manouras L, Descalzi G, Mitsi V, Zachariou V. RGS9-2 modulates sensory and mood related symptoms of neuropathic pain. Neurobiol Learn Mem. 2014;115:43–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Sutton LP, Khalatyan N, Savas JN, Martemyanov KA. Striatal rgs7 regulates depression-related behaviors and stress-induced reinstatement of cocaine conditioned place preference. ENeuro. 2021;8:ENEURO.0365-20.2020.

    Article  PubMed  PubMed Central  Google Scholar 

  26. Hollinger S, Hepler JR. Cellular regulation of RGS proteins: modulators and integrators of G protein signaling. Pharm Rev. 2021;54:8–59.

    Google Scholar 

  27. Stratinaki M, Varidaki A, Mitsi V, Ghose S, Magida J, Dias C, et al. Regulator of G protein signaling 4 is a crucial modulator of antidepressant drug action in depression and neuropathic pain models. Proc Natl Acad Sci USA. 2013;110:8254–9.

  28. Baliki M, Petre B, Torbey S, Herrmann K, Huang L, Schnitzer T, et al. Corticostriatal functional connectivity predicts transition to chronic pain. Nat Neurosci. 2013;15:1117–9.

    Article  Google Scholar 

  29. Descalzi G, Mitsi V, Purushothaman I, Gaspari S, Avrampou K, Loh YHE, et al. Neuropathic pain promotes adaptive changes in gene expression in brain networks involved in stress and depression. Sci Signal. 2017;10:1–18.

    Article  Google Scholar 

  30. Pryce, KD. et al. Oxycodone withdrawal induces HDAC1/HDAC2-dependent transcriptional maladaptations in the reward pathway in a mouse model of peripheral nerve injury. Nat. Neurosci. 2023:1–16.

  31. Gaspari S, Cogliani V, Manouras L, Anderson EM, Mitsi V, Avrampou K, et al. RGS9-2 modulates responses to oxycodone in pain-free and chronic pain states. Neuropsychopharmacology. 2017;42:1548–56.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Zachariou V, Georgescu D, Sanchez N, Rahman Z, DiLeone R, Berton O, et al. Essential role for RGS9 in opiate action. Proc Natl Acad Sci USA. 2003. https://doi.org/10.1073/pnas.2232594100.

  33. Avrampou K, Pryce KD, Ramakrishnan A, Sakloth F, Gaspari S, Serafini RA, et al. RGS4 maintains chronic pain symptoms in rodent models. J Neurosci. 2019;39:8291–304.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Samuels BA, Nautiyal KM, Kruegel AC, Levinstein MR, Magalong VM, Gassaway MM, et al. The behavioral effects of the antidepressant tianeptine require the Mu-opioid receptor. Neuropsychopharmacology. 2017;42:2052–63.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Gassaway MM, Rives ML, Kruegel AC, Javitch JA, Sames D. The atypical antidepressant and neurorestorative agent tianeptine is a μ-opioid receptor agonist. Transl Psychiatry. 2014;4:e411–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Stratinaki M, Varidaki A, Mitsi V, Ghose S, Magida J, Dias C, et al. Regulator of G protein signaling is a crucial modulator of antidepressant drug action in depression and neuropathic pain models. Proc Natl Acad Sci USA. 2013;110:8254–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Psifogeorgou K, Papakosta P, Russo SJ, Neve RL, Kardassis D, Gold SJ, et al. RGS9-2 is a negative modulator of μ-opioid receptor function. J Neurochem. 2007;103:617–25.

    Article  CAS  PubMed  Google Scholar 

  38. Mitsi V, Terzi D, Purushothaman I, Manouras L, Gaspari S, Neve RL, et al. 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. 2015;112:E5088–97.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Lin LC, Sibille E. Somatostatin, neuronal vulnerability and behavioral emotionality. Mol Psychiatry. 2015;20:377–87.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Girgenti MJ, Wohleb ES, Mehta S, Ghosal S, Fogaca MV, Duman RS. Prefrontal cortex interneurons display dynamic sex-specific stress-induced transcriptomes. Transl Psychiatry. 2019;9:292.

    Article  PubMed  PubMed Central  Google Scholar 

  41. Ren W, Centeno MV, Berger S, Wu Y, Na X, Liu X, et al. The indirect pathway of the nucleus accumbens shell amplifies neuropathic pain. Nat Neurosci. 2016;19:220–4.

    Article  CAS  PubMed  Google Scholar 

  42. Sakloth F, Manouras L, Avrampou K, Mitsi V, Serafini RA, Pryce KD, et al. HDAC6-selective inhibitors decrease nerve-injury and inflammation-associated mechanical hypersensitivity in mice. Psychopharmacology. 2020;237:2139–49.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Zhang J, Ma J, Trinh RT, Heijnen CJ, Kavelaars A. An HDAC6 inhibitor reverses chemotherapy-induced mechanical hypersensitivity via an IL-10 and macrophage dependent pathway. Brain Behav Immun. 2022;100:287–96.

    Article  PubMed  Google Scholar 

  44. Sanna MD, Galeotti N. The HDAC1/c-JUN complex is essential in the promotion of nerve injury-induced neuropathic pain through JNK signaling. Eur J Pharm. 2018;825:99–106.

    Article  CAS  Google Scholar 

  45. Sanna MD, Guandalini L, Romanelli MN, Galeotti N. The new HDAC1 inhibitor LG325 ameliorates neuropathic pain in a mouse model. Pharm Biochem Behav. 2017;160:70–5.

    Article  CAS  Google Scholar 

  46. Gaspari S, Papachatzaki MM, Koo JW, Carr FB, Tsimpanouli ME, Stergiou E, et al. Nucleus accumbens-specific interventions in RGS9-2 activity modulate responses to morphine. Neuropsychopharmacology. 2014;39:1968–77.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Psigfogeorgou K, Terzi D, Papachatzaki MM, Varidaki A, Ferguson D, Gold SJ, et al. A unique role of RGS9-2 in the striatum as a positive or negative regulator of opiate analgesia. J Neurosci. 2011;31:5617–24.

    Article  CAS  PubMed Central  Google Scholar 

  48. Chang PC, Pollema-Mays SL, Centeno MV, Procissi D, Contini M, Baria AT, et al. Role of nucleus accumbens in neuropathic pain: linked multi-scale evidence in the rat transitioning to neuropathic pain. Pain. 2014;155:1128–39.

    Article  PubMed  PubMed Central  Google Scholar 

  49. Baliki MN, Chialvo DR, Geha PY, Levy RM, Harden RN, Parrish TB, et al. Chronic pain and the emotional brain: specific brain activity associated with spontaneous fluctuations of intensity of chronic back pain. J Neurosci. 2006;26:12165–73.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Pallaki P, Georganta EM, Serafimidis I, Papakonstantinou MP, Papanikolaou V, Koutloglou S, et al. A novel regulatory role of RGS4 in STAT5B activation, neurite outgrowth and neuronal differentiation. Neuropharmacology. 2017;117:408–21.

    Article  CAS  PubMed  Google Scholar 

  51. Georgoussi Z, Leontiadis L, Mazarakou G, Merkouris M, Hyde K, Hamm H. Selective interactions between G protein subunits and RGS4 with the C-terminal domains of the mu- and delta-opioid receptors regulate opioid receptor signaling. Cell Signal. 2006;18:771–82.

    Article  CAS  PubMed  Google Scholar 

  52. Zhang XF, Hu XT, White FJ. Whole-cell plasticity in cocaine withdrawal: reduced sodium currents in nucleus accumbens neurons. J Neurosci. 1998;18:488–98.

    Article  PubMed  PubMed Central  Google Scholar 

  53. Goffer Y, Xu D, Eberle SE, D’amour J, Lee M, Tukey D, et al. Calcium-permeable AMPA receptors in the nucleus accumbens regulate depression-like behaviors in the chronic neuropathic pain state. J Neurosci. 2013;33:19034–44.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. García-González D, Dumitru I, Zuccotti A, Yen TY, Herranz-Pérez V, Tan LL, et al. Neurogenesis of medium spiny neurons in the nucleus accumbens continues into adulthood and is enhanced by pathological pain. Mol Psychiatry. 2021;26:7851.

    Article  PubMed  PubMed Central  Google Scholar 

  55. Schmidt HD, Duman RS. The role of neurotrophic factors in adult hippocampal neurogenesis, antidepressant treatments and animal models of depressive-like behavior. Behav Pharm. 2007;18:391–418.

    Article  CAS  Google Scholar 

Download references

Funding

Funding

This work was supported by NINDS NS086444 and NS111351 (VZ), the Hope for Depression Research Foundation (JAJ), and NIH T32 GM007280 (RAS).

Author information

Authors and Affiliations

  1. Nash Family Department of Neuroscience, Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA

    Randal A. Serafini, Molly Estill, Farhana Sakloth, Li Shen & Venetia Zachariou

  2. Department of Pharmacology, Physiology and Biophysics, Chobanian & Avedisian School of Medicine at Boston University, Boston, MA, USA

    Randal A. Serafini & Venetia Zachariou

  3. Department of Neuroscience, Columbia University, New York, NY, USA

    Elizabeth A. Pekarskaya

  4. Department of Psychiatry, Columbia University, New York, NY, USA

    Elizabeth A. Pekarskaya & Jonathan A. Javitch

  5. Division of Molecular Therapeutics, New York State Psychiatric Institute, New York, NY, USA

    Elizabeth A. Pekarskaya & Jonathan A. Javitch

  6. Department of Molecular Pharmacology and Therapeutics, Columbia University, New York, NY, USA

    Jonathan A. Javitch

Authors
  1. Randal A. Serafini
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Molly Estill
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Elizabeth A. Pekarskaya
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Farhana Sakloth
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Li Shen
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Jonathan A. Javitch
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Venetia Zachariou
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

RAS and VZ contributed to the conception and design of this work. RAS, ME, EAP, and FS acquired, analyzed, and interpreted data. RAS, EAP, LS, JAJ, and VZ contributed to drafting and revising the work. VZ, JAJ, and LS provided a final approval of the submitted version to be published. RAS and VZ agree to be accountable for all aspects of the work.

Corresponding author

Correspondence to Venetia Zachariou.

Ethics declarations

Competing interests

VZ declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. JAJ is an inventor on tianeptine-related patents owned by Columbia University. RAS, ME, EAP, FS, LS, and VZ declare no competing interests.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Serafini, R.A., Estill, M., Pekarskaya, E.A. et al. Tianeptine promotes lasting antiallodynic effects in a mouse model of neuropathic pain. Neuropsychopharmacol. 48, 1680–1689 (2023). https://doi.org/10.1038/s41386-023-01645-w

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41386-023-01645-w

Search

Advanced search

Quick links