Ethosuximide improves chronic pain-induced anxiety- and depression-like behaviors

https://doi.org/10.1016/j.euroneuro.2019.10.012Get rights and content

Highlights

  • Anxiety- and depression-like symptoms occurred in three animal models of chronic pain.

  • Ethosuximide, a T-type channel blocker used clinically as an antiepileptic, reduced both chronic pain and comorbidities.

  • A repurposing strategy for ethosuximide could be an attractive approach to improve not only pain but also the accompanying anxiety and depression.

Abstract

Chronic pain is a heavy burden disease. Current treatments are generally weakly effective or associated with adverse effects. New therapeutic approaches are therefore needed. Recent studies have suggested T-type calcium channels as an attractive target for the treatment of chronic pain. In this perspective, it was decided to perform a preclinical evaluation of the efficacy of ethosuximide, a T-type channel blocker used clinically as an antiepileptic, as a novel pharmacological treatment for chronic pain. Assessment of the effect of ethosuximide was thus made in both nociception and pain-related comorbidities as anxiety and depression are frequently encountered in chronic pain patients. Our results show that such symptoms occurred in three animal models of chronic pain designed to reflect traumatic neuropathic, chemotherapy-induced neuropathic and inflammatory pain conditions. Administration of ethosuximide reduced both chronic pain and comorbidities with a marked intensity ranging from partial reduction to a complete suppression of symptoms. These results make ethosuximide, and more broadly the inhibition of T-type calcium channels, a new strategy for the management of uncontrolled chronic pain, likely to improve not only pain but also the accompanying anxiety and depression.

Introduction

With a worldwide prevalence estimated at 20% (Goldberg and McGee, 2011), chronic pain is a heavy burden for individuals and society. For a large proportion of patients, chronic pain is accompanied by various comorbidities such as anxiety and depression which contribute to the deterioration of their quality of life (Conrad et al., 2013; World Health Organization technical report series, 2003). The prevalence of anxiety disorders in patients with chronic pain is up to 26% as against 7% to 18% in the general population (Global Burden of Disease Study 2013 Collaborators, 2015; Twillman, 2007), and signs of depression are estimated to occur in 50% of painful patients (Dworkin and Gitlin, 1991; Oliveira et al., 2018) who, in addition, are two to three times more likely to develop anxiety or depression (Demyttenaere et al., 2007; McWilliams et al., 2004; Price, 2000; Wilson et al., 2002). In parallel, patients with anxiety disorders have a higher risk of developing chronic pain (Sareen et al., 2005). Evidence also shows that anxiety and depression are amplifiers of pain perception (Klauenberg et al., 2008; Ploghaus et al., 2001).

These comorbidities have been widely documented in patients suffering from traumatic (Bailey et al., 2009; Gustorff et al., 2008; Radat et al., 2013) or iatrogenic (Bao et al., 2016; Thornton et al., 2008; Tofthagen et al., 2013; Ventzel et al., 2016) painful neuropathies. They have also been commonly reported in patients suffering from other etiologies of chronic pain, such as rheumatoid arthritis (Edwards et al., 2011; Goldenberg, 2010; Isik et al., 2007; Kojima et al., 2009; McWilliams et al., 2008; Sheehy et al., 2006). Unfortunately, the analgesic therapies for these chronic pain conditions and their associated comorbidities have limited efficacy and benefit-risk ratio. First line treatments for neuropathic pain (antidepressants and antiepileptics) are of limited efficacy (Finnerup et al., 2015). Chemotherapy-induced neuropathy have no treatment (Hershman et al., 2014; Poupon et al., 2015). Current drugs for the management of rheumatoid arthritis (Smolen et al., 2017) have also a limited effect on pain and entail serious adverse effects (Boyman et al., 2014; Laine et al., 2003; Solomon et al., 2017). Clearly, innovative treatments are needed to reduce pain and comorbidities in chronic pain patients and thereby to improve their quality of life.

Several studies have shown the interest of T-type calcium channels in different pain condition (Choi et al., 2007; Francois et al., 2013; Snutch and Zamponi, 2018; Picard et al., 2019), especially neuropathic (Bourinet et al., 2016) and inflammatory pain (Kerckhove et al., 2014). Ethosuximide, a non-specific blocker of T-type channels, has an analgesic effect on neuropathic (Dogrul et al., 2003; Flatters and Bennett, 2004; Hamidi et al., 2012; Kawashiri et al., 2012; Okubo et al., 2011) and inflammatory pain (Barton et al., 2005; Cheng et al., 2007; Munro et al., 2007; Shannon et al., 2005), but no study has yet assessed its effect, and more broadly that of T-type calcium channel inhibition, on anxiety and depression resulting from chronic pain.

The aim of the present study was to evaluate the effect of ethosuximide on the nociceptive and emotional (anxiety and depression) manifestations of neuropathic and inflammatory chronic pain. For this purpose, we used different well-established models of chronic pain: the spared nerve injury (SNI) (Shields et al., 2003) and oxaliplatin-induced peripheral neuropathy (OIPN) (Poupon et al., 2018) models of neuropathic pain and the complete Freund's adjuvant (CFA) model (Kerckhove et al., 2014) of monoarthritic pain. Five tests were performed assessing anxiety (elevated plus maze), depression (tail suspension test and forced swimming test) or both (novelty suppressed feeding test), and two tests assessing pain (von Frey and thermal place preference tests). The results presented here show that ethosuximide reduced nociception and improved anxiety- and depression-like behaviors observed in the three murine models of chronic pain.

Section snippets

Animals

Male mice C57BL6/J (20–25 g, Janvier, France) were acclimatized for a week before testing. They were housed under controlled environmental conditions (21–22 °C; 55% humidity, 12 h light/dark cycles, food and water ad libitum). All experiments were approved by the local ethics committees and performed according to European legislation (Directive 2010/63/EU) on the protection of animals used for scientific purposes, and complied with the recommendations of the International Association for the

Ethosuximide reduced hypersensitivity in two different neuropathic pain models

In the SNI model, mechanical hypersensitivity, symptom commonly found in patients suffering from traumatic neuropathy, was assessed by the von Frey test. Twenty-one days after surgery, the mechanical paw withdrawal threshold (PWT) decreased from 0.64 ± 0.17 g to 0.07 ± 0.02 g for the vehicle group and from 0.58 ± 0.15 g to 0.09 ± 0.06 g for the ethosuximide group (Fig. 1(A)). Ethosuximide administration significantly reduced the mechanical hypersensitivity from 20 min to 60 min after the

Discussion

This work shows that ethosuximide, a non-specific T-type calcium channel blockers used in humans as an anticonvulsant (Coulter et al., 1990; Leresche et al., 1998; Todorovic and Lingle, 1998), associates an analgesic action with an effect on anxiety- and depression-like symptoms in different chronic pain conditions. These effects were observed with multiple chronic pain models of a different nature (neuropathic and inflammatory) and etiology (post-traumatic and post-chemotherapy neuropathy) and

Role of the funding source

Funding for the Ph.D. (Nicolas Kerckhove) salary: European Fund for Regional Economic Development (FEDER), regional council of Auvergne and “Société Française d'Etude et de Traitement de la Douleur” (SFETD).

Funding for materials: INSERM, Université Clermont Auvergne, ANR (ANR-15-CE16-0012-01) and Agence Nationale de la Recherche of the French government through the program ‘‘Investissements d'Avenir’’ (I-Site CAP 20-25).

Contributors

Conceived and designed the experiments (AE, CM, NK, LD, JB, LB, GO), Performed the experiments (NK, JB, LB, GO), analyzed the data (CM, NK, GO, JB, LB), wrote the paper (AE, CM, NK, LD, LB, GO).

Conflict of interest

The authors have no conflict of interest to declare.

Acknowledgments

Nicolas Kerckhove is supported by fellowships from the European Fund for Regional Economic Development (FEDER), regional council of Auvergne and “Société Française d'Etude et de Traitement de la Douleur” (SFETD). This work was supported by INSERM, Université Clermont Auvergne and by ANR (ANR-15-CE16-0012-01). The authors acknowledge the support received from the Agence Nationale de la Recherche of the French government through the program ‘‘Investissements d'Avenir’’ (I-Site CAP 20-25).

References (88)

  • N.B. Finnerup et al.

    Pharmacotherapy for neuropathic pain in adults: a systematic review and meta-analysis

    Lancet Neurol.

    (2015)
  • S.J.L. Flatters et al.

    Ethosuximide reverses paclitaxel- and vincristine-induced painful peripheral neuropathy

    Pain

    (2004)
  • A. Francois et al.

    State-dependent properties of a new T-type calcium channel blocker enhance Ca(V)3.2 selectivity and support analgesic effects

    Pain

    (2013)
  • D.L. Goldenberg

    The interface of pain and mood disturbances in the rheumatic diseases

    Semin. Arthritis Rheum.

    (2010)
  • G.A. Hamidi et al.

    Ethosuximide reduces allodynia and hyperalgesia and potentiates morphine effects in the chronic constriction injury model of neuropathic pain

    Eur. J. Pharmacol.

    (2012)
  • N. Kerckhove et al.

    Ca(v)3.2 calcium channels: the key protagonist in the supraspinal effect of paracetamol

    Pain

    (2014)
  • S. Klauenberg et al.

    Depression and changed pain perception: hints for a central disinhibition mechanism

    Pain

    (2008)
  • L. Laine et al.

    Serious lower gastrointestinal clinical events with nonselective NSAID or coxib use

    Gastroenterology

    (2003)
  • L.A. McWilliams et al.

    Associations between arthritis and a broad range of psychiatric disorders: findings from a nationally representative sample

    J. Pain Off. J. Am. Pain Soc.

    (2008)
  • L.A. McWilliams et al.

    Depression and anxiety associated with three pain conditions: results from a nationally representative sample

    Pain

    (2004)
  • G. Munro et al.

    Pharmacological comparison of anticonvulsant drugs in animal models of persistent pain and anxiety

    Neuropharmacology

    (2007)
  • K. Okubo et al.

    Inhibition of T-type calcium channels and hydrogen sulfide-forming enzyme reverses paclitaxel-evoked neuropathic hyperalgesia in rats

    Neuroscience

    (2011)
  • V. Pereira et al.

    Role of the TREK2 potassium channel in cold and warm thermosensation and in pain perception

    Pain

    (2014)
  • L. Poupon et al.

    Targeting the TREK-1 potassium channel via riluzole to eliminate the neuropathic and depressive-like effects of oxaliplatin

    Neuropharmacology

    (2018)
  • A.S.C. Rice et al.

    Animal models and the prediction of efficacy in clinical trials of analgesic drugs: a critical appraisal and call for uniform reporting standards

    Pain

    (2008)
  • R.J. Rodgers et al.

    Factor analysis of spatiotemporal and ethological measures in the murine elevated plus-maze test of anxiety

    Pharmacol. Biochem. Behav.

    (1995)
  • F. Sekiguchi et al.

    T-type calcium channels: functional regulation and implication in pain signaling

    J. Pharmacol. Sci.

    (2013)
  • H.E. Shannon et al.

    Comparison of the effects of anticonvulsant drugs with diverse mechanisms of action in the formalin test in rats

    Neuropharmacology

    (2005)
  • S.D. Shields et al.

    Spared nerve injury model of neuropathic pain in the mouse: a behavioral and anatomic analysis

    J. Pain Off. J. Am. Pain Soc.

    (2003)
  • W. Toma et al.

    Effects of paclitaxel on the development of neuropathy and affective behaviors in the mouse

    Neuropharmacology

    (2017)
  • I. Yalcin et al.

    Emotional consequences of neuropathic pain: insight from preclinical studies

    Neurosci. Biobehav. Rev.

    (2014)
  • ZhuoM.

    Neural mechanisms underlying anxiety-chronic pain interactions

    Trends Neurosci.

    (2016)
  • T. Bao et al.

    Long-term chemotherapy-induced peripheral neuropathy among breast cancer survivors: prevalence, risk factors, and fall risk

    Breast Cancer Res. Treat.

    (2016)
  • S.R. Bodnoff et al.

    A comparison of the effects of diazepam versus several typical and atypical anti-depressant drugs in an animal model of anxiety

    Psychopharmacology

    (1989)
  • S. Boogaard et al.

    Predictors for persistent neuropathic pain – a Delphi survey

    Pain Phys.

    (2011)
  • E. Bourinet et al.

    T-type calcium channels in neuropathic pain

    Pain

    (2016)
  • O. Boyman et al.

    Adverse reactions to biologic agents and their medical management

    Nat. Rev. Rheumatol.

    (2014)
  • ChengJ.-K. et al.

    Effects of intrathecal injection of T-type calcium channel blockers in the rat formalin test

    Behav. Pharmacol.

    (2007)
  • ChoiS. et al.

    Attenuated pain responses in mice lacking Ca(V)3.2 T-type channels

    Genes Brain Behav.

    (2007)
  • ChoiY.-J. et al.

    Scolopendra pharmacopuncture ameliorates behavioral despair in mice stressed by chronic restraint

    J. Pharmacopunct.

    (2017)
  • R. Conrad et al.

    Temperament, character, and personality disorders in chronic pain

    Curr. Pain Headache Rep.

    (2013)
  • D.A. Coulter et al.

    Differential effects of petit mal anticonvulsants and convulsants on thalamic neurones: calcium current reduction

    Br. J. Pharmacol.

    (1990)
  • N.A. Duggett et al.

    Characterization of a rat model of bortezomib-induced painful neuropathy

    Br. J. Pharmacol.

    (2017)
  • R.H. Dworkin et al.

    Clinical aspects of depression in chronic pain patients

    Clin. J. Pain

    (1991)
  • Cited by (14)

    • Salvianolic acid B alleviates comorbid pain in depression induced by chronic restraint stress through inhibiting GABAergic neuron excitation via an ERK-CREB-BDNF axis-dependent mechanism

      2022, Journal of Psychiatric Research
      Citation Excerpt :

      Chronic pain complaints are frequently occurring among patients suffering from depression, and patients with physical pain are vulnerable to major depression (Sheng et al., 2017). Currently, different treatment regimens for comorbid chronic pain with depression have been proposed, such as the use of ethosuximide (Kerckhove et al., 2019) and the application of acupuncture (Yan et al., 2020). Chronic pain and depression usually occur jointly, and the mechanisms underlying this disorder remain to be understood (Laumet et al., 2020).

    View all citing articles on Scopus
    1

    These authors equally contributed to the paper.

    View full text