Ethosuximide improves chronic pain-induced anxiety- and depression-like behaviors
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).
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These authors equally contributed to the paper.