Neuropharmacology and Analgesia Evaluation of milnacipran, in comparison with amitriptyline, on cold and mechanical allodynia in a rat model of neuropathic pain Esther Berrocoso a,e , Juan-Antonio Mico a,e , Olivier Vitton d , Philippe Ladure c , Adrian Newman-Tancredi b,1 , Ronan Depoortère b, ⁎, Laurent Bardin b a Department of Neuroscience (Pharmacology and Psychiatry), Faculty of Medicine, University of Cadiz, 11003 Cadiz, Spain b Centre de Recherche Pierre-Fabre, 17, avenue Jean Moulin, 81106 Castres, France c Institut de Recherche Pierre Fabre, 31319 Labège Innopôle, France d Institut de Recherche Pierre Fabre/Pierre Fabre Médicaments, 81106 Castres, France e Ciber of Mental Health (CIBERSAM), Instituto de Salud Carlos III, Madrid, Spain abstract article info Article history: Received 24 August 2010 Received in revised form 10 December 2010 Accepted 12 January 2011 Available online 28 January 2011 Keywords: Allodynia Amitriptyline Neuropathic pain Milnacipran Rat Milnacipran, a serotonin/norepinephrine reuptake inhibitor (SNRI), has shown efficacy against several chronic pain conditions, including fibromyalgia. Here, we evaluated, in rats, its anti-allodynic effects following acute or sub-chronic treatment in a model of neuropathic pain (chronic constriction injury, CCI, of the sciatic nerve). Amitriptyline, a tricyclic antidepressant active pre-clinically and clinically against neuropathic pains, was added as a comparison compound. Upon acute i.p. administration, milnacipran was potently efficacious in the CCI model. It significantly reduced thermal allodynia in the cold (4 °C) plate test (MED = 2.5 mg/kg), and attenuated mechanical allodynia in the von Frey filaments test (MED = 10 mg/kg). Given sub-chronically (7 day, b.i.d.), milnacipran was effective at 10 mg/kg i.p. in both tests. Acute amitriptyline (10 mg/kg i.p.) was efficacious against mechanical, but less so against cold allodynia; under sub-chronic conditions, it was only active against mechanical allodynia. These data show that milnacipran is as efficacious as the reference compound amitriptyline in a pre-clinical model of injury-induced neuropathy, and demonstrate for the first time that it is active acutely and sub-chronically against cold allodynia. They also suggest that milnacipran has the potential to alleviate allodynia associated with nerve compression-induced neuropathic pain in the clinic (for example following discal hernia, avulsion or cancer-induced tissue damage). © 2011 Elsevier B.V. All rights reserved. 1. Introduction Neuropathic pain is a chronic/persistent state resulting from injury to the nervous system, consecutive to trauma, chronic inflammation, viral infection, or metabolic disturbances, i.e. diabetes (Dworkin et al., 2003). Its treatment is complicated, often poorly efficacious in the majority of patients, and resistant to opiate analgesics (Attal et al., 2006; Micó et al., 2006). Antidepressants, particularly tricyclic antidepressants, are commonly used in the treatment of various human chronic painful syndromes (Attal et al., 2006; Dworkin et al., 2007). For example, amitriptyline, which possesses a balanced ratio for inhibition of serotonin (5-HT) versus norepinephrine reuptake (Hyttel, 1994) is frequently used to treat neuropathic pain (Watson, 2000). However, its anticholinergic, antihistaminergic and antiadre- nergic properties contribute to a poor side-effect profile and limited patient tolerability (Micó et al., 2006). The development of serotonin and norepinephrine reuptake inhibitors (SNRIs), like milnacipran, offers an alternative to tricyclic antidepressants for management of chronic pain. Indeed, milnacipran (Savella®) has been FDA-approved for treating fibromyalgia, based on several positive clinical trials (Vitton et al., 2004; Gendreau et al., 2005; Clauw et al., 2008; Mease et al., 2009). This SNRI, like amitriptyline, is relatively balanced in its reuptake inhibition of these neurotransmitters (around 3-fold higher potency for blocking norepinephrine reuptake: Vaishnavi et al., 2004; Stahl et al., 2005). In addition, it has no significant activity for serotonergic, alpha- or beta- adrenergic, muscarinic, histamine, dopamine, or GABA receptors (Boyer and Briley, 1998). Although there have been reports on the effects of acute treatment with milnacipran in various pre-clinical models of pain (Iyengar et al., 2004; Suarez-Roca et al., 2006; Onal et al., 2007; Suzuki et al., 2008; Ikeda et al., 2009; Bardin et al., 2010), there appear to have been only three chronic administration studies. Hence, chronic daily adminis- tration of milnacipran: 1) alleviated thermal (radiant heat) but not European Journal of Pharmacology 655 (2011) 46–51 ⁎ Corresponding author at: Division of Neurobiology 2, Centre de Recherche Pierre Fabre, 17, avenue Jean Moulin, 81106 Castres, France. Tel.: +33 56371 4233; fax: +33 56371 4363. E-mail addresses: adrian.newman.tancredi@neuroact.com (A. Newman-Tancredi), ronan.depoortere@pierre-fabre.com (R. Depoortère). 1 Present address: NeuroAct Communication, 25 rue des, Généraux Ricard, 81100 Castres, France. 0014-2999/$ – see front matter © 2011 Elsevier B.V. All rights reserved. doi:10.1016/j.ejphar.2011.01.022 Contents lists available at ScienceDirect European Journal of Pharmacology journal homepage: www.elsevier.com/locate/ejphar