Chronic treatment with agonists of β 2 -adrenergic receptors in neuropathic pain Ipek Yalcin a , Luc-Henri Tessier a , Nathalie Petit-Demoulière a , Elisabeth Waltisperger a , Lutz Hein b , Marie-José Freund-Mercier a,c , Michel Barrot a, ⁎ a Institut des Neurosciences Cellulaires et Intégratives, Centre National de la Recherche Scientifique, Strasbourg, France b Institute of Pharmacology and Toxicology, University of Freiburg, Freiburg, Germany c University of Strasbourg, Strasbourg, France abstract article info Article history: Received 16 September 2009 Revised 8 October 2009 Accepted 8 October 2009 Available online 17 October 2009 Keywords: Adrenoceptor β 2 -adrenergic receptor Neuropathic pain β-mimetic Allodynia Formoterol Expression of β 2 -adrenoceptors (β 2 -ARs) within the nociceptive system suggested their potential implication in nociception and pain. Recently, we demonstrated that these receptors are essential for neuropathic pain treatment by antidepressant drugs. The aim of the present study was to investigate whether the stimulation of β 2 -ARs could in fact be adequate to alleviate neuropathic allodynia. Neuropathy was induced in mice by sciatic nerve cuffing. We demonstrate that chronic but not acute stimulation of β 2 - ARs with agonists such as clenbuterol, formoterol, metaproterenol and procaterol suppressed neuropathic allodynia. By using a pharmacological approach with the β 2 -AR antagonist ICI 118,551 or a transgenic approach with mice deficient for β 2 -ARs, we confirmed that the antiallodynic effect of these agonists was specifically related to their action on β 2 -ARs. We also showed that chronic treatment with the β 1 -AR agonist xamoterol or with the β 3 -AR agonist BRL 37344 had no effect on neuropathic allodynia. Chronic stimulation of β 2 -ARs, but not β 1 - or β 3 -ARs, by specific agonists is thus able to alleviate neuropathic allodynia. This action of β 2 -AR agonists might implicate the endogenous opioid system; indeed chronic clenbuterol effect can be acutely blocked by the delta-opioid receptor antagonist naltrindole. Present results show that β 2 -ARs are not only essential for the antiallodynic action of antidepressant drugs on sustained neuropathic pain, but also that the stimulation of these receptors is sufficient to relieve neuropathic allodynia in a murine model. Our data suggest that β 2 -AR agonists may potentially offer an alternative therapy to antidepressant drugs for the chronic treatment of neuropathic pain. © 2009 Elsevier Inc. All rights reserved. Introduction The β-adrenoceptors (AR) are members of the seven-transmembrane family of G protein coupled receptors (Hein and Kobilka, 1995; Hein, 2006). They are encoded by three genes, leading to β 1 -AR, β 2 -AR and β 3 -AR expression. These receptors are coupled to the stimula- tion of adenylyl cyclase activity through G s proteins, leading to the formation of the second messenger cAMP. The endogenous catecholamines adrenaline and noradrenaline activate these G-protein coupled receptors to transmit their signal across the plasma mem- brane. β 2 -ARs are widely distributed in the central nervous system as well as in the peripheral nervous system (Hein, 2006). They are mostly known for their role in the regulation of cardiovascular, airway, uterine, and other peripheral functions (Hein, 2006). In addition, these receptors have also been implicated in functions of the central nervous system, including the regulation of sympathetic tone, learning and memory, mood and food intake (Hein and Kobilka, 1995; Hein, 2006). Owing to these diverse functions, β 2 -ARs contribute to several pathologies and their treatment such as asthma (O'Byrne and Parameswaran, 2006), anxiety and depression (Yu et al., 1999; Zhang et al., 2003) and in diverse physiological disorders, including those associated with chronic pain conditions (Diatchenko et al., 2006; Elenkov et al., 2000). Noradrenaline can influence nociception and pain processing. Numerous studies have focused on the role of α 2 -adrenergic receptors in this processing (Crassous et al., 2007; Taylor, 2009), but less information is available concerning the role of β-ARs. β 2 -ARs are however expressed in areas directly participating in pain pathways (Nicholson et al., 2005), and human genetic studies also confirmed the contribution of β 2 -ARs to chronic pain disorders (Diatchenko et al., 2006). Recently, we showed that β 2 -ARs are essential for the antiallodynic action of antidepressant drugs (Yalcin et al., 2009a,b), which are clinically used as first-line treatments against neuropathic pain (Attal et al., 2006; Gilron et al., 2006; Moulin et al., 2007). These experiments revealed that neither α 2 -ARs, β 1 -ARs nor β 3 -ARs were critical for chronic antidepressant drug action against neuropathic pain (Yalcin et al., 2009a,b). In contrast, the absence or the blockade of β 2 -ARs totally suppressed the effect of chronic antidepressant drug treatment on mechanical allodynia. This was observed with tricyclic Experimental Neurology 221 (2010) 115–121 ⁎ Corresponding author. Nociception and Pain Department, Institute of Cellular and Integrative Neurosciences, 21 rue René Descartes, 67084 Strasbourg cedex, France. Fax: +33 388 613 347. E-mail address: mbarrot@unistra.fr (M. Barrot). 0014-4886/$ – see front matter © 2009 Elsevier Inc. All rights reserved. doi:10.1016/j.expneurol.2009.10.008 Contents lists available at ScienceDirect Experimental Neurology journal homepage: www.elsevier.com/locate/yexnr