title: The antiallodynic action of nortriptyline and terbutaline is mediated by β(2) adrenoceptors and δ opioid receptors in the ob/ob model of diabetic polyneuropathy.
abstract: Peripheral polyneuropathy is a frequent complication of diabetes. One of its consequences is neuropathic pain which is often chronic and difficult to treat. This pain management classically involves anticonvulsant drugs or tricyclic antidepressant drugs (TCA). We have previously shown that β2 adrenoceptors and δ opioid receptors are critical for TCA action in a traumatic model of neuropathic pain. In the present work, we used the obese leptin deficient mice (ob/ob) which are a genetic model of type 2 diabetes in order to study the treatment of diabetic polyneuropathy. ob/ob mice with hyperglycemia develop tactile bilateral allodynia. We investigated the action of the TCA nortriptyline and the β2 adrenoceptor agonist terbutaline on this neuropathic allodynia. The consequences of acute and chronic treatments were tested, and mechanical allodynia was assessed by using von Frey hairs. Chronic but not acute treatment with nortriptyline alleviates allodynia caused by the diabetic neuropathy. This effect depends on β2 adrenoceptors but not on α2 adrenoceptors, as shown by the blockade with repeated co-administration of the β2 adrenoceptor antagonist ICI118551 but not with repeated co-administration of the α2 adrenoceptor antagonist yohimbine. Direct stimulation of β2 adrenoceptors appears sufficient to relieve allodynia, as shown with chronic terbutaline treatment. δ but not mu opioid receptors seem important to these action since acute naltrindole, but not acute naloxonazine, reverses the effect of chronic nortriptyline or terbutaline treatment.
authors.affiliation: Institut des Neurosciences Cellulaires et Intégratives, Centre National de la Recherche Scientifique, Strasbourg, France.
authors.forename: Nada
authors.initials: N
authors.lastname: Choucair-Jaafar
authors.affiliation: Institut des Neurosciences Cellulaires et Intégratives, Centre National de la Recherche Scientifique, Strasbourg, France; Hôpitaux Universitaires de Strasbourg, Université de Strasbourg, Strasbourg, France.
authors.forename: Eric
authors.initials: E
authors.lastname: Salvat
authors.affiliation: Institut des Neurosciences Cellulaires et Intégratives, Centre National de la Recherche Scientifique, Strasbourg, France; Institut des Neurosciences Cellulaires et Intégratives, Université de Strasbourg, Strasbourg, France.
authors.forename: Marie-José
authors.initials: MJ
authors.lastname: Freund-Mercier
authors.affiliation: Institut des Neurosciences Cellulaires et Intégratives, Centre National de la Recherche Scientifique, Strasbourg, France; Institut des Neurosciences Cellulaires et Intégratives, Université de Strasbourg, Strasbourg, France. Electronic address: mbarrot@inci-cnrs.unistra.fr.
authors.forename: Michel
authors.initials: M
authors.lastname: Barrot
mesh_terms: D018759:Adrenergic Uptake Inhibitors / Q000627:therapeutic use*; D058666:Adrenergic beta-2 Receptor Agonists / Q000627:therapeutic use*; D000818:Animals; D003929:Diabetic Neuropathies / Q000150:complications / Q000188:drug therapy*; D004195:Disease Models, Animal; D006930:Hyperalgesia / Q000150:complications / Q000188:drug therapy*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008820:Mice, Obese; D009437:Neuralgia / Q000150:complications / Q000188:drug therapy*; D009661:Nortriptyline / Q000627:therapeutic use*; D017288:Pain Threshold / Q000187:drug effects; D017465:Receptors, Opioid, delta / Q000037:antagonists & inhibitors; D013726:Terbutaline / Q000627:therapeutic use*
chemical_list: D018759:Adrenergic Uptake Inhibitors; D058666:Adrenergic beta-2 Receptor Agonists; D017465:Receptors, Opioid, delta; D009661:Nortriptyline; D013726:Terbutaline
keywords: Antidepressant; Diabetes; Neuropathic pain; Terbutaline; β Adrenoceptors; δ Opioid receptors