title: Perisurgical amitriptyline produces a preventive effect on afferent hypersensitivity following spared nerve injury.
abstract: Following surgery, nerve injury can lead to persistent neuropathic pain. Pre-emptive and preventive analgesic treatments in the perioperative period aim to minimize nerve injury-induced pain. Here we demonstrate that a perioperative regimen of amitriptyline (10 mg/kg i.p. 30 min before and immediately after surgery, followed by oral amitriptyline 15-18 mg/kg/day in the drinking water for 7 days post-surgery) prevents hypersensitivity to a chemogenic stimulus (alphabeta-MeATP, a ligand for P2X3 receptors, together with noradrenaline or NA) in the spared nerve injury (SNI) model in rats. It also prevents hyposensitivity to capsaicin and NA. However, amitriptyline treatment had no effect on the development of mechanical allodynia. We investigated the role of NA mechanisms in the action of amitriptyline by using the neurotoxin 6-hydroxydopamine (6-OHDA) and by examining desipramine. Intrathecal treatment with 6-OHDA on the day of surgery reversed the preventive effect of amitriptyline on hypersensitivity to alphabeta-MeATP/NA, and desipramine exhibited a similar effect to amitriptyline. We also examined the effect of antibodies to the nerve growth factors glial-derived neurotrophic factor (GDNF) and brain-derived neurotrophic factor (BDNF), given intrathecally three times (days 0, 3 and 7) on the action of amitriptyline and observed that the interruption of GDNF and BDNF signaling impaired the prevention of hypersensitivity to alphabeta-MeATP/NA. This study indicates that tricyclic antidepressants given in the perioperative period may be useful in preventing nerve injury-induced sensory changes that contribute to the development of chronic post-surgical neuropathic pain.
authors.affiliation: Department of Pharmacology, Dalhousie University, Halifax, NS, Canada B3H 1X5.
authors.forename: Andre
authors.initials: A
authors.lastname: Arsenault
authors.forename: Jana
authors.initials: J
authors.lastname: Sawynok
mesh_terms: D000639:Amitriptyline / Q000627:therapeutic use*; D000818:Animals; D000929:Antidepressive Agents, Tricyclic / Q000627:therapeutic use*; D001522:Behavior, Animal / Q000187:drug effects; D019208:Brain-Derived Neurotrophic Factor / Q000378:metabolism; D003891:Desipramine / Q000627:therapeutic use; D051100:Glial Cell Line-Derived Neurotrophic Factor / Q000378:metabolism; D006930:Hyperalgesia / Q000209:etiology / Q000503:physiopathology / Q000517:prevention & control*; D007150:Immunohistochemistry; D008297:Male; D009475:Neurons, Afferent / Q000187:drug effects*; D009638:Norepinephrine / Q000502:physiology; D016627:Oxidopamine; D059348:Peripheral Nerve Injuries; D051381:Rats; D017207:Rats, Sprague-Dawley; D013565:Sympatholytics
chemical_list: D000929:Antidepressive Agents, Tricyclic; D019208:Brain-Derived Neurotrophic Factor; D051100:Glial Cell Line-Derived Neurotrophic Factor; D013565:Sympatholytics; D000639:Amitriptyline; D016627:Oxidopamine; D003891:Desipramine; D009638:Norepinephrine