Low doses of dextromethorphan have a beneficial effect in the treatment of neuropathic pain.
N-methyl-D-aspartate receptor (NMDAR) antagonists may be given in persistent neuropathic pain, but adverse events especially with ketamine may limit their clinical use. Less central and cognitive adverse events are described with dextromethorphan and memantine. These molecules have been explored in many preclinical and clinical studies, but data are conflicting as regards neuropathic pain alleviation. Dextromethorphan and memantine have been administered to animals after spinal nerve ligation (SNL) to evaluate their antinociceptive/cognitive effects and associated molecular events, including the phosphorylation of several tyrosine (pTyr(1336), pTyr(1472)) residues in the NR2B NMDAR subunit. Spinal nerve ligation and sham animals received dextromethorphan (10 mg/kg, i.p.), memantine (20 mg/kg, i.p.) or saline (1 mL/kg, i.p.). These drugs were administered once symptoms of allodynia and hyperalgesia had developed. Tests were carried out before and after surgery. Tactile allodynia, mechanical hyperalgesia and spatial memory were, respectively, evaluated by von Frey, Randall & Selitto and Y-maze tests and molecular events by Western blot analysis. Spinal nerve-ligated animals displayed nociception and impaired spatial memory. Dextromethorphan, but not memantine, reversed neuropathic pain (NP) symptoms, restored spatial memory integrity and decreased the expression of pTyr(1336)NR2B. Following postoperative administration of dextromethorphan, this study has demonstrated for the first time a concordance between behaviour, cognitive function and molecular events via pTyr(1336)NR2B for neuropathic pain alleviation. Confirmation of these findings in patients would constitute a major step forward in the treatment of neuropathic pain and in the improvement of cognitive function and quality of life.
Facultés de Médecine/Pharmacie, Laboratoire de Pharmacologie, Clermont Université, Université d'Auvergne, Pharmacologie Fondamentale et Clinique de la Douleur, F-63000, Clermont-Ferrand, France; Inserm, U1107 Neuro-Dol, F-63001, Clermont-Ferrand, France; Centre de Pharmacologie Clinique, CHU Clermont-Ferrand, Inserm CIC 501, F-63003, Clermont-Ferrand, France.
Véronique
V
Morel
Gisèle
G
Pickering
Monique
M
Etienne
Amandine
A
Dupuis
Anne-Marie
AM
Privat
Maryse
M
Chalus
Alain
A
Eschalier
Laurence
L
Daulhac
D000818:Animals; D003071:Cognition / Q000187:drug effects; D003915:Dextromethorphan / Q000008:administration & dosage / Q000494:pharmacology*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D018691:Excitatory Amino Acid Antagonists / Q000008:administration & dosage / Q000494:pharmacology*; D006930:Hyperalgesia / Q000188:drug therapy; D008297:Male; D018782:Maze Learning / Q000187:drug effects; D008559:Memantine / Q000494:pharmacology*; D009437:Neuralgia / Q000188:drug therapy*; D051381:Rats; D017207:Rats, Sprague-Dawley; D016194:Receptors, N-Methyl-D-Aspartate / Q000187:drug effects / Q000378:metabolism
D018691:Excitatory Amino Acid Antagonists; C121001:NR2B NMDA receptor; D016194:Receptors, N-Methyl-D-Aspartate; D003915:Dextromethorphan; D008559:Memantine
NMDA receptor; NR2B subunit; dextromethorphan; memantine; neuropathic pain symptoms; spinal nerve ligation