title: The antiallodynic action of pregabalin in neuropathic pain is independent from the opioid system.
abstract: BACKGROUND
  Clinical management of neuropathic pain, which is pain arising as a consequence of a lesion or a disease affecting the somatosensory system, partly relies on the use of anticonvulsant drugs such as gabapentinoids. Therapeutic action of gabapentinoids such as gabapentin and pregabalin, which act by the inhibition of calcium currents through interaction with the α2δ-1 subunit of voltage-dependent calcium channels, is well documented. However, some aspects of the downstream mechanisms are still to be uncovered. Using behavioral, genetic, and pharmacological approaches, we tested whether opioid receptors are necessary for the antiallodynic action of acute and/or long-term pregabalin treatment in the specific context of neuropathic pain.
  
  
  RESULTS
  Using the cuff model of neuropathic pain in mice, we show that acute pregabalin administration at high dose has a transitory antiallodynic action, while prolonged oral pregabalin treatment leads to sustained antiallodynic action, consistent with clinical observations. We show that pregabalin remains fully effective in μ-opioid receptor, in δ-opioid receptor and in κ-opioid receptor deficient mice, either female or male, and its antiallodynic action is not affected by acute naloxone. Our work also shows that long-term pregabalin treatment suppresses tumor necrosis factor-α overproduction induced by sciatic nerve constriction in the lumbar dorsal root ganglia.
  
  
  CONCLUSIONS
  We demonstrate that neither acute nor long-term antiallodynic effect of pregabalin in a context of neuropathic pain is mediated by the endogenous opioid system, which differs from opioid treatment of pain and antidepressant treatment of neuropathic pain. Our data are also supportive of an impact of gabapentinoid treatment on the neuroimmune aspect of neuropathic pain.
authors.affiliation: Institut des Neurosciences Cellulaires et Intégratives, Centre National de la Recherche Scientifique, Strasbourg, France Université de Strasbourg, Strasbourg, France mbarrot@inci-cnrs.unistra.fr.
authors.forename: Mélanie
authors.initials: M
authors.lastname: Kremer
authors.affiliation: Institut des Neurosciences Cellulaires et Intégratives, Centre National de la Recherche Scientifique, Strasbourg, France.
authors.forename: Ipek
authors.initials: I
authors.lastname: Yalcin
authors.affiliation: Institut des Neurosciences Cellulaires et Intégratives, Centre National de la Recherche Scientifique, Strasbourg, France.
authors.forename: Laurent
authors.initials: L
authors.lastname: Nexon
authors.affiliation: Institut des Neurosciences Cellulaires et Intégratives, Centre National de la Recherche Scientifique, Strasbourg, France Université de Strasbourg, Strasbourg, France.
authors.forename: Xavier
authors.initials: X
authors.lastname: Wurtz
authors.affiliation: Institut des Neurosciences Cellulaires et Intégratives, Centre National de la Recherche Scientifique, Strasbourg, France Université de Strasbourg, Strasbourg, France.
authors.forename: Rhian Alice
authors.initials: RA
authors.lastname: Ceredig
authors.affiliation: Institut des Neurosciences Cellulaires et Intégratives, Centre National de la Recherche Scientifique, Strasbourg, France.
authors.forename: Dorothée
authors.initials: D
authors.lastname: Daniel
authors.affiliation: Institut des Neurosciences Cellulaires et Intégratives, Centre National de la Recherche Scientifique, Strasbourg, France Université de Strasbourg, Strasbourg, France.
authors.forename: Rachael Aredhel
authors.initials: RA
authors.lastname: Hawkes
authors.affiliation: Institut des Neurosciences Cellulaires et Intégratives, Centre National de la Recherche Scientifique, Strasbourg, France Centre d'Etude et de Traitement de la Douleur, Hôpitaux Universitaires 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.
authors.forename: Michel
authors.initials: M
authors.lastname: Barrot
mesh_terms: D000284:Administration, Oral; D000818:Animals; D004305:Dose-Response Relationship, Drug; D005260:Female; D006930:Hyperalgesia / Q000150:complications* / Q000188:drug therapy*; D008297:Male; D008810:Mice, Inbred C57BL; D009270:Naloxone / Q000494:pharmacology / Q000627:therapeutic use; D009437:Neuralgia / Q000150:complications* / Q000188:drug therapy*; D000069583:Pregabalin / Q000008:administration & dosage / Q000627:therapeutic use*; D011957:Receptors, Opioid / Q000378:metabolism*; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors / Q000378:metabolism
chemical_list: D011957:Receptors, Opioid; D014409:Tumor Necrosis Factor-alpha; D009270:Naloxone; D000069583:Pregabalin
keywords: mechanical allodynia; neuropathic pain; opioid system; pregabalin; tumor necrosis factor-α; δ-opioid; κ-opioid; μ-opioid