title: Spinal cord transection-induced allodynia in rats--behavioral, physiopathological and pharmacological characterization.
abstract: In humans, spinal cord lesions induce not only major motor and neurovegetative deficits but also severe neuropathic pain which is mostly resistant to classical analgesics. Better treatments can be expected from precise characterization of underlying physiopathological mechanisms. This led us to thoroughly investigate (i) mechanical and thermal sensory alterations, (ii) responses to acute treatments with drugs having patent or potential anti-allodynic properties and (iii) the spinal/ganglion expression of transcripts encoding markers of neuronal injury, microglia and astrocyte activation in rats that underwent complete spinal cord transection (SCT). SCT was performed at thoracic T8-T9 level under deep isoflurane anaesthesia, and SCT rats were examined for up to two months post surgery. SCT induced a marked hyper-reflexia at hindpaws and strong mechanical and cold allodynia in a limited (6 cm2) cutaneous territory just rostral to the lesion site. At this level, pressure threshold value to trigger nocifensive reactions to locally applied von Frey filaments was 100-fold lower in SCT- versus sham-operated rats. A marked up-regulation of mRNAs encoding ATF3 (neuronal injury) and glial activation markers (OX-42, GFAP, P2×4, P2×7, TLR4) was observed in spinal cord and/or dorsal root ganglia at T6-T11 levels from day 2 up to day 60 post surgery. Transcripts encoding the proinflammatory cytokines IL-1β, IL-6 and TNF-α were also markedly but differentially up-regulated at T6-T11 levels in SCT rats. Acute treatment with ketamine (50 mg/kg i.p.), morphine (3-10 mg/kg s.c.) and tapentadol (10-20 mg/kg i.p.) significantly increased pressure threshold to trigger nocifensive reaction in the von Frey filaments test, whereas amitriptyline, pregabalin, gabapentin and clonazepam were ineffective. Because all SCT rats developed long lasting, reproducible and stable allodynia, which could be alleviated by drugs effective in humans, thoracic cord transection might be a reliable model for testing innovative therapies aimed at reducing spinal cord lesion-induced central neuropathic pain.
authors.affiliation: Centre de Psychiatrie et Neurosciences, Institut National de la Santé et de la Recherche Médicale, INSERM U894, Université Paris Descartes, Paris, France; Neuropsychopharmacologie, Faculté de Médecine Pierre et Marie Curie, site Pitié-Salpêtrière, Paris, France.
authors.forename: Saïd
authors.initials: S
authors.lastname: M'Dahoma
authors.affiliation: Centre de Psychiatrie et Neurosciences, Institut National de la Santé et de la Recherche Médicale, INSERM U894, Université Paris Descartes, Paris, France; Neuropsychopharmacologie, Faculté de Médecine Pierre et Marie Curie, site Pitié-Salpêtrière, Paris, France.
authors.forename: Sylvie
authors.initials: S
authors.lastname: Bourgoin
authors.affiliation: Centre de Psychiatrie et Neurosciences, Institut National de la Santé et de la Recherche Médicale, INSERM U894, Université Paris Descartes, Paris, France; Neuropsychopharmacologie, Faculté de Médecine Pierre et Marie Curie, site Pitié-Salpêtrière, Paris, France.
authors.forename: Valérie
authors.initials: V
authors.lastname: Kayser
authors.affiliation: Centre de Psychiatrie et Neurosciences, Institut National de la Santé et de la Recherche Médicale, INSERM U894, Université Paris Descartes, Paris, France; Neuropsychopharmacologie, Faculté de Médecine Pierre et Marie Curie, site Pitié-Salpêtrière, Paris, France.
authors.forename: Sandrine
authors.initials: S
authors.lastname: Barthélémy
authors.affiliation: Centre de Psychiatrie et Neurosciences, Institut National de la Santé et de la Recherche Médicale, INSERM U894, Université Paris Descartes, Paris, France; Neuropsychopharmacologie, Faculté de Médecine Pierre et Marie Curie, site Pitié-Salpêtrière, Paris, France.
authors.forename: Caroline
authors.initials: C
authors.lastname: Chevarin
authors.affiliation: Laboratoire de Neurobiologie des Signaux Intercellulaires, Centre National de la Recherche Scientifique, CNRS UMR 7101, Université Pierre et Marie Curie, Paris, France.
authors.forename: Farah
authors.initials: F
authors.lastname: Chali
authors.affiliation: Laboratoire de Neurobiologie des Signaux Intercellulaires, Centre National de la Recherche Scientifique, CNRS UMR 7101, Université Pierre et Marie Curie, Paris, France.
authors.forename: Didier
authors.initials: D
authors.lastname: Orsal
authors.affiliation: Centre de Psychiatrie et Neurosciences, Institut National de la Santé et de la Recherche Médicale, INSERM U894, Université Paris Descartes, Paris, France; Neuropsychopharmacologie, Faculté de Médecine Pierre et Marie Curie, site Pitié-Salpêtrière, Paris, France.
authors.forename: Michel
authors.initials: M
authors.lastname: Hamon
mesh_terms: D051700:Activating Transcription Factor 3 / Q000378:metabolism; D000704:Analysis of Variance; D000818:Animals; D016207:Cytokines / Q000378:metabolism; D005727:Ganglia, Spinal / Q000378:metabolism; D006358:Hot Temperature / Q000009:adverse effects; D006930:Hyperalgesia / Q000188:drug therapy* / Q000209:etiology* / Q000503:physiopathology*; D007649:Ketamine / Q000627:therapeutic use; D008297:Male; D009020:Morphine / Q000627:therapeutic use; D009419:Nerve Tissue Proteins / Q000378:metabolism; D010147:Pain Measurement; D010636:Phenols / Q000627:therapeutic use; D051381:Rats; D017207:Rats, Sprague-Dawley; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013119:Spinal Cord Injuries / Q000150:complications*; D000077432:Tapentadol
chemical_list: D051700:Activating Transcription Factor 3; C497108:Atf3 protein, rat; D016207:Cytokines; D009419:Nerve Tissue Proteins; D010636:Phenols; D007649:Ketamine; D009020:Morphine; D000077432:Tapentadol