title: Mice with a deletion of the major central myelin protein exhibit hypersensitivity to noxious thermal stimuli: involvement of central sensitization.
abstract: Null mutations in the gene encoding the major myelin protein of the central nervous system, proteolipid protein 1 (PLP1), cause an X-linked form of spastic paraplegia (SPG2) associated with axonal degeneration. While motor symptoms are the best known manifestations of this condition, its somatosensory disturbances have been described but poorly characterized. We carried out a longitudinal study in an animal model of SPG2 - mice carrying a deletion of the Plp1 gene (Plp-null mice). Plp-null mice exhibited severe early-onset thermal hyperalgesia, in the absence of thermal allodynia. We first performed an electrophysiological testing which showed an early decrease in peripheral and spinal conduction velocities in Plp null mice. Such as the abnormal sensitive behaviors, this slowing of nerve conduction was observed before the development of myelin abnormalities at the spinal level, from 3months of age, and without major morphological defects in the sciatic nerve. To understand the link between a decrease in nerve velocity and an increased response to thermal stimuli before the appearance of myelin abnormalities, we focused our attention on the dorsal horn of the spinal cord, the site of integration of somatosensory information. Immunohistochemical studies revealed an early-onset activation of astrocytes and microglia that worsened with age, associated later in age with perturbation of the expression of the sensory neuropeptides calcitonin-gene-related peptide and galanin. Taken together, these results represent complementary data supporting the hypothesis that Plp-null mice suffer from ganglionopathy associated with late onset central demyelination but with few peripheral nerve alterations, induced by the glial-cell-mediated sensitization of the spinal cord. The mechanism suggested here could underlie pain experiments in other leukodystrophies as well as in other non-genetic demyelinating diseases such as multiple sclerosis.
authors.affiliation: Clermont Université, Université d'Auvergne, Faculté de Médecine, BP 10448, F-63000 Clermont-Ferrand, France; Inserm U676, Hôpital Robert-Debré, Faculté de médecine Denis-Diderot, Université Paris-7, 75205 Paris cedex 13, France.
authors.forename: Bérengère
authors.initials: B
authors.lastname: Petit
authors.affiliation: Clermont Université, Université d'Auvergne, Laboratoire de Biophysique, BP 10448, F-63000 Clermont-Ferrand, France; Inserm U1107, NEURO-DOL, F-63001 Clermont-Ferrand, France.
authors.forename: Fabrice
authors.initials: F
authors.lastname: Giraudet
authors.affiliation: Clermont Université, Université d'Auvergne, Faculté de Médecine, BP 10448, F-63000 Clermont-Ferrand, France; Inserm U676, Hôpital Robert-Debré, Faculté de médecine Denis-Diderot, Université Paris-7, 75205 Paris cedex 13, France.
authors.forename: Céline
authors.initials: C
authors.lastname: Béchon
authors.affiliation: Division of Neurobiology 2, Pierre Fabre Research Center, 81106 Castres, France.
authors.forename: Laurent
authors.initials: L
authors.lastname: Bardin
authors.affiliation: Clermont Université, Université d'Auvergne, Laboratoire de Biophysique, BP 10448, F-63000 Clermont-Ferrand, France; Inserm U1107, NEURO-DOL, F-63001 Clermont-Ferrand, France.
authors.forename: Paul
authors.initials: P
authors.lastname: Avan
authors.affiliation: AP-HP, Hôpital Robert Debré, Service de Neurologie Pédiatrique, Centre de référence "leukodystrophies", 75019 Paris, France; Inserm U676, Hôpital Robert-Debré, Faculté de médecine Denis-Diderot, Université Paris-7, 75205 Paris cedex 13, France.
authors.forename: Odile
authors.initials: O
authors.lastname: Boespflug-Tanguy
authors.affiliation: Clermont Université, Université d'Auvergne, Faculté de Médecine, BP 10448, F-63000 Clermont-Ferrand, France; Inserm U676, Hôpital Robert-Debré, Faculté de médecine Denis-Diderot, Université Paris-7, 75205 Paris cedex 13, France. Electronic address: melina.begou@udamail.fr.
authors.forename: Mélina
authors.initials: M
authors.lastname: Bégou
mesh_terms: D000367:Age Factors; D000818:Animals; D059333:Central Nervous System Sensitization / Q000235:genetics*; D003216:Conditioning, Operant / Q000502:physiology; D019054:Evoked Potentials, Motor / Q000235:genetics; D005073:Evoked Potentials, Somatosensory / Q000235:genetics; D006181:H-Reflex / Q000235:genetics; D006358:Hot Temperature / Q000009:adverse effects; D006930:Hyperalgesia / Q000235:genetics* / Q000503:physiopathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009043:Motor Activity / Q000235:genetics; D018991:Myelin Proteolipid Protein / Q000172:deficiency* / Q000235:genetics; D009431:Neural Conduction / Q000235:genetics; D017288:Pain Threshold / Q000502:physiology*; D012584:Sciatic Nerve / Q000473:pathology / Q000503:physiopathology; D017384:Sequence Deletion / Q000235:genetics*; D013116:Spinal Cord / Q000473:pathology
chemical_list: D018991:Myelin Proteolipid Protein; C047516:Plp1 protein, mouse
keywords: Central sensitization; Dysmyelinating disease; Pain; Transgenic mice