title: Hedgehog Pathway-Mediated Vascular Alterations Following Trigeminal Nerve Injury.
abstract: Whereas neurovascular interactions in spinal neuropathic pain models have been well characterized, little attention has been given to such neurovascular interactions in orofacial neuropathic pain models. This study investigated in male Sprague-Dawley rats the vascular changes following chronic constriction injury (CCI) of the infraorbital nerve (IoN), a broadly validated preclinical model of orofacial neuropathic pain. Following IoN-CCI, an early downregulation of tight junction proteins Claudin-1 and Claudin-5 was observed within the endoneurium and perineurium, associated with increased local accumulation of sodium fluorescein (NaFlu) within the IoN parenchyma, as compared with sham animals. These events were evidence of local blood-nerve barrier disruption and increased vascular permeability. A significant upregulation of immunocytes (CD3, CD11b) and innate immunity (TLR2, TLR4) mRNA markers was also observed, suggestive of increased local inflammation. Finally, a significant downregulation of Hedgehog pathway readouts Patched-1 and Gli-1 was observed within the IoN after CCI and local injections of cyclopamine, a Hedgehog pathway inhibitor, replicated in naïve rats the molecular, vascular, and behavioral changes observed following IoN-CCI. These results suggest a major role of Hedgehog pathway inhibition in mediating local increased endoneurial and perineurial vascular permeability following trigeminal nerve injury, thus facilitating immunocytes infiltration, neuroinflammation development, and neuropathic pain-like aversive behavior.
authors.affiliation: 1 Centre de Psychiatrie et Neurosciences, Inserm U894, Paris, France.|2 Hôpital Bretonneau (AP-HP) & Faculté de chirurgie dentaire, Université Paris Descartes, Paris, France.
authors.forename: N
authors.initials: N
authors.lastname: Moreau
authors.affiliation: 1 Centre de Psychiatrie et Neurosciences, Inserm U894, Paris, France.|3 Groupe Hospitalier Pitié Salpêtrière, Université Paris Diderot, Paris, France.
authors.forename: W
authors.initials: W
authors.lastname: Dieb
authors.affiliation: 1 Centre de Psychiatrie et Neurosciences, Inserm U894, Paris, France.
authors.forename: A
authors.initials: A
authors.lastname: Mauborgne
authors.affiliation: 1 Centre de Psychiatrie et Neurosciences, Inserm U894, Paris, France.
authors.forename: S
authors.initials: S
authors.lastname: Bourgoin
authors.affiliation: 1 Centre de Psychiatrie et Neurosciences, Inserm U894, Paris, France.
authors.forename: L
authors.initials: L
authors.lastname: Villanueva
authors.affiliation: 1 Centre de Psychiatrie et Neurosciences, Inserm U894, Paris, France.
authors.forename: M
authors.initials: M
authors.lastname: Pohl
authors.affiliation: 1 Centre de Psychiatrie et Neurosciences, Inserm U894, Paris, France.|3 Groupe Hospitalier Pitié Salpêtrière, Université Paris Diderot, Paris, France.
authors.forename: Y
authors.initials: Y
authors.lastname: Boucher
mesh_terms: D000818:Animals; D002199:Capillary Permeability; D062445:Claudin-1 / Q000378:metabolism; D062507:Claudin-5 / Q000378:metabolism; D004195:Disease Models, Animal; D053823:Hedgehog Proteins / Q000378:metabolism*; D007113:Immunity, Innate; D007150:Immunohistochemistry; D008297:Male; D008856:Microscopy, Fluorescence; D051381:Rats; D017207:Rats, Sprague-Dawley; D020133:Reverse Transcriptase Polymerase Chain Reaction; D019108:Tight Junctions / Q000378:metabolism; D061221:Trigeminal Nerve Injuries / Q000378:metabolism*; D014277:Trigeminal Neuralgia / Q000378:metabolism*; D014704:Veratrum Alkaloids
chemical_list: D062445:Claudin-1; D062507:Claudin-5; D053823:Hedgehog Proteins; D014704:Veratrum Alkaloids; C000541:cyclopamine
keywords: blood vessels; endoneurium; inflammation; neuropathic pain; tight junctions; vascular permeability