title: The nitric oxide donor, isosorbide dinitrate, induces a cephalic cutaneous hypersensitivity, associated with sensitization of the medullary dorsal horn.
abstract: Nitric oxide donors are known to produce headache in healthy as well as migraine subjects, and to induce extracephalic cutaneous hypersensitivity in rodents. However, little is known on the effect of nitric oxide donors on cephalic cutaneous sensitivity. Combining behavioral, immunohistochemical, and in vivo electrophysiological approaches, this study investigated the effect of systemic administration of the nitric oxide donor, isosorbide dinitrate (ISDN), on cephalic and extracephalic cutaneous sensitivity and on neuronal activation within the medullary dorsal horn (MDH) in the rat. Systemic administration of ISDN increased selectively the first phase and interphase of the facial formalin test, but had no effect on the hindpaw formalin one. Monitoring neuronal activity within the MDH with phospho-ERK1/2 immunoreactivity revealed that ISDN alone did not activate MDH neurons, but significantly increased the number of formalin-evoked phospho-ERK1/2-immunoreactive cells in the ipsilateral, but not contralateral, MDH. Using in vivo electrophysiological unit recordings, we show that ISDN administration never affected the spontaneous activity of trigeminal wide dynamic range neurons, but, facilitated C-fiber-evoked responses in half the neurons tested. This research demonstrates that a nitric oxide donor, isosorbide dinitrate, induces selectively cephalic hyperalgesia that arises as a consequence of central sensitization in pain pathways that subserve meningeal nociception. This model better mimics the clinical condition and offers another possibility of studying the role of nitric oxide donor in the physiopathology of headache.
authors.affiliation: Université Clermont Auvergne, Inserm Neuro-Dol U1107, F-63000 Clermont-Ferrand, France.
authors.forename: José María
authors.initials: JM
authors.lastname: Flores Ramos
authors.affiliation: Université Clermont Auvergne, Inserm Neuro-Dol U1107, F-63000 Clermont-Ferrand, France; CHU Clermont-Ferrand, Service d'Odontologie, F-63100 Clermont-Ferrand, France.
authors.forename: Laurent
authors.initials: L
authors.lastname: Devoize
authors.affiliation: Université Clermont Auvergne, Inserm Neuro-Dol U1107, F-63000 Clermont-Ferrand, France.
authors.forename: Amélie
authors.initials: A
authors.lastname: Descheemaeker
authors.affiliation: Université Clermont Auvergne, Inserm Neuro-Dol U1107, F-63000 Clermont-Ferrand, France.
authors.forename: Jean-Louis
authors.initials: JL
authors.lastname: Molat
authors.affiliation: Université Clermont Auvergne, Inserm Neuro-Dol U1107, F-63000 Clermont-Ferrand, France.
authors.forename: Philippe
authors.initials: P
authors.lastname: Luccarini
authors.affiliation: Université Clermont Auvergne, Inserm Neuro-Dol U1107, F-63000 Clermont-Ferrand, France; CHU Clermont-Ferrand, Service d'Odontologie, F-63100 Clermont-Ferrand, France. Electronic address: radhouane.dallel@udamail.fr.
authors.forename: Radhouane
authors.initials: R
authors.lastname: Dallel
mesh_terms: D000818:Animals; D059333:Central Nervous System Sensitization / Q000187:drug effects* / Q000502:physiology; D004195:Disease Models, Animal; D005145:Face / Q000503:physiopathology; D005557:Formaldehyde; D006614:Hindlimb / Q000503:physiopathology; D006930:Hyperalgesia / Q000139:chemically induced* / Q000473:pathology / Q000503:physiopathology; D007548:Isosorbide Dinitrate / Q000633:toxicity*; D008297:Male; D008526:Medulla Oblongata / Q000187:drug effects* / Q000473:pathology / Q000503:physiopathology; D008881:Migraine Disorders / Q000503:physiopathology; D020030:Nitric Oxide Donors / Q000633:toxicity*; D010147:Pain Measurement; D020671:Posterior Horn Cells / Q000187:drug effects* / Q000473:pathology / Q000502:physiology; D011897:Random Allocation; D017207:Rats, Sprague-Dawley
chemical_list: D020030:Nitric Oxide Donors; D005557:Formaldehyde; D007548:Isosorbide Dinitrate
keywords: central sensitization; headache; hyperalgesia; migraine; pain; trigeminal