title: Dual orexin receptor antagonist 12 inhibits expression of proteins in neurons and glia implicated in peripheral and central sensitization.
abstract: Sensitization and activation of trigeminal nociceptors is implicated in prevalent and debilitating orofacial pain conditions including temporomandibular joint (TMJ) disorders. Orexins are excitatory neuropeptides that function to regulate many physiological processes and are reported to modulate nociception. To determine the role of orexins in an inflammatory model of trigeminal activation, the effects of a dual orexin receptor antagonist (DORA-12) on levels of proteins that promote peripheral and central sensitization and changes in nocifensive responses were investigated. In adult male Sprague-Dawley rats, mRNA for orexin receptor 1 (OX₁R) and receptor 2 (OX₂R) were detected in trigeminal ganglia and spinal trigeminal nucleus (STN). OX₁R immunoreactivity was localized primarily in neuronal cell bodies in the V3 region of the ganglion and in laminas I-II of the STN. Animals injected bilaterally with complete Freund's adjuvant (CFA) in the TMJ capsule exhibited increased expression of P-p38, P-ERK, and lba1 in trigeminal ganglia and P-ERK and lba1 in the STN at 2 days post injection. However, levels of each of these proteins in rats receiving daily oral DORA-12 were inhibited to near basal levels. Similarly, administration of DORA-12 on days 3 and 4 post CFA injection in the TMJ effectively inhibited the prolonged stimulated expression of protein kinase A, NFkB, and Iba1 in the STN on day 5 post injection. While injection of CFA mediated a nocifensive response to mechanical stimulation of the orofacial region at 2h and 3 and 5 days post injection, treatment with DORA-12 suppressed the nocifensive response on day 5. Somewhat surprisingly, nocifensive responses were again observed on day 10 post CFA stimulation in the absence of daily DORA-12 administration. Our results provide evidence that DORA-12 can inhibit CFA-induced stimulation of trigeminal sensory neurons by inhibiting expression of proteins associated with sensitization of peripheral and central neurons and nociception.
authors.affiliation: Missouri State University, 524 North Boonville Avenue, Springfield, MO 65806, United States.
authors.forename: R J
authors.initials: RJ
authors.lastname: Cady
authors.affiliation: Missouri State University, 524 North Boonville Avenue, Springfield, MO 65806, United States.
authors.forename: J E
authors.initials: JE
authors.lastname: Denson
authors.affiliation: Missouri State University, 524 North Boonville Avenue, Springfield, MO 65806, United States.
authors.forename: L Q
authors.initials: LQ
authors.lastname: Sullivan
authors.affiliation: Missouri State University, 524 North Boonville Avenue, Springfield, MO 65806, United States. Electronic address: pauldurham@missouristate.edu.
authors.forename: P L
authors.initials: PL
authors.lastname: Durham
mesh_terms: D000818:Animals; D001381:Azepines / Q000494:pharmacology*; D001562:Benzimidazoles / Q000494:pharmacology*; D002135:Calcium-Binding Proteins / Q000378:metabolism; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005620:Freund's Adjuvant; D008264:Macrophages / Q000187:drug effects / Q000502:physiology; D008297:Male; D008840:Microfilament Proteins / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D009457:Neuroglia / Q000187:drug effects* / Q000276:immunology; D009474:Neurons / Q000187:drug effects* / Q000276:immunology; D018377:Neurotransmitter Agents / Q000494:pharmacology*; D059225:Nociception / Q000187:drug effects* / Q000502:physiology; D064446:Orexin Receptors / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D017207:Rats, Sprague-Dawley; D012668:Trigeminal Ganglion / Q000187:drug effects / Q000276:immunology; D014279:Trigeminal Nucleus, Spinal / Q000187:drug effects / Q000276:immunology; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: C100745:Aif1 protein, rat; D001381:Azepines; D001562:Benzimidazoles; D002135:Calcium-Binding Proteins; C578627:Hcrtr1 protein, rat; C578625:Hcrtr2 protein, rat; D008840:Microfilament Proteins; D016328:NF-kappa B; D018377:Neurotransmitter Agents; D064446:Orexin Receptors; D012333:RNA, Messenger; C000595055:dual orexin receptor antagonist 12; D005620:Freund's Adjuvant; D017868:Cyclic AMP-Dependent Protein Kinases; D048049:Extracellular Signal-Regulated MAP Kinases; D048051:p38 Mitogen-Activated Protein Kinases
keywords: nociception; orexin; orexin receptor antagonist; pain; trigeminal nerve