title: Triptan-induced enhancement of neuronal nitric oxide synthase in trigeminal ganglion dural afferents underlies increased responsiveness to potential migraine triggers.
abstract: Migraine is a common neurological disorder often treated with triptans. Triptan overuse can lead to increased frequency of headache in some patients, a phenomenon termed medication overuse headache. Previous preclinical studies have demonstrated that repeated or sustained triptan administration for several days can elicit persistent neural adaptations in trigeminal ganglion cells innervating the dura, prominently characterized by increased labelling of neuronal profiles for calcitonin gene related peptide. Additionally, triptan administration elicited a behavioural syndrome of enhanced sensitivity to surrogate triggers of migraine that was maintained for weeks following discontinuation of drug, a phenomenon termed 'triptan-induced latent sensitization'. Here, we demonstrate that triptan administration elicits a long-lasting increase in identified rat trigeminal dural afferents labelled for neuronal nitric oxide synthase in the trigeminal ganglion. Cutaneous allodynia observed during the period of triptan administration was reversed by NXN-323, a selective inhibitor of neuronal nitric oxide synthase. Additionally, neuronal nitric oxide synthase inhibition prevented environmental stress-induced hypersensitivity in the post-triptan administration period. Co-administration of NXN-323 with sumatriptan over several days prevented the expression of allodynia and enhanced sensitivity to stress observed following latent sensitization, but not the triptan-induced increased labelling of neuronal nitric oxide synthase in dural afferents. Triptan administration thus promotes increased expression of neuronal nitric oxide synthase in dural afferents, which is critical for enhanced sensitivity to environmental stress. These data provide a biological basis for increased frequency of headache following triptans and highlight the potential clinical utility of neuronal nitric oxide synthase inhibition in preventing or treating medication overuse headache.
authors.affiliation: Department of Pharmacology, College of Medicine, University of Arizona, Tucson, AZ 85724, USA.
authors.forename: Milena
authors.initials: M
authors.lastname: De Felice
authors.forename: Michael H
authors.initials: MH
authors.lastname: Ossipov
authors.forename: Ruizhong
authors.initials: R
authors.lastname: Wang
authors.forename: Gregory
authors.initials: G
authors.lastname: Dussor
authors.forename: Josephine
authors.initials: J
authors.lastname: Lai
authors.forename: Ian D
authors.initials: ID
authors.lastname: Meng
authors.forename: Juliana
authors.initials: J
authors.lastname: Chichorro
authors.forename: John S
authors.initials: JS
authors.lastname: Andrews
authors.forename: Suman
authors.initials: S
authors.lastname: Rakhit
authors.forename: Shawn
authors.initials: S
authors.lastname: Maddaford
authors.forename: David
authors.initials: D
authors.lastname: Dodick
authors.forename: Frank
authors.initials: F
authors.lastname: Porreca
mesh_terms: D000818:Animals; D015740:Calcitonin Gene-Related Peptide / Q000378:metabolism; D004388:Dura Mater / Q000187:drug effects / Q000503:physiopathology; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000494:pharmacology; D008297:Male; D008881:Migraine Disorders / Q000503:physiopathology*; D009475:Neurons, Afferent / Q000187:drug effects* / Q000201:enzymology / Q000502:physiology; D052248:Nitric Oxide Synthase Type I / Q000037:antagonists & inhibitors / Q000378:metabolism*; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism; D010146:Pain / Q000188:drug therapy / Q000503:physiopathology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013315:Stress, Psychological / Q000188:drug therapy / Q000503:physiopathology; D018170:Sumatriptan / Q000008:administration & dosage / Q000494:pharmacology; D012668:Trigeminal Ganglion / Q000187:drug effects* / Q000503:physiopathology; D014363:Tryptamines / Q000008:administration & dosage / Q000494:pharmacology*
chemical_list: D004791:Enzyme Inhibitors; D014363:Tryptamines; D018170:Sumatriptan; D052248:Nitric Oxide Synthase Type I; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III; D015740:Calcitonin Gene-Related Peptide