title: Increased susceptibility to cortical spreading depression in an animal model of medication-overuse headache.
abstract: OBJECTIVE
  The objective of this article is to evaluate electrically evoked thresholds for cortical spreading depression (CSD) and stress-induced activation of trigeminal afferents in a rat model of medication-overuse headache (MOH).
  
  
  METHODS
  Sumatriptan or saline was delivered subcutaneously by osmotic minipump for six days to Sprague-Dawley rats. Two weeks after pump removal, animals were anesthetized and recording/stimulating electrodes implanted. The animals were pretreated with vehicle or topiramate followed by graded electrical stimulation within the visual cortex. CSD events were identified by decreased EEG amplitude and DC potential shift. Additional unanesthetized sumatriptan or saline-pretreated rats were exposed to bright light environmental stress and periorbital and hindpaw withdrawal thresholds were measured. Following CSD stimulation or environmental stress, immunohistochemical staining for Fos in the trigeminal nucleus caudalis (TNC) was performed.
  
  
  RESULTS
  Sumatriptan pre-exposure significantly decreased electrical stimulation threshold to generate a CSD event. Topiramate normalized the decreased CSD threshold as well as stress-induced behavioral withdrawal thresholds in sumatriptan-treated rats compared to saline-treated animals. Moreover, CSD and environmental stress increased Fos expression in the TNC of sumatriptan-treated rats, and these effects were blocked by topiramate. Environmental stress did not elicit cutaneous allodynia or elevate TNC Fos expression in saline-treated rats.
  
  
  CONCLUSIONS
  A previous period of sumatriptan exposure produced long-lasting increased susceptibility to evoked CSD and environmental stress-induced activation of the TNC that was prevented by topiramate. Lowered CSD threshold, and enhanced consequences of CSD events (increased activation of TNC), may represent an underlying biological mechanism of MOH related to triptans.
authors: Department of Pharmacology, University of Arizona College of Medicine, Tucson, AZ, USA.
authors: A Laine
authors: AL
authors: Green
authors: Department of Pharmacology, University of Arizona College of Medicine, Tucson, AZ, USA.
authors: Pengfei
authors: P
authors: Gu
authors: Department of Pharmacology, University of Arizona College of Medicine, Tucson, AZ, USA.
authors: Milena
authors: M
authors: De Felice
authors: Department of Neurology, Mayo Clinic Arizona, Phoenix, AZ, USA.
authors: David
authors: D
authors: Dodick
authors: Department of Pharmacology, University of Arizona College of Medicine, Tucson, AZ, USA.
authors: Michael H
authors: MH
authors: Ossipov
authors: Department of Pharmacology, University of Arizona College of Medicine, Tucson, AZ, USA frankp@u.arizona.edu.
authors: Frank
authors: F
authors: Porreca
mesh_terms: D000344:Afferent Pathways / Q000187:drug effects / Q000503:physiopathology; D000818:Animals; D013181:Cortical Spreading Depression / Q000187:drug effects* / Q000502:physiology*; D004195:Disease Models, Animal; D004558:Electric Stimulation; D005071:Evoked Potentials / Q000187:drug effects / Q000502:physiology; D051271:Headache Disorders, Secondary / Q000503:physiopathology*; D006801:Humans; D055104:Infusions, Subcutaneous; D008297:Male; D017207:Rats, Sprague-Dawley; D012307:Risk Factors; D012684:Sensory Thresholds / Q000187:drug effects / Q000502:physiology; D013315:Stress, Psychological / Q000150:complications / Q000503:physiopathology; D018170:Sumatriptan / Q000633:toxicity*; D014276:Trigeminal Nerve / Q000187:drug effects / Q000503:physiopathology
chemical_list: D018170:Sumatriptan
keywords: Fos; Migraine; TNC; cortical spreading depression (CSD); medication-overuse headache (MOH); topiramate; triptans