title: Medullary pain facilitating neurons mediate allodynia in headache-related pain.
abstract: OBJECTIVE
  To develop and validate a model of cutaneous allodynia triggered by dural inflammation for pain associated with headaches. To explore neural mechanisms underlying cephalic and extracephalic allodynia.
  
  
  METHODS
  Inflammatory mediators (IM) were applied to the dura of unanesthetized rats via previously implanted cannulas, and sensory thresholds of the face and hind-paws were characterized.
  
  
  RESULTS
  IM elicited robust facial and hind-paw allodynia, which peaked within 3 hours. These effects were reminiscent of cutaneous allodynia seen in patients with migraine or other primary headache conditions, and were reversed by agents used clinically in the treatment of migraine, including sumatriptan, naproxen, and a calcitonin gene-related peptide antagonist. Consistent with clinical observations, the allodynia was unaffected by a neurokinin-1 antagonist. Having established facial and hind-paw allodynia as a useful animal surrogate of headache-associated allodynia, we next showed that blocking pain-facilitating processes in the rostral ventromedial medulla (RVM) interfered with its expression. Bupivacaine, destruction of putative pain-facilitating neurons, or block of cholecystokinin receptors prevented or significantly attenuated IM-induced allodynia. Electrophysiological studies confirmed activation of pain-facilitating RVM "on" cells and transient suppression of RVM "off" cells after IM.
  
  
  CONCLUSIONS
  Facial and hind-paw allodynia associated with dural stimulation is a useful surrogate of pain associated with primary headache including migraine and may be exploited mechanistically for development of novel therapeutic strategies for headache pain. The data also demonstrate the requirement for activation of descending facilitation from the RVM for the expression of cranial and extracranial cutaneous allodynia, and are consistent with a brainstem generator of allodynia associated with headache disorders.
authors.affiliation: Department of Pharmacology, University of Arizona, Tucson, USA.
authors.forename: Rebecca M
authors.initials: RM
authors.lastname: Edelmayer
authors.forename: Todd W
authors.initials: TW
authors.lastname: Vanderah
authors.forename: Lisa
authors.initials: L
authors.lastname: Majuta
authors.forename: En-Tan
authors.initials: ET
authors.lastname: Zhang
authors.forename: Beatriz
authors.initials: B
authors.lastname: Fioravanti
authors.forename: Milena
authors.initials: M
authors.lastname: De Felice
authors.forename: Juliana G
authors.initials: JG
authors.lastname: Chichorro
authors.forename: Michael H
authors.initials: MH
authors.lastname: Ossipov
authors.forename: Tamara
authors.initials: T
authors.lastname: King
authors.forename: Josephine
authors.initials: J
authors.lastname: Lai
authors.forename: Shashi H
authors.initials: SH
authors.lastname: Kori
authors.forename: Andrew C
authors.initials: AC
authors.lastname: Nelsen
authors.forename: Keri E
authors.initials: KE
authors.lastname: Cannon
authors.forename: Mary M
authors.initials: MM
authors.lastname: Heinricher
authors.forename: Frank
authors.initials: F
authors.lastname: Porreca
mesh_terms: D000200:Action Potentials / Q000502:physiology; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000627:therapeutic use; D001920:Bradykinin / Q000008:administration & dosage; D015232:Dinoprostone / Q000008:administration & dosage; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004388:Dura Mater / Q000473:pathology / Q000502:physiology; D020773:Headache Disorders / Q000150:complications* / Q000188:drug therapy / Q000473:pathology; D006930:Hyperalgesia / Q000188:drug therapy / Q000209:etiology*; D007249:Inflammation / Q000139:chemically induced / Q000188:drug therapy / Q000473:pathology; D008297:Male; D008526:Medulla Oblongata / Q000473:pathology / Q000503:physiopathology*; D009474:Neurons / Q000187:drug effects / Q000502:physiology*; D018377:Neurotransmitter Agents / Q000494:pharmacology; D016761:Oncogene Proteins v-fos / Q000378:metabolism; D010147:Pain Measurement / Q000379:methods; D017288:Pain Threshold / Q000187:drug effects / Q000502:physiology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012701:Serotonin / Q000008:administration & dosage; D014309:Tripelennamine / Q000008:administration & dosage
chemical_list: D000893:Anti-Inflammatory Agents; D018377:Neurotransmitter Agents; D016761:Oncogene Proteins v-fos; D012701:Serotonin; D014309:Tripelennamine; D015232:Dinoprostone; D001920:Bradykinin