title: Diet-Induced Obesity Enhances TRPV1-Mediated Neurovascular Reactions in the Dura Mater.
abstract: OBJECTIVE
  Exploring the pathophysiological changes in transient receptor potential vanilloid 1 (TRPV1) receptor of the trigeminovascular system in high-fat, high-sucrose (HFHS) diet-induced obesity of experimental animals.
  
  
  BACKGROUND
  Clinical and experimental observations suggest a link between obesity and migraine. Accumulating evidence indicates that metabolic and immunological alterations associated with obesity may potentially modulate trigeminovascular functions. A possible target for obesity-induced pathophysiological changes is the TRPV1/capsaicin receptor which is implicated in the pathomechanism of headaches in a complex way.
  
  
  METHODS
  Male Sprague-Dawley rats were fed a regular (n = 25) or HFHS diet (n = 26) for 20 weeks. At the end of the dietary period, body weight of the animals was normally distributed in both groups and it was significantly higher in animals on HFHS diet. Therefore, experimental groups were regarded as control and HFHS diet-induced obese groups. Capsaicin-induced changes in meningeal blood flow and release of calcitonin gene-related peptide (CGRP) from dural trigeminal afferents were measured in control and obese rats. The distribution of TRPV1- and CGRP-immunoreactive meningeal sensory nerves was also compared in whole mount preparations of the dura mater. Metabolic parameters of the animals were assessed by examining glucose and insulin homeostasis as well as plasma cytokine concentrations.
  
  
  RESULTS
  HFHS diet was accompanied by reduced food consumption and greater fluid and energy intakes in addition to increased body weight of the animals. HFHS diet increased fasting blood glucose and insulin concentrations as well as levels of circulating proinflammatory cytokines interleukin-1β and interleukin-6. In obese animals, dural application of the archetypal TRPV1 agonist capsaicin resulted in significantly augmented vasodilatory and vasoconstrictor responses as compared to controls. Diet-induced obesity was also associated with enhanced basal and capsaicin-induced CGRP release from meningeal afferents ex vivo. Except for minor morphological changes, the distribution of dural TRPV1- and CGRP-immunoreactive afferents was similar in control and obese animals.
  
  
  CONCLUSIONS
  Our results suggest that obesity induced by long-term HFHS diet results in sensitization of the trigeminovascular system. Changes in TRPV1-mediated vascular reactions and CGRP release are pathophysiological alterations that may be of relevance to the enhanced headache susceptibility of obese individuals.
authors.affiliation: Department of Pharmacology and Pharmacotherapy, University of Debrecen, Debrecen, Hungary.
authors.forename: Balázs
authors.initials: B
authors.lastname: Marics
authors.affiliation: Department of Pharmacology and Pharmacotherapy, University of Debrecen, Debrecen, Hungary.
authors.forename: Barna
authors.initials: B
authors.lastname: Peitl
authors.affiliation: Department of Immunology, University of Debrecen, Debrecen, Hungary.
authors.forename: Kitti
authors.initials: K
authors.lastname: Pázmándi
authors.affiliation: Department of Immunology, University of Debrecen, Debrecen, Hungary.
authors.forename: Attila
authors.initials: A
authors.lastname: Bácsi
authors.affiliation: Department of Pharmacology and Pharmacotherapy, University of Debrecen, Debrecen, Hungary.
authors.forename: József
authors.initials: J
authors.lastname: Németh
authors.affiliation: Department of Physiology, University of Szeged, Szeged, Hungary.
authors.forename: Orsolya
authors.initials: O
authors.lastname: Oszlács
authors.affiliation: Department of Physiology, University of Szeged, Szeged, Hungary.
authors.forename: Gábor
authors.initials: G
authors.lastname: Jancsó
authors.affiliation: Department of Physiology, University of Szeged, Szeged, Hungary.
authors.forename: Mária
authors.initials: M
authors.lastname: Dux
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D001786:Blood Glucose / Q000187:drug effects; D015740:Calcitonin Gene-Related Peptide / Q000378:metabolism; D002211:Capsaicin / Q000494:pharmacology; D002560:Cerebrovascular Circulation / Q000187:drug effects; D004032:Diet / Q000009:adverse effects*; D004195:Disease Models, Animal; D004388:Dura Mater / Q000378:metabolism*; D004435:Eating / Q000502:physiology; D005215:Fasting / Q000097:blood; D007328:Insulin / Q000097:blood; D053583:Interleukin-1beta / Q000097:blood; D015850:Interleukin-6 / Q000097:blood; D008297:Male; D008578:Meninges / Q000098:blood supply; D009765:Obesity / Q000097:blood / Q000209:etiology* / Q000473:pathology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D018709:Statistics, Nonparametric; D050916:TRPV Cation Channels / Q000378:metabolism*
chemical_list: D001786:Blood Glucose; C000594089:IL1B protein, rat; D007328:Insulin; D053583:Interleukin-1beta; D015850:Interleukin-6; D050916:TRPV Cation Channels; D015740:Calcitonin Gene-Related Peptide; D002211:Capsaicin
keywords: calcitonin gene-related peptide; headache; meningeal blood flow; obesity; transient receptor potential vanilloid 1; trigeminal nociception