title: Nitric oxide synthase, calcitonin gene-related peptide and NK-1 receptor mechanisms are involved in GTN-induced neuronal activation.
abstract: OBJECTIVE
  Infusion of glyceryltrinitrate (GTN), a nitric oxide (NO) donor, in awake, freely moving rats closely mimics a universally accepted human model of migraine and responds to sumatriptan treatment. Here we analyse the effect of nitric oxide synthase (NOS) and calcitonin gene-related peptide (CGRP) systems on the GTN-induced neuronal activation in this model.
  
  
  METHODS
  The femoral vein was catheterised in rats and GTN was infused (4 µg/kg/min, for 20 minutes, intravenously). Immunohistochemistry was performed to analyse Fos, nNOS and CGRP and Western blot for measuring nNOS protein expression. The effect of olcegepant, L-nitro-arginine methyl ester (L-NAME) and neurokinin (NK)-1 receptor antagonist L-733060 were analysed on Fos activation.
  
  
  RESULTS
  GTN-treated rats showed a significant increase of nNOS and CGRP in dura mater and CGRP in the trigeminal nucleus caudalis (TNC). Upregulation of Fos was observed in TNC four hours after the infusion. This activation was inhibited by pre-treatment with olcegepant. Pre-treatment with L-NAME and L-733060 also significantly inhibited GTN induced Fos expression.
  
  
  CONCLUSIONS
  The present study indicates that blockers of CGRP, NOS and NK-1 receptors all inhibit GTN induced Fos activation. These findings also predict that pre-treatment with olcegepant may be a better option than post-treatment to study its inhibitory effect in GTN migraine models.
authors.affiliation: Danish Headache Centre, Department of Neurology, Glostrup Research Institute, Glostrup Hospital, University of Copenhagen, Denmark.
authors.forename: Roshni
authors.initials: R
authors.lastname: Ramachandran
authors.forename: Deepak Kumar
authors.initials: DK
authors.lastname: Bhatt
authors.forename: Kenneth Beri
authors.initials: KB
authors.lastname: Ploug
authors.forename: Anders
authors.initials: A
authors.lastname: Hay-Schmidt
authors.forename: Inger
authors.initials: I
authors.lastname: Jansen-Olesen
authors.forename: Saurabh
authors.initials: S
authors.lastname: Gupta
authors.forename: Jes
authors.initials: J
authors.lastname: Olesen
mesh_terms: D000818:Animals; D015740:Calcitonin Gene-Related Peptide / Q000378:metabolism*; D000077221:Calcitonin Gene-Related Peptide Receptor Antagonists; D004151:Dipeptides / Q000494:pharmacology; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D008297:Male; D008881:Migraine Disorders / Q000139:chemically induced / Q000188:drug therapy* / Q000378:metabolism*; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D064729:Neurokinin-1 Receptor Antagonists / Q000494:pharmacology; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D052248:Nitric Oxide Synthase Type I / Q000378:metabolism*; D005996:Nitroglycerin / Q000494:pharmacology*; D010879:Piperazines; D010880:Piperidines / Q000494:pharmacology; D020671:Posterior Horn Cells / Q000187:drug effects / Q000378:metabolism; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism; D011799:Quinazolines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D018040:Receptors, Neurokinin-1 / Q000378:metabolism*; D014276:Trigeminal Nerve / Q000098:blood supply / Q000378:metabolism; D014665:Vasodilator Agents / Q000494:pharmacology; D014851:Wakefulness
chemical_list: D000077221:Calcitonin Gene-Related Peptide Receptor Antagonists; D004151:Dipeptides; D004791:Enzyme Inhibitors; D064729:Neurokinin-1 Receptor Antagonists; D010879:Piperazines; D010880:Piperidines; D016760:Proto-Oncogene Proteins c-fos; D011799:Quinazolines; D018040:Receptors, Neurokinin-1; D014665:Vasodilator Agents; C103788:3-((3,5-bis(trifluoromethyl)phenyl)methyloxy)-2-phenylpiperidine; D052248:Nitric Oxide Synthase Type I; C496322:Nos1 protein, rat; D005996:Nitroglycerin; D015740:Calcitonin Gene-Related Peptide; D019331:NG-Nitroarginine Methyl Ester; C406305:olcegepant
keywords: L-nitro-arginine methyl ester (L-NAME); Nitric oxide (NO); awake rat model; glyceryltrinitrate (GTN); migraine; neuronal activation; nitric oxide synthase (NOS); olcegepant; sumatriptan; trigeminal vascular system