Nitric oxide synthase, calcitonin gene-related peptide and NK-1 receptor mechanisms are involved in GTN-induced neuronal activation

Roshni Ramachandran; Deepak Kumar Bhatt; Kenneth Beri Ploug; Anders Hay-Schmidt; Inger Jansen-Olesen; Saurabh Gupta; Jes Olesen

doi:10.1177/0333102413502735

Nitric oxide synthase, calcitonin gene-related peptide and NK-1 receptor mechanisms are involved in GTN-induced neuronal activation

Roshni Ramachandran, Deepak Kumar Bhatt, Kenneth Beri Ploug, Anders Hay-Schmidt, Inger Jansen-Olesen, Saurabh Gupta, Jes Olesen

Department of Clinical Medicine

45 Citations (Scopus)

Abstract

Background and aim: 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. Materials and methods: The femoral vein was catheterised in rats and GTN was infused (4 mg/kg/min, for 20 minutes, intravenously). Immunohistochemistry was performed to analyse Fos, nNOS and CGRP andWestern 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. Conclusion: 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.

Original language	English
Journal	Cephalalgia : an international journal of headache
Volume	34
Issue number	2
Pages (from-to)	136-147
Number of pages	12
ISSN	0333-1024
DOIs	https://doi.org/10.1177/0333102413502735
Publication status	Published - Feb 2014

Keywords

Animals
Calcitonin Gene-Related Peptide
Dipeptides
Disease Models, Animal
Enzyme Inhibitors
Humans
Male
Migraine Disorders
NG-Nitroarginine Methyl Ester
Neurokinin-1 Receptor Antagonists
Neurons
Nitric Oxide Synthase Type I
Nitroglycerin
Piperidines
Posterior Horn Cells
Proto-Oncogene Proteins c-fos
Quinazolines
Rats
Rats, Sprague-Dawley
Receptors, Calcitonin Gene-Related Peptide
Receptors, Neurokinin-1
Trigeminal Nerve
Vasodilator Agents
Wakefulness

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Nitric oxide synthase, calcitonin gene-related peptide and NK-1 receptor mechanisms are involved in GTN-induced neuronal activation. / Ramachandran, Roshni; Bhatt, Deepak Kumar; Ploug, Kenneth Beri et al.

In: Cephalalgia : an international journal of headache, Vol. 34, No. 2, 02.2014, p. 136-147.

Research output: Contribution to journal › Journal article › Research › peer-review

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title = "Nitric oxide synthase, calcitonin gene-related peptide and NK-1 receptor mechanisms are involved in GTN-induced neuronal activation",

abstract = "Background and aim: 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. Materials and methods: The femoral vein was catheterised in rats and GTN was infused (4 mg/kg/min, for 20 minutes, intravenously). Immunohistochemistry was performed to analyse Fos, nNOS and CGRP andWestern 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. Conclusion: 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.",

keywords = "Animals, Calcitonin Gene-Related Peptide, Dipeptides, Disease Models, Animal, Enzyme Inhibitors, Humans, Male, Migraine Disorders, NG-Nitroarginine Methyl Ester, Neurokinin-1 Receptor Antagonists, Neurons, Nitric Oxide Synthase Type I, Nitroglycerin, Piperidines, Posterior Horn Cells, Proto-Oncogene Proteins c-fos, Quinazolines, Rats, Rats, Sprague-Dawley, Receptors, Calcitonin Gene-Related Peptide, Receptors, Neurokinin-1, Trigeminal Nerve, Vasodilator Agents, Wakefulness",

author = "Roshni Ramachandran and Bhatt, {Deepak Kumar} and Ploug, {Kenneth Beri} and Anders Hay-Schmidt and Inger Jansen-Olesen and Saurabh Gupta and Jes Olesen",

year = "2014",

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doi = "10.1177/0333102413502735",

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pages = "136--147",

journal = "Cephalalgia, Supplement",

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T1 - Nitric oxide synthase, calcitonin gene-related peptide and NK-1 receptor mechanisms are involved in GTN-induced neuronal activation

AU - Ramachandran, Roshni

AU - Bhatt, Deepak Kumar

AU - Ploug, Kenneth Beri

AU - Hay-Schmidt, Anders

AU - Jansen-Olesen, Inger

AU - Gupta, Saurabh

AU - Olesen, Jes

PY - 2014/2

Y1 - 2014/2

N2 - Background and aim: 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. Materials and methods: The femoral vein was catheterised in rats and GTN was infused (4 mg/kg/min, for 20 minutes, intravenously). Immunohistochemistry was performed to analyse Fos, nNOS and CGRP andWestern 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. Conclusion: 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.

AB - Background and aim: 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. Materials and methods: The femoral vein was catheterised in rats and GTN was infused (4 mg/kg/min, for 20 minutes, intravenously). Immunohistochemistry was performed to analyse Fos, nNOS and CGRP andWestern 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. Conclusion: 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.

KW - Animals

KW - Calcitonin Gene-Related Peptide

KW - Dipeptides

KW - Disease Models, Animal

KW - Enzyme Inhibitors

KW - Humans

KW - Male

KW - Migraine Disorders

KW - NG-Nitroarginine Methyl Ester

KW - Neurokinin-1 Receptor Antagonists

KW - Neurons

KW - Nitric Oxide Synthase Type I

KW - Nitroglycerin

KW - Piperidines

KW - Posterior Horn Cells

KW - Proto-Oncogene Proteins c-fos

KW - Quinazolines

KW - Rats

KW - Rats, Sprague-Dawley

KW - Receptors, Calcitonin Gene-Related Peptide

KW - Receptors, Neurokinin-1

KW - Trigeminal Nerve

KW - Vasodilator Agents

KW - Wakefulness

U2 - 10.1177/0333102413502735

DO - 10.1177/0333102413502735

M3 - Journal article

C2 - 24000375

SN - 0800-1952

VL - 34

SP - 136

EP - 147

JO - Cephalalgia, Supplement

JF - Cephalalgia, Supplement

IS - 2

ER -

Nitric oxide synthase, calcitonin gene-related peptide and NK-1 receptor mechanisms are involved in GTN-induced neuronal activation

Abstract

Keywords

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