Effects of kynurenic acid analogue 1 (KYNA-A1) in nitroglycerin-induced hyperalgesia: Targets and anti-migraine mechanisms

Rosaria Greco, Chiara Demartini, Anna Maria Zanaboni, Elisa Redavide, Selena Pampalone, Joseph Toldi, F. Fülöp, Fabio Blandini, Giuseppe Nappi, Giorgio Sandrini, L. Vécsei, Cristina Tassorelli

Research output: Contribution to journalArticle

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Abstract

Background: Trigeminal sensitization represents a major mechanism underlying migraine attacks and their recurrence. Nitroglycerin (NTG) administration provokes spontaneous migraine-like headaches and in rat, an increased sensitivity to the formalin test. Kynurenic acid (KYNA), an endogenous regulator of glutamate activity and its analogues attenuate NTG-induced neuronal activation in the nucleus trigeminalis caudalis (NTC). The anti-hyperalgesic effect of KYNA analogue 1 (KYNA-A1) was investigated on animal models specific for migraine pain. Aim: Rats made hyperalgesic by NTG administration underwent the plantar or orofacial formalin tests. The effect of KYNA-A1 was evaluated in terms of nocifensive behavior and of neuronal nitric oxide synthase (nNOS), calcitonin gene-related peptide (CGRP) and cytokines expression in areas involved in trigeminal nociception. Results: KYNA-A1 abolished NTG-induced hyperalgesia in both pain models; NTG alone or associated to formalin injection induced an increased mRNA expression of CGRP, nNOS and cytokines in the trigeminal ganglia and central areas, which was reduced by KYNA-A1. Additionally, NTG caused a significant increase in nNOS immunoreactivity in the NTC, which was prevented by KYNA-A1. Conclusion: Glutamate activity is likely involved in mediating hyperalgesia in an animal model specific for migraine. Its inhibition by means of a KYNA analogue modulates nNOS, CGRP and cytokines expression at peripheral and central levels.

Original languageEnglish
Pages (from-to)1272-1284
Number of pages13
JournalCephalalgia
Volume37
Issue number13
DOIs
Publication statusPublished - Nov 1 2017

Fingerprint

Kynurenic Acid
Hyperalgesia
Nitroglycerin
Migraine Disorders
Nitric Oxide Synthase Type I
Calcitonin Gene-Related Peptide
Pain Measurement
Cytokines
Glutamic Acid
Animal Models
Pain
Trigeminal Ganglion
Nociception
Formaldehyde
Recurrence
Messenger RNA
Injections

Keywords

  • hyperalgesia
  • KYNA amides
  • migraine
  • nitroglycerin

ASJC Scopus subject areas

  • Clinical Neurology

Cite this

Greco, R., Demartini, C., Zanaboni, A. M., Redavide, E., Pampalone, S., Toldi, J., ... Tassorelli, C. (2017). Effects of kynurenic acid analogue 1 (KYNA-A1) in nitroglycerin-induced hyperalgesia: Targets and anti-migraine mechanisms. Cephalalgia, 37(13), 1272-1284. https://doi.org/10.1177/0333102416678000

Effects of kynurenic acid analogue 1 (KYNA-A1) in nitroglycerin-induced hyperalgesia : Targets and anti-migraine mechanisms. / Greco, Rosaria; Demartini, Chiara; Zanaboni, Anna Maria; Redavide, Elisa; Pampalone, Selena; Toldi, Joseph; Fülöp, F.; Blandini, Fabio; Nappi, Giuseppe; Sandrini, Giorgio; Vécsei, L.; Tassorelli, Cristina.

In: Cephalalgia, Vol. 37, No. 13, 01.11.2017, p. 1272-1284.

Research output: Contribution to journalArticle

Greco, R, Demartini, C, Zanaboni, AM, Redavide, E, Pampalone, S, Toldi, J, Fülöp, F, Blandini, F, Nappi, G, Sandrini, G, Vécsei, L & Tassorelli, C 2017, 'Effects of kynurenic acid analogue 1 (KYNA-A1) in nitroglycerin-induced hyperalgesia: Targets and anti-migraine mechanisms', Cephalalgia, vol. 37, no. 13, pp. 1272-1284. https://doi.org/10.1177/0333102416678000
Greco, Rosaria ; Demartini, Chiara ; Zanaboni, Anna Maria ; Redavide, Elisa ; Pampalone, Selena ; Toldi, Joseph ; Fülöp, F. ; Blandini, Fabio ; Nappi, Giuseppe ; Sandrini, Giorgio ; Vécsei, L. ; Tassorelli, Cristina. / Effects of kynurenic acid analogue 1 (KYNA-A1) in nitroglycerin-induced hyperalgesia : Targets and anti-migraine mechanisms. In: Cephalalgia. 2017 ; Vol. 37, No. 13. pp. 1272-1284.
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AU - Toldi, Joseph

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N2 - Background: Trigeminal sensitization represents a major mechanism underlying migraine attacks and their recurrence. Nitroglycerin (NTG) administration provokes spontaneous migraine-like headaches and in rat, an increased sensitivity to the formalin test. Kynurenic acid (KYNA), an endogenous regulator of glutamate activity and its analogues attenuate NTG-induced neuronal activation in the nucleus trigeminalis caudalis (NTC). The anti-hyperalgesic effect of KYNA analogue 1 (KYNA-A1) was investigated on animal models specific for migraine pain. Aim: Rats made hyperalgesic by NTG administration underwent the plantar or orofacial formalin tests. The effect of KYNA-A1 was evaluated in terms of nocifensive behavior and of neuronal nitric oxide synthase (nNOS), calcitonin gene-related peptide (CGRP) and cytokines expression in areas involved in trigeminal nociception. Results: KYNA-A1 abolished NTG-induced hyperalgesia in both pain models; NTG alone or associated to formalin injection induced an increased mRNA expression of CGRP, nNOS and cytokines in the trigeminal ganglia and central areas, which was reduced by KYNA-A1. Additionally, NTG caused a significant increase in nNOS immunoreactivity in the NTC, which was prevented by KYNA-A1. Conclusion: Glutamate activity is likely involved in mediating hyperalgesia in an animal model specific for migraine. Its inhibition by means of a KYNA analogue modulates nNOS, CGRP and cytokines expression at peripheral and central levels.

AB - Background: Trigeminal sensitization represents a major mechanism underlying migraine attacks and their recurrence. Nitroglycerin (NTG) administration provokes spontaneous migraine-like headaches and in rat, an increased sensitivity to the formalin test. Kynurenic acid (KYNA), an endogenous regulator of glutamate activity and its analogues attenuate NTG-induced neuronal activation in the nucleus trigeminalis caudalis (NTC). The anti-hyperalgesic effect of KYNA analogue 1 (KYNA-A1) was investigated on animal models specific for migraine pain. Aim: Rats made hyperalgesic by NTG administration underwent the plantar or orofacial formalin tests. The effect of KYNA-A1 was evaluated in terms of nocifensive behavior and of neuronal nitric oxide synthase (nNOS), calcitonin gene-related peptide (CGRP) and cytokines expression in areas involved in trigeminal nociception. Results: KYNA-A1 abolished NTG-induced hyperalgesia in both pain models; NTG alone or associated to formalin injection induced an increased mRNA expression of CGRP, nNOS and cytokines in the trigeminal ganglia and central areas, which was reduced by KYNA-A1. Additionally, NTG caused a significant increase in nNOS immunoreactivity in the NTC, which was prevented by KYNA-A1. Conclusion: Glutamate activity is likely involved in mediating hyperalgesia in an animal model specific for migraine. Its inhibition by means of a KYNA analogue modulates nNOS, CGRP and cytokines expression at peripheral and central levels.

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