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, Ferenc Fülöp, Fabio Blandini, Giuseppe Nappi, Giorgio Sandrini, László Vécsei, Cristina Tassorelli

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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
Issue number13
Publication statusPublished - Nov 2017



  • Journal Article

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Greco, R., Demartini, C., Zanaboni, A. M., 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, 37(13), 1272-1284. https://doi.org/10.1177/0333102416678000