The Journal of Headache and Pain

Official Journal of the "European Headache Federation" and of "Lifting The Burden - The Global Campaign against Headache"

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Volume 16 Supplement 1

1st Joint ANIRCEF-SISC Congress

Open Access

O041. GRIA3 (glutamate receptor, ionotropic, ampa 3) gene polymorphism influences cortical response to somatosensory stimulation in medication-overuse headache (MOH) patients

  • Cherubino Di Lorenzo1Email author,
  • Gianluca Coppola2,
  • Gaetano Grieco3,
  • Filippo Maria Santorelli4,
  • Esterina Pascale5 and
  • Francesco Pierelli5, 6
The Journal of Headache and Pain201516(Suppl 1):A49

Published: 28 September 2015

The Erratum to this article has been published in The Journal of Headache and Pain 2017 18:11


MigraineCentral SensitizationChronic MigraineursRs3761555 Single Nucleotide PolymorphismAnalyze Single Nucleotide Polymorphism


Medication-overuse headache (MOH) is a secondary form of chronic headache developed by migraineurs after prolonged symptomatic medication overuse. Bio-behavioural sensitization is a key mechanism in MOH pathophysiology, as evidenced by cortical somatosensory evoked potentials (SSEPs) studies. While episodic migraineurs, recorded between attacks, showed lower initial SSEP amplitudes and lack of habitation during stimulus repetition, in MOH patients the SSEPs were initially higher and further increased during stimulus repetition, resulting in a persistent sensitisation proportional to the duration of the headache chronification phase. The central sensitization seems to be strongly dependent by glutamate. Amongst various gene polymorphisms in the glutamatergic system, only the Glutamate Receptor Ionotropic AMPA 3 (GRIA3) was previously associated with migraine. The aim of our study was to verify whether GRIA3 rs3761555 single nucleotide polymorphism (SNP) could influence processes of central sensitization of MOH patients.


We measured SSEP amplitudes as a marker of sensitization, and SSEP habituation over two sequential blocks during uninterrupted peripheral stimulation in a well-characterized group of 60 MOH patients who underwent GRIA3 rs3761555 polymorphism analysis.


Sixty (47 females) MOH patients were enrolled in the study: 27 (9 males) resulted as T/T and 26 C/T and 7 (4 males) T/T. In the comparison among the three genotypes, the grand average of all the neurophysiological data did not emerge in terms of latencies and amplitudes. The analysis of block amplitude averages showed differences in SSEP 1st (p = 0.028) and 3rd (p = 0.023) block amplitude.


Our findings are consistent with the hypothesis that the glutamatergic system influences central sensitization processes in MOH patients, by plastic changes in the “pain matrix”, resulting in decreased nociceptive thresholds, increased responsiveness to peripheral stimuli and expansion of the receptive fields of central nociceptors. These phenomena are at the base of migraine chronification, maybe due to the higher levels of glutamate, as it is measured in the CSF of chronic migraineurs. Indeed, we observed that although MOH patients overall had notoriously larger SSEP 1st block amplitude than controls, and deficient habituation, GRIA3 rs3761555 SNP influenced the amplitude of blocks, according to a decreasing gradient from T/T to C/C subjects. Although the analyzed SNP functional consequences are unknown, it was highlighted as somehow implicated in migraine pathophysiology in two independent cohorts of patients, maybe by an altered transcriptional activity. Hitherto, we are not aware of other disorders potentially related to this SNP.

Written informed consent to publication was obtained from the patient(s).


Authors’ Affiliations

Don Carlo Gnocchi Onlus Foundation, Rome, Italy
Department of Neurophysiology of Vision and Neuro-ophthalmology, G. B. Bietti Foundation-IRCCS, Rome, Italy
IRCCS Neurological Institute “C. Mondino”, Laboratory of Neurogenetics, Pavia, Italy
IRCCS Fondazione Stella Maris, Molecular Medicine & Neurodegenerative Diseases, Pisa, Italy
Department of medico-surgical sciences and biotechnologies, “Sapienza" University of Rome, Rome, Italy
IRCCS Neuromed, Pozzilli, Italy


© Di Lorenzo et al. 2015

This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. The Creative Commons Public Domain Dedication waiver ( applies to the data made available in this article, unless otherwise stated.


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