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Trigeminal ganglion transcriptome analysis in 2 rat models of medication-overuse headache reveals coherent and widespread induction of pronociceptive gene expression patterns

Buonvicino, Danielaa; Urru, Matteoa; Muzzi, Mirkoa; Ranieri, Giuseppea; Luceri, Cristinab; Oteri, Claudiaa; Lapucci, Andreaa; Chiarugi, Albertoa,*

doi: 10.1097/j.pain.0000000000001291
Research Paper

We attempted to gather information on the pathogenesis of medication-overuse headache, as well as on the neurochemical mechanisms through which symptomatic medication overuse concurs to headache chronification. Transcriptional profiles were therefore evaluated as an index of the homeostasis of the trigeminovascular system in the trigeminal ganglion of female rats exposed for 1 month to daily oral doses of eletriptan or indomethacin. We report that both drug treatments change trigeminal ganglion gene expression to a similar extend. Of note, qualitative transcriptomic analysis shows that eletriptan and indomethacin prompt nearly identical, increased expression of genes coding for proteins involved in migraine pathogenesis and central pain sensitization such as neuropeptides, their cognate receptors, prostanoid, and nitric oxide–synthesizing enzymes, as well as TRP channels. These genes, however, were not affected in thoracic dorsal root ganglia. Of note, lowering of orofacial nociceptive thresholds, as well as forepaw hyperalgesia occurred in both indomethacin- and eletriptan-treated rats. Our study reveals that chronic rat exposure to 2 acute headache medications with completely different mechanisms of action prompts pain sensitization with highly similar induction of pronociceptive genes selectively within the trigeminal ganglion. Data further our understanding of medication-overuse headache pathogenesis and provide hints for specific mechanism–based treatment options.

Chronic rat exposure to eletriptan or indomethacin prompts similar induction of pronociceptive genes within the trigeminal ganglion, a condition explaining pathogenesis of medication-overuse headache.

aDepartment of Health Sciences, Section of Clinical Pharmacology and Oncology, University of Florence, Florence, Italy

bDepartment of NEUROFARBA, Division of Pharmacology and Toxicology, University of Florence, Florence, Italy

Corresponding author. Address: Department of Health Sciences, Section of Clinical Pharmacology and Oncology, University of Florence, Viale Pieraccini 6, 50139 Florence, Italy. Tel.: +39-055-4271230; fax: +39-055-4271280. E-mail address: alberto.chiarugi@unifi.it (A. Chiarugi).

Sponsorships or competing interests that may be relevant to content are disclosed at the end of this article.

Received March 19, 2018

Received in revised form May 10, 2018

Accepted May 14, 2018

© 2018 International Association for the Study of Pain
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