Original article. Potential risk of dihydroergotamine causing medicationoveruse headache: preclinical evidence

Abstract

Background: Overuse of abortive medication is a common factor contributing to an increase in headache frequency in patients with migraine. Whether or not chronic exposure to dihydroergotamine (DHE) can lead to this transformation remains uncertain. Objective: To determine the effect of acute and chronic DHE exposure on development of cortical spreading depression (CSD) and trigeminal nociception. Methods: The study comprised two experiments, namely acute and chronic exposure. In the acute experiment, a single dose of DHE (100 μg/kg) was given to male Wistar rats after successful induction of CSD. In the chronic experiment, DHE was given daily for the period of 0, 7, 14, and 28 days. CSD was induced 30 minutes after the final injection and the cortical field potential was recorded. Expression of c-Fos in caudal brainstem was used as an indicator of trigeminal nociception. Results: Acute exposure to DHE attenuated the expression of c-Fos in the caudal brainstem without change in CSD response. By contrast, chronic exposure (14 and 28 days) to DHE increased the area under the curve of CSD waveforms. In parallel with the change in the CSD, there was significant increase of c-Fos expression within 14 days exposure to DHE and the expression remained significantly elevated for up to the 28 days examined. Conclusion: Our study demonstrated that chronic DHE administration can increase cortical excitability and increase c-Fos expression in caudal brainstem. Our preclinical evidence suggests the possible adverse effect of chronic DHE use in causing chronification of headache.

Altered activity in the nucleus raphe magnus underlies cortical hyperexcitability and facilitates trigeminal nociception in a rat model of medication overuse headache

“…Drug Laboratories (Bangkok, Thailand). The acetaminophen dose used in present experiments was 200 mg/kg as consistent with previous studies [3, 6, 7, 10]. Normal saline was administered to rats in a vehicle-treated control group.…”

“…Persistent administration of a triptan to rats elicited periorbital cutaneous allodynia [5]. An increase in frequency of cortical spreading depression (CSD) and number of CSD-evoked c-Fos-immunoreactive (Fos-IR) cells in the trigeminal nucleus caudalis (TNC) was demonstrated in rats receiving acetaminophen or dihydroergotamine [3, 6]. The hypothesis of cortical hyperexcitability is supported by clinical evidence.…”

Involvement of nucleus raphe magnus in neuronal excitability of long term paracetamol-treated rats

“…Consistently, 30-days paracetamol administered rats showed an increase in the number of CSD wave (12). Moreover, a significant increase of area under the curve from the CSD amplitude in 30 days dihydroergotamine-treated rats was reported (21). All these previous studies were reported an alteration of CSD event which associate to a cortical hyperexcitability in long term drug-exposed animals.…”

“…Allodynia is a clinical manifestation that represents a state of central sensitization (5). Also, long term dihydroergotamine or paracetamol exposure can increase Fos expression in the TNC and cortex of rats which indicated an enhancement of neuronal activity (12,21).…”

Pathophysiology of Medication Overuse Headache—An Update

“…CSD‐evoked increases of 5‐HT 2A serotonin receptor expression and c‐Fos‐immunoreactivity in the cerebral cortex and TNC have been found in rats after chronic acetaminophen treatment . Increased CSD development and increased TNC c‐Fos immunoreactivity were also shown in rats chronically treated with dihydroergotamine . These findings suggest that chronic exposure to either antimigraine drugs or nonspecific analgesics can increase the excitability of cortical neurons, thus increasing susceptibility to develop CSD, facilitating the trigeminal nociceptive process.…”