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

Abstract

Background The pathogenesis of medication overuse headache (MOH) involves hyperexcitability of cortical and trigeminal neurons. Derangement of the brainstem modulating system, especially raphe nuclei may contribute to this hyperexcitability. The present study aimed to investigate the involvement of the nucleus raphe magnus (NRM) in the development of cortical and trigeminal hyperexcitability in a rat model of MOH. Results Chronic treatment with acetaminophen increased the frequency of cortical spreading depression (CSD) and the number of c-Fos-immunoreactive (Fos-IR) neurons in the trigeminal nucleus caudalis (TNC). In the control group, muscimol microinjected into the NRM increased significantly the frequency of CSD-evoked direct current shift and Fos-IR neurons in the TNC. This facilitating effect was not found in rats with chronic acetaminophen exposure. In a model of migraine induced by intravenous systemic infusion of nitroglycerin (NTG), rats with chronic exposure to acetaminophen exhibited significantly more frequent neuronal firing in the TNC and greater Fos-IR than those without the acetaminophen treatment. Muscimol microinjection increased neuronal firing in the TNC in control rats, but not in acetaminophen-treated rats. The number of Fos-IR cells in TNC was not changed significantly. Conclusion Chronic exposure to acetaminophen alters the function of the NRM contributing to cortical hyperexcitability and facilitating trigeminal nociception.

An underrepresented majority: A systematic review utilizing allodynic criteria to examine the present scarcity of discrete animal models for episodic migraine

“…While these limitations exist, it is our belief that the presence of extracephalic CA reflects increased synaptic density in nociceptive pathways, as demonstrated by increased staining for c-Fos positive neurons in animals subjected to the KCl, NTG, IS, and medication overuse protocols (40,80,97,140,141). This mirrors the increase in synaptic density seen in patients with chronic pain and offers an explanation for the increased susceptibility to CSD seen in models priming animals to stress (17,96,97,100,101).…”

“…This can lead to these experiments having significant cost in terms of time expenditure and drug expenses. Mechanistically, these studies show that chronic dosing of triptans, morphine, and acetaminophen increases excitability in cortical sensory regions and the trigeminal nucleus caudalis (93–99,101). There is also evidence that medication overuse in animals leads to increased susceptibility to both KCl- and NTG-induced CSD (96,97,100,101).…”

“…Mechanistically, these studies show that chronic dosing of triptans, morphine, and acetaminophen increases excitability in cortical sensory regions and the trigeminal nucleus caudalis (93–99,101). There is also evidence that medication overuse in animals leads to increased susceptibility to both KCl- and NTG-induced CSD (96,97,100,101). For morphine and NSAID dosing protocols, there is evidence that overuse increases whole-body CA, reflecting the allodynic features of CM (23–26,93,99).…”

“…It has been suggested that chronic use of analgesics may lead to loss of diffuse noxious inhibitory controls, leading to chronic pain states (92). For these reasons, animal models of migraine-like pain have been developed that rely on chronic dosing of opioids (93–95), triptans (96–99), and NSAIDs (99–101).…”

Entwicklung sekundärer Kopfschmerzen durch Exposition oder Übergebrauch einer Substanz

“…In genetischen Studien wurden polymorphe Varianten in Genen des dopaminergen Gensystems (DRD4, DRD2, SLC6A3) sowie in Genen, die mit der Entwicklung einer Drogenabhängigkeit (WSF1, BDNF, ACE, HDAC3) in Zusammenhang stehen, beschrieben, die möglicherweise die Anfälligkeit für MOH bestimmen oder als Determinanten für einen häufigen Drogenkonsum in Frage kommen [38]. Der chronische Gebrauch von Triptanen oder Analgetika führt zu einer abnormalen Modulation des serotonergen Systems [39,40], zur Sensibilisierung verschiedener nozizeptiver Signalwege [41][42][43][44] und sogar zu strukturellen Veränderungen in bestimmten Hirnstrukturen, wie dem ventromedialen präfrontalen Kortex (VMPFC), dem Nucleus accumbens und der Substantia nigra/der ventralen Tegmentfläche. Die pathophysiologischen Mechanismen der Entstehung des MOH sind teilweise vergleichbar mit Abhängigkeitsmechanismen und süchtig machenden Komponenten, die im Allgemeinen mit psychiatrischen Störungen in Verbindung gebracht werden [45].…”