Our findings indicate that 5-HT depletion enhances CSD-induced trigeminal nociception by increasing the cortical excitability and sensitivity of trigeminal nociceptive system. These findings may provide a better understanding regarding the relationship between low 5-HT and clinical headaches.

The pathogenesis of medication overuse headache is unclear. Clinical and preclinical studies have consistently demonstrated increased excitability of neurons in the cerebral cortex and trigeminal system after medication overuse. Cortical hyperexcitability may facilitate the development of cortical spreading depression, while increased excitability of trigeminal neurons may facilitate the process of peripheral and central sensitization. These changes may be secondary to the derangement of central, probably serotonin (5-HT)-, and perhaps endocannabinoid-dependent or other, modulating systems. Increased expression of excitatory cortical 5-HT2A receptors may increase the susceptibility to developing cortical spreading depression, an analog of migraine aura. A reduction of diffuse noxious inhibitory controls may facilitate the process of central sensitization, activate the nociceptive facilitating system, or promote similar molecular mechanisms to those involved in kindling. Low 5-HT levels also increase the expression and release of calcitonin gene-related peptide from the trigeminal ganglion and sensitize trigeminal nociceptors. Thus, derangement of central modulation of the trigeminal system as a result of chronic medication use may increase sensitivity to pain perception and foster or reinforce medication overuse headache. Keywords: medication overuse headache, serotonin, trigeminal system, sensitization, endogenous pain control system, diffuse noxious inhibitory controlOveruse of symptomatic medications is a common problem observed in patients with primary headaches, especially migraine and tension-type headache. In addition to other adverse effects, prolonged use of these abortive compounds can produce the paradoxical effect of deteriorating the underlying headache pathophysiology. This results in a clinical syndrome known as "medication overuse headache" (MOH). According to the International Classification of Headache Disorders (2nd edition), MOH refers to the frequent headache condition (15 days per month or more) that occurs in patients with primary headaches who regularly use 1 or more acute and/or symptomatic drugs for more than 3 months.1 This clinical syndrome is common. Population-based studies report the 1-year prevalence rate of MOH to be from 1% to 2%.2 The relative frequency is much higher in secondary and tertiary care centers.3 This disorder strongly affects the quality of life of patients and causes substantial economic burden.There is no clear explanation of how chronic abortive drug exposure can increase headache frequency and result in MOH. Some possible mechanisms have been summarized in recent reviews. [4][5][6] In this article, we review the recent studies, both clinical and preclinical, investigating the pathogenesis of this condition. Possible mechanisms underlying the process of medication-induced headache transformation are also proposed. SOME CLINICAL CLUESSome clinical features of MOH provide clues about its pathogenesis. First, MOH occurs mostly in patients with primary headaches. Ch...

The present study was conducted to determine the effect of acute (1 h) and chronic (daily dose for 30 days) paracetamol administration on the development of cortical spreading depression (CSD), CSD-evoked cortical hyperaemia and CSD-induced Fos expression in cerebral cortex and trigeminal nucleus caudalis (TNC). Paracetamol (200 mg/kg body weight, intraperitonealy) was administered to Wistar rats. CSD was elicited by topical application of solid KCl. Electrocorticogram and cortical blood flow were recorded. Results revealed that acute paracetamol administration substantially decreased the number of Fos-immunoreactive cells in the parietal cortex and TNC without causing change in CSD frequency. On the other hand, chronic paracetamol administration led to an increase in CSD frequency as well as CSD-evoked Fos expression in parietal cortex and TNC, indicating an increase in cortical excitability and facilitation of trigeminal nociception. Alteration of cortical excitability which leads to an increased susceptibility of CSD development can be a possible mechanism underlying medication-overuse headache.

These findings suggest that up-regulation of pro-nociceptive 5-HT(2A) receptor is an important step in the process of cortical hyper-excitation and nociceptive facilitation induced by chronic analgesic exposure.

Inhibition of NO production can counter both the cortical hyperexcitability and facilitation of trigeminal nociception that develop in the depleted 5-HT state. Therefore, NO is likely involved in the increase in both CSD events and CSD-evoked trigeminal nociception under decreased 5-HT conditions.