Supang Maneesri-le Grand

Involvement of Pro‐Nociceptive 5‐HT2A Receptor in the Pathogenesis of Medication‐Overuse Headache

(Headache 2010;50:185‐197)

Cortical hyperexcitability and mechanism of medication-overuse headache

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.

Pathophysiology of medication overuse headache--an update.

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.

Serotonin depletion leads to cortical hyperexcitability and trigeminal nociceptive facilitation via the nitric oxide pathway.

(Headache 2011;51:1152‐1160)

Serotonin depletion can enhance the cerebrovascular responses induced by cortical spreading depression via the nitric oxide pathway

Serotonin (5-HT) is an important neurotransmitter involved in the control of neural and vascular responses. 5-HT depletion can induce several neurological disorders, including migraines. Studies on a cortical spreading depression (CSD) migraine animal model showed that the cortical neurons sensitivity, vascular responses, and nitric oxide (NO) production were significantly increased in 5-HT depletion. However, the involvement of NO in the cerebrovascular responses in 5-HT depletion remains unclear. This study aimed to investigate the role of NO in the CSD-induced alterations of cerebral microvessels in 5-HT depletion. Rats were divided into four groups: control, control with L-NAME treatment, 5-HT depleted, and 5-HT depleted with L-NAME treatment. 5-HT depletion was induced by intraperitoneal injection with para-chlorophenylalanine (PCPA) 3 days before the experiment. The CSD was triggered by KCl application. After the second wave of CSD, N-nitro-l-arginine methyl ester (L-NAME) or saline was intravenously injected into the rats with or without L-NAME treatment groups, respectively. The intercellular adhesion molecules-1 (ICAM-1), cell adhesion molecules-1 (VCAM-1), and the ultrastructural changes of the cerebral microvessels were examined. The results showed that 5-HT depletion significantly increased ICAM-1 and VCAM-1 expressions in the cerebral cortex. The number of endothelial pinocytic vesicles and microvilli was higher in the 5-HT depleted group when compared to the control. Interestingly, L-NAME treatment significantly reduced the abnormalities observed in the 5-HT depleted group. The results of this study demonstrated that an increase of NO production is one of the mechanisms involved in the CSD-induced alterations of the cerebrovascular responses in 5-HT depletion.

The role of calcitonin gene-related peptide on the increase in transient receptor potential vanilloid-1 levels in trigeminal ganglion and trigeminal nucleus caudalis activation of rat.

Calcitonin gene-related peptide (CGRP) and transient receptor potential vanilloid-1 (TRPV1) play an important role in the development of pain and migraine pathogenesis. Increase in plasma CGRP levels is associated with delayed migraine-like attacks in migraine patients. Although several lines of evidence have indicated a key role of CGRP in migraine pain, its mechanisms remain unclear. In this study, we aimed to investigate the functional role of CGRP on trigeminal nociceptive pathway by determining the alteration in TRPV1 levels in trigeminal ganglion (TG) and the activation of trigeminal nucleus caudalis (TNC) of rat. Post intravenous injection of CGRP (600ng/kg) at 60min significantly increased the levels of TRPV1, CGRP, phosphorylated protein kinase C and phosphorylated cyclic AMP responsive element-binding protein in TG of rats. The number of small and medium TRPV1 and CGRP positive immunostaining neurons accompanying with co-localization of TRPV1 with CGRP neurons were significantly increased in TG of CGRP-injected rats. The sustained increase in c-Fos expression in TNC neurons was also observed in CGRP-injected rats. These results indicate that CGRP may participate in trigeminal nociceptive system sensitization by induced increase in TRPV1 and CGRP levels in TG neurons and activation of the central neurons in TNC.

Up-regulation of calcitonin gene-related peptide in trigeminal ganglion following chronic exposure to paracetamol in a CSD migraine animal model.

Previously, our group has demonstrated that chronic paracetamol (APAP) treatment induces alterations to the trigeminovascular nociceptive system in the cortical spreading depression (CSD) migraine animal model. The calcitonin gene related peptide (CGRP) is a key neuropeptide involved in the activation of the trigeminovascular nociceptive system. Therefore, this study examined the expression levels of CGRP in the trigeminal ganglion (TG) after chronic APAP exposure (0, 15, and 30 days) using a CSD model. Rats were divided into control, CSD only, APAP only and APAP treatment with CSD groups. A single injection (i.p.) of APAP (200 mg/kg body weight) was given to the 0-day APAP-treated groups, while the other APAP-treated groups received daily injections for 15 and 30 days. CSD was induced by the topical application of KCl to the parietal cortex. The protein expression of CGRP in the TG was evaluated by immunohistochemistry, and the CGRP mRNA level was investigated by real-time quantitative reverse transcription polymerase chain reaction. The results revealed that the induction of CSD significantly increased the level of CGRP protein but had no effect on CGRP mRNA level. Pretreatment with APAP 1 hour before CSD activation significantly reduced CGRP expression induced by CSD. In contrast, chronic treatment with APAP (15 and 30 days) significantly enhanced CGRP expression in both protein and mRNA levels when compared with the control groups. In combination with CSD, the expression of CGRP further increased in the animal with 30 day treatment. These findings indicate that chronic treatment with APAP induces an increase of CGRP expression in the TG. This alteration may be associated with the increased trigeminovascular nociception observed in our previous studies.

Chronic paracetamol treatment increases alterations in cerebral vessels in cortical spreading depression model

Recently, a number of non-beneficial effects of chronic treatment with paracetamol (APAP) have been reported in several systems, including circulatory system. In this study, the effects of acute (1 hour) and chronic (30 days) APAP treatments on cerebral microvessels in a cortical spreading depression (CSD) migraine animal model were investigated. Rats were divided into control, CSD only, and APAP treatment with or without CSD groups. A single dose (200 mg/kg body weight) or once-daily APAP treatment over 30 days was intraperitoneally injected into the acute and chronic APAP treated groups, respectively. CSD was induced by topical application of potassium chloride on the parietal cortex. Ultrastructural alterations and the expressions of cell adhesion molecules (ICAM-1 and VCAM-1) of the cerebral microvessels were monitored in all experimental groups. The results demonstrated that the induction of CSD caused ultrastructural alterations of the cerebral endothelial cells, as indicated by increases in microvillous and pinocytic formations and swelling of the astrocytic foot plates. The expression of ICAM-1 was significantly elevated in the CSD groups as compared with the control groups. Pretreatment with APAP 1 hour prior to CSD activation attenuated the alterations induced by CSD. However, chronic APAP treatment resulted in an enhancement of the ultrastructural alterations and the expressions of cell adhesion molecules in the cerebral microvessels that were induced by CSD. Interestingly, the rats that received chronic APAP treatment alone exhibited higher degrees of ultrastructural alterations and ICAM-1 expression than those in the control group. Based on these results, we suggest that short-term treatment with APAP has no effect on cerebral microvessels and that chronic APAP treatment can alter cerebral microvasculature, especially when combined with CSD activation.

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.