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Objectives.- To determine the involvement of 5-HT2A (5-HT2A) receptor in the process of trigeminal plasticity induced by chronic analgesic exposure and in the process of inflammatory-induced thermal hyperalgesia. Background.- Derangement in 5-HT2A serotonin receptor has been reported to implicate in pathogenesis of medication-overuse headache. No clear explanation concerning the precise roles of these receptors in the process. Methods.- Wistar rats were daily administered with paracetamol (200 mg/kg) for 30 days. On the next day, ketanserin, a 5-HT2A antagonist, or saline was given prior to cortical spreading depression (CSD) induction. Electrocorticogram, cortical blood flow, Fos and 5-HT2A-immunoreactivity in cortex and trigeminal pathway were studied. In the other experiment, complete Freund's adjuvant was injected into the rat hind paw to induce tissue inflammation. Three days later, ketanserin was given and noxious heat was applied to both inflamed and noninflamed paws. The response between 2 sides was compared by measuring paw withdrawal latency. Results.- Chronic paracetamol exposure led to an increase in CSD frequency and CSD-evoked Fos expression in cerebral cortex indicating the increase in neuronal excitability. Prolonged medication exposure also facilitated trigeminal nociception as evident by an increase in CSD-evoked Fos expression in trigeminal nucleus caudalis. The expression of 5-HT2A receptor in cerebral cortex and trigeminal ganglia was enhanced by chronic paracetamol administration. Pretreatment with ketanserin significantly attenuated these effects. The second experiment showed that ketanserin was able to lengthen the paw withdrawal latency in the inflamed side but did not alter nociceptive response in the noninflamed side. Conclusion.- These findings suggest that up-regulation of pro-nociceptive 5-HT2A receptor is an important step in the process of cortical hyper-excitation and nociceptive facilitation induced by chronic analgesic exposure. [ABSTRACT FROM AUTHOR]

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., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

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.

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., (Copyright © 2014 Elsevier Inc. All rights reserved.)

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., (© 2013 American Headache Society.)

Objective: To investigate the role of nitric oxide (NO) in the development of cortical hyperexcitability and trigeminal nociceptive facilitation induced by serotonin (5-HT) depletion., Background: Nitric oxide and 5-HT are important in the pathogenesis of primary headaches. An increase in cortical excitability and trigeminal nociception has been demonstrated in animals with low 5-HT levels. Although the mechanism underlying this increase is unclear, an alteration of the NO system is one possible explanation., Methods: Male Wistar rats were divided into control and 5-HT-depleted groups. 5-HT was depleted by i.p. injection of parachlorophenylalanine (100 mg/kg). Three days after injection, a microelectrode was inserted into the cerebral cortex for electrocorticograph recording and waves of cortical spreading depression (CSD) were triggered with KCl application. N-nitro-L-arginine methyl ester (L-NAME; 10 mg/kg by i.v. injection) or saline was given after the second CSD wave. Following the experiment, the cerebral cortex and brain stem were removed for anti-neuronal nitric oxide synthase (nNOS) and anti-Fos immunohistochemistry., Results: Relative to the control group, the 5-HT-depleted group exhibited a higher frequency of CSD waves, more nNOS-immunoreactive cells in both the cerebral cortex and brainstem and more Fos-immunoreactive cells in the trigeminal nucleus caudalis (TNC). In the control group, L-NAME application led to fewer nNOS-immunoreactive cells in the cerebral cortex and TNC, and fewer Fos-immunoreactive cells in the TNC; however, L-NAME was without effect on the CSD pattern. By contrast, in addition to decreased nNOS and Fos expression, L-NAME significantly reduced the frequency of CSD events in the 5-HT-depleted group., Conclusions: 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., (© 2011 American Headache Society.)

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.

Background: The attack of migraine has been observed to be associated with low level of serotonin (5-HT). Although the mechanism underlying this relationship is still unclear, change in cortical excitability or susceptibility of trigeminal system is a possible explanation., Objectives: The aim was to study the effect of 5-HT depletion on the development of cortical spreading depression (CSD) and CSD-evoked trigeminal nociception., Methods: Wistar rats were separated into low 5-HT and control groups (eight rats each). 5-HT was depleted by administration of para-chlorophenylalanine, a tryptophan hydroxylase inhibitor. CSD was induced by applying 3 mg of potassium chloride on parietal cortex. Cortical activity was monitored for 1 hour. Trigeminal nociception was determined using number of Fos-immunoreactive (Fos-IR) neurons in trigeminal nucleus caudalis as the indicator., Results: Application of KCl led to the development of series of depolarization shift characteristics for CSD. The development of these CSD waves was enhanced in low 5-HT state. The area under curve of each CSD wave and the number of CSD waves occurring within 1 hour were greater in low 5-HT group. No significant change in peak amplitude and duration of CSD wave was observed. The numbers of Fos-IR cells on ipsilateral and contralateral trigeminal nucleus caudalis were significantly greater in the low 5-HT group than those of the controls., Conclusion: 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.