Sensitization of trigeminal nociception specific for migraine but not pain of sinusitis.

Neurology. 2002;59:1450-1453.
Trigeminal pain processing was studied in 14 patients with unilateral migraine attacks and 14 age- and sex-matched patients with comparable unilateral headache from frontal sinusitis. Using a nociception-specific blink reflex method (nBR), a facilitation of nBR responses predominantly on the headache side was observed in migraine, but not in sinusitis. The facilitation of trigeminal nociception may be specific for migraine rather than a consequence of peripheral pain such as frontal sinusitis.
Comment: Here we have evidence for the central hyperexcitability of migraine, not found in the previously cited article by Boska et al. SJT     

Supraspinal modulation of trigeminal nociception and pain

Objective.— This study examined modulation of trigeminal pain/nociception by 2 supraspinal mechanisms: emotional controls of nociception and diffuse noxious inhibitory controls. Background.— Prior research suggests emotional picture viewing (emotional controls) and tonic noxious stimuli (diffuse noxious inhibitory controls) engage supraspinal mechanisms to modulate pain and nociceptive processes. It is currently unknown, however, whether emotional controls modulate trigeminal pain and nociception. Additionally, the influences of emotional controls and diffuse noxious inhibitory controls have not been compared in the same group of participants. Methods.— Noxious electrodermal stimuli were delivered to the trigeminal nerve using a concentric electrode designed to selectively activate nociceptive fibers. Trigeminal nociception and pain were assessed (34 participants) from the nociceptive blink reflex and pain ratings, respectively. Emotional controls were engaged by presentation of standardized picture stimuli (pleasant, neutral, and unpleasant) shown to reliably evoke pleasure-induced inhibition and displeasure-induced facilitation of pain and nociception. Diffuse noxious inhibitory controls were engaged with a forearm ischemia task. Results.— Trigeminal pain (self-report ratings) and nociception (blinks) were facilitated by unpleasant pictures and inhibited by pleasant pictures. Emotion induction (as assessed from trend analysis) explained 51% of the variance in trigeminal pain and 25% of the variance in trigeminal nociception. Additionally, forearm ischemia inhibited trigeminal pain but not nociception. The baseline vs ischemia comparison explained 17% of the variance in pain report and 0.1% of the variance in blinks. Supraspinal modulation by emotional controls and diffuse noxious inhibitory controls were uncorrelated. Conclusions.— Emotional controls and diffuse noxious inhibitory controls modulated trigeminal pain and emotional controls modulated trigeminal nociception. These procedures can be used to study supraspinal modulation of nociceptive processing in disorders of the trigeminal pain system, including headache.     

Abnormal habituation of 'nociceptive' blink reflex in migraine--evidence for increased excitability of trigeminal nociception

We studied the habituation of the 'nociceptive' blink reflex (nBR) in 15 healthy subjects and 17 migraine patients interictally as well as during unilateral migraine headache within six hours of onset and after treatment. In healthy volunteers the mean regression coefficient (MRC) was - 3.9 following right sided and - 4.9 left sided stimulation. This equals an amplitude loss of 19.5% (5 x -3.9) and 24.5% (5 x -4.9), respectively, across five consecutive sweeps. An augmentation of nBR responses was found in migraine patients interictally: MRC = 3.3 following stimulation of the headache side (HA) and MRC = 4.0 of the non-headache side (non-HA). The differences were statistically significant (anova: d.f. = 1, F = 25.8, P < 0.001). During the migraine attack MRCs were negative both before (-5.0, HA and - 4.0, non-HA) and after treatment (-2.6, HA and - 1.9 non-HA) and significantly differed from those outside the migraine attack (anova: d.f. = 2, F = 12.4, P < 0.001). The demonstrated lack of habituation of the nBR responses indicates an abnormal trigeminal nociceptive processing in migraine patients outside the migraine attack.     

Influences of smoking and caffeine consumption on trigeminal pain processing

Background

Many human and animal studies have shown the influence of nicotine and caffeine on pain perception and processing. This study aims to investigate whether smoking or caffeine consumption influences trigeminal pain processing.

Methods

Sixty healthy subjects were investigated using simultaneous recordings of the nociceptive blink reflex (nBR) and pain related evoked potentials (PREP) following nociceptive electrical stimulation on both sides of the forehead (V1). Thirty subjects were investigated before and after smoking a cigarette, as well as before and after taking a tablet of 400 mg caffeine.

Results

After smoking PREP showed decreased N2 and P2 latencies indicating central facilitation at supraspinal (thalamic or cortical) level. PREP amplitudes were not changed. NBR showed a decreased area under the curve (AUC) indicating central inhibition at brainstem level. After caffeine intake no significant changes were observed comparing nBR and PREP results before consumption.

Conclusions

Smoking influences trigeminal pain processing on supraspinal and brainstem level. In the investigated setting, caffeine consumption does not significantly alter trigeminal pain processing. This observation might help in the further understanding of the pathophysiology of pain disorders that are associated with excessive smoking habits such as cluster headache. Previous smoking has to be taken into account when performing electrophysiological studies to avoid bias of study results.     

Psychiatric comorbidity in medication overuse headache patients with pre-existing headache type of episodic tension-type headache.

BACKGROUND: Medication overuse headache (MOH) mostly evolves from migraine and episodic tension-type headache (ETTH). Chronic tension-type headache (CTTH) is another headache type that evolves over time from ETTH. It is well known that psychiatric comorbidity is high in MOH patients. AIM: To investigate the frequency of psychiatric comorbidity, and the intensity of depression and anxiety in MOH patients evolving from ETTH and to compare results with CTTH patients and MOH patients evolving from migraine. METHODS: Twenty-eight CTTH (Group C) and 89 MOH patients were included into the study. MOH patients were divided into two groups according to their pre-existing headache types: MOH patients with pre-existing ETTH (Group E, n = 31), and with pre-existing migraine (Group M, n = 58). All patients were interviewed with a psychiatrist and SCID-CV and SCID-II were applied. Beck Anxiety Inventory and Beck Depression Inventory scales were also performed. RESULTS: Eleven patients (39.3%) in Group C, 21 patients (67.7%) in Group E, and 31 patients (53.7%) in Group M were diagnosed to have comorbid psychiatric disorders. The psychiatric comorbidity was found significantly higher in Group E than Group C. In Group E, mood disorders were found significantly higher, but the difference between the two groups with regard to anxiety disorders was insignificant. Mean depression scores were significantly higher in Group E than Group C. The mostly diagnosed type was obsessive-compulsive personality disorder in all the three groups, and was statistically significant in Group M than Group C. CONCLUSION: Psychiatric comorbidity in MOH patients with pre-existing ETTH is common as in those with pre-existing migraine headache and MOH with regard to developing psychiatric disorders should be interpreted as a risk factor in chronic daily headache patients.     

Differences of anti-nociceptive mechanisms of migraine drugs on the trigeminal pain processing during and outside acute migraine attacks

The aim of this study was to investigate central anti-nociceptive mechanisms of i.v. acetylsalicylic acid (ASA) and oral zolmitriptan (ZOL) in migraine patients and healthy subjects using the 'nociceptive' blink reflex (nBR). Twenty-eight migraine patients received ASA (n = 14, 1000 mg i.v) or ZOL (n = 14, 5 mg p.o) during the acute migraine attack and interictally. Thirty healthy subjects received either ASA or ZOL vs. placebo using a double blind cross over design. nBR was recorded in all patients and subjects before, 60 and 90 min after treatment. ASA and ZOL did not inhibit nBR responses in healthy subjects. Both ASA and ZOL suppressed nBR responses (ASA by 68%, ZOL by 78%) only during the acute attack but not interictally. The data suggest, that the anti-nociceptive effects of migraine drugs on the trigeminal nociceptive processing are different during and outside an acute migraine attack.     

Iron deposition in pain-regulatory nuclei in episodic migraine and chronic daily headache by MRI

Background.— Progression of migraine toward a more disabling chronic form of at least 15 days/month is linked with frequency of attacks. Magnetic resonance imaging (MRI) findings of iron accumulation in the brain, especially in periaqueductal gray and red nucleus, have been correlated with both duration of illness and frequency of attacks. Methods.— This study therefore evaluated iron deposition as measured with MRI in basal ganglia and pain regulatory nuclei in neurologically healthy control volunteers and in patients with various migraine subtypes: episodic migraine (n = 10) with (n = 4) or without aura (n = 6), and chronic daily headache (n = 11), including medication overuse headache (MOH, n = 8), chronic tension‐type headache (n = 1), and primary chronic migraine (n = 2). The goal was to assess differences in iron deposition among migraine subtypes and controls in the hopes of linking the by‐products of frequent attacks or long duration of illness with these changes. Results.— The study sought to evaluate the tradeoff between sensitivity and specificity in T2 imaging of patients with migraine, and found that only T2 imaging in the globus pallidus was able to distinguish between episodic and chronic migraine, suggesting that this technique may be the most appropriate to assess migraine frequency. Patients with MOH did not demonstrate T2′ shortening. Conclusions.— Because iron accumulation should cause shortening of both T2 and T2′, although the lack of significance in observed T2′ difference could be due to increased variance in T2′ the measurement, these results suggest that a mechanism other than increased iron deposition may play a role in the genesis or pathophysiology of MOH.     

Behavioral dependence in patients with medication overuse headache: a cross-sectional study in consulting patients using the DSM-IV criteria

Objective.— The aim of this study was to assess behavioral dependence on migraine abortive drugs in medication‐overuse headache (MOH) patients and identify the predisposing factors. Background.— It is common occurrence that MOH patients relapse after medication withdrawal. Behavioral determinants of medication overuse should therefore be identified in MOH patients. Methods.— This was a cross‐sectional, multicenter study that included 247 MOH patients (according to International Classification of Headache Disorders, 2nd edition criteria) consulting in French headache specialty centers. Face‐to‐face interviews were conducted by senior neurologists using a structured questionnaire including the Diagnostic and Statistical Manual of Mental Disorders, 4th edition (DSM‐IV) criteria for the evaluation of dependence, Hospital Anxiety and Depression Scale for the evaluation of anxiety and depression, and 6‐item short‐form Headache Impact Test scale for the determination of functional impact. Results.— Most MOH patients had pre‐existing primary migraine (87.4%) and current migraine‐type headaches (83.0%). Treatments overused included triptans (45.8%), opioid analgesics alone or in combination (43.3% of patients), and analgesics (27.9%). Nonmigraine abortive substances (tobacco, caffeine, sedatives/anxiolytics) were overused by 13.8% of patients. Two‐thirds of MOH patients (66.8%) were considered dependent on acute treatments of headaches according to the DSM‐IV criteria. Most dependent MOH patients had migraine as pre‐existing primary headache (85.7%) and current migraine‐type headaches (87.9%), and most of them overused opioid analgesics. More dependent than nondependent MOH patients were dependent on psychoactive substances (17.6% vs 6.1%). Multivariate logistic analysis indicated that risk factors of dependence on acute treatments of headaches pertained both to the underlying disease (history of migraine, unilateral headaches) and to drug addiction (opioid overuse, previous withdrawal). Affective symptoms did not appear among the predictive factors of dependence. Conclusion.— In some cases, MOH thus appears to belong to the spectrum of addictive behaviors. In clinical practice, behavioral management of MOH should be undertaken besides pharmacological management.     

Medication‐Overuse Headache and Personality: A Controlled Study by Means of the MMPI‐2

(Headache 2010;50:198‐209) Objective.— The main aim of this study involves comparing the personality profiles of patients with medication‐overuse headache (MOH) and episodic headaches, in order to elucidate the role of personality characteristics, according to one of the most widely used and validated personality assessment tool: Minnesota Multiphasic Personality Inventory (MMPI‐2). Background.— Many studies have assessed the personality of headache patients by means of MMPI‐2 only using clinical and content scales. In this study the supplementary scales were also used as they evaluate different aspects of personality, particularly broad personality characteristics, generalized emotional distress and behavioral dyscontrol. Methods.— We recruited 219 subjects (151 women and 68 men) who were grouped in the following categories: MOH group (n = 82); episodic headache group (n = 82; 58 migraine aura; 6 migraine with aura; 6 frequent episodic tension‐type headache; 12 migraine+infrequent episodic tension‐type headache) and 1 group of 55 healthy controls. MMPI‐2 was employed. Data were computed with one‐way anova and post hoc analyses. Results.— Medication‐overuse headache and episodic headache patients (EH) showed a very similar pattern, differentiating each other only in the Hypochondriasis (Hs) (P = .007; MOH: mean 14.18 [SD 5.53]; EH: mean 11.93 [SD 5.88] and Health Concerns [HEA]) (P = .005; MOH: mean 14.06 [SD 5.38]; EH: mean 11.81 [SD 5.59]) scales. Surprisingly, no differences were found between the 3 groups in the scales measuring dependence‐related behavior such as Addiction Potential Scale (Aps) and Addiction Admission Scale (Aas). MOH and episodic headache patients scored significantly higher in the so‐called neurotic scales Hs (P < .0001; MOH: mean 14.18 [SD 5.53]; EH: mean 11.93 [SD 5.88]; Controls: mean 5.91 [SD 3.57]), Depression (D) (P < .0001; MOH: mean 26.44 [SD 7.01]; EH: mean 26.09 [SD 5.85]; Controls: mean 21.47 [SD 4.90]), and Hysteria (Hy) (P < .0001; MOH: mean 27.33 [SD 5.51]; EH: mean 26.81 [SD 5.68]; Controls: mean 21.95 [3.85]) and in many other scales such as Paranoia (Pa), Psychasthenia (Pt), Schizophrenia (Sc) while they scored significantly lower on Ego Strength (Es) and Dominance (Do) scales when compared with controls. Conclusions.— Patients with MOH and episodic headache showed very similar patterns, differentiating only in the Hypochondriasis and Health Concerns scales. Surprisingly, there were no significant differences in the scores of the scales measuring dependence‐related behavior. The clinical role of MMPI‐2 in discriminating MOH patients with dependency from drugs is discussed, in order to implement a complete tests' battery for headache patients' assessment.     

Increased activity of serotonin uptake in platelets in medication overuse headache following regular intake of analgesics and triptans

We investigated the effect of chronic administration of different pain medications on the activity of the serotonin transporter (SERT) in patients with medication overuse headache (MOH). We measured the kinetic of platelet 5-HT uptake (maximal velocity, V _max and the Michaelis–Menten constant, K _m) in patients with overuse of triptans (tMOH, n = 15) or analgesics (aMOH, n = 14) before and after drug withdrawal, as well as in headache-free healthy subjects (n = 15) and patients with episodic migraine (EM, n = 16). V _max was increased similarly in both, tMOH and aMOH compared to healthy subjects and patients with EM and normalized after withdrawal in parallel to the improvement of headache frequency. Average K _m was similar in all groups at baseline and not affected by the withdrawal. The data demonstrate a transient increase of SERT activity in patients with analgesic and triptan induced MOH but do not allow to differentiate whether the increase of serotonin uptake is caused by regular intake of analgesics or triptans or is a consequence of frequent headache attacks. An erratum to this article can be found at     

Clinical features of probable medication-overuse headache: a retrospective study in Japan

This study examined the clinical picture of probable medication-overuse headache (MOH) and the presence of any features peculiar to Japan. In a retrospective study of 47 patients, type of primary headache, type of medicine overused, method and result of withdrawal were investigated. Among the 47 patients, 80.9% had migraine only, and 85.1% overused combination medications. While 36 patients (76.6%) succeeded in withdrawal, five patients (10.6%) failed. One patient (2.1%) had not improved by 2 months after withdrawal and was diagnosed with chronic migraine and chronic tension-type headache without MOH. The remaining five patients (10.6%) dropped out. All dropout patients were recommended abrupt inpatient withdrawal, but chose abrupt outpatient withdrawal. As features peculiar to Japan, many patients with probable MOH overused combination analgesics, particularly females.     

Gordian knot: medication overuse headache

Overuse of any kind of headache drugs may lead to the development of the medication overuse headache (MOH). Clinical features of MOH depend on the substance class that has been overused. Overuse of analgesics leads to a chronic tension-type like headache, the overuse of triptans to daily migraine-like headache or to the increase of migraine frequency. The delay between the drug overuse and onset of daily headache is shortest for triptans (1.7 years), longer for ergots (2.7 years) and longest for analgesics (4.8 years). Treatment includes withdrawal followed by structured acute therapy and initiation of specific prophylactic treatment for the underlying primary headache. The relapse rate after a successful withdrawal is about 30%. Predictors for relapse are tension-type headache and the overuse of analgesics in combination with codeine, caffeine or opioids.     

Der gordische Knoten: medikamenteninduzierte Kopfschmerzen

Overuse of any kind of headache drugs may lead to the development of the medication overuse headache (MOH). Clinical features of MOH depend on the substance class that has been overused. Overuse of analgesics leads to a chronic tension-type like headache, the overuse of triptans to daily migraine-like headache or to the increase of migraine frequency. The delay between the drug overuse and onset of daily headache is shortest for triptans (1.7 years), longer for ergots (2.7 years) and longest for analgesics (4.8 years). Treatment includes withdrawal followed by structured acute therapy and initiation of specific prophylactic treatment for the underlying primary headache. The relapse rate after a successful withdrawal is about 30%. Predictors for relapse are tension-type headache and the overuse of analgesics in combination with codeine, caffeine or opioids.     

Thermal sensitivity in unilateral headaches

Thermal thresholds were measured in the face (first and second trigeminal area), over the mastoid process (C2-3 area), and in the hands in patients with migraine ( n =17), cluster headache ( n =22), and cervicogenic headache ( n =20). Significant symptomatic versus nonsymptomatic side differences were generally not found for any headache group. Cluster headache patients had significantly higher warm thresholds than controls ( n =24) for most of the cephalic points. Cervicogenic headache patients had significantly higher warm and cold thresholds than controls ( n =56) at several cephalic and noncephalic points. Warm thresholds over the mastoid process on the symptomatic side were higher in cervicogenic headache patients compared to the other groups. In migraine patients, thermal thresholds were similar to those in controls. Thus, we found no evidence of focal or unilateral peripheral somatic nerve dysfunction involving C or A-delta fibers in any of the studied headache groups, although a C2-3 root dysfunction in cervicogenic headache could not be excluded. A bilateral central sensory dysfunction in cluster headache and cervicogenic headache may be hypothesized but a generalized peripheral dysfunction can also explain our results.     

Update on Medication-overuse Headache

Medication-overuse headache (MOH) is a syndrome that can develop in migraineurs after overuse of antimigraine drugs, including opiates and triptans especially. MOH manifests as increased frequency and intensity of migraine attacks and enhanced sensitivity to stimuli that elicit migraine episodes. Although the mechanisms underlying MOH remain unknown, it is hypothesized that repeated use of antimigraine drugs could elicit increased headache attacks as a consequence of neuronal plasticity that may increase responsiveness to migraine triggers. Preclinical studies show that exposure to either opiates or triptans can induce pronociceptive neuroadaptive changes in the orofacial division of the trigeminal ganglia that persist even after discontinuation of the drug treatment. Additionally, medications can elicit increased descending facilitatory influences that may amplify evoked inputs from trigeminal afferents leading to behavioral hypersensitivity reminiscent of cutaneous allodynia observed clinically. Importantly, enhanced descending facilitation may manifest as an inhibition of diffuse noxious inhibitory control. Persistent, pronociceptive adaptations in nociceptors as well as within descending modulatory pathways thus may jointly contribute to the development of MOH.     

Low-frequency short-time nociceptive stimulation of the greater occipital nerve does not modulate the trigeminal system

Occipital stimulation in a small group of refractory chronic migraine and cluster headache patients has been suggested as a novel therapeutic approach with promising results. In an earlier study we have shown that a drug-induced block of the greater occipital nerve (GON) inhibits the nociceptive blink reflex (nBR). Now, we sought to examine the effects of low-frequency (3 Hz) short-time nociceptive stimulation of the GON on the trigeminal system. We recorded the nBR responses before and after stimulation in 34 healthy subjects. Selectivity of GON stimulation was confirmed by eliciting somatosensory evoked potentials of the GON upon stimulation. In contrast to an anaesthetic block of the occipital nerve, no significant changes of the R2-latencies and R2-response areas of the nBR can be elicited following GON stimulation. Various modes of electrical stimulation exist with differences in frequency, stimulus intensity, duration of stimulation and pulse width. One explanation for a missing modulatory effect in our study is the relatively short duration of the stimulation.     

Transformation of Episodic Migraine Into Daily Headache: Analysis of Factors

SYNOPSIS
Seventy-six percent of patients with daily headaches were found to have a history of episodic migraine in the past, more than half of them hormone dependent headache such as menstrual migraine. Various factors possibly influencing the transformation of episodic migraine into daily headaches were analyzed in a series of 61 patients who presented with daily headaches. Abnormal personality profile, especially neuroticism including depression, excessive stress, excessive use of medications such as caffeine containing analgesics, narcotic analgesics and ergotamine, and development of hypertension were found to be significant in the transformation of episodic migraine into daily headache.
The problem of daily headache is discussed. It is suggested that the majority of daily headaches are a continuum of episodic migraine, influenced and perpetuated by various factors such as neuroticism, excessive medication, stress, and development of hypertension. It is pointed out that diagnosis of tension headache under those circumstances is not justified.     

Obsessive-Compulsive Disorder and Migraine With Medication-Overuse Headache

Objective.— A strong association has been demonstrated between migraine, particularly in the chronic form and with medication overuse, and either major depression or various anxiety disorders. However, there has been less systematic research on the links between migraine with medication-overuse headache (MOH) and obsessive-compulsive disorder (OCD). A drug-seeking behavior shares with OCD the compulsive quality of the behavior. We investigated the relationship between OCD and MOH in migraineurs.
Methods.— A structured questionnaire was administered to subjects with: episodic migraine (EM) (n = 30), chronic migraine (CM) (n = 24), and MOH with a previous history of EM (n = 33) and 29 control subjects. Psychiatric diagnoses were made by a senior psychiatrist blinded to the diagnosis of migraine. Psychiatric assessment of OCD illness was evaluated by means of The Yale-Brown Obsessive Compulsive Scale (Y-BOCS).
Results.— In the subgroup of patients with MOH, psychiatric comorbidity (anxiety and mood disorders) was prevalent compared with CM, EM, and controls ( P  < .0001). Subclinical OCD was significantly prevalent in MOH patients with respect to other groups ( P  < .0002). Higher scores in Y-BOCS, as a measure of severity of obsessive-compulsive symptoms, were found in both MOH and CM compared with controls and EM.
Conclusions.— The excess of psychiatric comorbidity in patients with MOH can be related either to medication overuse or to chronification of headache. Among anxiety disorders, we observed a high rate of subclinical OCD. However, a direct link between compulsive behavior and medication overuse cannot be established yet. OCD in MOH might be underdiagnosed and undertreated.     

Psychiatric comorbidity in the evolution from migraine to medication overuse headache

We set out to study the role of psychiatric comorbidity in the evolution of migraine to medication overuse headache (MOH) by a comparative study of 41 migraineurs (MIG) and 41 patients suffering from MOH deriving from migraine. There was an excess risk of suffering from mood disorders [odds ratio (OR) = 4.5, 95% confidence interval (CI) 1.5, 13.5], anxiety (OR = 5, 95% CI 1.2, 10.7) and disorders associated with the use of psychoactive substances other than analgesics (OR = 7.6, 95% CI 2.2, 26.0) in MOH compared with MIG. Retrospective study of the order of occurrence of disorders showed that in the MOH group, psychiatric disorders occurred significantly more often before the transformation from migraine into MOH than after. There was no crossed-family transmission between MOH and psychiatric disorders, except for substance-related disorders. MOH patients have a greater risk of suffering from anxiety and depression, and these disorders may be a risk factor for the evolution of migraine into MOH. Moreover, MOH patients have a greater risk of suffering from substance-related disorders than MIG sufferers. This could be due to the fact that MOH is part of the spectrum of addictive disorders.     

Serotonin depletion, cortical spreading depression, and trigeminal nociception

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.