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PubMed2002

Idiopathic intracranial hypertension presenting as hemiplegic migraine.

UNLABELLED: A 14-y-old girl presented with a 2 h history of left hemiplegia preceded by mild left-sided sensory disturbance. She had experienced migraines for several years and there was a strong family history of migraine, including hemiplegic migraine in one of her sisters. Her hemiplegia and headache responded to sumatriptan but her headache and vomiting subsequently returned. She was found to have intracranial hypertension and developed papilloedema and paracentral scotomas. Further history revealed she had been taking minocycline for acne. CONCLUSION: An association between hemiplegic migraine and pseudotumour cerebri has not previously been reported. There may be a case for examining patients with pseudotumour cerebri for the calcium channel mutation (CACNA1A).

Adolescent↗
PubMed1998

Today's therapy of functional gastrointestinal disorders--does it help?

Functional gastrointestinal disorders are best understood by applying a bio-psycho-social model. The diseases are strongly associated with psychological factors, and in functional dyspepsia, low vagal activity might be a mediating mechanism by which psychological factors (like neuroticism and stress) influence gastrointestinal physiology and cause epigastric discomfort. Low vagal activity may be a manifestation of stress and a cause of impaired gastric accommodation to meals. Epigastric discomfort is elicited when the stomach is distended without prior (vagal) reflex relaxation. Conventional therapy for acid-related dyspepsia does not improve accommodation and hence, is ineffective. The beneficial effect of experimental therapy, like glyceryl trinitrate and sumatriptan, which improve gastric accommodation, gives very good prospects for further development. For patients with irritable bowel syndrome, today's therapy seems similarly inefficacious, but several new potentially effective drugs are at present undergoing clinical trials.

Antacids↗
PubMed1997

Various functions of PBMC from colon cancer patients are not decreased compared to healthy blood donors.

The immune surveillance hypothesis suggests impaired immune responses to participate in development of cancer. This may partly be due to increased amounts of PGE2 and histamine, which inhibit cellular immunity. These effects are mediated by cAMP, which is increased and thereby may down-regulate IL-2 and its receptor proteins in T helper cells. The proliferative responses and IL-2 synthesis of PBMC have earlier been shown to be reduced in patients with colon cancer. Recently immune modulating agents have been demonstrated to increase the proliferative response of PBMC in vitro, probably by inhibition of adenylate cyclase activity and induction of IL-2 mRNA expression. We have therefore studied the proliferative responses of PBMC from colon cancer patients to PWM and tested the effect of immune modulating agents, such as Serotonin, Sumatriptan, and Buspirone on these PBMC. We found no difference in levels of intracellular cAMP, IL-2 mRNA expression, IL-2R mRNA expression, or proliferative responses of PBMC from colon cancer patients compared to healthy blood donors. There was no effect of the immune modulating agents on PBMC from colon cancer patients.

Adult↗
PubMed2005

A PET study exploring the laterality of brainstem activation in migraine using glyceryl trinitrate.

Migraine is a common disabling condition likely to be associated with dysfunction of brain pathways involved in pain and other sensory modalities. A cardinal, indeed signature, feature of the disorder that led to its name is that the pain may be lateralized. H(2)15O-labelled PET was used to study 24 migraineurs and eight healthy controls. The migraineurs were divided into three groups according to the site of their headache: right, left or bilateral. In each group, a migraine was induced using a glyceryl trinitrate (GTN) infusion. The subjects were scanned at predefined points: pre-infusion, during GTN, during migraine and post-migraine. SPM99 software was used to analyse the data. Significant brainstem activation was seen in the dorsal lateral pons (P < 0.05 after small volume correction) during the migraine state versus the pain-free state when comparing migraineurs with controls. When each group was analysed separately, to investigate laterality, it was found that the dorsal pontine activation was ipsilateral in the right-sided and left-sided groups and bilateral in the bilateral headache group with a left-sided preponderance. Consistent with previous work, the activation persisted after pain was controlled by sumatriptan. These results suggest that lateralization of pain in migraine is due to lateralized brain dysfunction.

Adult↗
PubMed1998

Sudden death in an adolescent boy due to a colloid cyst of the third ventricle.

A 13-year-old boy died suddenly at night while asleep. A colloid cyst filled the third ventricle, obstructed the flow of cerebral spinal fluid, and led to prominent hydrocephalus. Acute ventricular distension with brain herniation resulted in death, whereas repeated previous episodes had led to cerebral compression and edema. Complaints included only episodic headache in the month prior to death. His pediatrician prescribed a course of Imitrex (sumatriptan) because of lack of neurologic signs or other symptoms and a family history of migraine headaches. The headaches persisted, however, and within 1 month the patient died. The difficulty of accurate clinical diagnosis in this case is common. Subtle signs or even lack of symptoms of increased intracranial pressure may prevent a timely diagnosis before the occurrence of deadly complications. This case report helps to remind both forensic medical examiners and clinicians that this entity, although rare, should remain in the differential diagnosis of headache in children and young adults and of hydrocephalus at autopsy. Timely diagnosis of this benign lesion can lead to a surgical cure.

Adolescent↗
PubMed1994

Raphé nucleus-evoked release of acetylcholinesterase from guinea-pig substantia nigra.

Acetylcholinesterase (AChE) is released from dopaminergic dendrites in the guinea-pig substantia nigra. This release, measured by a chemiluminescent assay, is increased following electrical stimulation of the dorsal raphé nucleus, which sends a 5-hydroxytryptaminergic input to the substantia nigra. Application of exogenous 5-hydroxytryptamine (5-HT) directly to the substantia nigra similarly enhanced release of AChE, whilst local application of cinanserin, a 5-HT antagonist, inhibited electrically-evoked release. Although the substantia nigra posseses a dense localization of 5-HT1D receptors, application of the 5-HT1D agonist sumatriptan did not effect AChE release. The results indicate that 5-HT, released from raphé-nigral afferent nerves, enhances the dendritic release of AChE, although this effect is unlikely to be mediated via 5-HT1D receptors.

Acetylcholinesterase↗
PubMed2001

Systemic drug treatment for chronic musculoskeletal pain.

OBJECTIVE: The purpose of this review was to determine how effective different classes of analgesic agents are in the management of chronic pain. METHODOLOGY: The literature search identified five systematic reviews and 18 randomized controlled trials to provide evidence about systemic drug treatment for chronic pain. RESULTS: Studies in the systematic reviews were mainly of low back pain, and studies in the randomized controlled trials were mainly of fibromyalgia. Other studies investigated of rheumatic pain, musculoskeletal pain, chronic low back pain, and temporomandibular pain. Classes of analgesic agents reviewed were antidepressants, nonsteroidal anti-inflammatory drugs, muscle relaxants, opioid analgesics, and a number of miscellaneous agents. CONCLUSIONS: For chronic pain, opioid analgesics provide benefit for up to 9 weeks (level 2). For chronic low back pain, the evidence shows that various types of nonsteroidal antiinflammatory drugs are equally effective or ineffective, and that antidepressants provide no benefit in the short to intermediate term (level 2). Muscle relaxants showed limited effectiveness (level 3) for chronic neck pain and for chronic low back pain for up to 4 weeks. For fibromyalgia, there is limited evidence (level 3) of the effectiveness of amitryptiline, ondansetron, zoldipem, or growth hormone, and evidence of no effectiveness for nonsteroidal anti-inflammatory drugs, malic acid with magnesium, calcitonin injections, or s-adenyl-L-methionine. For temporomandibular pain, oral sumatriptan is not effective (level 2). The remaining evidence was inadequate (level 4a) or contradictory (level 4b).

Analgesics, Opioid↗
PubMed1999

Multiple microvascular and astroglial 5-hydroxytryptamine receptor subtypes in human brain: molecular and pharmacologic characterization.

Physiologic and anatomic evidence suggest that 5-hydroxytryptamine (5-HT) neurons regulate local cerebral blood flow and blood-brain barrier permeability. To evaluate the possibility that some of these effects occur directly on the blood vessels, molecular and/or pharmacologic approaches were used to assess the presence of 5-HT receptors in human brain microvascular fractions, endothelial and smooth muscle cell cultures, as well as in astroglial cells which intimately associate with intraparenchymal blood vessels. Isolated microvessels and capillaries consistently expressed messages for the h5-HT1B, h5-HT1D, 5-HT1F, 5-HT2A but not 5-HT7 receptors. When their distribution within the vessel wall was studied in more detail, it was found that capillary endothelial cells exhibited mRNA for the h5-HT1D and for the 5-HT7 receptors whereas microvascular smooth muscle cells, in addition to h5-HT1D and 5-HT7, also showed polymerase chain reaction products for h5-HT1B receptors. Expression of 5-HT1F and 5-HT2A receptor mRNAs was never detected in any of the microvascular cell cultures. In contrast, messages for all 5-HT receptors tested were detected in human brain astrocytes with a predominance of the 5-HT2A and 5-HT7 subtypes. In all cultures, sumatriptan inhibited (35-58%, P < .05) the forskolin-stimulated production of cyclic AMP, an effect blocked by the 5-HT1B/1D receptor antagonists GR127935 and GR55562. In contrast, 5-carboxamidotryptamine induced strong increases (> or = 400%, P < .005) in basal cyclic AMP levels that were abolished by mesulergine, a nonselective 5-HT7 receptor antagonist. Only astroglial cells showed a ketanserin-sensitive increase (177%, P < .05) in IP3 formation when exposed to 5-HT. These results show that specific populations of functional 5-HT receptors are differentially distributed within the various cellular compartments of the human cortical microvascular bed, and that human brain astroglial cells are endowed with multiple 5-HT receptors. These findings emphasize the complex interactions between brain serotonergic pathways and non-neuronal cells within the CNS and, further, they raise the possibility that some of these receptors may be activated by antimigraine compounds such as brain penetrant triptan derivatives.

Astrocytes↗
PubMed2001

Activation of Erk mitogen-activated protein kinase proteins by vascular serotonin receptors.

We previously demonstrated that 5-hydroxytryptamine 2A (5-HT 2A ) receptor-mediated rat arterial contraction was dependent on activation of tyrosine kinases, including mitogen-activated protein kinase (MAPK) kinase. In the current study, we examined arterial smooth muscle for the presence of serotonin (5-hydroxytryptamine, 5-HT) 5-HT 1B, 5-HT 1D, 5-HT 1F, 5-HT 2A, 5-HT 2B, and 5-HT 7 receptor mRNA and hypothesized that, if present, activation of these receptors would stimulate the extracellular signal-regulated kinase (Erk) MAPK pathway and an Erk MAPK-dependent contraction. RT-PCR analyses of rat aortic smooth muscle cells, cultured and fresh, indicated the presence of 5-HT 1B, 5-HT 1D, 5-HT 1F, 5-HT 2A, 5-HT 2B, and 5-HT 7 receptor mRNA. The 5-HT 1B agonists RU24969 and CGS12066B, 5-HT 1B/1D/1F receptor agonist sumatriptan, and 5-HT 2B receptor agonist BW723C86 (10(-9) - 10(-4) M ) did not contract the aorta, nor did the 5-HT 7 receptor antagonist LY215840 leftward shift 5-HT-induced contraction. The 5-HT 1E/1F receptor agonist BRL54443 induced contraction, but this was abolished by the 5-HT 2A/2C receptor antagonist ketanserin (10 nM ); contraction was not observed with a different 5-HT 1F receptor agonist, LY344864. 5-HT and alpha-methyl-5-HT produced a concentration-dependent increase in Erk MAPK activity in cultured aortic smooth muscle cells and in aorta contracted with these agonists. All other agonists were inactive; a high concentration of BRL54443 (10 microM ) stimulated Erk MAPK activation (150% basal). Thus, while mRNA and possibly protein for multiple 5-HT receptors are present in aortic smooth muscle, only the 5-HT 2A receptor plays a significant role in directly modulating contractility and activating the Erk MAPK pathway.

Animals↗
PubMed2000

Emergency department management of pediatric migraine.

Migraine is a common pediatric emergency department problem. Since its pathophysiology is unclear and possibly multifactorial, a single treatment strategy is unlikely to be successful for all patients. A specific treatment that has been successful for a particular patient should be strongly considered. Otherwise, it is best to start with simple therapies such as acetaminophen, aspirin, or an NSAID if not already tried at home. For patients requiring more specific therapy, reasonable choices would be dihydroergotamine or a dopamine antagonist such as prochlorperazine. There are several newer agents studied in adults with examples being sumatriptan and naratriptan. These probably have a role in the adolescent and should be considered in the younger age group when other therapies have failed. When the headache has been prolonged, dexamethasone may be useful in decreasing inflammation and relieving pain. As illustrated in many of the above studies, monotherapy is often inadequate in achieving complete relief of headache pain in all patients. Most of the drugs discussed here address only one of the three etiologies thought to be involved in migraine pathogenesis, namely; the dopaminergic system. the serotonin system or inflammation. Presumably, therapy directed toward more than one of these etiologies at the same time may be more effective (11).

Adolescent↗
PubMed2003

Impairment of signal transduction in response to stimulation of the naturally occurring Pro279Leu variant of the h5-HT7(a) receptor.

The aim of this study, performed in stably transfected HEK293 cells, was to investigate whether expression of the naturally occurring Pro279Leu variant of the h5-HT7(a) receptor (located in the third intracellular loop) is associated with changes in the pharmacological properties and/or second messenger formation compared to the wild-type receptor. Radioligand binding of [3H]5-carboxamidotryptamine ([3H]5-CT) to membranes and stimulation of [3H]cAMP formation in whole cells evoked by 5-HT receptor agonists were determined. Maximum binding (B(max)) to, and affinity (K(D)) of [3H]5-CT for, the variant receptor and the wild-type receptor were equal. All agonists and antagonists investigated exhibited no differences in affinity between the variant receptor and the wild-type receptor. However, the intrinsic activity of the 5-HT receptor agonists 5-HT, 5-CT, RU24969 and 8-OH-DPAT in stimulating [3H]cAMP accumulation in the cells expressing the Pro279Leu variant was almost abolished and their potency was 2.9-4.3-fold lower. Despite its affinity for both receptor isoforms, sumatriptan did not stimulate the accumulation of cAMP. In individuals expressing the Pro279Leu variant of the h5-HT7(a) receptor, a considerable attenuation of its function may be predicted. This may have relevance for the action of new classes of drugs which affect circadian rhythm or psychiatric diseases, such as schizophrenia.

Binding, Competitive↗
PubMed1994

Treatment of the migraine attack.

Migraine is an episodic headache disorder that occurs with or without aura and is often accompanied by other symptoms. Treatment must address these associated symptoms as well as the headache, and it can involve either acute or preventive therapy alone or a combination of both. Acute therapy treats the individual attack; preventive therapy aims to reduce the frequency and severity of attacks. Drug choice requires careful consideration and depends on the character of the migraine attack. Acute drug therapy using sumatriptan, MK-462, 311C90, dihydroergotamine, nonsteroidal anti-inflammatory drugs, butorphanol, metoclopramide, and domperidone is discussed. Prophylactic drug therapy using valproate and fluoxetine is also discussed.

Female↗
PubMed1996

Neurotransmitters and neuropeptides in headache.

For many decades, headache and migraine were though to evolve from dilated cranial blood vessels. Vasoconstrictors such as ergotamine and, more recently, sumatriptan were considered appropriate treatments. With the introduction of animal models and the emergence of molecular pharmacology, this traditional concept has been challenged, and an important role for neuropeptides, neuronal receptors and neurogenic inflammation is emerging. Neurogenic inflammation develops within the meninges as a consequence of neuropeptide release from primary afferent fibers and has been hypothesized to be of important in migraine. Neurogenic inflammation provides protection for many organs, contributes to tissue repair and serves as a useful model to define the receptor population and peptide mechanisms of relevance to drug discovery in migraine. The possible role played by neurotransmitters and neuropeptides in migraine and their receptors as potential targets for treatment will be discussed.

Headache↗
PubMed2001

Headache and female hormones: what you need to know.

The normal female lifecycle is associated with hormonal milestones, including menarche, pregnancy, contraceptive use, menopause, and the use of replacement sex hormones. Attacks of migraine without aura, but not with aura, are more likely to occur 2 days before onset and on the first 2 days of menses, but they are not more severe than those that occur outside the perimenstrual period. Oral sumatriptan and naratriptan are effective as short-term perimenstrual prophylaxis. Postdural headache can occur during the postpartum period. The International Headache Society Task Force assessed the efficacy of treatment of women who had migraine with combined oral contraceptives and hormone replacement therapy, as well as the risk of ischemic stroke associated with their use. There is no contraindication to the use of oral contraceptives in women with migraine in the absence of migraine aura or other risk factors. There is a potentially increased risk of ischemic stroke in women with migraine who are using combined oral contraceptives and have additional risk factors that cannot easily be controlled, including migraine with aura. There is no compelling evidence that postmenopausal hormone replacement therapy either decreases or increases stroke risk.

Contraceptives, Oral, Combined↗
PubMed2004

Toward the definition of childhood migraine.

PURPOSE OF REVIEW: The intent of this review is to provide an update on the current understanding of the diagnostic criteria, classification, pathophysiology, evaluation, and management of pediatric migraine. RECENT FINDINGS: The International Headache Society has recently revised its diagnostic criteria and classification system in the 2004 International Criteria for Headache Disorders. These new criteria have incorporated many developmentally sensitive changes that will allow broader application in children and adolescents. Appreciation of the new classification system requires understanding of current views of the pathophysiology of migraine. Migraine is now viewed as an inherited disorder with a primary neuronal initiation of a cascade of neurochemical processes culminating in a spreading wave of cortical neuronal depolarization and regional oligemia. The evaluation of a child with headache begins with a thorough medical history and complete physical and neurologic examination. One of the key questions for the bedside clinician is when to perform further diagnostic studies. Extensive review concludes that the role of further ancillary diagnostic studies, specifically EEG and neuroimaging, is limited. The management of pediatric migraine requires a balance of biobehavioral measures coupled with agents for acute treatment and, if needed, daily preventive medicines. The pharmacologic management of pediatric migraine has been subjected to thorough review, and controlled data unfortunately are limited. The most rigorously studied agents for the acute treatment of migraine are ibuprofen, acetaminophen, and sumatriptan nasal spray, all of which have shown safety and efficacy in controlled trials. For preventive or prophylactic treatment in the population of children and adolescents with frequent, disabling migraine, flunarizine (not available in the United States) is the most efficacious agent, but encouraging data are emerging regarding the use of several antiepileptic agents such as topiramate, disodium valproate, levetiracetam, the antihistamine cyproheptadine, and the antidepressant amitriptyline. SUMMARY: Recent literature has reshaped the definition, evaluation, and management of pediatric migraine.

Adolescent↗
PubMed2003

The emergency management of headaches.

BACKGROUND: Sufferers of severe headaches present for emergent treatment when attacks are unusually severe or refractory to therapy. Secondary headaches must always be considered. REVIEW SUMMARY: Most severe attacks are due to migraine, but cluster headaches may present for emergent treatment as well. It is unusual for a tension-type headache to be severe, unless it is associated with migraine. Options for emergent treatment of migraine depend upon which treatments have been recently utilized and what associated symptoms are present. CONCLUSIONS: Options include neuroleptics, triptans, nonsteroidal antiinflammatory agents, ergots, and intravenous valproic acid. Cluster headaches are best managed with oxygen inhalation, injectable sumatriptan, or dihydroergotamine.

Cluster Headache↗
PubMed1995

Opposing roles for dopamine and serotonin at presynaptic receptors in the ventral tegmental area.

1. Dopamine D1 and 5HT1D receptors are found on the terminals of afferent GABA neurons that synapse on the ventral tegmental area (VTA) dopamine neurons. The role of these receptors in the actions of cocaine was investigated using intracellular recordings in a brain slice preparation. Synaptic potentials were generated in the slice and GABA-mediated inhibitory post-synaptic potentials (IPSP) were identified. 2. Stimulation of dopamine D1 receptors selectively enhanced the GABAB IPSP, and their effect was blocked by D1 antagonists. The magnitude of the IPSP was decreased when D1 antagonists were applied in isolation, suggesting tonic D1 receptor stimulation via dendritically released dopamine. 3. Cocaine had an opposite effect and selectively decreased the magnitude of GABAB IPSP. This action was mimicked by 5HT and the 5HT1D agonist sumatriptan, and attenuated by the 5HT1D/2C antagonist, metergoline. The action of cocaine was also mimicked by the 5HT-releasing agent, fenfluramine, and blocked by pre-incubation of the slice with the 5HT-depleting agent, para-chloroamphetamine. 4. The results of this study suggest that dopamine and 5HT have opposing roles in modulating GABA input into VTA dopamine neurons. The actions of cocaine on this interplay may have implications for understanding its addictive properties.

Animals↗
PubMedDate not supplied

5-Hydroxytryptamine-induced contraction of the marmoset aorta is mediated by a 5-HT1-like receptor.

1. 5-Hydroxytryptamine (5-HT) exerts both contractile and relaxant effects in the marmoset isolated aorta, actions that are unaffected by the 5-HT2 antagonist ketanserin. The aim of the present study was to define the receptors mediating the contractile activity of 5-HT in the marmoset aorta. 2. Contractile responses were elicited in aortic rings that were either: (i) precontracted submaximally with the thromboxane A2 agonist U44069 in order to amplify the responses; or (ii) exposed to N(omega)-nitro-L-arginine (100 micromol/L) plus LY 53857 (0.1 micromol/L; a 5-HT2 receptor antagonist shown previously to inhibit relaxation). The effect of 5-HT on adenosine 3',5'-cyclic monophosphate (cAMP) formation was also investigated. 3. The effects of agonists and antagonists comprised: (i) agonist potencies in the order 5-carboxamidotryptamine > 5-HT > sumatriptan > 8-hydroxy-2-(di-n-propylamino)tetralin; (ii) inhibition of contractile action of 5-HT by the 5-HT1D antagonist GR 127935; (iii) a contractile response to methysergide; (iv) a lack of effect of tropisetron, an antagonist of 5-HT3 and 5-HT4 receptors; and (v) inhibition of forskolin-stimulated cAMP formation by 5-HT (in the presence of LY 53857), indicative of negative coupling to adenylate cyclase. 4. The above effects fulfill the criteria for a 5-HT1-like receptor. In view of the previous finding that this contractile response is insensitive to ketanserin, it is concluded that the contractile effects of 5-HT in the marmoset aorta are mediated exclusively by a 5-HT1-like receptor.

Animals↗