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PubMed2001

A comparison of visual analog scale and categorical ratings of headache pain in a randomized controlled clinical trial with migraine patients.

A visual analog scale (VAS) method of assessing headache pain was compared with a standard categorical four-grade scale (4GS) in a randomized, placebo-controlled, double-blind, clinical trial involving 792 treated migraine outpatients who received oral rizatriptan 5 mg, sumatriptan 50 mg, or placebo for a moderate or severe headache. The VAS and 4GS were equally useful in demonstrating that the active drugs were superior to placebo at reducing headache pain, and in showing that the active drugs were similarly effective. For both rizatriptan and sumatriptan, slightly larger effect sizes were observed with the 4GS compared with the VAS. In analyses using data combined across all treatment groups, VAS and 4GS scores were highly correlated. Use of the VAS imposed additional administrative burdens. These findings suggest that the 4GS may be the preferred scale for assessing headache pain in clinical trials involving adult migraineurs.

Adolescent↗
PubMed1997

Possible mechanism of c-fos expression in trigeminal nucleus caudalis following cortical spreading depression.

Cortical spreading depression (CSD) is characterized by a transient, reversible depression of EEG activity which advances across the cortical surface at a velocity of 2-5 mm/min. CSD was originally linked to the aura phase of migraine, but recently also to migraine headache. The theory is that CSD activates meningeal trigeminal C-fibers causing neurogenic inflammation and pain (Moskowitz, M.A., Nozaki, K. and Kraig, R.P., Neocortical spreading depression provokes the expression of c-fos protein-like immunoreactivity within trigeminal nucleus caudalis via trigeminovascular mechanisms, J. Neurosci., 13 (1993) 1167-1177). The present study is an examination of the proposed link between CSD elicited in rats and activation of trigeminal nerve fibers. Multiple CSDs were elicited unilaterally for 1 h by KCl injections (1 M, 5 microliters) into the right hemisphere, while NaCl (1 M, 5 microliters) was injected into the left as control. After an additional 1 h the animals were sacrificed and trigeminal activation assessed by the expression of c-fos in trigeminal nucleus caudalis (TNC) using immunohistochemistry. The correlation between the number of CSDs and the extent of c-fos expression was determined. In addition the effect of sumatriptan (0.3 mg/kg) and morphine (3 mg/kg) given i.v. 30 min before elicitation of CSD was evaluated. CSD caused increased c-fos expression in lamina I and II of TNC where C-fibers, end, the response being greater ipsilaterally. Morphine, but not sumatriptan, reduced c-fos expression in both the ipsilateral and contralateral TNC by 71% (P < 0.05 and P = 0.19, respectively), confirming that nociceptors have been activated. No positive correlation was seen between the number of CSDs and the extent of c-fos expression in TNC. Instead we observed a positive, linear correlation between the number of KCl injections and the extent of c-fos expression in TNC (correlation coefficient r = 0.709, P < 0.05). We suggest that the C-fiber activation observed is caused by hyperosmolar KCl/NaCl and not CSD. Hence, our results do not support the hypothesis of Moskowitz et al. (Moskowitz, M.A., Nozaki, K. and Kraig, R.P., Neocortical spreading depression provokes the expression of c-fos protein-like immunoreactivity within trigeminal nucleus caudalis via trigeminovascular mechanisms, J. Neurosci., 13 (1993) 1167-1177) which links CSD with migraine headache.

Animals↗
PubMed1997

Competitive and silent antagonism of recombinant 5-HT1B receptors by amiloride.

1. The cyclic adenosine monophosphate (cAMP) response of the diuretic amiloride was compared with sumatriptan at recombinant human 5-HT1B (h5-HT1B) receptor sites in stably transfected Chinese hamster ovary (CHO-K1) cells. 2. Amiloride, free of intrinsic activity (pEC50 < 3.0), competitively antagonized the sumatriptan-mediated inhibition (pEC50: 7.37) of 100 microM forskolin-induced cAMP formation with a pA2 value of 4.46. 3. The antagonist feature was not shared by the amiloride derivative ethylisopropylamiloride, notwithstanding a slightly higher 5-HT1B receptor-binding affinity (pKi: 4.87) than that of amiloride (pKi: 4.70).

Amiloride↗
PubMed1999

Headache in Meniere's disease.

OBJECTIVE: We examined headache in 86 patients with severe or moderately severe Meniere's disease (MD) or with Meniere's syndrome (MS) chosen for intratympanic gentamicin treatment. Forty-five patients with vestibular neuronitis (VN) served as a control group. METHODS: In addition to a clinical examination, the patients filled out a questionnaire concerning their headache. RESULTS: Altogether 60 MD patients (70%) and 26 VN patients (58%) reported headache. Headache was severe in 35 MD patients (58%), moderate in 16 patients (27%) and slight in nine MD patients (15%), and as a whole more severe than that of the VN patients (P < 0.01). The MD patients exhibited significantly more occipital (P < 0.005) and neck headache (P < 0.005) than the VN patients. Analgesics had been used by 82%, antidepressants by 35%, sumatriptan by 13% and carbamazepine and/or amitriptyline by 12% of the MD patients suffering from headache. Pain relief was reported as good by 27%, satisfactory by 60%, poor by 5% of the MD patients and 8% could not rate the pain relief. In this study migraine was diagnosed in 5 MD patients. CONCLUSION: It is concluded that MD is associated with headache that can be handicapping, and tricyclic antidepressants with pain alleviating medication is often needed to treat the headache in MD whereas sumatriptan did not alleviate the headache of the non-migraine patients.

Adult↗
PubMed2003

A delayed class of BOLD waveforms associated with spreading depression in the feline cerebral cortex can be detected and characterised using independent component analysis (ICA).

An application of independent component analysis to blood oxygenation level- dependent MRI (BOLD-MRI) results was used to detect cerebrovascular changes that followed the initiation of cortical spreading depression (CSD) in feline brain. The cortical images were obtained from a horizontal plane at 28 s intervals before, and for 1.4-1.75 h after, KCl dissolved in agar (KCl/agar) had been directly applied to the left suprasylvian gyrus of 13 anesthetized cats for 10 min. It successfully resolved, for the first time, a novel class of prolonged, and delayed, biphasic BOLD waveforms. These were larger in amplitude ( approximately 20%), longer lasting and more delayed in onset (13-33 min) than the brief propagating (90 s) BOLD increase ( approximately 4%) already known to be associated with CSD on earlier occasions. Furthermore, such changes occurred in localized regions on the hemisphere ipsilateral to the site of stimulus application in 4 out of 5 control subjects rather than themselves generating propagating waves. Finally, the biphasic waveforms were consistently abolished in the 4 experimental animals studied following the i.v. administration of sumatriptan (0.3 mg kg(-1)), an antimigraine 5-HT(1B/1D) agonist, 15 min before the application of the transient stimulus. They were abolished in 2 out of 4 animals following the intraperitoneal (i.p.) administration of SB-220453 (tonabersat: 10 mg kg(-1), 90 min before stimulus application), a novel anticonvulsant that has recently been reported to inhibit CSD. ICA has thus been successful in detecting a novel localized, as opposed to propagating, signal of potential physiological significance hidden in complex BOLD- MRI data, whose sensitivity to sumatriptan may relate it to the cerebrovascular changes reported in the headache phase of migraine.

Animals↗
PubMed1999

The scientific basis of medication choice in symptomatic migraine treatment.

With the rapid advances in the treatment of acute attacks of migraine in the last few years and a number of new treatments, has come the practical clinical problem of comparing emerging acute attack therapies alone and with regard to current treatments. Acute migraine therapies can usefully be regarded as non-specific and specific, from the perspective of migraine, since some medicines, such as aspirin or paracetamol, are used to treat pain more broadly. In this review I will compare both non-specific and specific compounds. To some extent the introduction into trial then clinical use of sumatriptan, the first of the 5HT1B/1D agonists or triptans, brought new standards in both clinical trial design, and execution and clinical outcome. Thus sumatriptan has become the de facto gold standard and will be thus employed here. To be practical the discussion of the new triptans will be limited to those available widely, naratriptan, rizatriptan and zolmitriptan. There are two broad issues when comparing treatments: what end-point should be considered and then, how can different compounds be compared with respect to that end-point. In terms of end-points those used here relate to pain relief because they have been collected robustly in the clinical studies and, fortunately, rapid pain relief is what patients questioned in population-based studies rate highest in an acute attack medicine. Headache pain has been rated on a scale of nil, mild, moderate and severe and success rated as either a response, nil or mild pain, or headache free, nil pain, at two or four hours. The ideal comparison of the triptans would be a randomized controlled clinical trial directly comparing the medicines in each case. Given that these are not available for all the compounds and the well characterised placebo response in acute migraine studies, summary measures have been developed to express the differences between compounds to try and adjust for the varying placebo effect. The two most widely used are the therapeutic gain, response on active medication minus response on placebo, and the number-needed-to-treat (NNT). The NNT is the reciprocal of the therapeutic gain as a proportion. The strengths and weaknesses of this approach will be discussed, including the importance of the calculation of confidence intervals. It can be concluded that our current instruments are rather blunt and patient preference needs much greater study.

Acute Disease↗
PubMed1997

Characterization of putative 5-HT7 receptors mediating tachycardia in the cat.

1. It has been suggested that the tachycardic response to 5-hydroxytryptamine (5-HT) in the spinal-transected cat is mediated by '5-HT1-like' receptors since this effect, being mimicked by 5-carboxamidotryptamine (5-CT), is not modified by ketanserin or MDL 72222, but it is blocked by methiothepin, methysergide or mesulergine. The present study was set out to reanalyse this suggestion in terms of the IUPHAR 5-HT receptor classification schemes proposed in 1994 and 1996. 2. Intravenous (i.v.) bolus injections of the tryptamine derivatives, 5-CT (0.01, 0.03, 0.1, 0.3, 1, 3, 10 and 30 microg kg(-1)), 5-HT (3, 10 and 30 microg kg(-1)) and 5-methoxytryptamine (3, 10 and 30 microg kg(-1)) as well as the atypical antipsychotic drug, clozapine (1000 and 3000 microg kg(-1)) resulted in dose-dependent increases in heart rate, with a rank order of agonist potency of 5-CT >> 5-HT > 5-methoxytryptamine >> clozapine. 3. The tachycardic effects of 5-HT and 5-methoxytryptamine were dose-dependently antagonized by i.v. administration of lisuride (30 and 100 microg kg(-1)), ergotamine (100 and 300 microg kg(-1)) or mesulergine (100, 300 and 1000 microg kg(-1)); the highest doses of these antagonists used also blocked the tachycardic effects of 5-CT. Clozapine (1000 and 3000 microg kg(-1)) did not affect the 5-HT-induced tachycardia, but attenuated, with its highest dose, the responses to 5-methoxytryptamine and 5-CT. However, these doses of clozapine as well as the high doses of ergotamine (300 microg kg(-1)) and mesulergine (300 and 1000 microg kg(-1)) also attenuated the tachycardic effects of isoprenaline. In contrast, 5-HT-, 5-methoxytryptamine- and 5-CT-induced tachycardia were not significantly modified after i.v. administration of physiological saline (0.1 and 0.3 ml kg(-1)), the 5-HT(1B/1D) receptor antagonist, GR127935 (500 microg kg(-1)) or the 5-HT(3/4) receptor antagonist, tropisetron (3000 microg kg(-1)). 4. Intravenous injections of the 5-HT1 receptor agonists, sumatriptan (30, 100 and 300 microg kg(-1)) and indorenate (300 and 1000 microg kg(-1)) or the 5-HT4 receptor (partial) agonist cisapride (300 and 1000 microg kg(-1)) were devoid of effects on feline heart rate per se and failed to modify significantly 5-HT-induced tachycardic responses. 5. Based upon the above rank order of agonist potency, the failure of sumatriptan, indorenate or cisapride to produce cardioacceleration and the blockade by a series of drugs showing high affinity for the cloned 5-ht7 receptor, the present results indicate that the 5-HT receptor mediating tachycardia in the cat is operationally similar to other putative 5-HT7 receptors mediating vascular and non-vascular responses (e.g. relaxation of the rabbit femoral vein, canine external carotid and coronary arteries, rat systemic vasculature and guinea-pig ileum). Since these responses represent functional correlates of the 5-ht7 gene product, the 5-HT7 receptor appellation is reinforced. Therefore, the present experimental model, which is not complicated by the presence of other 5-HT receptors, can be utilized to characterize and develop new drugs with potential agonist and antagonist properties at functional 5-HT7 receptors.

5-Methoxytryptamine↗
PubMed1999

[3H]-Mesulergine labels 5-HT7 sites in rat brain and guinea-pig ileum but not rat jejunum.

1. The primary aim of this investigation was to determine whether binding sites corresponding to the 5-HT7 receptor could be detected in smooth muscle of the rat jejunum. Binding studies in rat brain (whole brain minus cerebellum) and guinea-pig ileal longitudinal muscle were also undertaken in order to compare the binding characteristics of these tissues. Studies were performed using [3H]-mesulergine, as it has a high affinity for 5-HT7 receptors. 2. In the rat brain and guinea-pig ileum, pKD values for [3H]-mesulergine of 8.0 +/- 0.04 and 7.9 +/- 0.11 (n = 3) and Bmax values of 9.9 +/- 0.3 and 21.5 +/- 4.9 fmol mg(-1) protein were obtained respectively, but no binding was detected in the rat jejunum. [3H]-mesulergine binding in the rat brain and guinea-pig ileum was displaced with the agonists 5-carboxamidotryptamine (5-CT) > 5-hydroxytryptamine (5-HT) > or = 5-methoxytryptamine (5-MeOT) > sumatriptan and the antagonists risperidone > or = LSD > or = metergoline > ritanserin > > pindolol. 3. Despite the lack of [3H]-mesulergine binding in the rat jejunum, functional studies undertaken revealed a biphasic contractile response to 5-HT which was partly blocked by ondansetron (1 microM). The residual response was present in over 50% of tissues studied and was found to be inhibited by risperidone > LSD > metergoline > mesulergine = ritanserin > pindolol, but was unaffected by RS 102221 (3 microM), cinanserin (30 nM), yohimbine (0.1 microM) and GR 113808 (1 microM). In addition, the agonist order of potency was 5-CT > 5-HT > 5-MeOT > sumatriptan. 4. In conclusion, binding studies performed with [3H]-mesulergine were able to detect 5-HT7 sites in rat brain and guinea-pig ileum, but not in rat jejunum, where a functional 5-HT7-like receptor was present.

5-Methoxytryptamine↗
PubMed2000

Effects of eletriptan on the peptidergic innervation of the cerebral dura mater and trigeminal ganglion, and on the expression of c-fos and c-jun in the trigeminal complex of the rat in an experimental migraine model.

Nociceptive axons and terminals in the supratentorial cerebral dura mater display an intense calcitonin gene-related peptide (CGRP) immunoreactivity. In an experimental migraine model, it has been shown that electrical stimulation of the rat trigeminal ganglion induced an increase in the lengths of CGRP-immunoreactive axons, increased size and number of pleomorphic axonal varicosities in the dura mater, and an increased number of c-jun and c-fos protein-expressing nerve cells in the trigeminal complex. We demonstrate the effect of the highly specific and moderately lipophilic serotonin agonist eletriptan (Pfizer) which prevents the effects of electrical stimulation in the dura mater. Eletriptan also affected the caudal trigeminal complex; it markedly reduced the numbers of the oncoprotein-expressing cells, mainly after stimulation and to some extent also in nonstimulated animals. Eletriptan also affected expression of CGRP in perikarya of trigeminal ganglion cells, insofar as the number of small nerve cells exhibiting a compact CGRP immunoreaction was decreased to one quarter of the original value. In all these respects, eletriptan acted in a similar way to sumatriptan, with the notable exception that eletriptan also blocked the stimulation-induced effects in the nucleus caudalis trigemini and the upper cervical spinal cord (trigeminal complex), whereas sumatriptan did not. It is concluded that eletriptan, acting on perikarya and both the peripheral and the central axon terminals of primary sensory neurons, exerts its antimigraine effect by an agonist action on 5-HT1B/1D receptors throughout the entire trigeminal system, probably by passing the blood-brain-barrier because of its lipophilic character.

Animals↗
PubMed1994

Function of the peripheral serotoninergic pathways in migraine: a proposal for an experimental model.

We propose a model for assessing the function of 5HT receptors in migraine by evaluating their expression on monocytes by means of double-labeling fluorocytometry (CD14-positive cells FITC-labeled). This model demonstrates that during headache induced in migraine without aura sufferers given isosorbide dinitrate followed by sumatriptan treatment 5HT expression on monocytes progressively increases. This increase may be due to the activation of 5HT turnover and to the increased availability of 5HT displaced by sumatriptan from cerebrovascular receptors during head pain.

Adult↗
PubMed1998

Level of nitric oxide-dependent cGMP in patients with migraine.

It is believed that nitric oxide (NO) plays a significant role in migraine attacks. This molecule is formed due to the conversion of L-arginine into L-citrulline. The target receptor for NO is ferrum in the heme group of cytoplasmic guanyl cyclase, the enzyme catalyzing cyclic guanosine monophosphate (cGMP) formation. To confirm this hypothesis, cGMP and nitrite level in the blood serum were measured in patients with migraine. The group under study included 37 subjects suffering from migraine with and without aura and 40 normal control subjects. The cGMP was measured during a migraine attack and 60 min following the administration of sumatriptan 6 mg subcutaneously. A statistically significant increase in cGMP level was observed in patients during a migraine attack compared to the controls. This level decreased after the administration of sumatriptan, but it was still higher than in the controls. No correlation was found between the increased cGMP level and pain intensification with clinical symptoms of migraine. The results suggest the participation of biochemical changes in migraine pathogenesis in the L-arginine-NO-cGMP pathway.

Adult↗
PubMed1994

Fenfluramine releases serotonin from human brain nerve endings by a dual mechanism.

Fenfluramine is the most widely used anorexigenic drug in humans. In animal experiments d-fenfluramine has been shown to act as a potent releaser of brain serotonin [5-hydroxytryptamine (5-HT)]. Here we have investigated the effects of d-fenfluramine on the release of [3H]5-HT from isolated nerve endings of human neocortex. The drug elicited release of unmetabolized [3H]5-HT, and this effect was concentration dependent. However, the mechanism of release seems to differ profoundly depending on the concentrations of d-fenfluramine used. At 5 microM, the release of [3H]5-HT was blocked by the 5-HT transporter inhibitor fluoxetine and was Ca2+ independent and insensitive to the human autoreceptor 5-HT1D agonist sumatriptan. The release of [3H]5-HT elicited by 0.5 microM d-fenfluramine was similarly blocked by fluoxetine, but it was strongly Ca2+ dependent and sensitive to sumatriptan. It is suggested that, at relatively high concentrations, d-fenfluramine largely diffuses into serotonergic terminals and causes release of 5-HT through the 5-HT carrier working in the inside-outside direction; at relatively low concentrations d-fenfluramine enters the terminals through the 5-HT transporter but elicits release of 5-HT by an exocytotic-like mechanism.

Calcium↗
PubMed1997

Regulation of serotonin release in the frontal cortex and ventral hippocampus of homozygous mice lacking 5-HT1B receptors: in vivo microdialysis studies.

To assess the involvement of the serotonin receptor subtype 5-HT1B as terminal autoreceptor regulating 5-HT release in mice, we compared basal values and potassium-evoked changes of extracellular 5-HT levels obtained by in vivo microdialysis in two serotoninergic terminal projection areas of conscious wild-type mice with those measured in homozygous mutant mice lacking the gene encoding the 5-HT1B receptor. In the frontal cortex and ventral hippocampus, basal and K+-evoked 5-HT release did not differ between the two strains of mice studied. The infusion via reverse microdialysis of the selective 5-HT1B receptor agonist CP-93,129 (500 nM) decreased significantly K+-evoked 5-HT release in the frontal cortex (by -44%) and ventral hippocampus (by -32%) of wild-type mice but had no effect in mutants. In a similar manner, the mixed 5-HT1B-5-HT1D receptor agonist sumatriptan (800 nM) decreased significantly K+-evoked 5-HT release in the frontal cortex (by -46%) of wild-type mice but had no effect in mutants. These results demonstrated that 5-HT1B knockout mice are not as sensitive to full (CP-93,129) and mixed (sumatriptan) 5-HT1B receptor agonists as are wild-type mice. These data provide in vivo evidence that, in mice, 5-HT1B, but not 5-HT1D, autoreceptors inhibit 5-HT release at nerve terminals located in the frontal cortex and ventral hippocampus.

Animals↗
PubMedDate not supplied

Alternatives in drug treatment of chronic paroxysmal hemicrania.

Indomethacin is the drug of first choice in chronic paroxysmal hemicrania with clear relief of pain as a diagnostic criterion. In a few cases, indomethacin is not tolerated because of side effects. Therefore, the efficacy of carbamazepine, verapamil, sumatriptan, acetylsalicylic acid, and oxygen as drugs in the prophylactic or acute treatment of chronic paroxysmal hemicrania was studied in a prospective open trial with 10 patients suffering from chronic paroxysmal hemicrania. The trial results, in accordance with a review of the literature, suggest that acetylsalicylic acid (and probably naproxen and diclofenac) and verapamil are the most effective drugs of second choice in chronic paroxysmal hemicrania. The efficacy of sumatriptan in this condition needs still to be clarified, although there is evidence for partial efficacy. Carbamazepine and oxygen did not show any significant influence on chronic paroxysmal hemicrania.

Adolescent↗
PubMedDate not supplied

Positron emission tomography studies in headache.

Positron emission tomography (PET) allows the quantitative measurement of regional cerebral flow (rCBF) in humans in quantitative terms. Gross changes in rCBF are due to variation in vessel diameter. Changes of rCBF also reflect synaptic activity (inhibition and excitation). Therefore, PET was used to monitor changes in blood flow during the aura and headache phase of a migraine attack and to investigate focal areas of increased or decreased blood flow, e.g., in the brain stem and midbrain. Hemispheric rCBF was unchanged in spontaneous migraine attacks without aura. This was true for the headache side as well as for the nonheadache side. Sumatriptan had no effects on cerebral blood flow. Regional cerebral blood flow was increased in midline brain stem structures during the headache phase, but also when the headache had been treated with sumatriptan. This persisting increased activity might reflect activity of a presumed migraine center in the brain stem. These changes are specific for migraine attacks and are not seen during attacks of cluster headache. Positron emission tomography measurements in the early phase of a migraine attack in a single subject showed flow reductions in the occipital cortex spreading forwards; an observation which would be compatible with the existence of spreading depression in humans. Our attempts to study the aura phase with PET have, to date, been unsuccessful.

Adult↗
PubMed2000

A pilot study to measure cognitive efficiency during migraine.

BACKGROUND AND OBJECTIVES: The measurement of cognitive efficiency during migraine has produced conflicting results primarily due to the types of tests used. The objectives of this pilot study were two-fold: to measure cognitive efficiency during migraine, compared to a migraine-free period, and to evaluate the effects of therapy with a 5-HT1 agonist (sumatriptan injection, 6 mg) on the cognitive efficiency of migraineurs during a migraine. METHOD: The Headache Care Center-Automated Neuropsychological Assessment Metrics was administered to 10 migraineurs, three times without a migraine, once during a migraine, and three times after administration of sumatriptan injection (6 mg). RESULTS: The results demonstrated a significant drop in cognitive efficiency during migraine and recovery 15 minutes after therapeutic injection. CONCLUSIONS: This pilot study is the first to document a significant drop in cognitive functioning during migraine and recovery after administration of a migraine-specific medication.

Cognition↗
PubMed2002

Clinical and pathophysiological characteristics of acute-onset functional dyspepsia.

BACKGROUND & AIMS: Functional bowel disorders may follow acute intestinal infection. In animals, postinflammatory dysmotility is associated with nitrergic dysfunction. The aim of this study was to identify and characterize patients with presumed postinfectious dyspepsia (PD) compared with unspecified-onset dyspepsia (UD). METHODS: A total of 400 consecutive dyspeptic patients filled out a questionnaire to assess whether their symptoms were of postinfectious origin. They underwent testing for Helicobacter pylori infection as well as gastric emptying and gastric barostat studies. Pharmacological studies of nitrergic gastric function were performed in controls, in patients with presumed PD, and in patients with UD using sumatriptan, an activator of nitrergic neurons, and amylnitrite, a nitric oxide donor. RESULTS: Presumed PD was present in 17% of the patients and associated with more prevalent early satiety, weight loss, nausea, and vomiting compared with UD. Both groups did not differ in H. pylori infection, gastric emptying, or gastric sensitivity. Impaired accommodation was significantly more prevalent in patients with presumed PD (67% vs. 30%; P < 0.05). Sumatriptan relaxed the stomach in controls and patients with UD but not in patients with presumed PD, whereas amyl nitrite relaxed the stomach in all subjects. CONCLUSIONS: A subset of dyspeptic patients has a history suggestive of postinfectious dyspepsia. These patients have a high prevalence of impaired accommodation attributable to a dysfunction at the level of gastric nitrergic neurons.

Adolescent↗
PubMed1997

Microiontophoretic application of serotonin (5HT)1B/1D agonists inhibits trigeminal cell firing in the cat.

Migraine is a common and debilitating condition. Its treatment has received considerable attention in recent times with the introduction into clinical use of the 5HT1B/1D agonist sumatriptan. It is known from human studies that the intracranial blood vessels and dura mater are important pain-producing structures since mechanical or electrical stimulation of these vessels, such as the superior sagittal sinus, causes pain. We have developed a model of craniovascular pain by stimulating the superior sagittal sinus and monitoring trigeminal neuronal activity using electrophysiological techniques. Cats were anaesthetized with alpha-chloralose (60 mg/kg, intraperitoneally), paralysed (gallamine 6 mg/kg, intravenously) and ventilated. The superior sagittal sinus was accessed and isolated for electrical stimulation by a mid-line circular craniotomy. The region of the dorsal surface of C2 spinal cord was exposed by a laminectomy and an electrode placed for recording evoked activity from sinus stimulation and spontaneous activity of the same cells. The electrode was a custom-made seven barrel glass microelectrode with the central barrel containing a tungsten recording wire. Signals were amplified and monitored on-line using a custom-written sampling program. Cells were recorded that were activated by electrical stimulation of the sinus and were also spontaneously activated. Cells fired with latencies consistent with A delta and C fibres, generally firing three or four times per stimulus (0.3 Hz, 250 microseconds duration, 100 V) delivered to the sinus. Both evoked and spontaneous firing could be inhibited by iontophoresis of ergometrine (9/10 cells), sumatriptan (2/3 cells) and zolmitriptan (9/15 cells) but not by saline (3/10 cells). These data are the first demonstration of inhibition of second order trigeminal neurons by direct local application of 5HT1B/1D agonists. Although intravenous administration of these compounds has demonstrated inhibition of sinus evoked firing in previous studies, it is not possible using the intravenous route to be clear at which anatomical site inhibition is taking place, whereas microiontophoresis offers a clear locus of action. These data demonstrate that the second order trigeminal nucleus synapse in the brainstem and upper cervical cord is the most likely site of action for brain penetrant anti-migraine drugs of the 5HT1B/1D class.

Afferent Pathways↗