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Biomedical subjects

Peter J Goadsby

Publications and source records attributed to Peter J Goadsby.

At least 37 records · Page 2Linked to original sources
PubMed2005

Topiramate inhibits cortical spreading depression in rat and cat: impact in migraine aura.

Cortical spreading depression is thought to be the pathophysiological correlate of the neurological symptoms in migraine with aura. Topiramate is an anti-epileptic drug that is also used as a migraine preventive. Ion homeostasis and excitatory amino acid efflux are major components of cortical spreading depression; so given the broad range of actions of topiramate, we examined its effect on cortical spreading depression. Cortical spreading depression was elicited by a needle stick in the cortex in surgically prepared rats and cats; laser Doppler probes were used to measure the cerebral blood flow and a recording electrode was used to measure electrical nerve cell activity. Topiramate at 30 mg kg(-1) was able to inhibit regional cerebral blood flow changes and cortical depolarization and spreading depression in all rats, and in 8 of 13 cats. We conclude that topiramate may act on mechanisms involved in the initiation and propagation of spreading depression, and that these mechanisms may be similar to those involved in the therapeutic role.

Analysis of Variance↗
PubMed2005

Patterns of fos expression in the rostral medulla and caudal pons evoked by noxious craniovascular stimulation and periaqueductal gray stimulation in the cat.

Functional imaging studies and clinical evidence suggest that structures in the brainstem contribute to migraine pathophysiology with a strong association between the brainstem areas, such as periaqueductal gray (PAG), and the headache phase of migraine. Stimulation of the superior sagittal sinus (SSS) in humans evokes head pain. Second-order neurons in the trigeminal nucleus that are activated by SSS stimulation can be inhibited by PAG stimulation. The present study was undertaken to identify pontine and medullary structures that respond to noxious stimulation of the superior sagittal sinus or to ventrolateral PAG stimulation. The distribution of neurons expressing the protein product (fos) of the c-fos immediate early gene were examined in the rostral medulla and caudal pons of the cat after (i) sham, (ii) stimulation of the superior sagittal sinus, (iii) stimulation of the superior sagittal sinus with PAG stimulation, or (iv) stimulation of the PAG alone. The structures examined for fos were the trigeminal nucleus, infratrigeminal nucleus, reticular nuclei, nucleus raphe magnus, pontine blink premotor area, and superior salivatory nucleus. Compared with all other interventions, fos expression was significantly greater in the trigeminal nucleus and superior salivatory nucleus after SSS stimulation. After PAG with SSS stimulation, on the side ipsilateral to the site of PAG stimulation, fos was significantly greater in the nucleus raphe magnus. These structures are likely to be involved in the neurobiology of migraine.

Afferent Pathways↗
PubMed2005

Migraine, allodynia, sensitisation and all of that ...

Migraine is the most common form of disabling primary headache. One common and often troublesome feature of the disorder is an abnormal sensory state where normally innocuous stimuli are felt as painful: allodynia. This occurs in about two-thirds of patients and manifests as common complaints, such as pain when touching the hair. The neurophysiological correlate of allodynia is sensitisation, an increased afferent barrage for an unchanged peripheral stimulus. Sensitisation may be peripheral, central or disinhibitory. The potential mechanisms of each of these and their possible manipulation by treatments of the acute attack are considered.

Animals↗
PubMed2005

A positron emission tomographic study in spontaneous migraine.

BACKGROUND: Functional brain imaging in acute migraine has proved challenging because of the logistic problems associated with an episodic condition. Since the seminal observation of brainstem activation in migraine, there has been only a single case substantiating this finding. OBJECTIVE: To test the hypothesis that brainstem activation could be detected in migraine and to refine the anatomic localization with higher-resolution positron emission tomography than previously used. DESIGN: Using positron emission tomography with radioactive water (H(2)15O), we studied acute migraine attacks occurring spontaneously. Five patients underwent imaging in ictal and interictal states, and the differences were analyzed by means of statistical parametric mapping. SETTING: Tertiary referral center. PATIENTS: Six volunteers with episodic migraine were recruited from advertisements in migraine newsletters. One patient was excluded because of use of preventive medication. MAIN OUTCOME MEASURE: Brainstem activation during migraine state vs interictal state. RESULTS: Two patients had a typical migrainous aura before the onset of the headache. All of the attacks studied fulfilled standard diagnostic criteria for migraine. Comparing the migraine scans with interictal scans, there was significant activation in the dorsal pons, lateralized to the left (small volume correction, P = .003). Activation was also seen in the right anterior cingulate, posterior cingulate, cerebellum, thalamus, insula, prefrontal cortex, and temporal lobes. There was an area of deactivation in the migraine phase also located in the pons, lateralized to the right. CONCLUSIONS: Our findings provide clear evidence of dorsal pontine activation in migraine and reinforce the view that migraine is a subcortical disorder modulating afferent neural traffic.

Adult↗
PubMed2005

Functional brain imaging in hemicrania continua: implications for nosology and pathophysiology.

Hemicrania continua is a strictly unilateral, continuous headache of mild to moderate intensity, with superimposed exacerbations of moderate to severe intensity that are accompanied by trigeminal autonomic features and migrainous symptoms. The syndrome is exquisitely responsive to indomethacin. Its clinical phenotype overlaps with that of the trigeminal autonomic cephalalgias and migraine, in which the hypothalamus and the brain stem, respectively, have been postulated to play central pathophysiologic roles. A recent positron-emission tomography study of a cohort of patients with hemicrania continua demonstrated significant activation of the contralateral posterior hypothalamus and ipsilateral dorsal rostral pons in association with the headache of hemicrania continua. In addition, there was activation of the ipsilateral ventrolateral midbrain, which extended over the red nucleus and the substantia nigra and bilateral pontomedullary junction. No intracranial vessel dilatation was obvious.

Brain↗
PubMed2005

Functional neuroimaging of primary headache disorders.

Until recently, primary headache disorders such as migraine and cluster headache were considered to be vascular in origin. However, advances in neuroimaging techniques, such as positron emission tomography, single photon emission computerized tomography, and functional magnetic resonance imaging, have augmented the growing clinical evidence that these headaches are primarily driven from the brain. This review covers functional imaging studies in migraine, cluster headache, rarer headache syndromes, and experimental head pain. Together with newer techniques, such as voxel-based morphometry and magnetic resonance spectrometry, functional imaging continues to play a role in elucidating and targeting the neural substrates in each of the primary headache syndromes.

Brain↗
PubMed2005

Can we develop neurally acting drugs for the treatment of migraine?

Serotonin (5-HT)(1B/1D) receptor agonists, which are also known as triptans, represent the most important advance in migraine therapeutics in the four millennia that the condition has been recognized. The vasoconstrictive activity of triptans produced a small clinical penalty in terms of coronary vasoconstriction but also raised an enormous intellectual question: to what extent is migraine a vascular problem? Functional neuroimaging and neurophysiological studies have consistently developed the theme of migraine as a brain disorder and, therefore, demanded that the search for neurally acting antimigraine drugs should be undertaken. The prospect of non-vasoconstrictor acute migraine therapies, potential targets for which are discussed here, offers a real opportunity to patients and provides a therapeutic rationale that places migraine firmly in the brain as a neurological problem, where it undoubtedly belongs.

Cardiovascular Physiological Phenomena↗
PubMed2005

Topiramate inhibits trigeminovascular activation: an intravital microscopy study.

Activation, or the altered perception of activation, of trigeminal nerves that innervate the cranial vasculature is considered to be a pivotal component of the pathophysiology of acute migraine. Calcitonin gene-related peptide (CGRP) levels are increased during migraine and after trigeminal nerve stimulation in the cat. Both CGRP and nitric oxide (NO) infusion causes headache and delayed migraine in migraineurs. Neurogenic stimulation of a cranial window, CGRP and NO injection all cause meningeal artery dilation in the rat when viewed using intravital microscopy. Topiramate is an antiepileptic drug with established efficacy as a migraine preventive, and has recently been shown to inhibit neurons of the trigeminocervical complex after superior sagittal sinus stimulation. In this study, we used intravital microscopy with neurogenic dural vasodilation, and CGRP- and NO-induced dilation to examine whether intravenous topiramate has effects on the trigeminovascular system. Topiramate was able to attentuate neurogenic dural vasodilation maximally after 15 min by 52% at 30 mg kg(-1) (t(5) = 6.78, n = 6); there was no significant inhibition at 10 mg kg(-1). There was also significant attenuation of the NO-induced dilation maximally after 15 min, at both 10 and 30 mg kg(-1) by 21% (t(6) = 6.09, n = 7) and 41% (t(6) = 5.3, n = 7), respectively. CGRP-induced dilation was not inhibited at either dose of topiramate. The study demonstrates that topiramate is likely to inhibit neurogenic dural vasodilation by inhibiting the release of CGRP from prejunctional trigeminal neurons, thus attenuating the dural vasodilation. Topiramate is not able to act postsynaptically at the blood vessels themselves as the CGRP-induced dilation was not attenuated. The data are consistent with an effect of topiramate on trigeminovascular activation which may form part of its preventive antimigraine mechanisms of action.

Animals↗
PubMed2005

New targets in the acute treatment of headache.

PURPOSE OF REVIEW: The aim of this article is to review recently identified targets for the acute treatment of primary headache disorders. RECENT FINDINGS: Calcitonin gene-related peptide (CGRP) receptor blockade has been shown to be an effective acute anti-migraine strategy and is a non-vasoconstrictor in terms of the mechanism of action. It is likely that direct blockade of CGRP release by inhibition of trigeminal nerves would be similarly effective in both migraine and cluster headache. Options for acute treatment based on preclinical work and initial clinical studies include: serotonin 5HT1F and 5HT1D receptor agonists, glutamate excitatory amino acid receptor antagonists, nitric oxide synthase inhibitors and adenosine A1 receptor agonists. Proof of principle studies with octreotide, a somatostatin receptor agonist, demonstrated it to be better than placebo in the acute treatment of cluster headache but not in the acute management of migraine. SUMMARY: The prospect of a non-vasoconstrictor acute migraine therapy offers a real opportunity to patients, and perhaps more importantly, provides a therapeutic rationale to plant migraine and cluster headache firmly in the brain as neurological problems.

Calcitonin Gene-Related Peptide↗
PubMed2005

Migraine pathophysiology.

A combination of basic science and human physiology, particularly functional neuroimaging, has radically altered our understanding of migraine with a focus on brain mechanisms for this common and disabling disorder. Genetic studies have begun to provide plausible targets for the basic molecular defect in terms of ion channels, albeit thus far in the rare condition of familial hemiplegic migraine (FHM). Migraine pathophysiology involves the trigeminovascular system and central nervous system modulation of the pain-producing structures of the cranium. The degree to which head pain results from the activation of the nociceptors of pain-producing intracranial structures, or to the facilitation or lack of inhibition of afferent signals, is not clear at this time. An understanding of the pain mechanism is likely to provide insights into the mechanisms underlying the more generalized sensory dysfunction that is so typical of migraine.

Animals↗
PubMed2005

Calcitonin gene-related peptide antagonists as treatments of migraine and other primary headaches.

Calcitonin gene-related peptide (CGRP) is a potent neuromodulator that is expressed in the trigeminovascular system and is released into the cranial circulation in various primary headaches. CGRP is released in migraine, cluster headache and paroxysmal hemicrania. The blockade of its release is associated with the successful treatment of acute migraine and cluster headache. CGRP receptor blockade has recently been shown to be an effective acute anti-migraine strategy and is non-vasoconstricting in terms of the mechanism of action. The prospect of a non-vasoconstricting therapy for acute migraine offers a real opportunity to patients, and perhaps more importantly, provides a therapeutic rationale to reinforce migraine as a neurological disorder.

Animals↗
PubMed2004

Propranolol modulates trigeminovascular responses in thalamic ventroposteromedial nucleus: a role in migraine?

Migraine is a common, debilitating condition affecting up to 15% of the population. The ventroposteromedial nucleus of the thalamus relays trigeminal sensory input to the primary somatosensory cortex. In vivo electrophysiological recordings were made from the cell bodies of thalamocortical relay neurons in rats. We investigated whether microiontophoretic ejection of beta antagonists could inhibit thalamocortical activity in response to superior sagittal sinus (SSS) stimulation. We also studied 'postsynaptic' actions of these drugs through their modulatory actions on L-glutamate-evoked third order neuronal firing. Propranolol inhibited responses to SSS stimulation (P < 0.001) and L-glutamate ejection (P < 0.001). This was due to an action on beta receptors as it could be partially reversed by co-ejection of isoproterenol (SSS, P = 0.02; L-glutamate, P = 0.006). Serotonin (5-HT) receptor antagonism did not contribute to propranolol's action since the 5-HT1A receptor antagonist, (S)-WAY 100135 (P = 0.2), and the 5-HT1B/1D receptor antagonist, GR127935 (P = 0.6), did not affect L-glutamate-evoked neuronal firing. Atenolol inhibited both responses (SSS, P = 0.003; L-glutamate, P < 0.001). The beta2 antagonist ICI 118,551 had no effect (SSS, P = 0.9; L-glutamate, P = 0.4), nor did the beta2 agonist procaterol (SSS, P = 0.6; L-glutamate, P = 0.9). SR 59230A (beta3 antagonist) also produced no significant inhibition (SSS, P = 0.7; L-glutamate, P = 0.2), indicating an inhibitory role for beta1 antagonists only. beta Blockers therefore may exert some of their therapeutic effects in migraine through beta1 adrenoceptor antagonist actions in the thalamus. Thalamic involvement in migraine is attractive given the complex and widespread nature of the sensory disturbance.

Adrenergic beta-Agonists↗
PubMed2004

GABAA receptor modulation of trigeminovascular nociceptive neurotransmission by midazolam is antagonized by flumazenil.

Studies of the pharmacology of trigeminocervical neurons with input from intracranial pain-producing structures have enhanced the understanding of the basic neurobiology of primary headache, such as migraine. Clinical observations of the treatment of migraine with medicines acting at the gamma-aminobutyric acid (GABA) GABAA receptor have lead to studies of their effects on models of trigeminovascular nociception. Extracellular recordings were made from neurons in the trigeminocervical complex activated by supramaximal electrical stimulation of superior sagittal sinus (SSS) in the cat. Intravenous administration of the benzodiazepine receptor agonist midazolam, resulted in a dose-dependent inhibition of superior sagittal sinus evoked trigeminocervical nucleus activity. The inhibition at 50 microg/kg midazolam was 65+/-11% compared to the baseline response (n=11). Intravenous administration of the benzodiazepine receptor antagonist flumazenil, resulted in a dose-dependent recovery of superior sagittal sinus evoked trigeminocervical nucleus activity. At a dose of 50 microg/kg, there was a 64+/-5% recovery (n=6). The data demonstrate a potent, reproducible effect of facilitation of GABA transmission at the GABAA receptor that results in inhibition of trigeminovascular nociceptive transmission. These data are consistent with the useful clinical effects reported with compounds that can augment GABAergic transmission in the central nervous system (CNS).

Animals↗
PubMed2004

Calcitonin gene-related peptide (CGRP) modulates nociceptive trigeminovascular transmission in the cat.

Calcitonin gene-related peptide (CGRP) is released into the cranial circulation of humans during acute migraine. To determine whether CGRP is involved in neurotransmission in craniovascular nociceptive pathways, we microiontophoresed onto neurons in the trigeminocervical complex and intravenously administered the CGRP receptor antagonists alpha-CGRP-(8-37) and BIBN4096BS. Cats were anaesthetised with alpha-chloralose, and using halothane during surgical preparation. A craniotomy and C1/C2 laminectomy allowed access to the superior sagittal sinus (SSS) and recording site. Recordings of activity in the trigeminocervical complex evoked by electrical stimulation of the SSS were made. Multibarrelled micropipettes incorporating a recording electrode were used for microiontophoresis of test substances. Cells recorded received wide dynamic range (WDR) or nociceptive specific (NS) input from cutaneous receptive fields on the face or forepaws. Cell firing was increased to 25-30 Hz by microiontophoresis of L-glutamate (n = 43 cells). Microiontophoresis of alpha-CGRP excited seven of 17 tested neurons. BIBN4096BS inhibited the majority of units (26 of 38 cells) activated by l-glutamate, demonstrating a non-presynaptic site of action for CGRP. alpha-CGRP-(8-37) inhibited a similar proportion of units (five of nine cells). Intravenous BIBN4096BS resulted in a dose-dependent inhibition of trigeminocervical SSS-evoked activity (ED50 31 microg kg(-1)). The maximal effect observed within 30 min of administration. The data suggest that there are non-presynaptic CGRP receptors in the trigeminocervical complex that can be inhibited by CGRP receptor blockade and that a CGRP receptor antagonist would be effective in the acute treatment of migraine and cluster headache.

Action Potentials↗
PubMed2004

Neurogenic vasodilation of dural blood vessels is not mediated by cholinergic transmission in the anaesthetised rat.

Dural vessel dilation induced by activation of trigeminal sensory fibres may be responsible for some component of the migraine attack. The presence in some patients with migraine and cluster headache of clinical features, such as lacrimation, suggests cranial parasympathetic activation and poses the question as to whether neurogenic meningeal dilatation has a cholinergic component. Rats were prepared in order to record on-line the diameter of a middle meningeal artery branch through a closed cranial window using an intravital microscope coupled to a video dimension analyser. Acetylcholine (1 microg, intravenously, i.v.) was administered before and after muscarinic receptor inhibition (n=5) with scopolamine (2 mg/kg, i.v.) or nicotinic receptor inhibition (n=6) with mecamylamine (4 mg/kg, i.v.). Further vasodilation was induced by electrical stimulation of the cranial window surface before and after muscarinic receptor inhibition with i.v. scopolamine (n=8). The mean dural vessel percentage increase caused by acetylcholine stimulation was significantly different before and after muscarinic receptor inhibition (P=0.045). Moreover, there was no difference between the post receptor inhibition values and those obtained after vehicle infusion (P=0.431). In contrast, no difference was detected in the effect of acetylcholine before and after nicotinic receptor inhibition (P=0.688). In the second experiment, where the effect of muscarinic receptor inhibition on the neurogenic dilation model was assessed, no significant difference was demonstrated (P=0.538). Cholinergic dilation of the rat dural arteries is mediated by muscarinic receptors, but this mechanism does not play a significant role in the rat dural vessel dilation induced by closed cranial window electrical stimulation.

Acetylcholine↗
PubMed2004

A meta-analysis for headache in systemic lupus erythematosus: the evidence and the myth.

Controversies in the occurrence and implications of headache in patients suffering from systemic lupus erythematosus (SLE) triggered us to conduct an extensive literature search in order to answer five clinical questions. (i) Is headache prevalence higher in SLE patients than in the general population? (ii) Is 'lupus headache' a separate entity? (iii) Is there a distinct pathogenetic mechanism of headache in SLE? (iv) Is headache related to CNS involvement or general SLE activity? (v) Is headache related to anxiety- and depression-like symptoms in SLE? All published articles reporting data from >30 SLE patients were classified into four classes (I, IIa, IIb and III) by the quality of their evidence. We found no prospective controlled study (class I), but we identified seven controlled (class II) and 28 uncontrolled studies (class III) that retrospectively investigated the occurrence of headache in SLE patients. Eight out of 35 studies applied the International Headache Society (IHS) criteria for headache classification, whereas only four uncontrolled studies investigated paediatric SLE populations (class III). Pooled data from eight studies (controlled and uncontrolled) that used the IHS criteria show that 57.1% of SLE patients reported any type of headache (migraine 31.7% and tension-type headache 23.5%). Pooled data from seven controlled studies showed that the prevalence of all headache types, including migraine, was not different from controls. Insufficient evidence was found for the concept of 'lupus headache'. No particular pathogenetic mechanism of headache in adult SLE patients has been identified, nor an association between headache and the disease status, including CNS involvement. There is no good evidence that headache is associated with anxiety and depression in SLE. Insufficient data (class III) do not allow safe conclusions for headache among paediatric SLE patients. These findings suggest that the occurrence of headache in adult SLE patients does not itself require further investigation and that headache in those patients should be classified according to IHS criteria and managed as primary headache if there is no specific indication of a role for SLE in the patient. These recommendations should be verified by a properly controlled and prospective study in both adult and paediatric populations.

Acute Disease↗