[Therapy of acute migraine attacks and prevention of migraine].
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Analgesics↗
Biomedical subjects
V Limmroth
Publications and source records attributed to V Limmroth.
A practical guide to the management and prevention of migraine.
Migraine is a paroxysmal disorder with attacks of headache, nausea, vomiting, photo- and phonophobia and malaise. Mild migraine attacks are treated with antiemetics followed by analgesics such as aspirin (acetylsalicylic acid), paracetamol (acetaminophen) or nonsteroidal anti-inflammatory drugs (NSAIDs). Moderate to severe attacks are treated by antiemetics combined with ergotamine or dihydroergotamine. Sumatriptan, a specific serotonin 5-HT1B/D receptor agonist, is used if attacks do not respond to ergotamine or if intolerable adverse effects occur. The new migraine drugs zolmitriptan, naratriptan, rizatriptan and eletriptan differ in their pharmacological profile from sumatriptan, but this translates into only minor differences in efficacy, headache recurrence and adverse effects. Migraine prophylaxis should be implemented when more than 3 attacks occur per month, if attacks do not respond to acute treatment or if the adverse effects of acute treatment are severe. Substances with proven efficacy include the beta-blockers metoprolol and propranolol and the calcium antagonist flunarizine. Drugs less effective or those with unpleasant adverse effects are the serotonin receptor antagonists (pizotifen, methysergide and lisuride), dihydroergotamine, cyclandelate, NSAIDs, valproic acid (sodium valproate) and amitriptyline. The efficacy of aspirin or magnesium is still under evaluation.
Analgesics↗
Indomethacin inhibits the natriuretic effects of neuropeptide Y in anesthetized rats.
Neuropeptide Y (NPY) is a unique modulator of renal function that enhances urine flow and sodium excretion despite marked reductions in renal blood flow. We investigated whether the cyclooxygenase inhibitor indomethacin alters the renal NPY effects in anesthetized rats. Treatment with 5 mg/kg indomethacin i.p. lowered urinary prostaglandin excretion by approximately 85%. Systemic infusion of NPY elevated mean arterial pressure by approximately 15 mm Hg and renovascular resistance by approximately 8.0 mm Hg/ml/min, whereas the related peptide YY3-36 (PYY3-36) did not. Nevertheless, both peptides enhanced urine flow rate by approximately 250 and approximately 100 microl/15 min, respectively, and sodium excretion by approximately 15 micromol/15 min. Treatment with indomethacin did not affect NPY- and PYY3-36-induced alterations of systemic and renovascular hemodynamics but completely abolished NPY- and PYY3-36-induced diuresis and natriuresis. Endogenous creatinine clearance was not affected by any treatment. We conclude that cyclooxygenase-derived arachidonic acid metabolites are not involved in the systemic or renal hemodynamic effects of NPY and PYY3-36 but mediate NPY- and PYY3-36-induced diuresis and natriuresis.
Anesthesia↗
Possible mechanisms of valproate in migraine prophylaxis.
Valproate has been shown to be an effective prophylactic treatment in migraine. Investigation of the mechanism of its antimigraine action is difficult due to the broad range of its biochemical effects and the complex nature of migraine pathophysiology. Valproate increases brain GABA levels and, in doing so, may suppress migraine-related events in the cortex, perivascular parasympathetics or trigeminal nucleus caudalis. There is experimental evidence that it suppresses neurogenic inflammation and directly attenuates nociceptive neurotransmission. In addition, valproate reportedly alters levels of excitatory and inhibitory neurotransmitters and exerts direct effects on neuronal membranes in vitro. Valproate's observed effect may ultimately result from a combination of actions at different loci.
Animals↗
Emerging treatments in headache.
Recent PET studies performed in humans during migraine attacks revealed a 'spreading depression-like' oligemia in the occipital cortex during the aura phase and a region of increased blood flow in the brainstem during the headache phase. Animal models were established to test new migraine drugs. A number of 5-HT agonists, the so-called 'triptans', will be available in future besides sumatriptan to treat acute migraine attacks. Migraine prophylaxis is still hampered by the fact that we do not understand the action of drugs used for this purpose and do not have an animal model. Nevertheless, new substances were introduced recently into the prophylaxis of migraine.
Animals↗
[Animal models and their results in relation to the therapy of migraine].
Until now, our understanding of migraine pathophysiology has been fairly incomplete. So far no animal model has allowed an explanation of all facets of the clinically heterogeneous condition migraine. However, it is now generally accepted that the migraine headache is due to activation of the trigeminal system. The model of neurogenic inflammation after stimulation of the trigeminal ganglion or systemic administration of capsaicin allows study of the inhibitory interactions between antimigraine compounds and peripheral trigeminal fibre terminals that sustain a sterile meningeal inflammation through release of allogenic and vasoactive neuropeptides, such as substance P and calcitonin gene-related peptide. Studies with the model of superior sagittal sinus stimulation have revealed central actions of antimigraine agents such as ergotamine and sumatriptan, but also acetylsalicylic acid on neurotransmission of trigeminal nociceptive input in the brainstem. A likely explanation for the slowly progressing neurological deficits is cortical spreading depression (CSD), which can easily be elicited in many species. However, CSD has not been observed in vivo in humans. The described models strongly influenced the development of new medications for migraine treatment and have improved our understanding of migraine pathophysiology.
English Abstract↗
Validity of brain MRI as the primary outcome criterion in multiple sclerosis phase II clinical trials.
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Brain↗
Changes in cerebral blood flow velocity after treatment with sumatriptan or placebo and implications for the pathophysiology of migraine.
Whether the primary mechanisms of migraine are vascular or neurogenic is, as yet, unresolved. In humans it is still unclear whether sumatriptan acts via constriction of dilated arteries or through other mechanisms. Doppler sonography is a non-invasive method for measuring blood flow velocities (BFV), an indirect marker of vessel diameter. This double-blind crossover placebo-controlled trial investigated changes in BFV in extra- and intracranial arteries in 132 migraine attacks (66 patients) before and after treatment with either 6 mg sumatriptan s.c. or placebo. Significant increases in BFV were observed only in the middle cerebral artery (MCA) and the basilar artery (BA) after administration of sumatriptan. However, the majority of the patients showed no change in BFV following sumatriptan. No difference in BFV could be detected between headache and non-headache side or between migraine and headache free periods. Despite a slight increase in BFV in intracerebral arteries, this study does not support the concept that vasoconstriction is sumatriptan's principal mechanism in pain relief.
Adult↗
Neurochemicals, estrogen and headache.
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Brain↗
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↗
GABAA-receptor-mediated effects of progesterone, its ring-A-reduced metabolites and synthetic neuroactive steroids on neurogenic oedema in the rat meninges.
1. The effects of progesterone, its A-ring-reduced metabolites, allopregnanolone, tetrahydroxydeoxycorticosterone and the synthetic neuroactive steroid alphaxalone were evaluated in a rat model of plasma extravasation within the meninges following unilateral electrical stimulation (ES) of the trigeminal ganglion (0.6 mA, 5 ms, 5 min) or substance P administration (1 nmol kg-1, i.v.). 2. When administered 55 min prior to electrical stimulation, progesterone (> or = 500 micrograms, s.c.) dose-dependently decreased plasma extravasation within the meninges (ED50: 650 micrograms) but not within conjunctiva and tongue. Promegestone (R5020), a non-metabolized progesterone agonist (1000 micrograms, i.p.) was ineffective. The administration of progestrone (> or = 500 micrograms s.c.) 55 min prior to substance P partially suppressed plasma extravasation within the meninges (ED50: 550 micrograms). 3. The GABAA-antagonist, bicuculline (ED50: 8.2 micrograms kg-1, i.p.) but not the GABAB-antagonist, phaclofen (100 micrograms kg-1, i.p.) attenuated the effects of progesterone after electrical stimulation and substance P administration. 4. The metabolites of progesterone, allopregnanolone (3 alpha-hydroxy-5 alpha- pregnan-20-one (THP); ED50: 0.58 micrograms kg-1, i.p.), tetrahydroxydeoxycorticosterone (3 alpha,21- dihydroxy-5 alpha-pregnan-20-one (THDOC); ED50: 1.2 micrograms kg-1, i.p.) as well as the synthetic steroid alphaxalone (3 alpha-hydroxy-5 alpha-pregnane-11,20-dione; ED50: 1.8 micrograms kg-1, i.p.) suppressed plasma extravasation dose-dependently following ES, whereas the epimer of allopregnanolone, 3 beta-hydroxy-5 alpha-pregnan-20-one (100 micrograms kg-1, i.p.), did not. Extravasation caused by SP administration was partially suppressed by allopregnanolone (> or = 1 microgram kg-1, i.p.) (ED50: 2.1 micrograms kg-1). 5. The effect of progesterone (1000 micrograms, s.c.) and allopregnanolone (100 micrograms kg-1, i.p.) on neurogenic plasma extravasation was reversed by bicuculline (10 micrograms kg-1, i.p.) or by a congener, bicuculline-methiodide (10 micrograms kg-1, i.p.) which does not cross the blood brain barrier. 6. Progesterone (1000 micrograms, s.c.) had no effect on mean arterial blood pressure or heart rate when measured for 60 min after administration. 7. These results indicate that neurosteroid modulation of a GABAA-receptor located outside the blood brain barrier suppresses neurogenic and substance P-induced plasma extravasation within the meninges. The findings are consistent with previously reported data showing that valproic acid and muscimol inhibit meningeal oedema by bicuculline-sensitive mechanisms. Drugs which activate GABAA-receptors and its modulatory sites might be clinically effective in the treatment of migraine and cluster headache.
Animals↗
Brain stem activation in spontaneous human migraine attacks.
Evidence from animal experiments shows that the brain stem is involved in the pathophysiology of migraine. To investigate human migraine, we used positron emission tomography to examine the changes in regional cerebral blood flow as an index of neuronal activity in the human brain during spontaneous migraine attacks. During the attacks, increased blood flow was found in the cerebral hemispheres in cingulate, auditory and visual association cortices and in the brain stem. However, only the brain stem activation persisted after the injection of sumatriptan had induced complete relief from headache and phono- and photophobia. These findings support the idea that the pathogenesis of migraine is related to an imbalance in activity between brain stem nuclei regulating antinociception and vascular control.
Adult↗
Suppression by the sumatriptan analogue, CP-122,288 of c-fos immunoreactivity in trigeminal nucleus caudalis induced by intracisternal capsaicin.
1. The effects of an intravenously administered sumatriptan analogue were examined on c-fos-like immunoreactivity (c-fos-LI), a marker of neuronal activation, evoked within trigeminal nucleus caudalis (TNC) and other brain stem regions 2 h after intracisternal injection of the irritant, capsaicin (0.1 ml, 0.1 mM), in pentobarbitone-anaesthetized Hartley guinea-pigs. 2. C-fos-LI was assessed in eighteen serial sections (50 microns) using a polyclonal antiserum. A weighted average, reflecting total expression within lamina I, IIo of TNC was obtained from three representative levels (i.e., at -0.225 mm, -2.475 mm and -6.975 mm.). 3. Capsaicin caused significant labelling within lamina I, IIo, a region containing axonal terminations of small unmyelinated C-fibres, as well as within the nucleus of the solitary tract, area postrema and medial reticular nucleus. A similar distribution of positive cells was reported previously after intracisternal injection of other chemical irritants such as autologous blood or carrageenin. 4. Pretreatment with a conformationally restricted sumatriptan analogue (with some selectivity for 5-HT1B and 5-HTID receptor subtypes) CP-122,288, reduced the weighted average by approximately 50-60% (P < 0.05) in lamina I, IIo at > or = 100 pmol kg-1, i.v., but did not decrease cell number within area postrema, nucleus of the solitary tract or medial reticular nucleus. A similar pattern was reported previously following sumatriptan, dihydroergotamine or CP-93,129 administration after noxious meningeal stimulation. 5. We conclude that modifications at the amino-ethyl side chain of sumatriptan dramatically enhance the suppression of c-fos expression within TNC, a finding consistent with its remarkable potency against neurogenic plasma protein extravasation within dura mater. CP-122,288 and related analogues may serve as an important prototype for drug development in migraine and related headaches.
Animals↗
Attenuation by valproate of c-fos immunoreactivity in trigeminal nucleus caudalis induced by intracisternal capsaicin.
1. Valproic acid, useful in the treatment of migraine, is an inhibitor of gamma aminobutyric acid (GABA) aminotransferase and activator of glutamic acid decarboxylase. Its mechanism in migraine remains obscure. The effects of valproic acid (2-propylpentanoic acid) were examined on the number of cells expressing c-fos-like immunoreactivity (c-fos-LI), a marker of neuronal activation, within the trigeminal nucleus caudalis (lamina I, IIo, TNC) 2 h after intracisternal injection of the irritant, capsaicin (0.1 ml; 15.25 micrograms ml-1), in urethane-anaesthetized Hartley guinea-pigs. Positive cells were counted in eighteen sections (50 microns) at three representative levels (rostral, middle and caudal) within lamina I, IIo of the TNC in 90 animals. 2. Numerous cells were labelled after capsaicin instillation (244 +/- 25; 1 ml; 15.25 mM) but not after capsaicin vehicle (11 +/- 1). Positive cells were also found within the medial reticular nucleus, the area postrema and the nucleus of the solitary tract. A similar distribution has been demonstrated previously after application of intracisternal irritants such as autologous blood or carrageenin. 3. Valproate (> or = 10 mg kg-1, i.p.) reduced labelled cells by 52% (P < 0.05) in lamina I, IIo but not within the area postrema, the nucleus of the solitary tract or the medial reticular nucleus. A similar finding was obtained previously after administration of sumatriptan, dihydroergotamine or the NK1 receptor antagonist RPR 100,893. 4. Pretreatment with bicuculline (30 micrograms kg-1; i.p.), a GABAA antagonist, but not phaclofen (1 mg kg-1) a GABAB antagonist, reversed the effect of valproate and increased c-fos positive cells within lamina I, IIo. Somewhat paradoxically, bicuculline by itself (30 micrograms kg-1 i.p.) decreased the number of labelled cells suggesting that more than a single GABAergic mechanism can suppress c-fos expression. 5. We conclude that the mechanism of action of valproate is mediated via GABAA receptors. Since valproate decreases both c-fos expression and as previously shown, neurogenic inflammation within the meninges, the GABAA receptor complex might provide an important target for drug development in migraine and related headaches.
Animals↗
Peripheral GABAA receptor-mediated effects of sodium valproate on dural plasma protein extravasation to substance P and trigeminal stimulation.
1. The GABA transaminase inhibitor and activator of glutamic acid decarboxylase, valproic acid is being used for the treatment of migraine. Its mechanism of action is unknown. We tested the effects of sodium valproate and GABAA-agonist muscimol on dural plasma protein ([125I]-bovine serum albumin) extravasation evoked by either unilateral trigeminal ganglion stimulation (0.6 mA, 5 ms, 5 Hz, 5 min) or substance P (SP) administration (1 nmol kg-1,i.v.) in anaesthetized Sprague-Dawley rats. 2. Intraperitoneal (i.p.) injection of sodium valproate or muscimol, but not baclofen (< or = 10 mg kg-1, i.p.) dose-dependently reduced dural plasma protein extravasation caused either by electrical trigeminal stimulation (ED50: 6.6 +/- 1.4 mg kg-1, i.p., and 58 +/- 18 micrograms kg-1, i.p. for valproate or muscimol, respectively) or by intravenous substance P administration (ED50: 3.2 +/- 1.4 mg kg-1, i.p. and 385 +/- 190 micrograms kg-1, i.p. for valproate or muscimol, respectively). 3. Valproate (6.6 mg kg-1, i.p.) or muscimol (58 micrograms kg-1, i.p.) had no effect on mean arterial blood pressure or heart rate when measured for 30 min after i.p. administration. 4. The GABAA-antagonist bicuculline (0.01 mg kg-1, i.p.) completely reversed the effect of valproate and muscimol on plasma extravasation following electrical stimulation or substance P administration, whereas the GABAB-receptor antagonist, phaclofen (0.01-1 mg kg-1, i.p.) did not. Bicuculline or phaclofen, given alone, did not alter the plasma extravasation response after either electrical stimulation or SP administration. 5. Valproate decreased plasma extravasation following substance P administration in adult animals, neonatally treated with capsaicin by a bicuculline-reversible mechanism. This suggests that GABAA receptors are not found primarily on those afferent neurones or fibres which are sensitive to capsaicin treatment in neonatal rats.6. We conclude that sodium valproate blocks plasma extravasation in the meninges through GABAA mediated postjunctional receptors probably within the meninges. The dosages required are comparable to those used clinically. Agonists and modulators at the GABAA receptor may become useful for the development of selective therapeutic agents for migraine and cluster headache.
Animals↗
The NOS inhibitor, 7-nitroindazole, decreases focal infarct volume but not the response to topical acetylcholine in pial vessels.
We examined whether 7-nitroindazole (7-NI), a putative inhibitor of neuronal nitric oxide synthase (nNOS), decreases cerebral infarction 24 h after proximal middle cerebral artery (MCA) occlusion. In preliminary experiments, we determined that 7-NI (25, 50, and 100 mg/kg i.p.) decreased nitric oxide synthase (NOS) activity within cerebral cortex by 40-60% when measured up to 120 min, but not 240 min after administration. At 25 or 50 mg/kg, 7-NI did not alter the systemic arterial blood pressure or the dilation of pial arterioles after topical acetylcholine (10 and 100 microM). To examine the effect of 7-NI on infarct size, 55 Sprague-Dawley halothane-anesthetized rats were subjected to proximal MCA occlusion (modified Tamura method). Five minutes after occlusion, 7-NI (25 or 50 mg/kg i.p.) or vehicle was injected. Animals treated with 25 or 50 mg/kg showed 25 and 27% reductions in infarct volume, respectively. Coadministration of L-arginine (300 mg/kg i.p.) plus 7-NI (25 mg/kg i.p.) reversed the effect. If, indeed, the effects of 7-NI are mediated by inhibition of nNOS activity, these results suggest that enzymatic products of the neuronal isoform promote ischemic injury and that they do so at least within the first few hours after permanent occlusion. The results also emphasize the importance of developing strategies to selectively inhibit the neuronal isoform inasmuch as we observed previously that administering the less selective NOS inhibitor, N omega-nitro-L-arginine (L-NA), in the same model either caused no change or increased the volume of ischemic injury.
Acetylcholine↗
[Drug-induced headache].
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Anti-Inflammatory Agents, Non-Steroidal↗
[Headache--what is the current status?].
Clinical and experimental evidence suggest, that migraine reflects a biological disorder of the brain. On the basis of a genetic predisposition, variations in internal rhythms may change the responsiveness towards external trigger factors. During the migraine attack changes occur in the cortical neuronal activity, in cerebral blood flow and in the activity of neuropeptide neurotransmitters such as substance P and calcitonin-gene-related-peptide. The consequence is an aseptic inflammation in the wall of dural arteries. Sumatriptan is a new agent which selectively acts at 5-HT-1D receptors in brain vessels and improves headache and autonomic symptoms in severe migraine attacks. Sumatriptan is also helpful in the treatment of headache attacks in cluster headache. The treatment of chronic tension-type headache requires the combination of tricyclics with behavioral techniques such as relaxation training.
Analgesics↗