Differential effects of the 5HT1B/1D receptor agonist naratriptan on trigeminal versus spinal nociceptive responses

In vivo electrophysiological assays in anesthetized rats have been used to compare the effects of the 5HT_1B/1D receptor agonist, naratriptan, on central trigeminal nociceptive processing from dural and cutaneous inputs with its effects on nociceptive processing in the spinal cord. Naratriptan inhibited responses of single trigeminal neurons, to noxious electrical and mechanical stimulation of the dura and face, dose dependently by a maximum of 67±3% and 70±18%, respectively, at 3 mg kg⁻¹ i.v. In contrast, naratriptan did not affect spinal dorsal horn neuronal responses to noxious mechanical stimulation of the hind-paw. These findings suggest that 5HT_1B/1D receptors have differential effects on nociceptive processing in the trigeminal versus spinal dorsal horns and provide a potential explanation for the lack of general analgesic effects of brain penetrant 5HT_1B/1D agonist antimigraine drugs.     

Differential distribution of 5HT1D- and 5HT1B-immunoreactivity within the human trigemino-cerebrovascular system: implications for the discovery of new antimigraine drugs

Sumatriptan, a 5HT_1B/1D-receptor agonist, is clinically effective as an antimigraine agent. Its therapeutic action may result partly from vasoconstriction of excessively dilated cranial blood vessels (a 5HT_1B-receptor mediated response). The antimigraine activity of sumatriptan may also result from inhibition of the release of vasoactive neuropeptides from trigeminal sensory fibres within the meninges. The identity of the 5HT_1B/1D-receptor subtype mediating this effect is unknown. Using 5HT_1D- and 5HT_1B-receptor-specific antibodies we have demonstrated a differential distribution of these receptor subtypes within the human trigemino-cerebrovascular system. Only 5HT_1B-receptor protein was detected on dural arteries. In contrast, only 5HT_1D-receptor protein was detected on trigeminal sensory neurones including peripheral and central projections to dural blood vessels and to the medulla. Within the medulla 5HT_1D-receptor protein was confined to discrete areas associated with the trigeminal sensory system. These findings have important implications for the design of new antimigraine drugs.     

Pharmacology of the Selective 5-HT1B/1D Agonist Frovatriptan

Objective.—To determine the pharmacological profile of frovatriptan.
Background.—Frovatriptan is a new 5-HT_1B/1D agonist developed for the treatment of migraine.
Methods.—Pharmacological studies were performed using in vitro and in vivo techniques.
Results.—Radioligand-binding studies showed that frovatriptan has a high affinity for 5-HT_1B and 5-HT_1D receptors, and moderate affinity for 5-HT_1A, 5-HT_1F, and 5-HT₇ receptors. In vitro, frovatriptan acts as a potent full agonist at human cloned 5-HT_1B and 5-HT_1D receptors, and as a moderately potent full agonist at 5-HT₇ receptors. Studies of frovatriptan in isolated human arteries demonstrated a lower threshold for constriction of cerebral than coronary vasculature and a bell-shaped dose-response curve was apparent in the coronary arteries. In anesthetized dogs, frovatriptan administration produced no measurable effect on cardiac function or on blood pressure. Frovatriptan had no effects on coronary blood flow following transient coronary artery occlusion, whereas sumatriptan produced a prolonged and significant decrease in coronary blood flow.
Conclusion.—The pharmacology of frovatriptan suggests that it should be an effective agent for the acute treatment of migraine, with a low potential for undesirable peripheral effects.     

Autoradiographic distribution of [3H]sumatriptan-binding sites in post-mortem human brain

The anatomical distribution of [³H]sumatriptan-binding sites was analysed in brain tissue sections from 11 subjects. Relevant concentrations of [³H]sumatriptan-binding sites were seen in areas such as visual cortex>locus niger>globus pallidus>layers IV-V of the frontal cortex>subiculum>entorhinal cortex>nucleus tractus solitarius>nucleus trigeminalis caudalis. This distribution of [³H]sumatriptan-binding sites in the human brain shows some differences when compared with that of 5HT_1D receptors, confirming that, besides 5HT_1D,sumatriptan also binds to 5HT_1F receptor subtype. Some species differences are evident between the distribution of [³H]sumatriptan-binding sites in the human brain and that reported for guinea-pig and rat brains, emphasizing that caution is needed in extrapolating experimental data from animals to humans. Furthermore, these data help to explain some of the therapeutic actions of sumatriptan. The remarkable levels of binding found in areas such as nucleus tractus solitarius and nucleus trigeminalis caudalis suggest that in migraine attacks sumatriptan could exert its specific anti-emetic effects and, partly at least, induce analgesia by directly acting over these brain nuclei.     

Serotonin type 1D receptors (5HTR) are differentially distributed in nerve fibres innervating craniofacial tissues

We tested the hypothesis that the 5HT_1DR, the primary antinociceptive target of triptans, is differentially distributed in tissues responsible for migraine pain. The density of 5HT_1DR was quantified in tissues obtained from adult female rats with Western blot analysis. Receptor location was assessed with immunohistochemistry. The density of 5HT_1DR was significantly greater in tissues known to produce migraine-like pain (i.e. circle of Willis and dura) than in structures in which triptans have no antinociceptive efficacy (i.e. temporalis muscle). 5HT_1DR-like immunoreactivity was restricted to neuronal fibres, where it colocalized with calcitonin gene-related peptide and tyrosine hydroxylase immunoreactive fibres. These results are consistent with our hypothesis that the limited therapeutic profile of triptans could reflect its differential peripheral distribution and that the antinociceptive efficacy reflects inhibition of neuropeptide release from sensory afferents. An additional site of action at sympathetic efferents is also suggested.     

The antagonist properties of S 11978 on 5HT3 receptors in N1E-115 neuroblastoma cells

Summary— The effects of the novel antagonist S 11978 (Endo-7-[(8-methyl-8-azabicyclo[3,2,1]-3-octyl)oxycarbonyl] benzo[b] thiophene) on 5HT₃ receptors were examined in N1E-115 mouse neuroblastoma x rat glioma hybrid cells, with radioligand binding and whole cell patch clamp techniques. The 5HT₃ receptor ligand [³H] quipazine was displaced by ICS 205–930, GR 38032F and S 11978 with K_I values of 2.25 nM, 36.5 nM and 1.75 nM respectively. Electrophysiological studies showed that S 11978 is a potent 5HT₃ antagonist: IC₅₀ values for inhibition of 5HT-induced inward current by ICS 205–930, GR 38032F and S 11978 were 0.22 nM, 0.63 nM and 0.43 nM respectively at a holding potential of-65 mV. It is concluded that S 11978 is a potent, high affinity 5HT₃ receptor antagonist.     

Combination of aspirin and metoclopramide produces a synergistic antithrombotic effect in a canine model of coronary artery thrombosis

Summary— We compared the antithrombotic properties of low doses of aspirin (0.03, 0.1 mg kg⁻¹ intravenously [iv]) and metoclopramide (0.1, 0.3 mg kg⁻¹ iv) alone or in combination. The animal model chosen for this study involved the generation of cyclic flow variations (CFV) in the circumflex coronary artery of anaesthetized dogs as a result of a critical coronary stenosis associated with a controlled arterial lesion at the site of stenosis. Subsequent regular CFV represent sequential thrombus formation and embolization in the damaged vessel. Neither aspirin nor metoclopramide alone demonstrated antithrombotic properties at the doses tested. However, the combination of aspirin 0.1 mg kg⁻¹ iv and metoclopramide 0.3 mg kg⁻¹ iv produced a significant antithrombotic effect, reducing the frequency of large CFV from 6.7 ± 0.5 to 0.8 ± 0.4 cycles h⁻¹ ( P < 0.01) and increasing minimum mean coronary blood flow from 5.0 ± 1.1 to 23.7 ± 2.6 mL min⁻¹ ( P < 0.01). This result apparently reflects an antithrombotic synergism between aspirin and metoclopramide since the effects of the combination were greater than the combined effects of the individual treatments. The antithrombotic influence of metoclopramide could be due to its 5HT₂-antagonist or α₂-antagonist properties, both of which would inhibit platelet aggregation. This demonstration of a synergistic antithrombotic action of the combination of aspirin and metoclopramide is of interest since these two agents are often combined in clinical use. Its therapeutic relevance, however, remains to be established.     

Tolerability and efficacy of naratriptan tablets with long-term treatment (6 months)

This open-label study was conducted to examine the long-term tolerability and efficacy of the novel 5HT₁ agonist naratriptan tablets 2.5 mg used to treat all migraine attacks for 6 months. Patients could reduce the dose to 1 mg in the event of intolerable adverse events. The results demonstrate that the majority (median 83%) of attacks treated with naratriptan tablets 2.5 mg were not associated with an adverse event. Among attacks treated with naratriptan tablets 2.5 mg (+optional 2.5 mg for headache recurrence), the most frequently reported adverse event was nausea (4% of attacks after a single naratriptan dose). Both the overall incidence of adverse events and the incidences of specific adverse events were no higher during months 4–6 of treatment compared with months 1–3. Only 5 of 414 patients elected to reduce their naratriptan dose to 1 mg. Headache relief 4 h postdose was reported in a mean of 68% of 6770 moderate or severe migraine attacks treated with naratriptan tablets 2.5 mg. The median number of naratriptan tablets used per attack was 1.0 (mean 1.25); patients treated only a median 7% of attacks (mean 13%) with a 2nd naratriptan tablet for headache recurrence. Patients rated naratriptan tablets as good or excellent in 61% of 7566 treated attacks. In summary, the data from this study demonstrate that naratriptan tablets 2.5 mg were very well tolerated and effective for the acute treatment of migraine for 6 months in a situation closely resembling actual clinical use.     

Sumatriptan blocks spreading depression in isolated chick retina

Spreading depression is a neurohumoral phenomenon that has been related to the pathophysiology of migraine. The recently introduced 5HT_1D agonist anti-migraine compound sumatriptan blocks neurogenic extravasation and induces cerebral vasoconstriction, but the actual mechanism of action against migraine remains obscure. Retinal spreading depression (RSD) velocity has been measured in isolated chick retinas in the presence of 0.05-2.00:nM sumatriptan. This drug reversibly blocks RSD in a concentration-dependent manner. Since the preparation is blood-vessel free, this effect must be related to the nervous tissue.     

Effects of vasopressin on human renal arteries

The effects of vasopressin were studied in isolated rings from branches (2–3mm in external diameter) of human renal arteries obtained from 18 patients undergoing nephrectomy for non-obstructive neoplasia. In arterial rings under resting tension, vasopressin produced concentration-dependent and endothelium-independent contractions with an EC₅₀ of 9.1×10⁻¹⁰molL⁻¹. The vasopressin V₁ receptor antagonist d(CH₂)₅Tyr(Me)AVP (10⁻⁶molL⁻¹) displaced the control curve to vasopressin 564-fold to the right in a parallel manner. In precontracted arterial rings and previously treated with the V₁ antagonist (10⁻⁶molL⁻¹) vasopressin caused endothelium-independent relaxation. The relaxation to vasopressin was reduced significantly by indomethacin (10⁻⁶molL⁻¹) and unaffected by the V₁/V₂ receptor antagonist desGly d(CH₂)₅- d -Tyr(Et)ValAVP (10⁻⁶molL⁻¹) or by N ^G-nitro- l -arginine methyl ester (10⁻⁴molL⁻¹). These observations indicate that vasopressin is primarily a constrictor of human renal arteries by V₁-receptor stimulation. Vasopressin causes prostaglandin-mediated dilatation of human renal arteries only if V₁-receptor blockade is present. The effects of vasopressin on human renal arteries may be relevant in those clinical situations characterized by increased plasma vasopressin levels.     

Safety trial with the 5HT1B/1D agonist avitriptan (BMS-180048) in patients with migraine who have experienced pressure, tightness, and/or pain in the chest, neck, and/or throat following sumatriptan

We investigate whether symptoms of pressure, tightness, and/or pain in the chest, neck, and/or throat after administration of the 5HT_1B/1D agonist avitriptan were associated with objective impairment of the myocardial function on 12-lead electrocardiogram (ECG), continuous ECG (Holter) monitoring, and echocardiography. Migraine sufferers who in two-thirds of alt attacks treated with sumatriptan had experienced chest/throat/neck symptoms were chosen for study. Baseline measures included vital signs, a 12-lead ECG and an echocardiogram. Patients ( n =51) who had no clinically significant abnormality at baseline received a high dose (150 mg) of avitriptan orally outside of a migraine attack. If pressure, tightness, and/or pain in the chest, neck, and/or throat occurred, an ECG was obtained, and a repeat echocardiogram was done while the symptoms were present in order to monitor for impairment of myocardial function. If symptoms of these types did not occur within 60 min after administration of the study drug, a second echocardiogram was obtained. Forty-five patients (88%) reported at least one adverse event and 23 (45%) experienced pressure, tightness, and/or pain in the chest, neck, and/or throat after administration of avitriptan. No clinically significant myocardial abnormalities were observed in any patient, even in those who had experienced the targeted symptoms. No other serious adverse event occurred. We concluded that the typical 5HT_1B/1D agonist-induced chest/throat/neck symptoms are most unlikely to be of cardiovascular origin.     

5HT2 receptors in cerebral cortex of migraineurs studied using PET and 18F-fluorosetoperone

Since the brain 5HT₂ receptors might be implicated in migraine pathogenesis, we have used positron emission tomography and ¹⁸F-fluorosetoperone, a 5HT₂ specific radioligand, to investigate in vivo the cortical 5HT₂ receptors in migraine subjects. Nine migraineurs who had either migraine with and without aura ( n = 5) or only migraine without aura ( n = 4) were studied between attacks. Twelve unmedicated healthy subjects of similar mean age were used as controls. Brain radioactivity was measured after ¹⁸F-setoperone IV injection for 90 min. A decrease of the regional specific distribution volumes (SDV) of the ligand was observed both in migraineurs and in controls. The age adjusted group means of SDV did not differ between patients and controls for the whole and for the right or left frontal, temporal, parietal and occipital cortex. These results suggest that cortical 5HT₂ receptors may be unaltered between attacks in migraine sufferers.     

Rizatriptan wafer–sublingual vs. placebo at the onset of acute migraine

Rizatriptan wafer is a 5HT_1B/1D agonist for use in the acute treatment of migraine. It is a freeze-fried formulation, approved for oral administration, which dissolves on the tongue and is swallowed with saliva. In this study the efficacy of sublingually administered rizatriptan 10-mg wafer was evaluated in a randomized, double-blind, placebo-controlled, out-patient study involving 39 migraineurs. Patients were instructed to treat a migraine at the onset of pain in order to evaluate time of onset of pain relief and pain relief at 1 h. The average time to onset of relief was 25 min for patients treated with rizatriptan wafer and 27 min for patients treated with placebo. At 1 h, 50% of the patients receiving rizatriptan wafer and 50% of the patients receiving placebo experienced significant relief. Implications and potential reasons for a high placebo response are discussed.     

Medullary hypotensive effect of endothelin1 in anaesthetized animals

Summary— In anaesthetized animals, systemic injection of ET₁ at doses from 3 to 100 ng·kg⁻¹ provoked only a transient hypotensive effect. At 300 ng·kg⁻¹ we observed the classical biphasic effect, consisting of a transient lowering of the arterial pressure followed by a long-lasting hypertensive effect. Direct injection of the peptide into the vertebral artery of anaesthetized animals only affected arterial pressure (AP) when the blood-brain barrier was permeabilised. Under these conditions, a dose-dependent decrease in AP was observed, which was not associated with a significant effect on the heart rate. Micro-injections of the peptide in the medullary nucleus reticularis lateralis area (NRL), a medullary vasopressive centre, at doses of 30 to 60 ng·kg⁻¹ led to a significant reduction in mean arterial pressure (MAP) (17 ± 4% and 36.5 ± 6%) respectively without a significant change in heart rate. These effects lasted less than 2 hours. These results suggest a possible role of ET₁ as a neuromodulator involved in the central regulation of vasomotor tone, in the NRL region.     

Methysergide

Methysergide is a semisynthetic ergot alkaloid ergometrine derivative, introduced in pharmacotherapy for migraine prophylaxis as a specific serotonin (5HT) receptor antagonist. Methysergide is not just a 5HT₂ antagonist, it is also a 5HT₁ agonist. Open and controlled studies attest to methysergide's efficacy. It may be more effective in resistant cases with a high attack frequency and may act synergistically with ergotamine and dihydroergotamine (DHE) for breakthrough attacks. Contraindications include pregnancy, peripheral vascular disorders, severe arteriosclerosis, coronary artery disease, severe hypertension, thrombophlebitis or cellulitis of the legs, peptic ulcer disease, fibrotic disorders, lung diseases, collagen disease, liver or renal function impairment, valvular heart disease, debilitation, or serious infection. Methysergide can induce retroperitoneal fibrosis and pleural and heart valve fibrosis with an estimated incidence of 1 in 5,000 treated patients. Therefore, it should be reserved for severe cases in which other migraine preventive drugs are not effective.     

Pathophysiology and pharmacology of migraine. Is there a place for antiemetics in future treatment strategies?

This article reviews the pathophysiology and pharmacology of emesis in relation to migraine pathogenesis. Also, the place of antiemetic and gastrointestinal prokinetic agents in current and future acute migraine treatment strategies is reviewed. The mechanisms of action of current and novel acute migraine therapies are considered with respect to the neurogenic and vascular hypotheses. Control of migraine-associated nausea and vomiting is often achieved with the benzamide dopamine D₂ receptor antagonist metoclopramide. This drug also has 5HT₃ receptor antagonist activity and reproducibly stimulates gastric motility to increase the availability of orally administered drugs. Other antiemetic and gastroprokinetic agents with potential value for the treatment of migraine-associated nausea and vomiting could speed absorption of oral antimigraine therapies without central nervous system side effects. Domperidone, a dopamine D₂ receptor antagonist that does not cross the blood brain barrier is relatively free of the central side-effect liability of metoclopramide. Cisapride, a benzamide 5HT₄ receptor agonist gastrointestinal prokinetic drug, lacks dopamine antagonist activity. A controlled comparison of these agents as migraine co-therapies could provide information on the importance of peripheral and central mechanisms in migraine-associated nausea and vomiting and improve antimigraine treatment options.     

Effect of colchiceine and ursodeoxycholic acid on hepatocyte and erythrocyte membranes and liver histology in experimentally induced carbon tetrachloride cirrhosis in rats

Colchiceine and ursodeoxycholic acid (UDCA) are drugs currently in use as therapy for different types of liver damage. We evaluated their ability to reverse the damage induced by carbon tetrachloride (CCl₄) in rats. Six groups were analysed: (1) CCl₄ (0.4 g kg⁻¹, i.p., three times a week) for 13 weeks; (2) CCl₄ for 8 weeks followed by colchiceine (60 μg kg⁻¹) + CCl₄ for 5 weeks; (3) CCl₄ for 8 weeks and thereafter UDCA (25 mg kg⁻¹) + CCl₄ for 5 weeks. Groups 4, 5 and 6 were appropriate controls of colchiceine, UDCA and vehicles respectively. Na⁺,K⁺- and Ca²⁺-ATPase activities and the cholesterol–phospholipid (CH/PL) ratio from erythrocyte and hepatocyte membranes were quantified. Membrane enzymatic activities and CH/PL ratios were affected more in group 1 than groups 2 and 3. We concluded that colchiceine and UDCA were effective drugs in this model of liver damage.     

Anti-Migraine Drug Interactions with Cloned Human 5-Hydroxytryptamine 1 , Receptor Subtypes

SYNOPSIS
Multiple 5-hydroxytryptamine (5-HT) receptors have been identified in humans. A subgroup of these receptors (designated 5-HT ₁ receptors) have been hypothesized to be involved in the mechanism of action of acute anti-migraine drugs. At present, this hypothesis cannot be tested directly in human tissues due to technical limitations. However, recent molecular biological advances have allowed for the development of assays employing cloned human 5-HT ₁ receptors expressed in cells by DNA transfection. This study analyzed the ability of ergotamine, dihydroergotamine, 5-HT and sumatriptan to interact with the four known human 5-HT ₁ receptor subtypes. The four acute anti-migraine agents interacted with all 4 human 5-HT ₁ receptor subtypes with less than 1 μM affinity. However, drug affinities for the human 5-HT _1B and 5-HT _1D receptors correlate most closely with the rank order of clinical dosages used to treat a migraine attack. Therefore, these data indicate that human 5-HT _1B and/or 5-HT _1D receptors are likely to mediate the therapeutic efficacy of acute anti-migraine drugs.     

Intensity dependence of the cortical auditory evoked potentials as a surrogate marker of central nervous system serotonin transmission in man: demonstration of a central effect for the 5HT1B/1D agonist zolmitriptan (311C90, Zomig ®).

As shown in animal studies, 5HT_1B/1D agonists can inhibit activity in the trigeminal nucleus caudalis, which may be advantageous for their antimigraine effect. To demonstrate a possible central nervous system (CNS) action of these compounds in man we studied their effect on the intensity dependence of the cortical auditory evoked potentials (IDAPs), thought to be inversely related to central serotonergic transmission. An amplitude/stimulus intensity function (ASF) slope was computed in healthy volunteers and migraine patients between attacks before and 2 h after oral 311C90 (zolmitriptan "Zomig") 10 mg ( n =14), 311C90 5 mg ( n =7), sumatriptan 100 mg ( n =14), dexfenfluramine 15 mg ( n =4), lorazepam 1.25 mg ( n =4) and placebo ( n =14). 311C90 10 mg and, to a lesser degree, 5 mg significantly increased the mean ASF slope ( p =0.007 and 0.05 vs placebo). There was a significant positive correlation between plasma levels of 311C90 and ASF slope changes. Sumatriptan and lorazepam had little effect, but dexfenfluramine produced a significant ASF slope decrease. 311C90 is able to modify a CNS activity that is modulated by serotonin, i.e. the IDAP. This effect is probably the consequence of its super or lipophilicity compared to sumatriptan and of activation of prejunctional 5HT_1B/1D autoreceptors, which lowers central serotonin release and thus the preactivation level of sensory cortices.     

Platelet aggregation of migraineurs during and between attacks

Platelet aggregation induced by ADP, collagen and platelet-activating factor was studied in common (migraine without aura) and classical migraine (migraine with aura) patients during and between attacks. The EC₅₀ values for ADP and platelet-activating factor were significantly higher, whilst that for collagen was significantly lower in classical migraine patients during headache-free intervals compared to healthy volunteers. The EC₅₀ values obtained for common migraine sufferers during symptom-free periods were similar to those of controls. During attacks, the EC₅₀ value for ADP, but not for collagen and platelet-activating factor, was significantly higher than that of the controls. In healthy subjects a positive correlation was found between ADP and collagen-induced aggregation. In contrast, there was a U-shaped correlation matrix in classical migraine patients. The present observations show that platelet aggregation is altered in migraine patients and this raises the possibility that platelet-activating factor may be involved in the pathogenesis of migraine.