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PubMed1998

Evidence for different 5-HT1B/1D receptors mediating vasoconstriction of equine digital arteries and veins.

5-hydroxytryptamine (5-HT) is a potent vasoconstrictor of equine digital arteries and veins which may play a role in the ischaemic disease, laminitis. The present investigation compared the properties of 5-HT1B/1D receptors in arteries with those in veins using isolated rings of equine digital blood vessels. The 5-HT1B/1D receptor-selective agonists, anpirtoline and sumatriptan were 17.9 and 10 times more potent and produced 4.1 and 5.6 times greater maximum contractions, respectively, in veins when compared to arteries. Other agonists tested were of equal potency and produced the same maximum responses in veins and arteries. Propranolol competitively inhibited 5-HT1B/1D receptor mediated responses in arteries, with a pKB of 6.7, but had no significant effects on responses in veins at 1 microM. Metergoline competitively inhibited 5-HT1B/1D receptor mediated responses in veins, with a pKB of 8.1, but had no significant effect in arteries at 0.1 microM. These data suggest that 5-HT1B/1D receptors mediating vasoconstriction in equine digital arteries are pharmacologically different to those found in digital veins.

Animals↗
PubMed1998

Cranial vascular effects of zolmitriptan, a centrally active 5-HT1B/1D receptor partial agonist for the acute treatment of migraine.

The anti-migraine drug zolmitriptan is a novel 5-HT1B/1D receptor partial agonist which, unlike sumatriptan, has been shown to cross the intact blood-brain barrier. In this study we examined whether or not the ability to access the cerebro-vascular intima affects the way in which a centrally-active 5-HT1B/1D receptor agonist influences cranial haemodynamics. The effects of zolmitriptan on carotid arterial blood flow distribution were studied in anaesthetised cats using radiolabelled microspheres. Zolmitriptan (10-1000 microg kg(-1) i.v.) selectively reduced arteriovenous-anastomotic (AVA) conductance producing a maximum decrease of 92.5+/-2.3%. The drug also produced a modest reduction in extra-cerebral conductance (23.9+/-6.5% maximum reduction at 30 microg kg(-1), i.v.), but was without effect on cerebral conductance. Using laser doppler flowmetry in anaesthetised cats, zolmitriptan (1-30 microg kg(-1), i.v.) produced dose-dependent decreases in ear microvascular conductance (15+/-5 to 60+/-6%) which mirrored decreases in carotid arterial conductance (12+/-11 to 61+/-5%). By contrast, zolmitriptan at doses up to 1000 microg kg(-1) was without effect on cerebral microvascular conductance. Although zolmitriptan crosses the blood-brain barrier and can therefore access the cerebro-vascular intima, this study suggests that this property does not adversely affect cerebrovascular function.

Animals↗
PubMed2001

Pediatric headache.

Headaches are frequent in children and adolescents and at times can be extremely disabling. Disability scales, such as the MIDAS scale, have been useful in helping follow adult patients. Modifications of this scale have been helpful in following pediatric and adolescent patients. Greater attention has been paid to epidemiology and classification of headache in children. Studies are being done on serotonin 1B/1D agonist for treating acute migraine, and this agent has been found to be efficacious despite a high placebo response. It is anticipated that FDA approval of sumatriptan nasal spray in adolescents is forthcoming. Despite advancements, there is no wonder drug. There continues to be a need for studying preventive therapies in a double-blind, placebo-controlled environment, and plans are under way for such studies. Many adult patients with chronic daily headaches report that their headaches began in childhood and adolescence. A better understanding of diagnostic criteria, early diagnosis, and more effective treatment may be the key to influencing the prevalence of headaches in adults. Continued research is the only answer to the questions raised by the most recent studies in this population.

Adolescent↗
PubMed2001

4991W93 inhibits release of calcitonin gene-related peptide in the cat but only at doses with 5HT(1B/1D) receptor agonist activity?

Calcitonin gene-related peptide (CGRP) is a marker for trigeminovascular activation and is released during the headache phase of migraine and cluster headache. CGRP may have a role in migraine through its potent cranial vasodilator effects, or by an action on trigeminal nerve activity, both of which are targeted by 5HT(1B/1D) agonist drugs. CP122,288, a conformationally restricted analogue of sumatriptan that is a potent inhibitor of neurogenic plasma protein extravasation (PPE), was ineffective at inhibiting CGRP release at a single low dose; and is also ineffective as an acute anti-migraine compound. However, it remained unclear as to whether, as a class, the conformationally-restricted triptan analogues could have inhibitory effects on CGRP in higher doses. 4991W93, a conformationally restricted analogue of zolmitriptan, is also a potent inhibitor of PPE at doses without 5HT(1B/1D)-mediated effects, that was developed as an anti-migraine drug, and thus was suitable to test whether higher doses of such conformationally restricted triptan analogues could inhibit trigeminal-evoked CGRP release. The superior sagittal sinus (SSS) was stimulated in 14 anaesthetised cats and external jugular vein blood samples were analysed by radioimmunoassay for CGRP levels before, 1 min after SSS stimulation, and 1 min after SSS stimulation in the presence of 4991W93. Stimulation of the SSS resulted in release of CGRP from the external jugular vein. 4991W93 at a dose of 0.1 and 10 microg/kg, selected for maximal PPE blocking effects in rodents, was ineffective at inhibiting CGRP release, with an SSS stimulation level of 78+/-4 pmol/l compared to a post-4991W93 level of 79+/-3 pmol/l (n=4). In comparison CGRP release was inhibited after a dose of 100 microg/kg 4991W93 from 64+/-6 to 36+/-3 pmol/l (n=5). Given that 4991W93 is inactive clinically at non-vascular doses, it seems clear that the 5HT(1B/1D) agonist effects of the compound are necessary for blockade of CGRP release and thus any anti-migraine action. Taken with the clinical results, these data emphasise the importance of CGRP release in migraine, and suggest that other non-5HT-based pharmacological targets may account for PPE blockade in animal studies.

Animals↗
PubMed1996

Serotonin efflux in the rat ventral lateral geniculate nucleus assessed by fast cyclic voltammetry is modulated by 5-HT1B and 5-HT1D autoreceptors.

Fast cyclic voltammetry (FCV) was used to measure electrically stimulated monoamine efflux in the rat ventral lateral geniculate nucleus (vLGN). The electrochemical characteristics of the released species resembled 5-HT but not dopamine or noradrenaline. Amine efflux was abolished by the sodium channel blocker tetrodotoxin (0.1 microM), Ro 4-1284 (1.0 microM), the fast-acting reserpine analogue, and removal of Ca2+ from the superfusate. Amine efflux was unaffected by the monoamine oxidase inhibitor clorgyline (0.1 microM). Of paroxetine (0.1 microM), desipramine (50 nM) and vanoxerine (0.5 microM), selective blockers of 5-HT, noradrenaline and dopamine uptake respectively, only paroxetine increased monoamine efflux (to 194 +/- 25%, mean +/- SEM) and prolonged the removal half-life (to 638 +/- 105%). The non-specific 5-HT1 antagonist methiothepin (0.2 microM) increased 5-HT efflux on long (20 pulses at 20 Hz) but not short trains (20 pulses at 100 Hz). When tested on pseudo-one-pulse stimulations (5 pulses, 100 Hz), the selective 5-HT1A agonist 8-OHDPAT (1.0 microM) had no effect. CP 93129 (0.3 microM), the selective 5-HT1B agonist, decreased 5-HT efflux to 37 +/- 4% of control and was antagonised by the 5-HT1B blocker isamoltane (0.5 microM) and by the 5-HT1D/B antagonist GR 127935 (50 nM). The preferential 5-HT1D agonist sumatriptan (0.5 microM) also decreased 5-HT efflux, to 55 +/- 6% and was antagonised by GR 127935 (50 nM) but not isamoltane (0.5 microM). These results suggest that 5-HT released in the vLGN can be measured by FCV. Furthermore, released 5-HT is taken up by the 5-HT transporter and may be under the influence of 5-HT1B and 5-HT1D autoreceptors.

2H-Benzo(a)quinolizin-2-ol, 2-Ethyl-1,3,4,6,7,11b-↗
PubMed1998

Selective labelling of 5-HT7 receptor recognition sites in rat brain using [3H]5-carboxamidotryptamine.

The aim of the present study was to establish a radioligand binding assay to selectively label the native 5-HT7 receptor expressed in rat brain. In rat whole brain (minus cerebellum and striatum) homogenate, (+/-)-pindolol (10 microM)-insensitive [3H]5-CT ([3H]5-carboxamidotryptamine; 0.5 nM) specific binding (defined by 5-HT, 10 microM) displayed a pharmacological profile similar to the recombinant 5-HT7 receptor, although the Hill coefficients for competition curves generated by methiothepin, ritanserin, sumatriptan, clozapine and pimozide were significantly less than unity. In homogenates of rat hypothalamus, (+/-)-pindolol (10 microM)-insensitive [3H]5-CT recognition sites also resembled, pharmacologically, the 5-HT7 receptor, although pimozide still generated Hill coefficients significantly less than unity. Subsequent studies were performed in the additional presence of WAY100635 (100 nM) to prevent [3H]5-CT binding to residual, possibly, 5-HT1A sites. Competition for this [3H]5-CT binding indicated the labelling in whole rat brain homogenate of a homogenous population of sites with the pharmacological profile of the 5-HT7 receptor. Saturation studies also indicated that (+/-)-pindolol (10 microM)/WAY 100635 (100 nM)-insensitive [3H]5-CT binding to homogenates of whole rat brain was saturable and to an apparently homogenous population of sites which were labelled with nanomolar affinity (Bmax=33.2+/-0.7 fmol mg(-1) protein, pKd=8.78+/-0.05, mean+/-S.E.M., n=3). The development of this 5-HT7 receptor binding assay will aid investigation of the rat native 5-HT7 receptor.

8-Hydroxy-2-(di-n-propylamino)tetralin↗
PubMed2002

Specific labelling of serotonin 5-HT(1B) receptors in rat frontal cortex with the novel, phenylpiperazine derivative, [3H]GR125,743. A pharmacological characterization.

Although several tritiated agonists have been used for radiolabelling serotonin (5-hydroxytryptamine, 5-HT)(1B) receptors in rats, data with a selective, radiolabelled antagonist have not been presented. Inasmuch as [3H]GR125,743 specifically labels cloned, human and native guinea pig 5-HT(1B) receptors and has been employed for characterization of cerebral 5-HT(1B) receptor in the latter species [Eur. J. Pharmacol. 327 (1997) 247.], the present study evaluated its utility for characterization of native, cerebral 5-HT(1B) sites in the rat. In homogenates of frontal cortex, [3H]GR125,743 (0.8 nM) showed rapid association (t(1/2)=3.4 min), >90% specific binding and high affinity (K(d)=0.6 nM) for a homogeneous population of receptors with a density (B(max)) of 160 fmol/mg protein. In competition binding studies, affinities were determined for 15 chemically diverse 5-HT(1B) agonists, including 2-[5-[3-(4-methylsulphonylamino)benzyl-1,2,4-oxadiazol-5-yl]-1H-indole-3-yl]ethylamine (L694,247; pK(i), 10.4), 5-carboxamidotryptamine (5-CT; 9.7), 3-[3-(2-dimethylamino-ethyl)-1H-indol-6-yl]-N-(4-methoxybenzyl)acrylamide (GR46,611; 9.6), 5-methoxy-3-(1,2,5,6-tetrahydro-4-pyridinyl)-1H-indole (RU24,969; 9.5), dihydroergotamine (DHE; 8.6), 5-H-pyrrolo[3,2-b]pyridin-5-one,1,4-dihydro-3-(1,2,3,6-tetrahydro-4-pyridinyl (CP93,129; 8.4), anpirtoline (7.9), sumatriptan (7.4), 1-[2-(3-fluorophenyl)ethyl]-4-[3-[5-(1,2,4-triazol-4-yl)-1H-indol-3-yl]propyl]piperazine (L775,606; 6.4) and (minus sign)-1(S)-[2-[4-(4-methoxyphenyl)piperazin-1-yl]ethyl]-N-methyl-3,4-dihydro-1H-2-benzopyran-6-carboxamide (PNU109,291; <5.0). Similarly, affinities were established for 13 chemically diverse antagonists, including N-[4-methoxy-3-(4-methylpiperazin-1-yl)phenyl]-3-methyl-4-(4-pyridyl)benzamide (GR125,743; pK(i), 9.1), (-)cyanopindolol (9.0), (-)-tertatolol (8.2), N-(4-methoxy-3-(4-methylpiperazin-1-yl)phenyl]-2'-methyl-4'-(5-methyl-1,2,4-oxadiozol-3-yl)biphenyl-4-carboxamide (GR127,935; 8.2), N-[3-(1,4-benzodioxan-5-yl)piperidin-4-yl]N-(indan-2yl)amine (S18127; 7.9), metergoline (7.8), (-)-pindolol (7.6), 1'-methyl-5-[2'-methyl-4'-(5-methyl-1,2,4-oxadiazol-3-yl)-biphenyl-4-ylcarbonyl]-2,3,6,7-tetrahydro-5H-spiro[furo[2,3-f]indole-3,4'-piperidine] (SB224,289; 7.5) and ketanserin (<5.0). These rank orders of affinity correspond to the binding profile of 5-HT(1B) rather than 5-HT(1D) receptors. The low affinities of L775,066 and PNU109,291 versus L694,247 should be noted, as well as the low affinity of ketanserin as compared to SB224,289. Finally, in line with species differences, the affinities of several ligands including CP93,129, RU24,969, (-)-pindolol and (-)-propanolol in rat 5-HT(1B) sites were markedly different to guinea pig 5-HT(1B) sites labelled with [3H]GR125,743. In conclusion, [3H]GR125,743 is an appropriate tool for the radiolabelling of native, rat 5-HT(1B) receptors and permitted determination of the affinities of an extensive series of ligands at these sites.

Animals↗
PubMed1999

The Pregnancy Registry program at Glaxo Wellcome Company.

Registries can be used to provide an early warning system for potential teratogenic effects associated with the use of specific medications during pregnancy. Glaxo Wellcome has developed 5 international registries: (1) the Acyclovir Pregnancy Registry, (2) the Antiretroviral Pregnancy Registry, (3) the Lamotrigine Pregnancy Registry, (4) the Sumatriptan Pregnancy Registry, and (5) the Bupropion Pregnancy Registry. The purpose of these registries is to gain more information about the potential teratogenicity of these drugs during pregnancy. Two potential limitations of such registry data are recognized: (1) the utility of the data collected depends on the size of the sample; and (2) the registered patients may not be representative of all patients using the medication. However, these types of registry reports can be a valuable and cost-effective way to collect data regarding the use of medications during pregnancy when conventional methods (eg, cohort studies) are not appropriate or feasible.

Adverse Drug Reaction Reporting Systems↗
PubMed2001

Oral triptans (serotonin 5-HT(1B/1D) agonists) in acute migraine treatment: a meta-analysis of 53 trials.

BACKGROUND: The triptans, selective serotonin 5-HT(1B/1D) agonists, are very effective acute migraine drugs with a well- developed scientific rationale. Seven different triptans will soon be clinically available, making evidence-based selection guidelines necessary. Triptan trials have similar designs, facilitating meta-analysis; this will provide a foundation for using triptans in clinical practice. METHOD: We asked pharmaceutical companies and the principal investigators of company-independent trials for raw patient data of all double-blind, randomised, controlled, clinical trials of oral triptans in migraine. We calculated summary estimates across studies for important efficacy and tolerability parameters, and separately summarised direct comparator trials. RESULTS: 53 clinical trials (12 unpublished) involving 24089 patients, met the criteria for inclusion. Mean results for 100 mg sumatriptan were 59% (95% CI 57-60) for 2 h headache response (improvement from moderate or severe to mild or no pain); 29% (27-30) for 2 h pain free (improvement to no pain); 20% (18-21) for sustained pain free (pain free by 2 h and no headache recurrence or use of rescue medication 2-24 h post dose); and 67% (63-70) for consistency (response in at least two of three treated attacks); placebo-subtracted proportions for patients with at least one adverse event (AE) were 13% (8-18), for at least one central nervous system AE 6% (3-9), and for at least one chest AE 1.9% (1.0-2.7). Compared with these data, 10 mg rizatriptan showed better efficacy and consistency, and similar tolerability; 80 mg eletriptan showed better efficacy, similar consistency, but lower tolerability; 12.5 mg almotriptan showed similar efficacy at 2 h but better other results; 2.5 mg naratriptan and 20 mg eletriptan showed lower efficacy and (the first two) better tolerability; 2.5 mg and 5 mg zolmitriptan, 40 mg eletriptan, and 5 mg rizatriptan showed very similar results. The results of the 22 trials that directly compared triptans show the same overall pattern. We received no data on frovatriptan, but publicly available data suggest lower efficacy. INTERPRETATION: At marketed doses, all oral triptans were effective and well tolerated. 10 mg rizatriptan, 80 mg eletriptan, and 12.5 mg almotriptan provide the highest likelihood of consistent success.

Acute Disease↗
PubMed2001

Current options for the prevention and treatment of migraine.

BACKGROUND: Migraine is a common condition affecting approximately 18% of women and 6% of men in the United States. The goals of managing migraine are 2-fold: to prevent attacks from occurring and to effectively and rapidly end them when they do occur. OBJECTIVE: This article reviews the acute and prophylactic treatment of migraine. METHODS: Information for inclusion in this review was identified through a search of MEDLINE from 1995 to the present. Search terms included migraine, acute treatment, prophylactic treatment, preventive treatment, and individual drug names. RESULTS: Preventive measures for migraine include lifestyle changes (eg, avoiding migraine triggers and maintaining regular sleep, eating, and work habits) and drug therapy. Beta-blockers, calcium channel blockers, tricyclic antidepressants, and anticonvulsants are among the more common drug classes used for migraine prophylaxis, but preventive therapy must be individualized, taking into account efficacy, potential adverse effects, co-existing medical conditions, and drug costs. Many medications are available for the acute treatment of migraine, including over-the-counter analgesics and prescription drugs. Of the latter, the 5-hydroxytryptamine(1B/1D)-receptor agonists, or triptans, are the most recently introduced class. Each of the 4 available triptans (sumatriptan, zolmitriptan, naratriptan, and rizatriptan) is effective in ending a migraine attack, but comparative trials have shown differences between individual drugs in the time to pain relief and the percentage of patients who obtain pain relief. CONCLUSIONS: Medications to prevent or reduce the frequency of migraine tend to be less specific and effective than medications for the acute treatment of migraine. As a class, triptans are generally well tolerated and may be considered drugs of choice for the acute treatment of moderate to severe migraine.

Female↗
PubMed2001

Migraine treatment outcomes with rizatriptan in triptan-naive patients: a naturalistic study.

BACKGROUND: The 5-hydroxytryptamine(1B/1D) agonists, or triptans, are the newest class of drugs to become available for the acute treatment of migraine. The class currently includes sumatriptan, zolmitriptan, naratriptan, and rizatriptan. The efficacy of rizatriptan in the acute treatment of migraine has been established against placebo and other oral triptans in controlled comparative trials. OBJECTIVE: The US Migraine Assessment Protocol (USMAP) collected data on the use of rizatriptan in a naturalistic setting reflecting clinical practice. This paper presents results for patients enrolled in the USMAP study who had never taken a triptan before the study. METHODS: At enrollment, 216 patients completed a questionnaire describing their responses to their current nontriptan medications. They were then given specially packaged samples of 4 standard 10-mg rizatriptan tablets and 4 orally disintegrating 10-mg rizatriptan tablets (wafers) and were asked to take a different formulation for each of their next 2 attacks, the sequence to be at their discretion. Within approximately 24 hours after taking rizatriptan, patients were to call a toll-free number to report their responses to rizatriptan using an interactive voice-response system. RESULTS: Within 2 hours after initial dosing of rizatriptan, significantly more patients taking either the rizatriptan tablet or the rizatriptan wafer reported onset of pain relief, had become largely symptom free, and were able to resume usual activities compared with their baseline responses to nontriptans (P < 0.05). In addition, compared with their baseline responses to nontriptans, significantly more patients taking either rizatriptan formulation had mild or no pain 2 hours after dosing (P < 0.05). More than twice as many patients taking the rizatriptan tablets or wafers were either somewhat or very satisfied with the medication compared with their satisfaction with nontriptans (P < 0.05). CONCLUSIONS: In the naturalistic setting of this study, migraineurs who had not previously taken a triptan medication reported more rapid relief of pain, more effective pain relief, and more rapid resumption of normal activities when taking rizatriptan tablets or wafers than when taking a nontriptan medication. Patients dissatisfied with their current nontriptan migraine therapy may benefit from treatment with rizatriptan.

Activities of Daily Living↗
PubMed1998

Cultured astrocytes express messenger RNA for multiple serotonin receptor subtypes, without functional coupling of 5-HT1 receptor subtypes to adenylyl cyclase.

The literature describing the expression of 5-HT receptor subtypes by astrocytes is controversial and incomplete. It is clear that primary cultures of astrocytes express receptors of the 5-HT2 family coupled to phospholipase C and of the 5-HT7 receptor family positively coupled to adenylyl cyclase. Cultured astrocytes have also been reported to express receptors of the 5-HT1 family, although the exact subtypes present are unknown. In the present study we have investigated which of the known rat G-protein coupled 5-HT receptor mRNAs are expressed by cultured astrocytes. Reverse transcriptase-polymerase chain reaction (RT-PCR) revealed expression of 5-HT1A, 5-HT1B, 5-HT1D, 5-HT1F, 5-HT2A, 5-HT2B, 5-HT2C, 5-HT5B, 5-HT6 and 5-HT7 receptor mRNAs in astrocytes derived from 2-day old rats and cultured for 10-12 days. Messenger RNAs for 5-HT4 and 5-HT5A receptors were not detected. The functional expression of 5-HT1 receptor subtypes was investigated by measuring the ability of 5-HT1 receptor agonists: 8-OH-DPAT (5-HT1A receptors), RU24969 (5-HT1A, 5-HT1B, 5-HT1D, and 5-HT1F receptors) or sumatriptan (5-HT1B, 5-HT1D, and 5-HT1F receptors) to modulate forskolin or isoproterenol stimulated cAMP production. These compounds, at concentrations up to 10 microM, did not significantly attenuate cAMP production. These results indicate that although astrocytes express mRNA for each of the five 5-HT1 receptor subtypes which have been isolated from the rat, these receptors are not coupled to the inhibition of adenylyl cyclase.

Adenylyl Cyclases↗
PubMed2003

S+ -flurbiprofen but not 5-HT1 agonists suppress basal and stimulated CGRP and PGE2 release from isolated rat dura mater.

Neurogenic inflammation of the meninges, expressed in plasma extravasation and vasodilatation, putatively contributes to certain types of headache. Both, non-steroidal antiinflammatory drugs (NSAIDs) and serotonin-1 (5-HT1) receptor agonists are similarly effective antimigraine drugs but their mechanism of action is unclear. The clinical observation that sumatriptan lowered plasma levels of calcitonin gene-related peptide (CGRP), found increased during migraine attacks, drew attention to a possible inhibition of pro-inflammatory neuropeptide release from trigeminal afferents. An isolated preparation of fluid-filled rat skull cavities was used to study effects of NSAIDs and 5-HT(1B/D) agonists on the dura stimulated by inflammatory mediators (bradykinin, histamine and serotonin, 10(-5)M each). The release of immunoreactive CGRP (iCGRP) and immunoreactive PGE(2) (iPGE(2)) was measured in 5-min samples of superfusates using enzyme immunoassays. S(+)-flurbiprofen (10(-6)M) strongly reduced the basal and stimulated iCGRP release and abolished iPGE(2) release; R(-)-flurbiprofen showed much less effect on iPGE(2) liberation and did not influence iCGRP release. The 5-HT(1B/D) agonists naratriptan and CP93,129 were ineffective on both iCGRP and iPGE(2) release. Inspite of its weak COX blocking effect, R(-)-flurbiprofen is reported to exert antinociceptive effects, although it has not been tested in migraine. Only the potent COX blocker S(+)-flurbiprofen also suppressed iCGRP release while the 5-HT(1B/D) agonists were ineffective. Thus, inhibition of meningeal neuropeptide secretion is not a common action principle of the drugs that could be essential for their antimigraine effects.

Animals↗
PubMed1999

Serotonin modulates synaptic transmission in immature rat ventrolateral medulla neurons in vitro.

Patch-clamp recordings in whole-cell configuration were made from ventrolateral medulla neurons of brainstem slices from 8-12-day-old rats. 5-Hydroxytryptamine (3-30 microM) concentration-dependently suppressed excitatory and inhibitory postsynaptic currents evoked by focal stimulation. An augmentation of inhibitory synaptic currents by 5-hydroxytryptamine was noted in a small number of neurons. 5-Hydroxytryptamine depressed synaptic currents with or without causing a significant change in holding currents and membrane conductances; the inward or outward currents induced by exogenously applied glutamate or GABA/glycine were also not significantly changed by 5-hydroxytryptamine. In paired-pulse paradigms designed to evaluate a presynaptic site of action, 5-hydroxytryptamine suppressed synaptic currents but enhanced the paired-pulse facilitation. 5-Hydroxytryptamine reduced the frequency of miniature excitatory postsynaptic currents without significantly affecting the amplitude. 5-Carboxamidotryptamine, 8-hydroxy-2(di-n-propylamino)tetralin, sumatriptan and N-(3-trifluoromethylphenyl)piperazine which exhibit 5-hydroxytryptamine1 receptor agonist activity, depressed synaptic currents with different potencies, with 5-carboxamidotryptamine being the most potent. The non-selective 5-hydroxytryptamine1 receptor antagonist pindolol attenuated the presynaptic effect of 5-hydroxytryptamine, whereas the 5-hydroxytryptamine1A antagonist pindobind-5-hydroxytryptamine1A and 5-hydroxytryptamine2 receptor antagonist ketanserin were ineffective. Our results indicate that 5-hydroxytryptamine suppressed synaptic transmission in ventrolateral medulla neurons by activating presynaptic 5-hydroxytryptamine1 receptors, probably the 5-hydroxytryptamine1B/5-hydroxytryptamine1D subtype. In addition, 5-hydroxytryptamine augmented inhibitory synaptic currents in a small number of neurons the site and mechanism of this potentiating action are not known.

Animals↗
PubMed2000

Autoradiography of receptor-activated G-proteins in post mortem human brain.

The agonist-stimulated guanosine 5'-(gamma-[(35)S]thio)triphosphate binding assay was used to anatomically localize receptor-activated G-proteins by autoradiography in post mortem human brain. The optimal conditions for guanosine 5'-(gamma-[(35)S]thio)triphosphate binding to human brain sections were established in post mortem samples of the prefrontal cortex, hippocampus, basal ganglia, brainstem and cerebellar cortex. An excess of GDP (2mM) was required to decrease basal activity and obtain effective stimulation by specific agonists. guanosine 5'-(gamma-[(35)S]Thio)triphosphate binding was increased after stimulation with specific agonists of different G-protein-coupled receptors. They include cannabinoid (WIN55212-2), mu-opioid ([D-Ala(2),N-Me-Phe(4), Gly(5)-ol]enkephalin), serotonin-1A [(+/-)-8-hydroxy-2-(di-n-propylamino)tetralin] and serotonin-1B/1D (sumatriptan), cholinergic muscarinic receptors (carbachol) and alpha(2)-adrenoceptors (UK14304). Such stimulation reached 1458%, 440%, 188%, 219%, 61% and 339%, respectively, over the basal levels. In tissue sections, the use of the above-mentioned agonists (10(-4)M) showed patterns of anatomical distribution similar to those already described by receptor autoradiography, with high densities over the hippocampus (serotonin-1A receptors), cortex (alpha(2)-adrenoceptors) and striatum (mu-opioid receptors). The highest binding levels were reached with the cannabinoid receptor agonist in most of the analysed brain regions. Carbachol produced only moderate stimulation of those same regions. The blockage of agonist-stimulated guanosine 5'-(gamma-[(35)S]thio)triphosphate binding by selective antagonists verified that the effect was receptor mediated. This technique provides a method to identify modifications of the receptor-mediated activation of G-proteins in post mortem human brain with anatomical resolution. It also provides valuable information on the level of drug efficacy in the human species.

Adult↗
PubMed1998

Interactions between the presynaptic alpha2-autoreceptor and presynaptic inhibitory heteroreceptors on noradrenergic neurones.

The noradrenergic neurones of the autonomic nervous system (postganglionic sympathetic neurones) and of the central nervous system are endowed with presynaptic receptors by which noradrenaline release is inhibited by noradrenaline itself (via the alpha2-autoreceptor) and by other transmitters and mediators (via heteroreceptors). Frequently, but not consistently, inhibitory interactions exist between auto- and heteroreceptors. This holds true for the following heteroreceptors: adenosine A1, cannabinoid CB1, dopamine D2/D3, histamine H3, 5-hydroxytryptamine (serotonin) 5-HT(1B), imidazoline, muscarine M2, delta opioid, kappa opioid, mu opioid, orphan opioid (ORL1), prostaglandin EP3, and somatostatin SRIF1. Such interactions (which have also been obtained in human tissue) may, if not considered, prevent the identification of a putative heteroreceptor or the quantitative estimation of the effect mediated by this receptor, and they may explain drug interactions in humans in vivo; many ligands at the alpha2-autoreceptor and at the heteroreceptors may be simultaneously used for therapeutic reasons (e.g., carbachol, clonidine, dopamine, sumatriptan, mianserin, and misoprostol) or abused (e.g., heroin, LSD, and delta9-tetrahydrocannabinol in hashish or marijuana).

Animals↗
PubMed1997

Opioids in headache treatment. Is there a role?

There may be a population of patients subject to frequent headache and in whom optimal analgesic effect is obtained only by frequent but controlled use of opiate drugs and in whom adverse drug effects are minimal. It is emphasized again that the reality is that there are currently a large amount of opioids being prescribed for headache patients because of patients' demands. One of the major considerations for physicians prescribing such treatment is familiarity with the legal guidelines. The federal law requires physicians to register if they are to maintain or detoxify with opioids addicts defined as "any individual who habitually uses any narcotic drug so as to endanger the public morals, health, safety, or welfare, or is so far addicted to the use of narcotic drugs as to have lost the power of self-control with reference to his addiction." A subsequent regulation, however, stated that the law was not intended to impose any limitation on prescription of narcotics for intractable pain. There are also many different state regulations covering, for example, limitations on amounts to be prescribed and reporting of patients who are habitual narcotic users. Obviously, headache patients who request liberal amounts of opioids must be screened. There has been considerable recent effort to provide guidelines regarding which patients with nonmalignant pain might be poor candidates for opioid treatment by reason of both probable treatment failure and risk of drug overuse. Many of these guidelines are not relevant to headache patients in whom pain is rarely continuous and rarely demands scheduled analgesia, as is often the case with pain of other types. There is general agreement that any previous history of any type of substance abuse is an important indicator of danger of recurrence of such behavior. Evaluation of psychological state and personality structure is of great importance. The more evidence of emotional disturbance, the greater the danger both of poor results and of drug abuse. In the chronic daily headache population, treatment failure has been found to correlate with abnormalities on the Minnesota Multiphasic Personality Inventory (MMPI). It is possible that formal psychological testing prior to the prescription of opioid drugs will prove of value in identifying those headache patients at greatest risk for drug abuse. The importance of making opioid treatment part of a multifaceted pain program has been emphasized. Portenoy emphasizes the need for (1) careful discussion with the patient (and often family) of the potential side effects of the drugs, and (2) scrupulous monitoring of adherence to the appropriate dosage and maintenance of prescription by a single physician. The more psychological disturbance evidenced by the patient, the more the risk with failure of drug treatment and of drug abuse. Finally, the analgesic needs of the patient with frequent migraine are different from those of the patient with tension-type headache. Migraine infrequently occurs more than two or three times a week for any period and usually responds to ergotamine, dihydroergotamine, sumatriptan, or a phenothiazine. Addition of codeine or oxycodone for the occasional intractable attack may be needed. When demands in a migraine patient for opioids in amounts greater than 10 to 15 tablets per month occur, there is obvious cause for concern. The opioid agonist-antagonist butorphanol, now available in nasal inhalation form, is alleged to have low abuse potential because it tends to produce dysphoria (an unpleasant emotional state) rather than the euphoria of other opioids. It is therefore unscheduled. The drug, however, does have abuse potential, and the limits needed to be placed on its use are still uncertain. Markley recently recommended a restriction to not more than two bottles (30 treatments) per month. The population with frequent tension-type headaches presents the major problem. Large numbers of these patients use drugs--often in combination

Analgesics, Opioid↗
PubMed1997

Pediatric migraine.

Migraine headaches are relatively common, affecting approximately 5% of all children. Although the differential diagnosis is extensive, a complete history and physical will usually lead to the correct diagnosis without laboratory or radiologic studies for most children. In cases of migraine complicated by neurologic problems, such as hemiplegia or ophthalmoplegia, neuroradiologic studies may be helpful to establish the diagnosis of complicated migraine. Treatment of migraine in children consists primarily of avoidance of triggers, rest, and simple analgesics. Behavior therapy, including relaxation-response training, has been shown to be an effective adjunct in managing both the frequency and intensity of the migraine attack. Use of pharmacologic agents for abortive and prophylactic therapy has not been extensively supported by well-designed, well-controlled research. In general, use of these agents should be restricted to the small group of children with frequent, severe attacks. Sumatriptan, a 5-HT1 receptor agonist, has shown promise in adult patients but future gains in treatment will be achieved only after a better understanding of the cause and pathogenesis of migraine.

Child↗