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PubMed2006

EFNS guideline on the drug treatment of migraine - report of an EFNS task force.

Migraine is one of the most frequent disabling neurological conditions with a major impact on the patients' quality of life. To give evidence-based or expert recommendations for the different drug treatment procedures of the different migraine syndromes based on a literature search and an consensus in an expert panel. All available medical reference systems were screened for all kinds of clinical studies on migraine with and without aura and on migraine-like syndromes. The findings in these studies were evaluated according to the recommendations of the EFNS resulting in level A,B, or C recommendations and good practice points. For the acute treatment of migraine attacks, oral non-steroidal anti-inflammatory drugs (NSAIDs) and triptans are recommended. The administration should follow the concept of stratified treatment. Before intake of NSAIDs and triptans, oral metoclopramide or domperidon is recommended. In very severe attacks, intravenous acetylsalicylic acid or subcutaneous sumatriptan are drugs of first choice. A status migrainosus can probably be treated by steroids. For the prophylaxis of migraine, betablockers (propranolol and metoprolol), flunarizine, valproic acid, and topiramate are drugs of first choice. Drugs of second choice for migraine prophylaxis are amitriptyline, naproxen, petasites, and bisoprolol.

Advisory Committees↗
PubMed2004

Assessment of anti-migraine potential of a novel alpha-adrenoceptor agonist S19014: effects on porcine carotid and regional haemodynamics and human coronary artery.

Taking into account the drawbacks associated with the use of triptans, attempts are being made to explore other avenues for the treatment of migraine. Recently, it has been shown that both alpha1- and alpha2-adrenoceptors mediate the constriction of porcine carotid arteriovenous anastomoses, which has effectively served as an experimental model predictive of anti-migraine activity. The present study investigated the effects of a novel alpha-adrenoceptor agonist S19014 (spiro[(1,3-diazacyclopent-1-ene)-5 : 2'-(4',5'-dimethylindane)] fumarate) on carotid and systemic haemodynamics in anaesthetized pigs, and on human isolated coronary arteries. Increasing doses of S19014 (1-30 micro g/kg, i.v.) produced a dose-dependent initial short-lasting vasopressor response and a decrease of total carotid blood flow and conductance. The carotid blood flow and conductance changes were exclusively due to constriction of carotid arteriovenous anastomoses (capillary blood flow increased) and were accompanied by an increase in arterio-jugular venous oxygen saturation difference. Whereas prazosin (100 micro g/kg, i.v.) was ineffective, rauwolscine (300 micro g/kg, i.v.) attenuated the responses to S19014. The compound did not much affect the distribution of cardiac output to peripheral organs when compared with the vehicle group. Furthermore, S19014 only slightly contracted the human isolated coronary artery and its contractions, contrary to those of sumatriptan, were not increased in blood vessels pre-contracted with U46619. These results suggest that (i) the systemic and carotid vascular effects of S19014 are mainly mediated by alpha2-adrenoceptors, and (ii) S19014 could be effective in the treatment of migraine with an improved cardiovascular tolerance.

Adrenergic alpha-Agonists↗
PubMed2004

Transformed migraine and medication overuse in a tertiary headache centre--clinical characteristics and treatment outcomes.

Studies suggest that a substantial proportion of headache sufferers presenting to headache clinics may overuse acute medications. In some cases, overuse may be responsible for the development or maintenance of a chronic daily headache (CDH) syndrome. The objectives of this study are to evaluate patterns of analgesic overuse in patients consulting a headache centre and to compare the outcomes in a group of patients who discontinued medication overuse to those of a group who continued the overuse, in patients with similar age, sex and psychological profile. We reviewed charts of 456 patients with transformed migraine (TM) and acute medication overuse defined by one of the following criteria: 1. Simple analgesic use (>1000 mg ASA/acetaminophen) > 5 days/week; 2. Combination analgesics use (caffeine and/or butalbital) > 3 tablets a day for > 3 days a week; 3. Opiate use > 1 tablet a day for > 2 days a week; 4. Ergotamine tartrate use: 1 mg PO or 0.5 mg PR for > 2 days a week. For triptans, we empirically considered overuse > 1 tablet per day for > 5 days per week. Patients who were able to undergo detoxification and did not overuse medication (based on the above definition) after one year of follow-up were considered to have successful detoxification (Group 1). Patients who were not able to discontinue offending agents, or returned to a pattern of medication overuse within one year were considered to have unsuccessful detoxification (Group 2). We compared the following outcomes after one year of follow-up: Number of days with headache per month; Intensity of headache; Duration of headache; Headache score (frequency x intensity). The majority of patients overused more than one type of medication. Numbers of tablets taken ranged from 1 to 30 each day (mean of 5.2). Forty-eight (10.5%) subjects took >10 tablets per day. Considering patients seen in the last 5 years, we found the following overused substances: Butalbital containing combination products, 48%; Acetaminophen, 46.2%; Opioids, 33.3%; ASA, 32.0%; Ergotamine tartrate, 11.8%; Sumatriptan, 10.7%; Nonsteroidal anti-inflammatory medications other than ASA, 9.8%; Zolmitriptan, 4.6%; Rizatriptan, 1.9%; Naratriptan, 0.6%. Total of all triptans, 17.8%. Of 456 patients, 318 (69.7%) were successfully detoxified (Group 1), and 138 (30.3%) were not (Group 2). The comparison between groups 1 and 2 after one year of follow-up showed a decrease in the frequency of headache of 73.7% in group 1 and only 17.2% in group 2 (P < 0.0001). Similarly, the duration of head pain was reduced by 61.2% in group 1 and 14.8% in group 2 (P < 0.0001). The headache score after one year was 18.8 in group 1 and 54 in group 2 (P < 0.0001). A total of 225 (70.7%) successfully detoxified subjects in Group 1 returned to an episodic pattern of migraine, compared to 21 (15.3%) in Group 2 (P < 0.001). More rigorous prescribing guidelines for patients with frequent headaches are urgently needed. Successful detoxification is necessary to ensure improvement in the headache status when treating patients who overuse acute medications.

Adolescent↗
PubMed2004

Clinical profile and practice experience of almotriptan.

Patients expect their acute migraine treatment to have a rapid onset of action, achieve complete pain relief that is sustained for 24 h, and to have a good tolerability profile. Almotriptan has a favourable pharmacokinetic profile that translates clinically to a rapid onset of action and consistent absorption regardless of age, sex, food intake and status of the acute migraine attack. In addition, almotriptan is not associated with any clinically relevant drug-drug interactions. Pain-free status at 2 h postdose is achieved by approximately 39% of patients receiving almotriptan in clinical trials. Recurrence of headaches within 24 h is low with almotriptan (<22%). Almotriptan has a sustained pain-free rate of 25-27%, which in a meta-analysis of triptans was superior to sumatriptan 100 mg. Almotriptan therapy is associated with a low incidence of adverse events, including those affecting the central nervous system and chest.

Acute Disease↗
PubMed1993

A single amino acid difference accounts for the pharmacological distinctions between the rat and human 5-hydroxytryptamine1B receptors.

Molecular cloning of the rat and human 5-hydroxytryptamine1B (5-HT1B) receptors has revealed that the primary amino acid sequence of these two receptors is > 90% identical. Despite this high degree of primary sequence homology, these two receptors have significantly different pharmacological properties. A mutant human 5-HT1B receptor was constructed in which Thr355 was replaced by Asn, the corresponding residue at this position in the rat 5-HT1B receptor. The pharmacology of the mutant human 5-HT1B receptor was very similar to that of the rat 5-HT1B receptor. Specifically, the mutant receptor had much higher affinity for pindolol, [125I]-iodocyanopindolol, propranolol, and CP-93,129 than the wild-type receptor. In contrast, the mutant had significantly lower affinity for sumatriptan, N,N-dipropyl-5-carboxamidotryptamine, 5-methoxy-N,N-dimethyltryptamine, methysergide, metergoline, and rauwolscine. These data suggest that a single amino acid difference at position 355 is responsible for the pharmacological differences between the rat and human 5-HT1B receptors.

Amino Acid Sequence↗
PubMed1991

Vasodilator effect of 8-OH-DPAT in the isolated perfused mesenteric bed of the rat: no evidence for involvement of 5-HT1A receptors.

1. In the isolated perfused mesenteric bed of the rat, bolus administration or infusion of the selective 5-HT1A receptor agonist 8-hydroxy-2-(di-n-propyl-amino) tetralin (8-OH-DPAT; bolus 0.3-90 nmoles, infusion 0.03-30 microM) caused dose-related decreases in phenylephrine-induced tone. 2. These vasodilator responses were not modified by the 5-HT1A receptor antagonists BMY7378 (0.3 microM) or cyanopindolol (0.1 microM). 3. A number of compounds, having a range of affinities for 5-HT1A receptors, were tested in the mesentery and also for antagonist activity at alpha 1-adrenoceptors in the rabbit isolated aorta. 4. The potency of 8-OH-DPAT, flesinoxan, ipsapirone, sumatriptan and phentolamine, at decreasing phenylephrine-induced tone in the mesentery correlated closely with antagonist potency at alpha 1-adrenoceptors (r = 0.99) but not with affinity at 5-HT1A binding sites (r = -0.2). 5. It is concluded that the vasodilator effect of 8-OH-DPAT in the mesenteric bed of the rat most probably reflects alpha 1-adrenoceptor antagonist activity.

8-Hydroxy-2-(di-n-propylamino)tetralin↗
PubMed1991

Characterization of the 5-HT receptor mediating endothelium-dependent relaxation in porcine vena cava.

1. 5-Hydroxytryptamine (5-HT) relaxes rings of neonatal porcine isolated vena cava by both an endothelium-dependent and an endothelium-independent mechanism. The receptor mediating the latter response has been shown to be a 5-HT1-like receptor (positively coupled to adenylyl cyclase) located on the vascular smooth muscle. The features of the endothelium-dependent response to 5-HT in this preparation are now described. 2. In ring preparations contracted with the stable thromboxane-A2-mimetic, U-46619 (10 nM), and in the presence of the 5-HT2 receptor antagonist ketanserin (1 microM), low concentrations of 5-HT (1-100 nM) evoked an endothelium-dependent, rapid, 'spike-like' relaxation. Higher concentrations of 5-HT (0.1-10 microM) elicited a more sustained, but endothelium-independent relaxation. 3. Relaxation induced by low concentrations (1-100 nM) of 5-HT was abolished by endothelium removal, and was markedly (but not totally) inhibited by the guanylate cyclase inhibitor, methylene blue (10 microM) or by the inhibitor of endothelium-derived nitric oxide (NO) synthesis, L-NG-monomethylarginine (L-NMMA; 100-500 microM). 4. The endothelium-dependent response to 5-HT was mimicked by alpha-methyl-5-HT, 5-methoxytryptamine, tryptamine and 2-methyl-5-HT, but not by sumatriptan or 8-hydroxy-di-n-propylaminotetralin (8-OH-DPAT) at concentrations up to 10 microM. In contrast, relaxation evoked by 5-carboxamidotryptamine (5-CT) was endothelium-independent. 5. The endothelium-dependent relaxation induced by 5-HT or alpha-methyl-5-HT was antagonized by methysergide, methiothepin, cyproheptadine and metergoline, but not by ketanserin, spiperone, ondansetron, verapamil, cyanopindolol, mesulergine, ICS 205-930, or indomethacin. 6. These results suggest that the endothelium-dependent relaxation of porcine vena cava induced by 5-HT is largely mediated by the release of NO (although other endothelium-derived relaxing factors may also be involved) and that 5-HT is acting at a receptor which is not '5-HT1-like', 5-HT2, 5-HT3 or 5-HT4 and is not comparable to recognised 5-HT receptor ligand binding sites. The characteristics of this receptor are discussed in relation to the endothelial 5-HT receptor types in other blood vessels.

15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5↗
PubMed1991

Investigation into the 5-hydroxytryptamine receptor mediating smooth muscle relaxation in the rat oesophagus.

1. An investigation has been made into the 5-hydroxytryptamine (5-HT) receptor mediating relaxation of rat oesophagus in preparations precontracted with carbachol. 2. In tissues treated with pargyline (100 microM) and in the presence of corticosterone (30 microM) and cocaine (30 microM) the potency of 5-HT and 5-methoxytyramine (5-MeOT) was not changed but the maximum response to these agonists was reduced. Thus there was no evidence of metabolism and/or uptake through an amine depleting mechanism. 3. The relaxant concentration-effect curves to 5-HT were shifted to the left in a concentration-related manner by isobutylmethylxanthine (1 and 10 microM), suggesting the involvement of adenosine 3':5'-cyclic monophosphate in these responses. 4. 5-HT produced concentration-related relaxations of rat oesophagus with an EC50 value of 0.24 microM. Several indole agonists were tested and the following rank order of potency of key agonists obtained: 5-HT greater than alpha-methyl-5-hydroxytryptamine = 5-carboxamidotryptamine (5-CT) greater than 5-MeOT. In contrast, 2-methyl-5-hydroxytryptamine, sumatriptan and 8-hydroxy-2-(di-n-propylamino) tetralin were weak or inactive. 5. The substituted benzamides, metoclopramide, cisapride, renzapride and R,S-zacopride acted as partial agonists, producing 60-70% of the 5-HT maximum. 6. The relaxation responses to 5-HT were neither inhibited by antagonists selective for 5-HT1 or 5-HT2 receptors nor by the 5-HT3 receptor antagonists, ondansetron, granisetron or MDL 72222. 7. The relaxation responses induced by 5-HT, 5-CT, 5-MeOT and renzapride were selectively inhibited by high concentrations of ICS 205-930 with pKB values of approximately 6. 8. The 5-HT receptor mediating relaxation in rat oesophagus cannot be designated 5-HT1, 5-HT2 or 5-HT3 under the current 5-HT classification, but the observed effects are consistent with stimulation of the putative 5-HT4 receptor.

Animals↗
PubMed1993

Effects of capsaicin and 5-HT3 antagonists on 5-hydroxytryptamine-evoked release of calcitonin gene-related peptide in the guinea-pig heart.

1. The effect of 5-hydroxytryptamine (5-HT) on the release of calcitonin gene-related peptide (CGRP) was studied directly in the isolated perfused heart and indirectly in the isolated left atria of guinea-pig. 2. 5-HT injection into the guinea-pig isolated and perfused heart evoked a dose-dependent (1-100 microM) release of CGRP-like immunoreactivity (LI) that was abolished by in vitro pretreatment with capsaicin and was not affected by indomethacin. 3. Chlorophenyldiguanide (CPD, 100 microM), but not 8-hydroxy-dipropylaminotetralin (8-OH-DPAT, 100 microM), sumatriptan (100 microM) or 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI, 100 microM) evoked a release of CGRP-LI. Ondansetron (10 microM) or ICS205-930 (20 microM) completely abolished the 5-HT (100 microM)-evoked CGRP-LI release. 4. In the isolated electrically driven left atria of the guinea-pig 5-HT (1-10 microM) and CPD (3-100 microM) produced a positive inotropic response, which was abolished by capsaicin pretreatment. 8-OH-DPAT (10 microM) and DOI (10 microM) were inactive. Ondansetron inhibited the response to 5-HT with a pA2 of 6.50 (CL 6.08-6.91). 5. It is concluded that 5-HT causes a release of CGRP in the whole heart and a positive inotropic response in the isolated atria of guinea-pig. Both these effects are sensitive to capsaicin pretreatment and to 5-HT3 antagonists.

Animals↗
PubMed1993

Effects of 5-HT-receptor and alpha 2-adrenoceptor ligands on the haemodynamic response to acute central hypovolaemia in conscious rabbits.

1. We set out to elucidate the pharmacological mechanisms by which alpha 2-adrenoceptor and 5-HT-receptor ligands affect the haemodynamic response to acute central hypovolaemia in conscious rabbits. 2. Acute central hypovolaemia was produced by inflating an inferior vena caval cuff so that cardiac output fell at a constant rate of approximately 8.5% of its baseline level per min. 3. Drugs were administered into the fourth cerebral ventricle in either 154 mM NaCl (saline) or 20% w/v 2-hydroxypropyl-beta-cyclodextrin (beta-CDX). After vehicle treatments, the haemodynamic response to acute central hypovolaemia had the usual two phases. During Phase I, systemic vascular conductance fell in proportion to cardiac output so that mean arterial pressure fell by only 8 mmHg. Phase II commenced when cardiac output had fallen to approximately 60% of its baseline level, when vascular conductance rose abruptly and arterial pressure fell to < or = 40 mmHg. The haemodynamic response was not dependent on the vehicle used (saline or beta-CDX). 4. Methysergide delayed the occurrence of Phase II in a dose-dependent manner, and prevented it at a dose of 30- 600 nmol (geometric mean = 186 nmol). The effects and potency of methysergide were not dependent on the vehicle used, indicating that beta-CDX can be used as a vehicle for fourth ventricular administration of lipophilic drugs to conscious rabbits. Clonidine (10 nmol) reversed the effects of a critical dose of methysergide. 5. Phase II was also prevented by 8-hydroxy-2-(di-n-propylamino)tetralin (5-HT1A-selective agonist, geometric mean critical dose (range) = 13.1 (10-30) nmol), sumatriptan (5-HT1D-selective agonist, 72.1 (10-300) nmol), mesulergine (5-HT2/1C-selective antagonist, 173 (30-1000) nmol), idazoxan (alpha 2-adrenoceptor-selective antagonist, 548 (100-3000) nmol), and mianserin (5-HT2/1C-selective antagonist, 548 (100-3000) nmol). It was not affected by MDL 72222 (5-HT3-selective antagonist, 300 nmol) or ketanserin (5-HT2/1C-selective antagonist, 3000 nmol). 6. To characterize the nature of alpha 2-adrenoceptors in rabbit brainstem, we examined the binding of [3H]-rauwolscine to membrane homogenates of whole brainstem. [3H]-rauwolscine bound to a population of sites with the characteristics of alpha 2A-adrenoceptors. 7. From these results we suggest that activation of 5-HT1A receptors in the brainstem can prevent Phase II of the response to acute central hypovolaemia in conscious rabbits. Our results do not support the notion of an endogenous 5-hydroxytryptaminergic mechanism mediating Phase II. The mechanism by which the alpha 2-adrenoceptor antagonists yohimbine and idazoxan prevent Phase II remains to be elucidated. However, their potency relative to other 5-HT-receptor ligands indicates that an agonist action at 5-HT1A-receptors is more likely than an antagonist action at alpha 2-adrenoceptors.

2-Hydroxypropyl-beta-cyclodextrin↗
PubMed1993

5-HT1B receptors mediate potent contractile responses to 5-HT in rat caudal artery.

5-Hydroxytryptamine (5-HT) evoked potent contractile responses in phenoxybenzamine-treated ring segments of rat caudal artery, partially contracted with U46619. Responses were mimicked by 5-HT1-selective agonists with the potency order: RU24969 > 5-carboxamidotryptamine > 5-HT = CP-93,129 >> sumatriptan. 8-Hydroxy-N,N-dipropylaminotetralin was virtually inactive. Responses were unaffected by spiperone (0.1 microM) and mesulergine (1.0 microM), but were antagonized competitively by (+/-)-cyanopindolol affording agonist-independent pKB estimates of 8.4 to 8.9. The pharmacological profile of this receptor is consistent with that of the 5-HT1B subtype. Since the 5-HT1B receptor is the rodent homologue of the 5-HT1D beta subtype, it might be anticipated that 5-HT1D beta receptors will be found to mediate vasoconstrictor responses in non-rodent species.

15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5↗
PubMed1993

Characterization of the 5-hydroxytryptamine receptor mediating the positive inotropic response in guinea-pig isolated left atria.

1. 5-Hydroxytryptamine (5-HT), in the presence of propranolol (1 microM), atropine (3 microM) and ketanserin (1 microM), induced a positive inotropic response of guinea-pig isolated electrically paced left atria (pEC50 = 7.52). The positive inotropic response was mimicked by alpha-methyl-5-HT (pEC50 = 7.26) and 5-carboxamidotryptamine (5-CT; pEC50 = 6.56) but not by sumatriptan or 1-(m-chlorophenyl) piperazine (m-CPP). 2. The 5-HT induced positive inotropic response was competitively antagonized by both mesulergine (pA2 = 7.68) and methiothepin (pA2 = 6.67). Methysergide was a surmountable antagonist at 3 nM producing a rightward shift in the 5-HT concentration-response curve giving an apparent pA2 = 9.2 with no significant reduction in the maximum. At higher concentrations, methysergide behaved as an insurmountable antagonist, significantly reducing the maximum response to 5-HT as well as producing rightward shifts in the 5-HT concentration-response curves. 3. The 5-HT-induced positive inotropic response was not antagonized by either tropisetron (10 microM) or yohimbine (10 microM). 4. The guinea-pig atrial 5-HT receptor does not satisfy the criteria for any of the currently recognised 5-HT receptor subtypes and appears to have some similarities to the atypical 5-HT receptors previously described in other peripheral tissues.

Animals↗
PubMed1994

Further characterization of 5-hydroxytryptamine receptors (putative 5-HT2B) in rat stomach fundus longitudinal muscle.

1. The present study was undertaken to isolate and characterize pharmacologically homogeneous populations of 5-hydroxytryptamine (5-HT) receptors from a possible mixed receptor population mediating concentration of the longitudinal muscle of rat stomach fundus. Our aim was to extend the pharmacological characterization of the 5-HT2B receptor which is reported to be expressed in this preparation. 2. To minimize spontaneous activity and any influence of circular muscle on the contractile response, narrow (1-1.5 x 20 mm) segments of mucosa-denuded longitudinal muscle were used. Under these conditions, blockade of monoamine oxidase with pargyline (100 microM for 15 min) caused a leftward displacement of concentration-effect curves for both 5-methoxytryptamine (5-MeO-T) and tryptamine. Neither pargyline nor a number of uptake inhibitors affected responses to 5-HT. 3. In pargyline pretreated preparations, the order of potency of a number of tryptamine analogues was as follows: 5-MeO-T > or = alpha-Me-5-HT > or = 5-HT > 5-carboxamidotryptamine (5-CT) > tryptamine > 2-Me-5-HT. In addition several ligands known to act as agonists at either 5-HT2A or 5-HT2C receptors including 1-m-chlorophenylpiperazine (m-CPP), Ru 24969, MK 212 and SCH 23390 were also agonists in rat fundus whilst sumatriptan, renzapride and 8-hydroxy-2-(di-n-propylamino) tetralin (8-OH-DPAT) were very weak or inactive. With the exception of 2-Me-5-HT and m-CPP, most agonists produced monophasic concentration-effect curves consistent with an interaction at a single site. High concentrations of 2-Me-5-HT evoked relaxations which were blocked by phentolamine (1 MicroM) suggesting an interaction with alpha-adrenoceptors. m-CPP often evoked biphasic concentration-effect curves with a second contractile phase which was insensitive to yohimbine at concentrations higher than required for antagonism of responses to 5-HT.4. LY 53857, methiothepin, methysergide, ritanserin and ICI 170809 were potent but non-surmountable antagonists of 5-HT in rat fundus. In contrast, several ligands behaved as surmountable antagonists with the following order of potency: rauwolscine >yohimbine = mesulergine > mianserin = SB 204070 >WY 26703 > SB 200646> pirenpirone> renzapride. DAU 6285, granisetron, spiperone, ketanserin,phentolamine and GR 127935 did not affect responses to 5-HT at concentrations up to 1 pM. The agonist and concentration independent profile of antagonism supported a single site interaction for both agonists and antagonists.5. We conclude that despite small differences concerning the enantiomeric selectivity and affinity of rauwolscine and yohimbine, the close pharmacological identity of 5-HT receptors in rat stomach fundus and the recently cloned 5-HT2B receptor is maintained. SB 200646, which demonstrates some selectivity for 5-HT receptors in rat stomach fundus, should provide a useful ligand for confirmation of this view and allow discrimination of 5-HT2B function both in vitro and in vivo.

Animals↗
PubMed1994

Inhibition of excitatory non-adrenergic non-cholinergic bronchoconstriction in guinea-pig airways in vitro by activation of an atypical 5-HT receptor.

1. The effect of 5-hydroxytryptamine (5-HT) was studied on excitatory neurally mediated non-adrenergic non-cholinergic (NANC) contractions evoked by electrical field stimulation (EFS) in guinea-pig isolated bronchi. 2. 5-HT (0.1-100 microM) produced a concentration-dependent inhibition of the excitatory NANC response with 50.9 +/- 5.0% (n = 5, P < 0.01) inhibition at 100 microM. This inhibition was not significantly affected by the 5-HT2 antagonist, ketanserin (1 microM) when inhibitions (+/- ketanserin) at each concentration of 5-HT were compared by unpaired t tests; however, this concentration appeared to produce a leftward shift (approximately 10 fold) of the 5-HT concentration-inhibition curve. Ketanserin (1 microM) was effective in blocking bronchoconstriction evoked by activation of 5-HT2A receptors on airway smooth muscle. In the presence of ketanserin (1 microM) 5-HT (100 microM) evoked an inhibition of 57.4 +/- 5.9% (n = 5, P < 0.01) with an EC50 of 0.57 microM. 3. Inhibition evoked by 5-HT (0.1-100 microM) was unaffected by the alpha-adrenoceptor antagonist phentolamine (1 microM), the beta 2-adrenoceptor antagonist, ICI 118551 (0.1 microM), the 5-HT1A/B antagonist, cyanopindolol (1 microM) or the 5-HT3/4 antagonist, ICS 205-930 (1 microM). 4. Methiothepin (0.1 microM) produced an insurmountable inhibition of the effect of 5-HT (0.1-100 microM), reducing the maximum inhibition produced by 5-HT (100 microM) to 30.2 +/- 5.0% (n = 5, P < 0.001) and suggesting a non-competitive antagonism. Methiothepin inhibited the effect of 5-HT (10 microM) in a concentration-dependent manner with an IC50 of 81 nM. 5. Selective 5-HT receptor agonists were also tested on excitatory NANC responses. 5-Carboxamidotryptamine (5-CT, 0.1-100 MicroM) was the most potent, producing a concentration-dependent inhibition with an EC50 of 0.13 MicroM. Calculation of approximate IC25 values (concentration of the agonist required to give a 25% inhibition of the excitatory NANC response) gave a rank order of potency 5-CT > 5-HT> > 8-hydroxy-dipropylaminotetralin (8-OH-DPAT) >alpha-methyl-5-hydroxytryptamine (alpha-Me-5HT). Sumatriptan, 5-methoxytryptamine (5-MeOT) and 2-methyl-5-hydroxytryptamine (2-Me-5HT) were essentially inactive with IC25> 100 MicroM.6. 5-HT (10 microM) did not significantly affect contractile responses to exogenously applied substance P(1 nM-10 Microm).7. The effect of 5-HT was unchanged after incubation with the nitric oxide (NO) synthase inhibitor L-NG-nitroarginine methyl ester (L-NAME, 100 Microm). However, pretreatment with charybdotoxin (ChTX,0.1-30 nM), a blocker of the large conductance Ca2+-activated K+channel (K+ca), produced a concentration-dependent inhibition of the effect of 5-HT (10 MicroM).8. 5-HT evokes a concentration-dependent inhibition of e-NANC bronchoconstriction in guinea-pig isolated bronchi but does not affect cumulative concentration-dependent contractile responses to substance P, suggesting that inhibition is via a prejunctional receptor. Effects of selective antagonists and agonists suggest that an atypical 5-HT receptor mediates this inhibition. The inhibitory effect of 5-HT does not involve the production of NO, but may involve the opening a ChTX-sensitive K+ca channel.These data suggest that an atypical 5-HT receptor inhibits the release of neuropeptides from sensory C fibres and may act as other inhibitory neuromodulators via the opening of a common K'channel.

Animals↗
PubMed1994

On the nature of the 5-HT receptor subtype inhibiting acetylcholine release in the guinea-pig ileum.

1. The nature of the 5-hydroxytryptamine (5-HT) receptor subtype controlling acetylcholine release and contraction induced by stimulation of the neurokinin NK3 receptor has been studied in the longitudinal muscle-myenteric plexus preparation from guinea-pig ileum. 2. In preparations preloaded with [3H]-choline, the selective NK3 agonist, senktide, produced a concentration-dependent increase in tritium overflow, an index of [3H]-acetylcholine release. Low concentrations of neurokinin B, also markedly increased tritium efflux. 3. The senktide-induced acetylcholine release was markedly increased by the same concentration of methysergide and mesulergine. The 5-HT2A/2C agonist DOI (1 microM) inhibited the tritium overflow while 8-OH-DPAT, sumatriptan and ketanserin (1 microM each) were without effect on the senktide-induced tritium efflux. 4. The contractile response to senktide in the guinea-pig ileum was attenuated by atropine, 0.1 microM. Methysergide, a 5-HT1/2 receptor antagonist, and mesulergine, a 5-HT2A/2B/2C receptor antagonist, (1 microM each), enhanced the contractile effect of the NK3 receptor agonist. 5. It is concluded that the acetylcholine release induced by a NK3 receptor agonist is inhibited by stimulation of a 5-HT receptor, possibly of the 5-HT2C or 5-HT2C subtype.

Acetylcholine↗
PubMed1995

Vascular 5-HT1-like receptors mediating vasoconstriction and vasodilatation: their characterization and distribution in the intact canine cardiovascular system.

1. In anaesthetized dogs, intra-left atrial administration of 5-hydroxytryptamine (5-HT) and selected tryptamine analogues (5-carboxamidotryptamine, 5-CT; 5-methyl tryptamine, 5-MT; alpha-methyl 5-hydroxytryptamine, alpha-HT; sumatriptan, Sum) in the presence of ketanserin and MDL72222 (5-HT2 and 5-HT3 receptor antagonists, respectively), produced dose-related changes in carotid, coronary and renal vascular conductance mediated by vascular 5-HT1-like receptors. 2. In the carotid vascular bed, 5-HT, 5-MT, alpha-HT and Sum were vasoconstrictors with a rank order of potency (comparing ED50 values) of 5-HT = Sum > 5-MT > alpha-HT. By contrast in this vascular bed, 5-CT was a potent vasodilator. 3. In the coronary vascular bed, 5-HT, 5-CT, 5-MT and alpha-HT were vasodilators with a rank order of potency (comparing ED50 values) of 5-CT > 5-HT > 5-MT > alpha-HT. In this vascular bed, Sum was without effect. 4. In the renal vascular bed, 5-HT, 5-CT, 5-MT, alpha-HT and Sum were vasoconstrictors with a rank order of potency (comparing ED50 values) of 5-CT > 5-HT > Sum > 5-MT > alpha-HT. 5. The coronary (and carotid) vasodilator responses to 5-CT were antagonized by the 5-HT1-like receptor antagonists, spiperone (1 mg kg-1) and methiothepin (0.1 mg kg-1), whereas the renal vasoconstrictor responses to this tryptamine analogue were antagonized only by methiothepin. 6. It is concluded from these studies that agonist finger-printing in vivo, using tryptamine analogues,identifies and confirms the functional presence of at least two pharmacologically distinct subtypes of the 5-HT1-like receptor in the intact canine cardiovascular system. These two subtypes are located on the vascular smooth muscle and mediate direct vasoconstriction and vasodilatation responses in vivo.7. In addition, these studies confirm that the distribution of these subtypes within the major vascular beds, shows a marked heterogeneity. The carotid vascular responses to the tryptamine analogue sindicate the presence of both the vasodilator and the vasoconstrictor subtypes. The coronary vascular responses to these analogues are, however, consistent with presence of the vasodilator subtype, only. By contrast, the renal vascular responses to these analogues indicates only the presence of the vasoconstrictor subtype.

Animals↗
PubMed1995

Evidence that 5-hydroxytryptamine release in rat dorsal raphé nucleus is controlled by 5-HT1A, 5-HT1B and 5-HT1D autoreceptors.

Electrically stimulated 5-hydroxytryptamine (5-HT) release was monitored in slices of rat dorsal raphé nucleus (DRN) by fast cyclic voltammetry. Pseudo-single pulse stimulations (5 pulses at 100 Hz) were used to enable the effect of various receptor agonists to be seen without competition from endogenously released transmitter. The selective 5-HT1A receptor agonist, (+)-8-OH-DPAT (1.0 microM) decreased stimulated 5-HT release to 31 +/- 3% of controls. This decrease was inhibited by the 5-HT1A receptor antagonists, (+)-WAY-100135 (1.0 microM) and WAY-100635 (0.1 microM) but not by the 5-HT1D/B antagonist, GR127935 (0.05 microM). The selective 5-HT1B receptor agonist, CP-93129 (0.3 microM) decreased stimulated 5-HT release to 61 +/- 4% of control. This effect was antagonized by the 5-HT1B receptor antagonist, isamoltane (0.5 microM) but not by (+)-WAY-100135. The 5-HT1D agonist, sumatriptan (0.5 microM) decreased stimulated 5-HT release to 52 +/- 2% of controls. This decrease was blocked by GR-127935 but not by WAY-100635. These results suggest that 5-HT release in the rat DRN is under the control of 5-HT1A, 5-HT1B and 5-HT1D autoreceptors.

Animals↗
PubMed1995

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↗