Search PubMed⌕ Search

SEARCH · Search PubMed

Results for “Sumatriptan”

Search indexed PubMed citations on genomics, clinical trials, systematic reviews and public health. Explore titles, authors and supplied subject terms, then open the PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 1,099 records · Page 61Linked to original sources
PubMed1999

L-NAME, a nitric oxide synthase inhibitor, modulates cholinergic antinociception.

Systemic administration of sumatriptan and buspirone (20 mg/kg: 5-HT1A agonists) produced antinociception against acetic acid-induced writhing. The antinociceptive effect was potentiated by cholinomimetic physostigmine (0.05 mg/kg i.p.) and blocked by the muscarinic antagonist atropine (5 mg/kg i.p.). Naloxone, an opiate antagonist, failed to reverse the sumatriptan- or buspirone-induced antinociception, but pindolol (10 mg/kg), a nonselective 5-HT1A antagonist, blocked this response. Sumatriptan- or buspirone-induced antinociception was significantly potentiated by L-NAME (a nitric oxide [NO] synthase inhibitor) although L-NAME (20 mg/kg) given alone had no effect on the nociceptive threshold. Recent studies have suggested that the L-arginine/NO/cGMP pathway is involved in the modulation of pain perception. The present results suggest that NO may play a role in cholinergic antinociception-mediated 5-HT1A receptor stimulation and that NO exerts an inhibitory action on cholinergic analgesia.

Acetic Acid↗
PubMedDate not supplied

[The cluster headache: a clinical model of immunologic receptor pathology?].

It is well established that cluster headache shows impaired functions at their neuroimmunomodulatory system level. Defect in receptor expression for 5-HT, IL-1 and IL-2 have been found in these patients. Sumatriptan, a molecule with agonistic activity for 5-HT1D receptor, truncates cluster headache attacks in 74% of patients. Flow cytometric analysis of monocytes expressing 5-HT receptor in cluster headache patients showed different trends clearly correlated with the clinical response to sumatriptan. Our findings strongly support the concept that cluster headache patients who are non responders to sumatriptan could present a block in their 5-HT receptor possibly due to specific autoantibodies for this receptor site.

Adult↗
PubMed1993

Acute and prophylactic treatment of migraine: practical approaches and pharmacologic rationale.

The antimigraine efficacy of many drugs may be mediated less through their primary modes of action than through the common pathway of serotonergic transmission stabilization. Migraine treatment may be symptomatic, acute/abortive, or prophylactic. Because oral drug absorption is impaired during attacks, parenteral agents are more appropriate for acute therapy. Acute agents include ergots and ergotamine derivatives, narcotics, and sumatriptan succinate. Agents that activate the 5-HT3 receptors must be administered with an antiemetic. Sumatriptan succinate, a specific 5-HT1 receptor agonist, does not necessitate adjunctive antiemetics. Stabilization regimens, such as those using valproate, may favorably alter the natural history of migraine. Sumatriptan succinate is appropriate both for acute attacks and for symptomatic management during stabilization. beta-Blockers, tricyclic antidepressants, and calcium antagonists may be used prophylactically.

Anti-Inflammatory Agents, Non-Steroidal↗
PubMed1993

Expression of mRNA for the serotonin 5-hydroxytryptamine1D beta receptor subtype in human and bovine cerebral arteries.

Serotonin [5-hydroxytryptamine (5-HT)] has been implicated in the pathophysiology of migraine, and the clinical efficacy of the 5-HT1B/5-HT1D receptor agonist sumatriptan points to neural and/or vascular 5-HT1D receptors as relevant targets in migraine therapy. We characterized the human and/or bovine 5-HT1D receptor subtype in cerebral blood vessels pharmacologically by correlation analysis and molecularly by Northern blot hybridization of cerebrovascular RNA extracts. Pharmacological analysis showed that sumatriptan was less potent than 5-HT in inducing contraction in freshly isolated human cerebral arteries and revealed an overall pharmacological profile positively and significantly correlated with that published for the 5-HT1D alpha (r = 0.746, p = 0.021) and 5-HT1D beta (r = 0.942, p = 0.0001) cloned human receptor subtypes. These results are suggestive of a contractile 5-HT1D beta receptor subtype but are not conclusive. However, Northern blots revealed the presence of mRNA transcripts for the 5-HT1D beta subtype, but not the 5-HT1D alpha subtype, in bovine (approximately 2.2 kilobases) and human (approximately 4.5 kilobases) cerebral blood vessels. Expression of either subtype could not be detected in intraparenchymal microvessels or capillaries isolated from bovine or human cerebral cortex. These results clearly indicate that the beneficial effect of sumatriptan in migraine attack, if vascularly related, is mediated by contractile 5-HT1D beta receptors most likely located on cerebral blood vessels at the surface of the brain. This study points to the 5-HT1D beta receptor subtype as the putative cerebrovascular target for migraine therapeutic agents.

Animals↗
PubMedDate not supplied

Congenital (?) Horners syndrome and ipsilateral headache.

A 31-year-old woman had left-sided miosis, ptosis, and hypopigmented iris probably since birth. At 22, she developed intermittent headaches, always in the left frontotemporal region. These headaches lasted from 1 to 2 days and recurred every 1-2 months. Pain attacks were pressing-pulsatile in character, moderate in intensity, and frequently accompanied by nausea, vomiting, and moderate phono- and photophobia. Various treatment alternatives, such as conventional analgesics and ergotamine failed to improve the attacks. Pizotifen was partially effective. The results of pupillometry and evaporimetry studies were consistent with a 3rd neuron sympathetic hypofunction on the symptomatic side. Autonomic studies and clinical features were consistent with a congenital Horner's syndrome. Conceivably, a sympathetic hypofunction may play a role in the pathogenesis of such headache or in its lateralization. Indomethacin and sumatriptan both seemed to provide absolute pain relief. Some clinical features, the fact that the IHS criteria for migraine are fulfilled and that sumatriptan is efficient, demonstrate the similarity to migraine. The coexistence of strict unilaterality of pain and the probable, complete response to indomethacin indicate a similarity to hemicrania continua in its remitting form. Further information on the effect of sumatriptan in hemicrania continua will help clarify the position of this case vs. hemicrania continua. At this stage, it is probably not possible to classify this case properly.

Adult↗
PubMed1997

Pharmacological characterization of the "silent" 5-hydroxytryptamine1B-like receptors of rabbit ear artery.

Serotonin acts on 5-hydroxytryptamine (5-HT)1B-like receptors in isolated rabbit ear artery precontracted with phenylephrine (PHE). These receptors are inactive, or "silent," in untreated vessels. Ear artery rings were mounted in tissue baths for the measurement of isometric contraction to further characterize these 5-HT1B-like receptors. The 5-HT1-selective receptor agonist sumatriptan failed to contract the untreated ear artery rings but caused a powerful, concentration-dependent contraction in PHE-precontracted vessels. The 5-HT1A/rat 1B receptor antagonist propranolol (1 microM) had no effect, whereas the 5-HT1B receptor antagonists rauwolscine (0.1 microM) and GR127935 (1-100 nM) markedly inhibited the contraction to sumatriptan. In vessels precontracted with phenylephrine, nifedipine reduced and calcium-free medium abolished the contractile response to serotonin. Relaxation to the adenylate cyclase activator forskolin was studied in contracted ear artery rings. Low concentrations (0.1-0.3 microM) of forskolin rapidly and completely relaxed ear artery rings contracted with PHE. In contrast, when PHE-precontracted vessels were contracted with either serotonin or sumatriptan, forskolin caused little or no relaxation at low concentrations and only partial relaxation at 10- to 30-fold higher concentrations. The resistance of these vessels to relaxation by forskolin was markedly reduced in the presence of GR127935 or in ear artery rings from pertussis toxin-treated rabbits. However, pertussis toxin treatment had no effect on the contractile response of PHE-precontracted ear artery rings to serotonin. It is concluded that the silent 5-HT1-like receptor of rabbit ear artery closely resembles the 5-HT1B receptor subtype. This receptor is inversely coupled to adenylate cyclase through a pertussis toxin-sensitive G protein; however, this coupling is unlikely to contribute to the serotonin-induced contraction of PHE-precontracted ear artery rings. Instead, this contraction is mediated at the second-messenger level by pertussis toxin-insensitive influx of calcium.

Adenylate Cyclase Toxin↗
PubMed1998

Cerebral blood flow effects of sodium valproate in drug combinations in the baboon model.

Sodium valproate (CAS 1069-66-5, Epilim) has been used in the management of epilepsy during the last three decades. Although important information on the pharmacological actions and efficacy of sodium valproate has accrued to date, limited research has been conducted on its effects on cerebral blood flow. In recent years, with the aid of SPECT (single photon emission computed tomography) and PET (positron emission tomography) it has been shown that marked cerebral blood flow changes occur in epileptic patients. Furthermore it was established recently that sodium valproate influences the cerebral blood flow in children by decreasing the flow significantly. The present study investigated the effects of sodium valproate on the cerebral blood flow, using 99mTc-HMPAO (hexamethylpropylene amino oxime) and SPECT, in a primate model, as well as the effects of its drug interactions with therapeutic agents that influence cerebrovascular dynamics, e.g. sumatriptan, nimodipine and acetazolamide. The current study using single dose treatment with sodium valproate did not detect a decrease or increase of the cerebral blood flow when compared with control baseline results. Drug interaction between sodium valproate and nimodipine may occur as a reduction of 25% in cerebral blood flow from the baseline control was observed in this case. The effects observed for the combinations of sodium valproate respectively with sumatriptan and acetazolamide are attributed to the influences of the sumatriptan (decrease) and acetazolamide (increase) alone. The cerebral blood flow effects of these drugs and possible interactions during an acute epileptic seizure need to be investigated.

Acetazolamide↗
PubMed1996

Pharmacology of cloned human 5-HT1D receptor-mediated functional responses in stably transfected rat C6-glial cell lines: further evidence differentiating human 5-HT1D and 5-HT1B receptors.

This study was undertaken to investigate the pharmacology of human serotonin (5-HT)1D receptor sites by measuring two functional cellular responses, inhibition of forskolin-stimulated cAMP formation and promotion of cell growth, using transfected rat C6-glial cell lines and a broad series of 5-HT receptor agonists. Stable and separate transfection of a pcDNA3 or pRcRSV plasmid, each containing a cloned human 5-HT1D receptor gene, in rat C6-glial cells was confirmed with RT-PCR of 5-HT1D receptor mRNA and radioligand binding with [3H] 5-carboxamidotryptamine (5-CT) and [3H] sumatriptan. The 5-HT1D receptor density was 350 and 1050 fmol/mg protein for the C6-glial/pcDNA3/5-HT1D and C6-glial/pRcRSV/5-HT1D cell line, and forskolin (100 microM)-induced cAMP formation was inhibited by 45 and 78% in the presence of 1 microM 5-HT, respectively. A comparison of the intrinsic agonist activities for sixteen 5-HT receptor ligands with their corresponding binding affinities for the human 5-HT1D receptor site showed similar results for both cell lines with the exception of the partial agonist m-trifluoro-phenyl-piperazine (TFMPP). Three classes of compounds were observed: 1) efficacious agonists, such as 5-CT, 5-methoxytryptamine, 5-HT, sumatriptan, bufotenine, 5-methoxy-3(1,2,3,6-tetrahydro-4-pyridinyl)1H-indole (RU 24,969), tryptamine and 8-hydroxy-2(di-n-propilamino)tetralin (8-OH-DPAT), with agonist potency close to their binding affinity; 2) the partial agonists metergoline, 7-trifluoromethyl-4(4-methyl-1-piperazinyl)-pyrolo-(1,2-a) quinoxaline (CGS 12066B), 1-naphthylpiperazine and 2'-methyl-4-(5-methyl-[1,2,4]oxadiazol-3-yl)-biphenyl-4-carboxylic acid [4-methoxy-3-(4-methylpiperazin-1-yl)-phenyl]-amide (GR 127,935) with marked intrinsic agonist activity but at concentrations higher than their binding affinity; and 3) the silent antagonists ritanserin, ketanserin and methiothepin, apparently free of intrinsic agonist activity, with antagonist potency close to their binding affinity. The cAMP data were further supported by the observed promotion of cell growth by stimulation of both transfected cell lines with sumatriptan under serum-free conditions; half-maximal stimulation was obtained at 4.4 nM (C6-glial/pcDNA3/5-HT1D) fully in agreement with its EC50-value (5.7 nM) for inhibition of cAMP formation. This growth promoting effect was antagonised by 1 microM methiothepin and not observed in pcDNA3-plasmid-transfected and non-transfected C6-glial cells. A comparative study with a C6-glial/pcDNA3/5-HT1B cell line expressing a similar amount of cloned human 5-HT1B receptors (Bmax: 360 fmol/mg protein) showed almost no intrinsic agonist activity for metergoline, 1-naphtylpiperazine and GR 127,935. Together with the 5-HT1D receptor binding selectivity and antagonist activity of ketanserin and ritanserin, the findings define important pharmacological differences between cloned human 5-HT1D and 5-HT1B receptor sites.

Animals↗
PubMed1992

5-Hydroxytryptamine-induced contractions of the human isolated saphenous vein: involvement of 5-HT2 and 5-HT1D-like receptors, and a comparison with grafted veins.

The receptors mediating the contractile effect of 5-hydroxytryptamine (5-HT) on the human isolated saphenous vein, obtained from 42 patients undergoing coronary bypass surgery, have been further characterized using a number of 5-HT-related drugs. The rank order of agonist potency was 5-carboxamidotryptamine (5-CT) approximately 5-HT greater than methysergide approximately sumatriptan approximately alpha-methyl-5-HT approximately 5-methoxy-3-(1,2,3,6-tetrahydropyridin-4-yl)-1H-indolesuccinate (RU 24969) approximately 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane hydrochloride (DOI) greater than 2-methyl-5-HT greater than 8-hydroxy-2(di-n-propylamino)tetralin (8-OH-DPAT). Flesinoxan was inactive as an agonist. Ketanserin (1 mumol/l) hardly affected sumatriptan-induced contractions but it caused a rightward shift of the upper part of the concentration-response curve of 5-HT and 5-CT. The same concentration of ketanserin caused a parallel rightward shift of the concentration-response curves of alpha-methyl-5-HT and DOI with pKB values of 7.1 and 7.1, respectively. The responses to sumatriptan were antagonized by methiothepin (0.1 mumol/l), metergoline (0.1 and 1 mumol/l), rauwolscine (1 mumol/l) and cyanopindolol (1 mumol/l); the calculated pKB values were 7.3, 6.9, 7.3, 6.7 and 6.5, respectively. Contractions to 5-HT were antagonized by methysergide (1 mumol/l), methiothepin (0.1 mumol/l; pKB = 7.1), ICS 205-930 (1 mumol/l; pKB = 5.9) and flesinoxan (30 mumol/l; pKB = 5.3). Remarkably, the contractions elicited by 2-methyl-5-HT were not attenuated by ICS 205-930, but were antagonized by methiothepin (0.1 mumol/l) and, more markedly, by ketanserin (1 mumol/l).(ABSTRACT TRUNCATED AT 250 WORDS)

Coronary Artery Bypass↗
PubMed1996

Promotion of cell growth by stimulation of cloned human 5-HT1D receptor sites in transfected C6-glial cells is highly sensitive to intrinsic activity at 5-HT1D receptors.

5-Hydroxytryptamine (serotonin, 5-HT), essentially known as a neurotransmitter and vasoactive agent, also functions as a mitogen in various cell types through several different second messenger systems. Stimulation of cloned human 5-HT1D receptor sites by sumatriptan in stably transfected rat C6-glial/5-HT1D cells promotes cell growth (Pauwels et al. (1996) Naunyn-Schmiedeberg's Arch Pharmacol 353:144-156). In the present study, the pharmacology of this growth response was investigated using a broad series of 5-HT receptor ligands. The data were compared with the responses obtained by measuring inhibition of forskolin-stimulated cAMP formation. 5-HT (EC50: 25 nM) promoted cell growth of C6-glial/5HT1D cells, and this in contrast to the absence of any measurable effect in pcDNA3-plasmid transfected and non-transfected C6-glial cells. The 5-HT effect could be mimicked by the following compounds (EC50 in nM): zolmitriptan (0.41), 2'-methyl-4'-(-methyl[1,2,4] oxadiazol-3-yl)biphenyl-4-carboxylic acid [4-methoxy-3-(4-methylpiperazin-1-yl)phenyl]amid (GR 127,935;0.86), naratriptan (0.92), metergoline (1.9), sumatriptan (2.9), (N,N-dimethyl-2-[5-(1,2,4-triazol-1-ylmethyl)-1H-indol-3-yl] ethylamine (MK-462; 3.0), and R(+)-8-(hydroxy-2-(di-n-propylamino)tetralin (R(+)-8-OH-DPAT; 30.7). These EC50 -values correspond to the compounds binding affinities at the human 5-HT1D receptor site and, with the exception of GR 127,935 and metergoline also to the EC50-values found by measuring over 5 min inhibition of forskolin (100 microM)-stimulated cAMP formation. Prolonged exposure of GR 127,935(3 h) and metergoline (30 min) to cells yielded EC50 values in the cAMP assay more close to those measured in the mitogenic response. The growth response to sumatriptan, 5-HT, GR 127,935 and metergoline was blocked by the apparently silent antagonist methiothepin, ritanserin and ketanserin with potencies similar to blockade of inhibition of stimulated cAMP formation. The 8-OH-DPAT effect also is likely mediated by 5-HT1D receptors; stereoselectivity was found with its enantiomers at this receptor site and the effect was blocked by ketanserin (1 microM) but not by spiperone (1 microM). Micromolar concentrations of the 5-HT1B receptor agonist 3-(1,2,5,6-tetrahydro)-4-pyridil-5-pyrrolo[3,2-b]pyril-5-one (CP 93,129) and of the 5-HT2 receptor agonist 1-(2,5-dimethoxy-4-iodophenyl_-2-aminopropane (DOI) induced cell growth with a potency that accorded with the affinity of these compounds for the human 5-HT1D receptor site. These effects were sensitive to ketanserin (1 microM) antagonism, but not to blockade by beta-adrenergic blockers and the 5-HT2 receptor antagonist 2-anilino-N-[2-(3-chlorophenoxy)-propyl] acetamidine hydroiodide (BW 501-C-67). The findings suggest that 5-HT1A, 5-HT1B and 5-HT2 receptors are not implicated in 5-HT-stimulated C6-glial/5-HT1D cell growth. In conclusion, human 5-HT1D receptors are involved in the growth of C6-glial/5-HT1D cells. This cellular response is highly sensitive to the intrinsic activity of compounds at 5-HT1D receptors.

Animals↗
PubMed2002

Characterization of 5-HT receptor subtypes mediating contraction in human umbilical vein. 2. Evidence of involvement of 5-HT1B receptors using functional studies.

Previous studies have shown that a heterogeneous 5-HT receptor population may be involved in vasoconstrictor actions of 5-HT in human umbilical vein (HUV). The aim of the present study was to evaluate whether the 5-HT(1B/1D) receptor subtype mediates contraction in this tissue. 5-HT(1B/1D)-mediated responses can be enhanced or unmasked after exposure to threshold or sub-threshold KCl concentrations. In HUV rings, when 5-HT, alpha-Me-5HT or bradykinin concentration-response curves (CRC) were generated in the presence or absence of sub-threshold concentrations of KCl, there were not significant differences between the control and the treated rings. On the other hand, sumatriptan, the classic selective 5-HT(1B/1D) receptor agonist, produced a concentration-related contraction that was potentiated in the presence of sub-threshold KCl concentration. In addition, L-694,247, the novel selective 5-HT(1B/1D) receptor agonist, displayed a concentration-dependent contraction with high potency in HUV. The presence of sub-threshold concentrations of KCl produced a marked leftward shift of its CRCs.GR-55562, a 5-HT(1B/1D)-selective antagonist, competitively blocked sumatriptan CRCs with an estimated p A(2) of 8.00 and a slope not different from unity. Likewise, SB-216641, a selective 5-HT(1B) antagonist, produced a parallel rightward shift of sumatriptan CRCs in HUV. The Schild analysis yielded a p A(2) of 9.29, with a slope not different from unity. In addition, L-694,247 contractile responses were competitively blocked by SB-216641 with an estimated p A(2) value of 9.12 and a Schild slope not different from unity. On the other hand, ketanserin behaved as a weak antagonist of L-694,247-induced responses, yielding a calculated p A(2) value of 6.40. In summary, the results obtained in this study support that the 5-HT(1B) receptor subtype is involved in vasoconstrictor responses in HUV.

Dose-Response Relationship, Drug↗
PubMed2004

Functional 5-HT receptors in human occipital artery.

5-HT receptors were studied in human occipital arteries, obtained from patients during neurosurgery. We detected mRNA for the following receptors (incidence): 5-HT(1B) (14/18), 5-HT(1D) (15/18), 5-HT(2A) (16/18), 5-HT(2B) (8/8), 5-HT(4(a)) (13/18), 5-HT(4(b)) (5/18), 5-HT(4(g)) (7/18), 5-HT(4(i)) (1/18), 5-HT(7(a/b)) (10/18) and 5-HT(7(d)) (12/18). 5-HT contracted and relaxed arterial rings at low (-logEC(50) M=7.0) and high (-logEC(50) M=4.2) concentrations, respectively. 5-HT-evoked contractions were antagonized partially by both 5-HT(1B)-selective SB224289 (200 nM) and 5-HT(2A)-selective ketanserin (1 microM) but not by 5-HT(1D)-selective BRL15572 (500 nM) or prazosin (1 microM). Sumatriptan caused contractions (-logEC(50) M=6.8, intrinsic activity with respect to 5-HT=0.3). Sumatriptan-evoked contractions were antagonized by SB224289 with high potency (pK(B)=9.4) but not by BRL15572. 5-HT-induced relaxations were resistant to blockade by 5-HT(1B)-selective SB224289 (1 microM), 5-HT(1D)-selective BRL15572, 5-HT(2B)-selective SB204741 (1 microM), 5-HT(4)-selective GR113808 (100 nM) and 5-HT(7)-selective SB269970 (1 microM), and a combination of SB204741 and SB269970, inconsistent with an involvement of 5-HT(1B), 5-HT(1D), 5-HT(2B), 5-HT(4) and 5-HT(7) receptors. Triton X-100 treatment of the arteries abolished acetylcholine-induced relaxations of rings precontracted by prostaglandin F(2alpha), but a reduction of the relaxant effects of 5-HT did not reach significance. Nitro-L-arginine (1 mM) reduced 5-HT-induced relaxations, suggesting a contribution of nitric oxide released from endothelial cells. Ketanserin (1 microM) prevented the relaxant effects of 5-HT. We conclude that 5-HT contracts human occipital artery through 5-HT(1B) receptors at low concentrations and through 5-HT(2A) receptors at high concentrations. Sumatriptan contracts mostly through 5-HT(1B) receptors. These results are consistent with the 5-HT(1B) and 5-HT(2A) mRNA data. 5-HT-induced relaxation is mediated, in part, through ketanserin-sensitive receptors, but 5-HT(1B), 5-HT(1D), 5-HT(2B), 5-HT(4) and 5-HT(7) receptors appear not to be involved.

Adolescent↗
PubMed2006

Effects of current and prospective antimigraine drugs on the porcine isolated meningeal artery.

Vasoconstriction to agonists at serotonin (5-hydroxytryptamine; 5-HT) receptors and alpha-adrenoceptors, as well as vasodilatation induced by alpha-CGRP, have been well described in the porcine carotid circulation in vivo. The present study sets out to investigate the effects of current and prospective antimigraine drugs on porcine meningeal artery segments in vitro. Sumatriptan, ergotamine, dihydroergotamine, isometheptene and clonidine failed to contract the meningeal artery, but 5-HT, noradrenaline and phenylephrine induced concentration-dependent contractions. The contractions to 5-HT were competitively antagonized by the 5-HT(2A) receptor antagonist ketanserin, whilst those to noradrenaline were antagonized by alpha(1)-(prazosin), alpha(2)-(rauwolscine and yohimbine) and alpha(2C/2B)-(OPC-28326) adrenoceptor antagonists. Whilst dobutamine and salbutamol were ineffective, alpha-CGRP produced concentration-dependent relaxations that were antagonized by the CGRP(1) receptor antagonist olcegepant. In agreement with their lack of contractile effect, sumatriptan and ergotamine failed to influence forskolin-stimulated cyclic AMP accumulation in the porcine meningeal artery; in contrast, both compounds decreased forskolin-stimulated cyclic AMP accumulation in the human isolated saphenous vein, where they induced contractions. Finally, using RT-PCR, we could demonstrate the presence of mRNAs encoding for several 5-HT receptors (5-HT(1B), 5-HT(1D), 5-HT(1F), 5-HT(2A) and 5-HT(7)) and adrenoceptors (alpha(1A), alpha(1B), alpha(1D), alpha(2A), alpha(2B), alpha(2C), beta(1) and beta(2)), as well as that for the calcitonin receptor like receptor, a component of the CGRP(1) receptor. These results suggest that: (i) the porcine meningeal artery may not be involved in the vasoconstriction of the carotid vascular bed elicited by antimigraine drugs in anaesthetized pigs, and (ii) the mismatch between the presence of receptor mRNA and the lack of response to sumatriptan, dobutamine and salbutamol implies that mRNAs for the 5-HT(1B) receptor and beta(1)- and beta(2)-adrenoceptors are probably unstable, or that their density is too low for being translated as receptor protein in sufficient quantities.

Adrenergic alpha-Agonists↗
PubMed2000

Zolmitriptan (a 5-HT1B/1D receptor agonist with central action) does not increase symptoms in obsessive compulsive disorder.

RATIONALE: Non-selective serotonin (5-HT) receptor agonists like meta-chlorophenylpiperazine and MK-212 have been used to explore the role of 5-HT in obsessive compulsive disorder (OCD). The results of these studies and the findings of autoradiography and neuroimaging studies, pointed to a possible role of the 5-HT1B/1D receptor in the pathophysiology of OCD. Recently the selective 5-HT1B/1D receptor agonist sumatriptan was used to further explore the role of the 5-HT1B/1D receptor in OCD. Equivocal results with respect to the increase of obsessive compulsive symptoms in patients with OCD were reported. In one study a significant increase in plasma growth hormone (GH) concentration was observed, although sumatriptan does not pass the blood-brain barrier. OBJECTIVES: In order to further explore the role of the 5-HT1B/1D receptor in the pathophysiology of OCD, we performed this study, following the same design as Ho Pian et al. (Psychopharmacology 140:365-370). METHODS: In the present study we performed a randomized, double-blind, placebo-controlled, cross-over design with zolmitriptan (5 mg per os), a selective 5-HT1B/1D receptor agonist with better brain penetrating properties than sumatriptan. RESULTS: We could not detect any changes in obsessive compulsive symptoms, mood, or anxiety levels, although we found a (nonsignificant) increase in plasma GH levels. CONCLUSIONS: Based upon these findings, no evidence was found for a specific role of the 5-HT1B/1D receptor in OCD. It should be noted, however, that challenge studies in OCD are difficult to perform. Perhaps in the future better challenge paradigms will make it possible to further explore the role of specific receptor types in OCD.

Adult↗
PubMed1993

Stereoselective actions of the isomers of metitepine at 5-HT1D receptors in the guinea pig brain.

The present studies examined the relative antagonist potencies of the optical isomers of the 5-HT receptor antagonist metitepine at the 5-HT1D binding site labelled by the novel radioligand serotonin-O-carboxymethylglycyl [125]iodotyrosinamide ([125I]GTI), and at the terminal 5-HT autoreceptor in guinea pig frontal cortex, a proposed model of 5-HT1D receptor activation. The pharmacological specificity of the [125I]GTI binding site in guinea pig frontal cortex was similar to previously published studies in the bovine cortical 5-HT1D recognition site labelled with [3H]5-HT. The (+) isomer of metitepine displaced [125I]GTI binding with a lower affinity (64 nM) than did the (-) isomer (18 nM), which was equiactive with the racemic mixture. The (-) isomer of metitepine was more effective than the (+) isomer at attenuating the inhibitory effects of 5-HT and sumatriptan at the guinea pig terminal 5-HT autoreceptor; the apparent pA2 of the (-) isomer was 8.0 (sumatriptan) and 7.7 (5-HT) while the apparent pA2 of the (+) isomer was 7.1 (sumatriptan) and 6.8 (5-HT). The (-) isomer was more effective than the (+) isomer at enhancing stimulated [3H]5-HT release. These findings support the identification of the guinea pig 5-HT terminal autoreceptor as a 5-HT1D receptor and reinforce the species homology between the 5-HT1B and 5-HT1D receptors.

Animals↗
PubMed1995

5-HT1D receptors regulate 5-HT release in the rat raphe nuclei. In vivo voltammetry and in vitro superfusion studies.

The aim of the present study was to characterize the pharmacological profile of 5-hydroxytryptamine (5-HT) receptors modulating 5-HT release in the mesencephalic raphe region. In a first series of experiments, differential normal pulse voltammetry and nafion-coated electrodes were used to measure extracellular 5-HT in the dorsal raphe of anesthesized rats. The intravenous administration of the selective 5-HT1A agonist 8-OH-DPAT (30 micrograms/kg) and the 5-HT1 agonist TFMPP (0.5 mg/kg) reduced the 5-hydroxyindole signal by 23% and 18%, respectively. Pretreatment with the 5-HT1A antagonist (+)WAY100135 (0.5 mg/kg IV) 30 minutes before the injection of the agonists, blocked the effect of 8-OH-DPAT but not that of TFMPP. The effect of TFMPP was blocked by (+/-)mianserin, a drug with high affinity for the rat 5-HT1D receptor, suggesting a role of this receptor subtype in the modulation of 5-HT release at the cell body level of 5-HT neurons. This was confirmed by in vitro superfusion experiments using mesencephalic raphe slices. The prototypical 5-HT1 agonist 5-carboxy-amiditryptamine (5-CT) and the 5-HT1B/1D agonist sumatriptan (1-1,000 nM) induced a concentration-dependent inhibition of the electrically evoked release of [3H]5-HT from preloaded raphe slices. 8-OH-DPAT (100 nM) produced an inhibitory effect similar to that of sumatriptan (100 nM). The selective 5-HT1B agonist CP 93129 (10-10,000 nM), had no effect in raphe slices, but it dose dependently inhibited [3H]5-HT release from hippocampal slices where autoreceptors are of the 5-HT1B subtype. The inhibitory effect of 5-CT was blocked by the 5-HT1/2 antagonist methiothepin (1 microM), the 5-HT1A antagonist S-UH-301 (1 microM), and the 5-HT1B/1D antagonist GR 127935 (1 microM). That of 8-OH-DPAT was blocked by S-UH-301 (1 microM) but not by GR 127935 (1 microM), and that of sumatriptan was blocked by GR 127935 (1 microM) but not by S-UH-301 (1 microM). These results show that, together with 5-HT1A autoreceptors, 5-HT1D receptors negatively modulate the somatodendritic release of 5-HT.

Animals↗
PubMed2005

Differential effects of two analgesic drugs, morphine chlorhydrate and acetylsalicylic acid, on thalamic mast cell numbers in rat.

Thalamic mast cells (TMCs), the only immunocytes known to infiltrate the brain in physiological conditions, respond to pharmacological agents including sumatriptan - a serotonergic anti-migraine agent - that increases their number. We analysed the effects of two other main analgesics: morphine chlorhydrate, a micro opioid agonist, and acetylsalicylic acid (ASA), a non-steroidal anti-inflammatory drug. All three drugs have specific modes of action, and morphine and ASA, unlike sumatriptan, are also known to interact with peripheral mast cells. Only ASA was effective in promoting TMC number decrease. TMCs, unlike other mast cells, do not express cyclooxygenase (COX) - the key enzyme in the production of prostanoids and the main site of action of ASA - thus dismissing a direct local cellular COX-mediated action. Direct TMC COX-independent mechanisms or effects mediated via distant populations of COX-positive cells such as platelets, leptomeningeal, endothelial and peripheral mast cells are thus probable. ASA, morphine and sumatriptan have distinct TMC effects, suggesting that the TMC number variations they induce are more likely to derive from systemic vasoactive actions than from pharmacological mechanisms devoted to pain relief.

Analgesics↗
PubMed2006

Bias from industry trial funding? A framework, a suggested approach, and a negative result.

Bias from funding sources of trials would threaten their validity. Meta-analyses of high quality acute pain and migraine trials were used to explore the hypothesis that industry funding of clinical trials produced more favourable results than non-profit sponsorship. Analyses were planned to evaluate whether industry-sponsored trials had different results from trials funded by academic or other non-profit sources, but of 176 trials, only two were supported by non-profit sources, while 31 provided no statement of support. An alternative method is proposed within industry-sponsored trials, looking at conflicting industry interests for the same drug, used either as test or comparator treatment. Fifty-three trials used an analgesic as test and 90 as comparator, allowing comparisons to be made for aspirin 600/650 mg, ibuprofen 400 mg, paracetamol (acetaminophen) 1000 mg, rofecoxib 50 mg and sumatriptan 50 and 100 mg. Only for sumatriptan 50 and 100 mg, with the outcome of headache response at 2 h, was there any significant difference between the drug used as a test or as a comparator. The direction was for higher (worse) NNTs with sumatriptan as comparator. Investigating potential industry bias through the funding source of trials is unlikely to be adequate because of a dearth of trials funded by non-profit organisations. We propose a method based on potential conflict of interest within industry-sponsored trials. Using this method, established clinical trial results in acute pain and migraine appear to be unbiased.

Adverse Drug Reaction Reporting Systems↗