5-HT1D Receptor Agonist Research Articles

447 Modulation of Patient Reported Outcomes and Opioid Consumption Following Open Craniotomy: The Efficacy and Safety of Subcutaneous Sumatriptan

INTRODUCTION: Traditional pain management regimens following open craniotomy commonly employ opioid medications. As a medication class, opioids present a considerable adverse effect profile and the potential for medication abuse. Alternative medication regimens to better address post-craniotomy pain while mitigating opioid-related adverse effects are insufficiently studied. However, as a dural-based 5-HT1D receptor agonist that regulates vasoconstriction and inflammatory peptide signaling, sumatriptan shows promise to improve pain scores and reduce opioid requirements. METHODS: This is a single academic center, retrospective cohort study of 130 consecutive adult patients undergoing open craniotomy between 7/2015 and 8/2021. Patients were divided between a Control and Sumatriptan cohort contingent upon administration of a single 6mg subcutaneous injection of sumatriptan within 1-hour of surgery completion and prior to opioid administration. Opioid consumption at 6, 12 and 24-hours postoperative and admission total, inpatient length of stay (LOS) and 30-day global representation/readmission were evaluated. RESULTS: 130 patients were equally divided between the Sumatriptan and Control cohorts for analysis. No difference in baseline demographics was noted. A significant reduction of mean pain score at 6, 12 and 24-hours following surgery substantially favored the Sumatriptan cohort (p < 0.05). Further, a nonsignificant reduction in opioid requirements was observed at all timepoints favoring the sumatriptan cohort (p > 0.05). 30-day global ED evaluation and readmission rates between cohorts were similar (p > 0.05). Overall LOS in the Sumatriptan and Control cohorts were 5.3 ± 3.6 vs 6.5 ± 5.6 days (p > 0.05). No difference in the rate of incisional or intracerebral hemorrhage was noted between cohorts (p > 0.05). CONCLUSIONS: In the present study, patients in the Sumatriptan cohort demonstrated enhanced pain control and reduced opioid requirements suggesting sumatriptan represents a safe and efficacious agent for the modulation of pain following open craniotomy.

The role of hippocampal 5-HT1D and 5-HT1F receptors on learning and memory in rats.

Serotonin is a neurotransmitter, which is involved in memory via its receptors. The 5-HT1D and 5-HT1F receptors mainly exist in the hippocampus, which plays an important role in memory processing. However, few studies have assessed the effect of these serotonin receptors on memory. We evaluated the effect of a 5-HT1D receptor agonist, PNU142633, 5-HT1D receptor antagonist, BRL15572 hydrochloride, and 5-HT1F receptor agonist, LY344864, on the recognition and avoidance memory in the hippocampus area. Fifty adult male Wistar rats weighing 200-250 g were divided into the control, sham-operated, PNU, BRL, and LY groups (n=10 per group). Bilateral guide cannulas were implanted into the dentate gyrus area of the hippocampus. The drugs were administered at the dose of 1 μg/μl before the novel object recognition (NOR) and passive avoidance learning (PAL) tests. The results showed that in the NOR test, the administration of PNU and LY had no significant effect on recognition index; however, the recognition index was increased by BRL. In the PAL test, the administration of PNU had no significant effect on recognition index, but the administration of BRL and LY increased the time spent in the dark compartment of the apparatus and decreased the step-through latency into the dark compartment apparatus. It can be concluded that the inhibition of the hippocampal 5-HT1D receptor improved cognition memory but impaired avoidance memory. Activation of the hippocampal 5-HT1F receptor had no effect on cognitive memory but impaired avoidance memory.

FPT, a 2-Aminotetralin, Is a Potent Serotonin 5-HT1A, 5-HT1B, and 5-HT1D Receptor Agonist That Modulates Cortical Electroencephalogram Activity in Adult Fmr1 Knockout Mice.

There are no approved medicines for fragile X syndrome (FXS), a monogenic, neurodevelopmental disorder. Electroencephalogram (EEG) studies show alterations in resting-state cortical EEG spectra, such as increased gamma-band power, in patients with FXS that are also observed in Fmr1 knockout models of FXS, offering putative biomarkers for drug discovery. Genes encoding serotonin receptors (5-HTRs), including 5-HT1A, 5-HT1B, and 5-HT1DRs, are differentially expressed in FXS, providing a rationale for investigating them as pharmacotherapeutic targets. Previously we reported pharmacological activity and preclinical neurotherapeutic effects in Fmr1 knockout mice of an orally active 2-aminotetralin, (S)-5-(2'-fluorophenyl)-N,N-dimethyl-1,2,3,4-tetrahydronaphthalen-2-amine (FPT). FPT is a potent (low nM), high-efficacy partial agonist at 5-HT1ARs and a potent, low-efficacy partial agonist at 5-HT7Rs. Here we report new observations that FPT also has potent and efficacious agonist activity at human 5-HT1B and 5-HT1DRs. FPT's Ki values at 5-HT1B and 5-HT1DRs were <5 nM, but it had nil activity (>10 μM Ki) at 5-HT1FRs. We tested the effects of FPT (5.6 mg/kg, subcutaneous) on EEG recorded above the somatosensory and auditory cortices in freely moving, adult Fmr1 knockout and control mice. Consistent with previous reports, we observed significantly increased relative gamma power in untreated or vehicle-treated male and female Fmr1 knockout mice from recordings above the left somatosensory cortex (LSSC). In addition, we observed sex effects on EEG power. FPT did not eliminate the genotype difference in relative gamma power from the LSSC. FPT, however, robustly decreased relative alpha power in the LSSC and auditory cortex, with more pronounced effects in Fmr1 KO mice. Similarly, FPT decreased relative alpha power in the right SSC but only in Fmr1 knockout mice. FPT also increased relative delta power, with more pronounced effects in Fmr1 KO mice and caused small but significant increases in relative beta power. Distinct impacts of FPT on cortical EEG were like effects caused by certain FDA-approved psychotropic medications (including baclofen, allopregnanolone, and clozapine). These results advance the understanding of FPT's pharmacological and neurophysiological effects.

A 5-HT1D -receptor agonist protects Dravet syndrome mice from seizure and early death.

Mutations in the SCN1A gene encoding the Nav1.1 sodium channel cause several forms of epilepsy, the most severe is Dravet syndrome (DS). DS patients are at high risk for sudden death and seizures are often triggered by fever or hyperthermia. To improve understanding of how serotonergic ligands might influence DS in this study, we tested several drugs for their effect on hyperthermia-induced seizure using a mouse model of DS consisting of a heterozygous loss of function of Scn1A. We found that a mixed 5-HT2A/2C receptor agonist had no effect while a mixed 5-HT1B/D receptor agonist had a modest effect reducing the severity of seizures. Hypothesizing selective agonists may be more effective, we tested selective 5-HT1B and 5-HT1D receptor agonists, CP-93129 and GR-46611, respectively. Of these GR-46611 significantly increased the threshold of hyperthermia-induced seizure and lowered seizure severity. Given chronically at 1mgkg-1 day-1 , GR-46611 also significantly improved survival of DS mice. Thus, 5-HT1D -receptors may represent a meaningful target for pharmacotherapy for DS with potential relevance for related forms of epilepsy, particularly those with a known sensory trigger such as heat.

Sumatriptan inhibits the electrophysiological activity of ASICs in rat trigeminal ganglion neurons

Sumatriptan, a selective serotonin 5-HT1 receptor agonist, is an effective therapeutic for migraine attacks. However, the molecular mechanisms underlying sumatriptan migraine relief are still not fully understood. Here, we found that acid-sensing ion channels (ASICs), pH sensors, are peripheral targets of sumatriptan against migraine. Sumatriptan can inhibit the electrophysiological activity of ASICs in the trigeminal ganglion (TG) neurons. In the present study, sumatriptan decreased proton-gated currents mediated by ASICs in a concentration-dependent manner. In addition, sumatriptan shifted concentration-response curves for protons downwards, with a decrease of 37.3 ± 4.6% in the maximum current response but with no significant change in the pH0.5 value. Sumatriptan inhibition of ASIC currents was blocked by 5-HT1D receptor antagonist BRL 15572, but not by 5-HT1B antagonist SB 224289. Moreover, the sumatriptan inhibition of ASICs can be mimicked by the 5-HT1D receptor agonist L-694,247, but not by the 5-HT1B agonist CP-93129. Sumatriptan inhibition of ASIC currents was also reversed by G-protein αi subunit inhibitor PTX and 8-Br-cAMP, suggesting the inhibition may involve the intracellular signal transduction. Finally, sumatriptan decreased the number of action potentials induced by acid stimuli in rat TG neurons. Our results indicated that the anti-migraine drug, sumatriptan, inhibited ASICs in rat TG neurons via 5-HT1D receptor subtype and a cAMP-dependent signal pathway. These observations add to the understanding of the mechanisms that underlie the clinical effectiveness of anti-migraine sumatriptan.

Effect of a 5-HT1D receptor agonist on the reinstatement phase of the conditioned place preference test and hippocampal long-term potentiation in methamphetamine-treated rats

Methamphetamine (METH)-seeking relapse is associated with memory and synaptic plasticity changes. Serotonin is a key neuromodulator in this process. While there is a known distribution of 5-HT1D receptors in reward and memory areas, such as the hippocampus, its physiological function is currently unknown. Here, we evaluated effect of a 5-HT1D receptor agonist, PNU142633, on the reinstatement of METH-seeking behavior and long-term potentiation. Rats were implanted with a cannula into lateral ventricle, then treated with saline or METH (5 mg/kg) during the acquisition phase of the conditioned place preference (CPP) test. On day 13 of the extinction phase, METH groups were divided into four groups: METH (0: saline, 1, or 2.5 (priming METH) mg/kg; i.p.) + vehicle (5 µl/rat) or a priming dose of METH (2.5 mg/kg; i.p.) + PNU (2 µg/5 µl; i.c.v.) and their preference scores were calculated on reinstatement day (day 14). Immediately following this, electrophysiology was performed to assay the field excitatory postsynaptic potential (fEPSP) slope and population spike (PS) amplitude between groups. The results showed that CPP induction by METH gradually declined to extinction on days 12 and 13. A priming METH treatment significantly increased preference for the METH-paired chamber when compared with other groups, but pre-treatment with PNU significantly attenuated this effect. PS amplitude and fEPSP slopes in vehicle + priming METH rats were greater when compared with other groups. Furthermore, PNU attenuated the priming METH-induced increase in PS amplitude. These findings suggest that PNU can decrease synaptic transmission and prevent METH reinstatement in rats.

Sublingual Delivery of Frovatriptan: An Indication of Potential Alternative Route.

Frovatriptan, a 5-HT1B and 5-HT1D receptor agonist, is used for the treatment of acute migraine attack. This molecule is classified into second line therapy because of its slow onset of action (peak response obtained after 4 hours of administration) and low bioavailability (25%). Moreover, its therapy is the most costly among all triptans. Attempt has been made in present work to suggest a way out to fasten its onset of action and to enhance its bioavailability. Prepared tablets were evaluated by physicochemical tests, in vitro permeation studies, ex vivo permeation studies, and histopathological studies. Suitable mathematical calculations were performed to calculate the minimum amount of bioavailability that could be enhanced. Tablets containing chitosan (5% w/w) were found to give optimum results. Prepared tablets can double the bioavailability of frovatriptan and can initiate its response within 10 minutes of its administration. Suggestive alternative has the potential to increase the efficacy of frovatriptan for treating acute migraine attack.

Peripheral 5-HT1D and 5-HT7 serotonergic receptors modulate sympathetic neurotransmission in chronic sarpogrelate treated rats

5-HT2 receptor activation induces vasoconstriction, hypertension and platelet aggregation; therefore, its blocking may be useful in cardiovascular diseases, probably due to alterations in the modulation of serotonergic system. The aim of this study was to evaluate whether 5-HT2 receptor blockade changes serotonergic modulation of sympathetic neurotransmission in pithed rats. Serotonergic modulation of sympathetic neurotransmission was investigated in Wistar rats treated with sarpogrelate, a 5-HT2 receptor antagonist, during 14 days (30mg/kg/day). After central nervous system destruction, we conducted electrical stimulation throughout the spinal cord flow to study the 5-HT-related products action on adrenergic system. 5-Hydroxytryptamine exerted inhibition of sympathetic outflow in sarpogrelate-treated pithed rats. This effect was mimicked and enhanced by 5-CT (5-HT1/7 receptor agonist). L-694,247 and AS-19, 5-HT1D and 5-HT7 receptor agonists respectively, reproduced this action. Pretreatment with LY310762+SB258719 (5-HT1D and 5-HT7 receptor antagonists, respectively) completely abolished 5-CT inhibitory action. The nature of this action was prejunctional since these agonists did not modify the pressor responses induced by exogenous noradrenaline. Western Blot analysis confirmed a higher expression of 5-HT1D receptors in sarpogrelate-treated rats. Experimental 5-HT2 receptor blockade induces changes in the 5-HT receptors involved in the serotonergic inhibition of sympathetic-induced pressor responses. Prejunctional activation of 5-HT1D and 5-HT7 receptors induces a significantly higher serotonergic inhibition on adrenergic neurotransmission in sarpogrelate-treated pithed rats. The antagonism of 5-HT2 receptors produces an enhancement of serotonergic sympathoinhibitory effect, which may explain the beneficial effects of this blockade in cardiovascular disorders where 5-hydroxytryptamine plays a crucial role.

Effect of serotonergic system on AVP secretion induced by physical exercise

The present study was undertaken in order to establish the possible involvement of serotonergic receptors in the control of physical exercise-stimulated vasopressin secretion. Twenty-one healthy men (divided in three groups of seven) underwent bicycle-ergometer tests until exhaustion: exercise control test (n=21), exercise plus ondansetron, selective 5-HT3 antagonist (n=7), exercise plus buspirone, selective 5-HT1A receptor agonist (n=7), exercise plus sumatriptan, selective 5-HT1D receptor agonist (n=7). AVP levels, physiological and biochemical variables were measured and compared during tests. Results showed that exercise-induced AVP rise did not change after the administration of buspirone and sumatriptan. In contrast, the administration of ondansetron significantly reduced physical exercise-induced AVP rise. Mean peak levels during physical exercise were 4.9 times higher than basal values in the control test and 2.6 times higher than basal values in the ondansetron plus exercise test. These data demonstrate that 5-HT3 serotonergic receptors at least partially mediate the AVP response to physical exercise. On the other hand, 5-HT1A and 5-HT1D serotonergic receptors do not appear to be involved in the control of AVP secretion during exercise.

Sumatriptan Inhibits Synaptic Transmission in the Rat Midbrain Periaqueductal Grey

BackgroundThere is evidence to suggest that the midbrain periaqueductal grey (PAG) has a role in migraine and the actions of the anti-migraine drug sumatriptan. In the present study we examined the serotonergic modulation of GABAergic and glutamatergic synaptic transmission in rat midbrain PAG slices in vitro.ResultsSerotonin (5-hydroxytriptamine, 5-HT, IC50 = 142 nM) and the selective serotonin reuptake inhibitor fluoxetine (30 μM) produced a reduction in the amplitude of GABAA-mediated evoked inhibitory postsynaptic currents (IPSCs) in all PAG neurons which was associated with an increase in the paired-pulse ratio of evoked IPSCs. Real time PCR revealed that 5-HT1A, 5-HT1B, 5-HT1D and 5-HT1F receptor mRNA was present in the PAG. The 5-HT1A, 5-HT1B and 5-HT1D receptor agonists 8-OH-DPAT (3 μM), CP93129 (3 μM) and L694247 (3 μM), but not the 5-HT1F receptor agonist LY344864 (1 – 3 μM) inhibited evoked IPSCs. The 5-HT (1 μM) induced inhibition of evoked IPSCs was abolished by the 5-HT1B antagonist NAS181 (10 μM), but not by the 5-HT1A and 5-HT1D antagonists WAY100135 (3 μM) and BRL15572 (10 μM). Sumatriptan also inhibited evoked IPSCs with an IC50 of 261 nM, and reduced the rate, but not the amplitude of spontaneous miniature IPSCs. The sumatriptan (1 μM) induced inhibition of evoked IPSCs was abolished by NAS181 (10 μM) and BRL15572 (10 μM), together, but not separately. 5-HT (10 μM) and sumatriptan (3 μM) also reduced the amplitude of non-NMDA mediated evoked excitatory postsynaptic currents (EPSCs) in all PAG neurons tested.ConclusionThese results indicate that sumatriptan inhibits GABAergic and glutamatergic synaptic transmission within the PAG via a 5-HT1B/D receptor mediated reduction in the probability of neurotransmitter release from nerve terminals. These actions overlap those of other analgesics, such as opioids, and provide a mechanism by which centrally acting 5-HT1B and 5-HT1D ligands might lead to novel anti-migraine pharmacotherapies.

Actions of sumatriptan on myenteric neurones: relief from an old headache in the enteric nervous system?

Actions of sumatriptan on myenteric neurones: relief from an old headache in the enteric nervous system?

New targets in acute migraine treatment

Migraine is a common and highly disabling neurological problem, whose acute treatment was revolutionized by the triptans, serotonin 5-HT1B/1D receptor agonists. Some patients do not respond to triptans, while others are not suitable for them largely because of contraindications based on vascular disease. The exploration of nonvasoconstrictor treatments for acute migraine offers the prospect of dramatic improvements in patient care, as well as important insights into the mechanisms of migraine. Possibilities for such developments include, calcitonin gene-related peptide receptor antagonists, serotonin 5-HT1F and 5-HT1D receptor agonists, glutamate excitatory amino acid receptor antagonists, nitric oxide synthase inhibitors and adenosine A1 receptor agonists. Taken together, the future for migraine and affected patients is bright and promising.

Effect of 5-hydroxytryptamine on neurogenic vasoconstriction in the isolated, autoperfused hindquarters of the rat

1. In the present study, we analysed the effect of different doses of 5-hydroxytryptamine (5-HT; intravenous infusions of 0.001-40 microg/kg per min) in the autoperfused hindquarters of the rat subjected to electrical stimulation (frequencies of 0.5-20 Hz) of the lumbar chains, investigating the relationship between the adrenergic and serotonergic systems in this vascular bed. 2. Because we observed that 5-HT inhibited the increases in perfusion pressure induced by electrical stimulation of the lumbar chains, we used different agonists and antagonists to analyse the mechanism of action of 5-HT. 3. The effect of 5-HT was inhibited by methiothepin (a non-specific 5-HT receptor antagonist), but not by ritanserin (a selective 5-HT2 receptor antagonist). The effects of 5-HT were mimicked by 5-carboxamidotryptamine (a 5-HT1 receptor agonist) and L-694 247 (a selective 5-HT1D receptor agonist), but not by 8-hydroxy-2-dipropylaminotetralin (a 5-HT1A receptor agonist), CGS-12066B (a 5-HT1B receptor agonist), alpha-methyl-5-HT (a 5-HT2 receptor agonist), 1-(3-chlorophenyl) piperazine (a 5-HT2C receptor agonist) or 1-phenylbiguanide (a 5-HT3 receptor agonist). The selective 5-HT1D/1B receptor antagonist BRL 15572 inhibited the effect of the agonist L-694 247. 4. Our data suggest that 5-HT inhibits the increases in perfusion pressure induced by the electrical stimulation of the lumbar chains, acting on presynaptic 5-HT1D receptors and decreasing the release of noradrenaline from the sympathetic nerves in the hindquarter vascular bed of the rat.

New targets in the acute treatment of headache

The aim of this article is to review recently identified targets for the acute treatment of primary headache disorders. Calcitonin gene-related peptide (CGRP) receptor blockade has been shown to be an effective acute anti-migraine strategy and is a non-vasoconstrictor in terms of the mechanism of action. It is likely that direct blockade of CGRP release by inhibition of trigeminal nerves would be similarly effective in both migraine and cluster headache. Options for acute treatment based on preclinical work and initial clinical studies include: serotonin 5HT1F and 5HT1D receptor agonists, glutamate excitatory amino acid receptor antagonists, nitric oxide synthase inhibitors and adenosine A1 receptor agonists. Proof of principle studies with octreotide, a somatostatin receptor agonist, demonstrated it to be better than placebo in the acute treatment of cluster headache but not in the acute management of migraine. The prospect of a non-vasoconstrictor acute migraine therapy offers a real opportunity to patients, and perhaps more importantly, provides a therapeutic rationale to plant migraine and cluster headache firmly in the brain as neurological problems.

Anxiogenic effects of Sumatriptan in panic disorder: A double-blind, placebo-controlled study

Several lines of evidence point to serotonergic abnormalities in patients with panic disorder (PD). Our goal was to further examine central serotonergic function in panic patients using autonomic and subjective responses to the postsynaptic serotonin 5-HT1D receptor agonist Sumatriptan. Using a double-blind, randomized, placebo-controlled design, we assessed autonomic and subjective responses to oral Sumatriptan (100 mg) and placebo in 15 patients with PD, free of medication. Subjective responses were measured using the Hamilton Anxiety Rating Scale (HAM-A), National Institute of Mental Health Anxiety Scale (NIMHA), a modified version of the Panic Symptom Inventory (PI), Hamilton Depression Rating Scale (HAM-D), and Montgomery-Asberg Depression Rating Scale (MADRS). PD patients exhibited significantly enhanced autonomic and subjective responses following challenge with Sumatriptan. We observed an increased pulse rate and augmentation of various parameters measured on different anxiety scales. A constant inclination of aggravation of the measured parameters was detected during the hour post challenge. Oral administration of Sumatriptan, a 5-HT1D agonist, has been associated with an anxiogenic effect in PD patients.

Neuroendocrine challenge with a 5-HT1D receptor agonist differentiates between two subtypes of bipolar disorder according to polarity of onset

Neuroendocrine challenge with a 5-HT1D receptor agonist differentiates between two subtypes of bipolar disorder according to polarity of onset

Receptor-Based 3D QSAR Analysis of Serotonin 5-HT1D Receptor Agonists

A three-dimensional quantitative structure-activity relationship study (3D QSAR) has been successfully applied to explain the binding affinities for the serotonin 5-HT1Dreceptor of a triptan series. The paper describes the development of a receptor-based 3D QSAR model of some known agonists and recently developed triptans on the 5-HT1Dserotonergic receptor, showing a significant correlation between predicted and experimentally measured binding affinity (pIC50). The pIC50values of these agonists are in the range from 5.40 to 9.50. The ligand alignment obtained from dynamic simulations was taken as basis for a 3D QSAR analysis applying the GRID/GOLPE program. 3D QSAR analysis of the ligands resulted in a model of high quality (r2= 0.9895,q2LOO= 0.7854). This is an excellent result and proves both the validity of the proposed pharmacophore and the predictive quality of the 3D QSAR model for the triptan series of serotonin 5-HT1Dreceptor agonists.

Decreased sensitivity of 5-HT(1D) receptors in melancholic depression.

Brain serotonin (5-HT) function is abnormal in major depression, but the involvement of different 5-HT receptor subtypes has been little studied. The availability of selective ligands now makes it possible to test the sensitivity of 5-HT(1D) receptors in patients with depression. The aim of the study was to use the 5-HT(1D) receptor agonist, zolmitriptan, to test the sensitivity of 5-HT(1D) receptors in patients with depression before and after treatment with selective serotonin reuptake inhibitors (SSRIs). We measured the growth hormone response to zolmitriptan (5 mg orally) in patients with major depression before and after SSRI treatment. A matched sample of healthy subjects acted as a control group. The growth hormone response to zolmitriptan was blunted in patients with a melancholic depressive syndrome. SSRI treatment produced a marked reduction in zolmitriptan-induced growth hormone release. Patients with melancholic depression have impaired sensitivity of the post-synaptic 5-HT(1D) receptors that mediate growth hormone release. The reduction in 5-HT(1D) receptor sensitivity following SSRI treatment is probably an adaptive response to increased levels of synaptic 5-HT.

Gastric motor effects of triptans: open questions and future perspectives

Sumatriptan is a 5-HT1B/Dreceptor agonist of documented efficacy in relieving migraine and associated symptoms such as nausea and vomiting. In the past decade, several studies reported an important delay of gastric emptying induced by sumatriptan in healthy humans. The impact of this gastric motor effect of sumatriptan in migraineurs is difficult to predict: a further delay in gastric emptying could be detrimental (i.e. increased nausea and epigastric symptoms) in patients already having delayed gastric emptying. However, in patients with functional dyspepsia, sumatriptan is also reported to improve gastric accommodation to a meal and reduce perception of gastric distention, hence relieving epigastric symptoms. Thus, reduced visceral perception could be a mechanism involved in reducing nausea during a migraine attack. Paradoxically, sumatriptan is reported both to relieve the nausea of a migraine attack and to have nausea as a side effect. Although careful analysis of the time of onset of nausea may offer a clue as to the origin of this symptom, available data do not support definite conclusions, all the more so because the gastric motor effect of second-generation triptans are still unexplored. Taken together, the available evidence warrants further studies to clarify the following issues: first, the mechanism responsible for the gastric motor effect of sumatriptan [receptor subtype(s) involved; central vs peripheral mechanism]; secondly, the effects on gastric motility/visceral sensitivity of second-generation triptans (which are 5-HT1B/Dreceptor agonists) and more recent selective 5-HT1Dreceptor agonists (proposed as investigational antimigraine agents with less potential to induce coronary vasoconstriction through 5-HT1Breceptors); finally, the possible use of drugs improving gastric accommodation to a meal in the management of those dyspeptic patients with impaired fundic relaxation/altered visceral sensitivity.

Sumatriptan elicits both constriction and dilation in human and bovine brain intracortical arterioles.

1. Little is known about serotonin (5-HT) receptors present on brain microvessels that are innervated by brainstem serotonergic neurons. Using 5-HT, sumatriptan and subtype selective 5-HT(1) receptor agonists and/or the 5-HT(1) receptor antagonist GR127935, we characterized the 5-HT receptors involved in regulating microvascular tone of pressurized intracortical arterioles (approximately 40--50 microm) isolated from human and bovine cerebral cortex. The role of nitric oxide (NO) on these responses was assessed with the N(omega)-nitro-L-arginine (L-NNA, 10(-5) M), an inhibitor of NO synthesis. Bovine pial arteries were studied for comparative purposes. 2. At spontaneous tone, 5-HT induced a dose-dependent constriction of human and bovine microarteries (respective pD(2) values of 7.3+/-0.2 and 6.9+/-0.1); a response potently inhibited by GR127935 (pIC(50) value of 8.5+/-0.1) in bovine microvessels. 3. In both species, the 5-HT(1) receptor agonist sumatriptan induced a biphasic response consisting of a small but significant dilation at low concentrations (1 and/or 10 nM) followed by a constriction at higher doses (pD(2) for contraction of 6.9+/-0.1 and 6.6+/-0.2 in human and bovine vessels, respectively). Pre-incubation with L-NNA abolished the sumatriptan-induced dilation and significantly shifted the dose-response of the constriction curve to the left. In contrast, the selective 5-HT(1D) (PNU-109291) and 5-HT(1F) (LY344864) receptor agonists were devoid of any vasomotor effect. 4. In bovine pial vessels, 5-HT and sumatriptan elicited potent constrictions (respective pD(2) of 7.2+/-0.1 and 6.6+/-0.1), a weak dilation being occasionally observed at low sumatriptan concentrations. 5. A significant negative correlation was observed between pial and intracortical vessels diameter and the extent of the dilatory response to 10(-9) M sumatriptan. Together, these results indicate that sumatriptan, most likely via activation of distinctly localized microvascular 5-HT(1B) receptors, can induce a constriction and/or a dilation which is sensitive to inhibition of NO synthesis and dependent on the size and, possibly, the existing tone of the vessels.