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

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

The role of 5-hydroxytryptamine (5-HT) receptor subtypes and plasticity in the 5-HT systems in the regulation of nociceptive sensitivity

This review shows that the role of 5-hydroxytryptamine (5-HT) in the regulation of nociception depends on the 5-HT receptor subtypes involved and on long-term functional changes in the 5-HT receptors. Stimulation of the 5-HT₁ receptors, as well as of the 5-HT₂ and 5-HT₃ receptors, may reduce nociceptive sensitivity. In addition, activation of 5-HT₂ and 5-HT₃ receptors may also enhance nociceptive sensitivity. Up- or down-regulation of the 5-HT receptors may result in long-lasting changes, plasticity, in the 5-HT systems. Lesioning of 5-HT neurons induces denervation supersensitivity to 5-HT, and prolonged stimulation of 5-HT receptors may produce subsensitivity to 5-HT. In the spinal cord denervation supersensitivity to 5-HT may depend on reduced release of substance P (SP). An increase in the release of SP, on the other hand, may reduce the effects of 5-HT receptor activation. Long-term treatment with antidepressants which are used in clinical pain therapy appears to up-regulate the 5-HT₁ receptors and to down-regulate the 5-HT₂ receptors.     

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

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

Stress-induced alterations of somatodendritic 5-HT1A autoreceptor sensitivity in the rat dorsal raphe nucleus — in vitro electrophysiological evidence

Summary— Somatodendritic 5-HT_1A autoreceptors play a key role in the control of the electrical and metabolic activity of serotoninergic neurons in the dorsal raphe nucleus. These neurons also possess intracellular glucocorticoid receptors which may be involved in the well established modulation of serotonin (5-hydroxytryptamine, 5-HT) metabolism by corticosterone in stressed animals. The possible mediation by somatodendritic 5-HT_1A autoreceptors of such corticosterone-dependent changes in serotoninergic neuron activity was investigated using an in vitro electrophysiological approach. 5-HT_1A autoreceptor-mediated inhibition of the firing of serotoninergic neurons was examined in brain stem slices from rats whose serum corticosterone concentrations had been markedly increased (+ 100–200%) by two different stressful conditions. Immobilization for 30 or 90 min (restraint stress) did not modify the concentration-dependent inhibition of the firing of serotoninergic neurons by the 5-HT_1A receptor agonist ipsapirone. In contrast, placing the rats in novel uncontrolled environmental conditions for 16 h significantly reduced the cell response to ipsapirone, indicating a decreased sensitivity of somatodendritic 5-HT_1A autoreceptors. Such a change was not observed in adrenalectomized rats subjected to the same stressful conditions. These data show that some forms of stress can reduce the 5-HT_1A autoreceptor-dependent inhibitory control of the electrophysiological activity of serotoninergic neurons in the dorsal raphe nucleus. Both the nature and duration of stress seem to be critical factors for triggering the (corticosterone-dependent) mechanism(s) responsible for the functional desensitization of 5-HT_1A autoreceptors in stressed rats.     

Exclusion of 5-HT2A and 5-HT2C Receptor Genes as Candidate Genes for Migraine

Several lines of investigation suggest that the serotonergic system may be involved in the pathogenesis of migraine. In particular, drugs which block 5-HT₂ receptor subtypes appear to be effective migraine prophylactic agents. Therefore, chromosomal DNA regions overlapping the 5-HT_2A (13q14-q22) and 5-HT_2c (Xq22-25) receptor loci were analyzed for possible linkage to the clinical diagnosis of migraine. No evidence for linkage to either chromosomal region was found, although a small subset of migrainous families showed positive likelihood of odds (LOD) scores. However, a homogeneity (HOMOG) analysis provided no statistical evidence for locus heterogeneity. The coding region of the 5-HT_2A and 5-HT_2c receptor genes was also analyzed in migraine patients and unaffected controls using polmerase chain reaction and direct sequencing. No mutations were found in the deduced amino acid sequence of either receptor in the sample of migraineurs tested. These results indicate that DNA-based mutations in the 5-HT_2A and 5-HT_2c receptors are not generally involved in the pathogenesis of migraine.     

Stress-induced 5-HT1A receptor desensitization: protective effects of Ginkgo biloba extract (EGb 761)

Summary— The effects of sub-chronic cold stress on the functioning of hippocampal 5-HT_1A receptors in old isolated rats and the possible protective effects of Ginkgo biloba extract (EGb 761) were investigated. Cold exposure during five days, produced a significant reduction of the inhibitory effect of 8-hydroxy-2-(di-n-propylamino)tetraline (8-OH-DPAT) on forskolin-stimulated adenylyl cyclase activity. In contrast, neither the affinity nor the density of hippocampal [³H]8-OH-DPAT binding sites were affected indicating that the reduced sensitivity of 5-HT_1A receptors induced by stress is probably due to a modification of their coupling mechanisms to adenylyl cyclase. The stress-induced desensitization of 5-HT_1A receptors was prevented by the administration of EGb 761 (50 mg/kg per os /14 days). These results clearly indicate that 5-HT_1A receptors are desensitized by stress and point out the reduced capacity of old rats to cope with the adverse effects of a chronic stressor. EGb 761 appears to restore the age-related decreased capacity to adapt to a chronic stressor.     

5-HT1B Receptor Polymorphism and Clinical Response to Sumatriptan

The 5-HT₁ receptor agonist, sumatriptan, is highly effective in the treatment of migraine. Some patients, however, do not respond or experience recurrence of the headache. In addition, some patients report chest symptoms after sumatriptan. We investigated whether these different responses could be attributed to genetic diversity of the 5-HT_1B receptor, which most likely mediates the therapeutic action and the coronary side effects of sumatriptan. Allele frequencies of two polymorphisms in the 5-HT_1B receptor gene ( G861C and T-261G ) were investigated in migraine patients with consistently good response to sumatriptan (n=14), with no response (n=12), with recurrence of the headache (n=12), with chest symptoms (n=13), and in patients without chest symptoms (n=27). Allele frequencies (G:0.74; C:0.26 at nt 861 and T:0.39; G:0.61 at nt -261) did not differ between patient groups, indicating that genetic diversity of the 5-HT_1B receptor does not seem to be involved in the different clinical responses to sumatriptan.     

Biochemical and electrophysiological properties of SR 57746A, a new, potent 5-HT1A receptor agonist

Summary— SR 57746A (1-[2-(naphth-2-yl) ethyl]-4-(3-trifluoromethylphenyl)-1, 2, 5, 6 tetra-hydropyridine hydrochloride) binds competitively, and with high affinity (K_i = 2.0 ± 0.7 nM) to 5-HT_1A receptors from rat hippocampus in vitro , but has much less affinity for other 5-HT receptor subtypes (IC₅₀ > 650 nM). SR 57746A produces a concentration-dependent inhibition of forskolin-stimulated adenylate cyclase activity in rat hippocampal homogenates, with a maximal effect identical to that of 8-OH-DPAT, suggesting that SR 57746A behaves as a full agonist in tthis experimental model. SR 57746A potently displaces [³H]8-OH-DPAT binding to rat hippocampal membranes ex vivo , with an ID₅₀ of 11.1 mg/kg po, 30 min after administration, and 2.8 mg/kg po, 2 h after administration. This effect of SR 57746A is long-lasting (at least 24 hours at 10 mg/kg po). SR 57746A does not modify the levels of 5-HT or DA in various brain areas, but decreases the concentrations of 5-HIAA, and increases those of DOPAC, HVA and 3-MT. Following iv administration, SR 57746A (0.095 to 0.25 mg/kg) inhibits the spontaneous firing of dorsal raphe neurones, but does not modify the activity of DA neurones in the substantia nigra or ventral tegmental area. Thus, SR 57746A is a potent, selective and full agonist at 5-HT_1A receptors in vitro and vivo.     

Role of peripheral 5-HT(4), 5-HT(6), and 5-HT(7) receptors in development and maintenance of secondary mechanical allodynia and hyperalgesia

The role of 5-hydroxytryptamine (5-HT)₄, 5-HT₆, and 5-HT₇ receptors in formalin-induced secondary allodynia and hyperalgesia in rats was assessed. Formalin produced acute nociceptive behaviors (flinching and licking/lifting) followed by long-term secondary mechanical allodynia and hyperalgesia. Pretreatment (−10 min) with cromoglycate (195-1950 nmol/paw) partially inhibited acute nociceptive behaviors and completely prevented secondary allodynia and hyperalgesia on day 6 after injection. Ipsilateral peripheral pretreatment with the selective 5-HT₄ (ML-10302, 1-100 nmol/paw), 5-HT₆ (EMD-386088, 0.001-0.01 nmol/paw), and 5-HT₇ (LP-12, 0.01-100 nmol/paw) receptor agonists significantly increased secondary allodynia and hyperalgesia in both paws. In contrast, ipsilateral peripheral pretreatment with the selective 5-HT₄ (GR-125487, 1-100 nmol/paw), 5-HT₆ (SB-258585, 0.00001-0.001 nmol/paw), and 5-HT₇ (SB-269970, 0.1-10 nmol/paw) receptor antagonists significantly prevented formalin-induced secondary allodynia and hyperalgesia in both paws. The pronociceptive effect of ML-10302 (100 nmol/paw), EMD-386088 (0.01 nmol/paw), and LP-12 (100 nmol/paw) were completely prevented by GR-125487 (5-HT₄ antagonist, 1 nmol/paw), SB-258585 (5-HT₆ antagonist, 0.00001 nmol/paw), and SB-269970 (5-HT₇, antagonist, 0.01 nmol/paw), respectively. Ipsilateral peripheral posttreatment with cromoglycate or GR-125487 (1-100 nmol/paw), SB-258585 (0.001-0.1 nmol/paw), and SB-269970 (0.1-10 nmol/paw) reversed formalin-induced secondary allodynia and hyperalgesia in both paws. Results suggest that a barrage of afferent input induced by 5-HT at peripheral 5-HT₄, 5-HT₆, and 5-HT₇ receptors participate in the development and maintenance of formalin-induced long-term secondary allodynia and hyperalgesia in the rat.     

福尔马林致痛大鼠背根节内5-HT受体亚型mRNA的表达变化

目的:探讨外周5-HT受体亚型在外周伤害性感受中的作用.方法:用反转录PCR技术观察大鼠单侧足底皮下注射福尔马林致痛后背根节内5-HT1～7受体亚型mRNAs的表达变化.结果:在大鼠足底皮下注射福尔马林后1 h,注射侧腰段背根节内5-HT1A、5-HT1B、5-HT2A、5-HT3、5-HT4和5-HT7受体亚型mRNAs的表达水平显著升高,而5-HT1D、5-HT1F、5-HT2C、5-HT5A和5-HT6受体亚型mRNAs的表达在福尔马林致痛后无明显变化.在正常和福尔马林致痛大鼠的背根节内均未检测到5-HT1E、5-HT2B和5-HT5B受体亚型mRNAs的表达.结论:5-HT1A、5-HT1B、5-HT2A、5-HT3、5-HT4和5-HT7受体亚型可能参与了福尔马林诱导的炎性痛,且它们在外周伤害性信息的传递方面可能发挥不同的作用.     

Serotonin induces vasoconstriction of smooth muscle cell-rich neointima through 5-hydroxytryptamine2A receptor in rabbit femoral arteries

Summary.  Background:  Smooth muscle cell (SMC)-rich intima is a morphological feature of atherosclerotic lesions that is observed in eroded plaque and spastic arteries. Arteries with SMC-rich intima are susceptible to vasoconstriction or vasospasm against some vasoactive agents. Objective:  The present study evaluates the contribution of SMC-rich intima to thrombogenic vasoconstriction. Methods:  We established SMC-rich neointima by damaging rabbit femoral arteries using balloons and then measured the isometric tension of the femoral strips against 5-hydroxytryptamine (5-HT), adenosine diphosphate, adenosine triphosphate and thrombin. Results:  Among these agents, only 5-HT induced a hypercontractile response of the injured arteries with SMC-rich neointima, compared with non-injured arteries. Smooth muscle cells of both the neointima and media expressed 5-HT_2A receptor, and sarpogrelate, a selective 5-HT_2A receptor antagonist significantly inhibited the hypercontraction. Furthermore, 5-HT induced contraction of separated neointima and hypercontraction of separated media compared with non-injured media. Sarpogrelate and fasudil, a specific Rho-kinase inhibitor, significantly suppressed such contraction of both the neointima and media of injured arteries. Conclusions:  These results suggest that 5-HT plays a crucial role in thrombogenic vasoconstriction, and that SMC-rich intima as well as media directly contributes to the hypercontractile response of atherosclerotic vessels through the 5-HT_2A receptor and the Rho-kinase pathway.     

Naratriptan has a selective inhibitory effect on trigeminovascular neurones at central 5-HT1A and 5-HT(1B/1D) receptors in the cat: implications for migraine therapy

The triptans are agonists at serotonin (5-HT)1B/1D receptors; however, they are also active at 5-HT1A and 5-HT1F receptors. We conducted this series of experiments to further elucidate the site of action of naratriptan using a well-established animal model of trigeminovascular stimulation. Following electrical stimulation of the superior sagittal sinus of the cat, single cell responses (n=83) were recorded in the trigeminal nucleus caudalis. Most cells (91%) also responded to electrical and mechanical stimulation of cutaneous or mucosal facial receptive fields. The microiontophoretic application of naratriptan resulted in a significant suppression of the response to sagittal sinus stimulation (response suppressed by 47 +/- 4%, P<0.001). The effect of naratriptan was significantly attenuated by application of either the 5-HT(1B/1D) receptor antagonist GR-127935 (P<0.001) or the 5-HT1A antagonist WAY-100635 (P<0.05). The response of single cells to receptive field stimulation was also suppressed by microiontophoretic application of naratriptan, but by only 20 +/- 3%. Intravenous administration of naratriptan resulted in a similar selective suppression of sagittal sinus vs. receptive field responses in trigeminal neurones. These results indicate that naratriptan has a central effect in the trigeminovascular system, selectively inhibiting afferent activity in craniovascular neurones, via both 5-HT(1B/1D) and 5-HT1A receptors.     

Comparative tolerability of oral 5-HT1B/1D agonists

OBJECTIVES: To compare the relative tolerability of 5-HT1B/1D agonists and to investigate the relationships (if any) among systemic exposure, lipophilicity, and clinical tolerability for 5-HT1B/1D agonists. METHODS: Post hoc correlations were sought among the following variables: absolute dose (= administered dose x oral bioavailability), Cmax, LogDpH7.4 (LogD), frequencies of all, neurological and dizziness/somnolence/drowsiness adverse events, adjusted for corresponding placebo-associated frequencies. RESULTS: For effective doses of all drugs with available data, absolute dose-response relationships exist for adverse event frequencies. The overall rank order of the frequency of adverse events was as follows: naratriptan < sumatriptan = rizatriptan < zolmitriptan. With the exception of eletriptan, 5-HT1B/1D agonists exhibit correlations between absolute dose, Cmax (R = 0.97), and LogD (R = 0. 71). For neurological and dizziness/somnolence/drowsiness adverse event frequencies, the overall rank order was sumatriptan < naratriptan < rizatriptan < zolmitriptan. Neither LogD nor absolute dose size predicted adverse event frequencies. CONCLUSIONS: Triptans may be distinguished in terms of their tolerability. Effectiveness, absolute dose size, and lipophilicity are related for the 5-HT1B/1D agonists considered here, except eletriptan. Adverse event frequencies cannot be predicted from in vitro measures of lipophilicity, in vivo estimates of absolute bioavailability, dose size, or any combination of these variables. Since these drugs are all agonists at 5-HT1B/1D receptors in the low nanomolar range, but differ in their tolerability profiles, adverse effects are not likely to be mediated through 5-HT1B/1D receptors. Drugs of this class must be studied individually and on a reasonably large scale in clinical development programs.     

Lasmiditan and 5-Hydroxytryptamine in the rat trigeminal system; expression,release and interactions with 5-HT1 receptors

Background5-Hydroxytryptamine (5-HT) receptors 1B, 1D and 1F have key roles in migraine pharmacotherapy. Selective agonists targeting these receptors, such as triptans and ditans, are effective in aborting acute migraine attacks and inhibit the in vivo release of calcitonin gene-related peptide (CGRP) in human and animal models. The study aimed to examine the localization, genetic expression and functional aspects of 5- HT_1B/1D/1F receptors in the trigeminal system in order to further understand the molecular sites of action of triptans (5-HT_1B/1D) and ditans (5-HT_1F).MethodsUtilizing immunohistochemistry, the localization of 5-HT and of 5-HT_1B/1D/1F receptors was examined in rat trigeminal ganglion (TG) and combined with quantitative polymerase chain reaction to quantify the level of expression for 5-HT_1B/1D/1F receptors in the TG. The functional role of these receptors was examined ex vivo with a capsaicin/potassium induced 5-HT and CGRP release.Results5-HT immunoreactivity (ir) was observed in a minority of CGRP negative C-fibres, most neuron somas and faintly in A-fibres and Schwann cell neurolemma. 5-HT_1B/1D receptors were expressed in the TG, while the 5-HT_1F receptor displayed a weak ir. The 5-HT_1D receptor co-localized with receptor activity-modifying protein 1 (RAMP1) in Aδ-fibres in the TG, while 5-HT_1B-ir was weakly expressed and 5-HT_1F-ir was not detected in these fibres. None of the 5-HT₁ receptors co-localized with CGRP-ir in C-fibres.5-HT_1D receptor mRNA was the most prominently expressed, followed by the 5-HT_1B receptor and lastly the 5-HT_1F receptor. The 5-HT_1B and 5-HT_1D receptor antagonist, {"type":"entrez-nucleotide","attrs":{"text":"GR127935","term_id":"238377770"}}GR127935, could reverse the inhibitory effect of Lasmiditan (a selective 5-HT_1F receptor agonist) on CGRP release in the soma-rich TG but not in soma-poor TG or dura mater. 5-HT release in the soma-rich TG, and 5-HT content in the baseline samples, negatively correlated with CGRP levels, showing for the first time a physiological role for 5-HT induced inhibition.ConclusionThis study reveals the presence of a subgroup of C-fibres that store 5-HT. The data shows high expression of 5-HT_1B/1D receptors and suggests that the 5-HT_1F receptor is a relatively unlikely target in the rat TG. Furthermore, Lasmiditan works as a partial agonist on 5-HT_1B/1D receptors in clinically relevant dose regiments.Supplementary InformationThe online version contains supplementary material available at 10.1186/s10194-022-01394-z.     

Serotonin (5-HT) and Migraine

SYNOPSIS
Serotonin, or 5-hydroxytryptamine [5-HT], is a biogenic amine implicated in controlling feeding behavior, thermoregulation, sexual behavior, and sleep. 5-HT receptors recognize at least three types of molecular structures: G protein coupled receptors, ligand gated ion channels, and transporters. It is now believed that there are at least seven different families of receptors, many of which have subtypes. The nervous system can be compared to a group of well-modulated neural networks functioning in parallel. The serotonergic system may modulate these networks rather than actually mediate individual responses. Circumstantial evidence suggests a link between 5-HT and migraine. Platelet HT decreases during an attack, and in some cases increased levels of metabolites are found. Many antimigraine drugs interact with 5-HT and its receptors.     

Pharmacological analysis of the cardiac effects of 5-HT and some 5-HT receptor agonists in the pithed rat

Summary— A pharmacological analysis of the effects of 5-HT on heart rate has been performed in the pithed rat. 5-HT induced a dose-dependent increase in heart rate whereas 5-HT, receptor agonists — 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT), 5-methoxy-N,N-dimethyl-tryptamine (5-MeODMT), 5-methoxy 3-(1,2,3,6-tetrahydro-4-piridinyl) 1H indole (RU 24969) and 1-(m-trifluoromethylphenyl)-piperazine (TFMPP) — failed to increase heart rate. The increase in heart rate induced by the selective 5-HT₂ receptor agonist 1-(2,5-dimethoxy-4-iodo-phenyl)-2-aminopropane (DOI) was not significant. The dose-response curve to 5-HT for its tachycardic effects was shifted two-fold to the right by ketanserin and LY 53857 and nine-fold to the right by methiothepin. The effects of high doses of 5-HT (higher than 100 μg/kg iv) were antagonized by methiothepin, (-)propranolol, 2-{2-[4(O-methoxyphenyl)-piperazine-1-yl]-ethyl}4,4-dimethyl-1,3 (2H-4H) isoquinoline-dione (AR-C 239) and by pretreatment with reserpine. The 5-HT₁ receptor antagonists, pindolol and spiroxatrine, the 5-HT₃ receptor antagonist MDL 72222 and the α₂-adrenoceptor blocking agent idazoxan failed to antagonize the tachycardia induced by 5-HT. It is concluded that in the pithed rat, the tachycardia induced by 5-HT remained unexplained (implication of 5-HT₂ receptors probably different from the classical vascular 5-HT₂ receptor, or implication of 5-HT_1C receptors?). Moreover, at high doses (higher than 100 μ/kg iv), 5-HT may increase heart rate by releasing catecholamines.     

Pronociceptive role of peripheral and spinal 5-HT7 receptors in the formalin test

The possible pronociceptive role of peripheral and spinal 5-HT7 receptors in the formalin test was assessed. Local administration of 5-HT7 (SB-269970, 2.5-77.1 nmol/paw), but not 5-HT(1A) (WAY-100635, 1-60 nmol/paw), receptor antagonist significantly reduced formalin-induced flinching. Local 5-hydroxytryptamine (5-HT, 3-100 nmol/paw) or 5-carboxamidotryptamine (5-CT, 0.3-3 nmol/paw) (a 5-HT7/1A receptor agonist) augmented, in a dose-dependent manner, 0.5% formalin-induced nociceptive behavior. The local pronociceptive effect of 5-HT or 5-CT was significantly reduced by SB-269970 (25 and 77.1 nmol/paw), but not by WAY-100635 (10 nmol/paw). 5-HT7 receptors were observed in myelinated and unmyelinated axons of the digital nerves in rat hindpaw. Intrathecal SB-269970 (2.5-77.1 nmol/rat) or WAY-100635 (1-50 nmol/rat) did not modify 1% formalin-induced nociceptive behavior. Spinal 5-HT (25-200 nmol/rat) significantly reduced formalin-induced flinching behavior during phase 2. At lower doses (0.1-3 nmol/rat) intrathecal 5-CT dose-dependently increased flinching during phase 2. In contrast, higher doses (10-30 nmol/rat) of 5-CT reduced formalin-induced nociceptive behavior during both phases. The spinal pronociceptive effect of 5-CT was reduced by SB-269970 (7.7-77 nmol/rat), but not by WAY-100635 (10 nmol/rat). In addition, the spinal antinociceptive effect of 5-CT was partially reversed by WAY-100635 (10 nmol/rat). The spinal antinociceptive effect of 5-HT was unaffected either by SB-269970 (77 nmol/rat) or WAY-100635 (10 nmol/rat). Data suggest that 5-HT7, but not 5-HT1A, receptors play a pronociceptive role in peripheral and spinal sites in the rat formalin test.     

Characterization of the human basilar artery contractile response to 5-HT and triptans

To study the contractile responses of the human basilar artery to 5-hydroxytryptamine (5-HT), sumatriptan, zolmitriptan and naratriptan, and to characterize the 5-HT receptor subtypes involved on those responses, human basilar artery rings were prepared for isometric contraction, protein isolation and Western blotting analysis. Concentration-response (CR) curves were made for all agonists in the absence or in the presence of selective antagonists at 5-HT1B (cyanopindolol), 5-HT1D (BRL 15,572) and 5-HT2 (ketanserin) receptors. We also used anti-5-HT1B and 5-HT1D receptor antibodies to search for the expression of protein of these receptor subtypes. From the CR curves, the relative intrinsic activity and potency of these agonists were determined. The ranking order for the intrinsic activity was 5-HT > or = sumatriptan > zolmitriptan > or = naratriptan, whereas that for the potency was zolmitriptan > or = 5-HT > or = sumatriptan > naratriptan. Our results also show that the human basilar artery seems to have a mixed population of 5-HT1B/1D receptors mediating the contractile response to triptans, which is also suggested by the expression of both receptor subtypes. There is also a population of 5-HT2 receptors for which the antimigraine drugs used have no apparent affinity. From this study, one can conclude that the second generation triptans have lower contractile capacity than sumatriptan, suggesting that they have a better cerebrovascular safety profile.     

5-HT1F receptor agonists in acute migraine treatment: a hypothesis

Serotonin-1F receptor (5-HT1F) agonists may relieve acute migraine without vasoconstriction. We conducted a review of preclinical and clinical data that assessed the potential link between migraine and 5-HT1F activation. (i) A high correlation exists between the potency of various 5-HT1 receptor agonists in the guinea pig dural plasma protein extravasation assay and their 5-HT1F receptor binding affinity. (ii) 5-HT1F receptors are on the trigeminal system, and may participate in blocking migraine pain transmission through the trigeminal ganglion and nucleus caudalis. (iii) 5-HT1F receptors are located on glutamate-containing neurones and their activation might inhibit glutamate release; glutamate excess may play a role in migraine. (iv) Selective 5-HT1F receptor agonists (LY334370; LY344864) are effective in preclinical migraine models and are non-vasoconstrictive. (v) LY334370 is effective in acute migraine, and does not cause any symptoms/signs of coronary vasoconstriction. Preclinical experiments and clinical observations argue for a role of selective 5-HT1F agonists in migraine.