- Review Article
- Open Access
Does sumatriptan cross the blood–brain barrier in animals and man?
© Springer-Verlag 2009
Received: 24 August 2009
Accepted: 27 October 2009
Published: 10 December 2009
Sumatriptan, a relatively hydrophilic triptan, based on several animal studies has been regarded to be unable to cross the blood–brain barrier (BBB). In more recent animal studies there are strong indications that sumatriptan to some extent can cross the BBB. The CNS adverse events of sumatriptan in migraine patients and normal volunteers also indicate a more general effect of sumatriptan on CNS indicating that the drug can cross the BBB in man. It has been discussed whether a defect in the BBB during migraine attacks could be responsible for a possible central effect of sumatriptan in migraine. This review suggests that there is no need for a breakdown in the BBB to occur in order to explain a possible central CNS effect of sumatriptan.
The triptans, 5-HT1B/1D receptor agonists, are effective drugs in the treatment of migraine attacks [1–4]. It has been debated for a long time whether the triptans act during migraine attacks on the peripheral nociceptive input or on the nociceptive system in the CNS [5, 6]. Triptans can theoretically decrease peripheral nociception either by a selective cranial vasoconstriction, the rationale for its development [6, 7] or an effect on trigeminovascular nerves . A peripheral effect on trigeminal vascular nerves was indicated by the blocking effect of sumatriptan of neurogenically mediated plasma extravasation . Inhibitors of neurogenic inflammation (NI) were, however, ineffective in the treatment of migraine  and it is thus difficult to ascribe a pivotal role for NI in migraine. In 1996 it was, based on the effect of zolmitriptan, suggested that inhibition of trigeminal neurons in the brain stem by lipophilic triptans may play a role in the anti-migraine effect of these drugs and that these results offered the prospect of a third pathophysiological target site for triptans .
The prototype of a triptan is sumatriptan, the first developed triptan . Apparently this drug, which is relatively hydrophilic, did not in several animal studies [5, 11–14] cross the blood–brain barrier (BBB) in sufficient amount to cause a pharmacological effect in the trigeminal nucleus caudalis [5, 12, 13] or frontal cortex . In contrast, other more lipophilic triptans, such as zolmitriptan [5, 15], naratriptan , rizatriptan , and eletriptan , caused an inhibition of nociception in the trigeminal nucleus caudalis in these animal models of migraine.
In contrast to earlier studies [7, 19] it was recently stated that “this central site of action is consistent with the evidence that sumatriptan can rapidly cross the blood–brain barrier into the central nervous system after systemic administration”. This was, however, based on a pharmacokinetic study using sumatriptan 3.2 mg/kg  far above the therapeutic dose of 100 μg/kg.
In recent studies from 2004 and 2009 a presynaptic inhibition of sumatriptan (300–600 μg/kg) in the trigeminal nucleus caudalis was found  and reversal of facial allodynia by sumatriptan  was observed.
In the following, animal studies on sumatriptan will be reviewed and possible explanation for the discrepancy among studies will be suggested. Next, CNS adverse events after triptans in migraine patients and normal subjects will be reviewed.
It is concluded that both the animal and the human studies suggest that sumatriptan to some minor extent can penetrate into the CNS across the BBB both in animals and in man. The minor penetration of sumatriptan into the CNS is, however, sufficient to cause pharmacological effects most likely because the drug is potent 5-HT1B/1D receptor agonist [1, 3].
Review of studies in animals
The penetration of systemically administered 14C-labeled sumatriptan into the central nervous system was investigated in the mouse . Only 0.006% of total radioactivity was found in the brain indicating poor brain penetration by sumatriptan . In another study no sumatriptan was found in the brain with whole body assay in rats .
Studies on the central nervous system effect of sumatriptan in animals
Dose of sumatriptan
Indicates passage of sumatriptan across BBB
Sleight et al. (1990) 
50 and 500 μg/kg (i.p.) (guinea pig)
Extracellular 5-HT levels in the frontal cortex as measured by microdialysis
No effect of systemic sumatriptan (sumatriptan 10−8–10−7 M in microlysate caused a decrease of 5-HT)
Skingle et al. (1990) 
Dose 1–100 mg/kg (rodents)
Antinociceptive effect by (various tests)
No antinociceptive effect (in some tests 100 mg/kg had an effect)
Nozaki et al. (1992) 
720 nmol/kg (300 μg/kg) (rat)
c-fos expression in the trigeminal nucleus caudalis after autologous blood in cisterna magna
Sumatriptan reduced c-fos positive cells in trigeminal nucleus caudalis by 31%
(−/+) see commenta
Moskowitz et al. (1993) 
300 μg/kg (rats
c-fos expression in trigeminal nucleus caudalis after repeated CSD
Sumatriptan reduced c-fos expression
(−/+) see commenta
Kaube et al. (1993) 
100 μg/kg (cat)
Single units activity and trigeminal somatosensory evoked potentials after SSS stimulation
No effect of sumatriptan (after blood–brain barrier disruption with mannitol sumatriptan decreased the peak-to-peak amplitude of evoked potentials)
Shepheard et al. (1995) 
1,000 μg/kg (rat)
Expression of c-fos mRNA in trigeminal nucleus caudalis after stimulation of trigeminal ganglion
No effect of sumatriptan (after blood–brain barrier disruption with mannitol sumatriptan decreased expression of c-fos mRNA with 63%
Ghehardini et al. 1996 
5–30 mg/kg (mouse))
Antinociceptive effect (hot-plate test)
There was an antinociceptive effect, most likely mediated by the 5-HT1A receptor
Mitsikostas et al. (1996) 
0.3–0.9 mg/kg (rat)
Brain monoamines concentration
0.6 mg/kg decreased hypothalamic serotonin concentration
Hoskin and Goadsby (1996) 
85 μg/kg (cat)
c-fos expression in trigeminal nucleus caudalis after dilatation of SSS
Reduction of c-fos expression
(+/−) see commentsb
Knyihár-Csillik et al. (1997) 
120 μg/kg (rat)
c-fos in caudal trigeminal nucleus after stereo electrical stimulation of the trigeminal ganglion
No effect of sumatriptan on c-fos expression
Ingvardsen et al. (1997) 
300 μg/kg (rat)
c-fos in TNC after CSD
No effect of sumatriptan on c-fos expression
Hoskin and Goadsby (1998) 
85 μg/kg (rat)
c-fos expression in trigeminal nucleus caudalis after SSS stimulation
No effect on c-fos expressionb
Read et al. (1999) 
300 μg/kg (rat)
Nitric oxide formation in the cerebral cortex after nitroglycerin
Decrease of NO formation
Read and Parsons 
300 μg/kg (rat and cat)
Nitric oxide formation in the cerebral after CSD
Decrease of NO formation and decrease of partial oxygen tension
Read et al. (2001) 
300 μg/kg (rat)
CGMP after CSD
No effect on brain stem cGMP after 3 days
Johnson et al. (2001) 
3.2 mg/kg (rat)
Measurements of sumatriptan concentrations in microdialysate. Central release of 5-HT
Concentrations of sumatriptan up to 8 nM was observed. No effect on central release of 5-HT
Kayser et al. (2002) 
100 μg/kg (rat)
Mechanical allodynia-like behaviour after ligature of n. infraorbitalis
A significant reduction of mechanical allodynia-like behaviour on injured and contralateral side of the facec
Dobson et al. (2004) 
300–1,000 μg/kg (rat)
Serotonin synthesis in brain
Given acutely a decrease in 5-HT synthesis in certain regions of the brain was observed
Pardutz et al. (2004) 
600 μg/kg (rat)
Nitroglycerin-induced nNOS immunoreactive neurones in trigeminal nucleus caudalis
nNOS expression could not be prevented
Levy et al. (2004) 
300 μg/kg (rat)
Changes in spontaneous activity of trigeminal peripheral and central neurones after inflammatory soup on dura
Sumatriptan blocked the induction of central sensitization most likely by a presynaptic inhibition
Edelmayer et al. (2009) 
600 μg/kg (rat)
Prevention of facial allodynia after inflammatory mediators on the dura
Sumatriptan prevented or reversed facial allodynia
Bates et al. (2009) 
600 μg/kg i.p. and 0.06 μg intrathecal (mouse)
Prevention of thermal and mechanical allodynia
Systemic sumatriptan inhibited thermal allodynia but not mechanical allodynia. Intrathecal sumatriptan inhibited both
The clinically used dose of subcutaneous sumatriptan 6 mg corresponds to approximately 100 μg/kg, but the dose used in animal studies varied widely from 50 μg/kg to 100 mg/kg (Table 1). In nine studies [5, 11–14, 24–27], there was no effect of sumatriptan in the animal model. In one study an antinociceptive effect was found after 5–30 mg/kg, most likely mediated by the 5-HT1A receptor . In contrast, an effect of sumatriptan 100–1,000 μg/kg on the CNS was found in nine studies [21, 22, 29–35].
In one study sumatriptan 300 μg/kg blocked c-fos protein-like immunoreactivity within trigeminal nucleus caudalis following irritation of meningeal afferents induced by blood . In another study from the same group of investigators sumatriptan 300 μg/kg reduced c-fos protein-like immunoreactivity in the trigeminal nucleus caudalis (TNC) after repeated cortical spreading depression . In the authors opinion the effects of sumatriptan were most likely due to an effect on the peripheral part of the afferent fibres of the trigeminal nerve but they add: “of course, the studies reported herein do not exclude the unlikely possibility that this hydrophilic 5-HT analogue blocks c-fos protein-like immunoreactibility within the TNC directly” .
In a later study from 1997 with the same problem it was found that morphine 3 mg/kg, but not sumatriptan 300 μg/kg, decreased c-fos expression in TNC after multiple CSD . These results have been disputed .
In one study sumatriptan acutely in a dose of 100 μg/kg and 1 mg/kg, as well as zolmitriptan 100 μg/kg, decreased 5-HT synthesis rate in many brain region in rats including the dorsal raphe nucleus . Chronically, sumatriptan (300 μg/kg per day) induced significant increases in the 5-HT synthesis rate in many projection areas but had no effect in the dorsal raphe nucleus . Overall, these findings indicate that not only zolmitriptan, but also sumatriptan affect brain serotonergic neurotransmission .
One study used very high doses of sumatriptan: in a pharmacokinetic–pharmacodynamic study in rats from 2001  on the serotonergic effects and extracellular levels of eletriptan, zolmitriptan and sumatriptan, using a very high dose of 2.5 mg/kg i.v., it was shown that the three drugs with different lipophilicity had similar extracellular levels in the brain. On the other hand, sumatriptan did not exert a serotonergic effect, as did zolmitriptan and eletriptan, most likely because sumatriptan is less potent in this system than the two other triptans . In addition, non-equipotent doses of the two triptans compared with sumatriptan were used, see later. The problem with this study is evident: the usual subcutaneous dose of sumatriptan in man is 6 mg, corresponding to 100 μg/kg, whereas the dose is 32 times higher in this rat study . This could indicate that a saturable, expulsion process limiting the access of the three triptans to the CNS exists. In fact, eletriptan distribution in the CNS is limited by the P-glycoprotein-mediated efflux [39, 40] whereas sumatriptan and zolmitriptan are subjected to non-P-glycoprotein-mediated efflux .
What could be the explanation for this different effect of sumatriptan in these various animal models of migraine? In two of these studies in which sumatriptan had no effect [12, 13], an effect of sumatriptan was observed after disruption of the BBB with mannitol. The potential for a CNS effect of a triptan, including sumatriptan, is thus present in the animal models used [12, 13] as also demonstrated by the effect of zolmitriptan [5, 15], naratriptan , rizatriptan  and eletriptan  in these models with intact BBB.
The dictum was thus in the beginning, based on pharmacokinetic studies [7, 19] that sumatriptan had only minimal or no passage within the central nervous system. Most early animal studies apparently supported, with different methodology, the lack of penetration of sumatriptan across the BBB [11–13, 24]. Later animal studies have shown in some but not in all (Table 1) investigations that sumatriptan in these animal models, mostly of migraine, did exert an effect inside the BBB.
CNS effects in migraine patients and other subjects
In human postmortem brains [3H]sumatriptan binding sites have been found in among others, globus pallidus > cortex > hippocampus . In the brain stem the highest [3H]sumatriptan binding sites were seen in the substantia nigra, the trigeminal nucleus, nucleus of the tractus solitarius and periaqueductal gray . If sumatriptan can cross the BBB in sufficient amounts, one would thus expect CNS adverse events after therapeutic use of the drug.
Some migraine patients complain of sleepiness/tiredness, difficulty in thinking and dizziness  after sumatriptan. In a meta-analysis of oral triptans, sumatriptan 100 mg caused 6% (95% CI 3–9%) more CNS adverse events than placebo . This could indicate a CNS effect of sumatriptan. Similarly, zolmitriptan 2.5 mg caused 9% (965 CI 4–14%) more CNS adverse events than placebo . The CNS adverse events of triptans can, however, be partly ascribed to migraine symptoms being unmasked by effective treatment since responders to eletriptan had more CNS AEs than non-responders to eletriptan . However, in one large RCT  any CNS adverse events were more frequent after sumatriptan 100 mg (29.6%) (n = 386) than after rizatriptan 10 mg (22.5%) (n = 385)  despite the fact that the two drugs were equipotent for headache relief after 2 h . In addition, rare cases of central nervous system AEs such as akathesia, acute dystonia and pathological laughter have been described after subcutaneous and oral sumatriptan used in the treatment of migraine and cluster headache [48–50].
That CNS adverse events can occur after triptans outside migraine attacks was shown in a placebo-controlled study in female healthy volunteers . The results showed that sumatriptan 50 mg and rizatriptan 10 mg caused small but clear effects on the CNS, mainly mild sedative effects, which were less than sedation after the active control drug, temazepam 20 mg . In addition, sumatriptan caused a significant increase in the EEG alpha power compared with placebo for the frontal leads, whereas this was not the case for rizatriptan . In another study it was shown that zolmitriptan 5 and 10 mg, but not sumatriptan 100 mg, had an effect on cortical auditory-evoked potential in man . In one placebo-controlled study in male subjects with a history of substance abuse subcutaneous sumatriptan 8 and 16 mg was psychoactive, was discriminated from placebo, produced a dose-related decrease on euphoria score and elevated scores on measures of apathic sedation and disliking . These studies demonstrate that normal therapeutic doses do exert a CNS effect in non-migrainous subjects.
In a recent positron emission tomographic (PET) study in six migraine patients, it was shown that subcutaneous sumatriptan 6 mg normalizes the migraine attack-related increase in brain serotonin synthesis , thus demonstrating convincingly that sumatriptan can exert an effect on the brain in migraineurs during an attack.
In a double-blind, placebo-controlled study in migraine patients, subcutaneous sumatriptan 6 mg caused an increase of the duration of the early exteroceptive suppression period of temporalis muscle activity both during the migraine attack and during the migraine interval , whereas there was no effect on contingent negative variation .
In another study on glyceryl trinitrate-induced migraine, during attacks there was an increase in slow rhythmic activity of the theta and delta range and a decrease of activity in the alpha and beta range . The abnormalities disappeared after a sumatriptan injection . One cannot exclude, however, that the effect of sumatriptan in this study is due to an effect on migraine per se.
In one study on obsessive–compulsive disorder (OCD) the sumatriptan treated subjects’ OCD symptoms worsening, as measured by The Yale Brown scale, was significant compared to placebo (p < 0.02) . In another study no such effect was observed .
Exercise capacity was decreased after subcutaneous sumatriptan 6 mg in one placebo-controlled study . The authors’ conclusion was that it could be a peripheral effect of the drug because “sumatriptan is a selective 5-HT (1B/1D) receptor agonist that does not cross the blood–brain barrier” . It was thus regarded as an established fact, based on [12, 13], that sumatriptan does not penetrate the BBB.
In one review it was concluded that the incidence of CNS adverse events is correlated (r = 0.68) to the lipophilic attributes of the triptans , whereas in two other reviews this was not the case [62, 63]. Re-analysing of the data from the first review  with the use of equipotent triptan doses sumatriptan 100 mg (instead of 50 mg) and eletriptan 40 mg (instead of 80 mg) shows, however, that there is no correlation (r = 0.324, p = 0.438, Spearman’s nonparametric test), as would be expected since the triptans are subjected to different efflux systems from the brain .
Overall, the triptans, apart from almotriptan 12.5 mg and the low dose of naratriptan, 2.5 mg , result in CNS adverse events with a relatively low incidence which indicates an effect on the CNS. These CNS adverse events of triptans, especially sleepiness/tiredness, can in some cases be a problem in the clinical use of the drugs, including sumatriptan .
Comments on the possible effects of sumatriptan inside the BBB
Are the doses of the different triptans used in these animal studies comparable? In one study investigating parenteral sumatriptan and zolmitriptan, it was stated that clinically comparable doses were used . Thus sumatriptan 85 μg/kg and zolmitriptan 30 μg/kg were used. There are RCTs with subcutaneous sumatriptan [64, 65], but none with parenteral zolmitriptan. Equipotency must therefore be judged from oral comparative RCTs. Based on one large comparative RCTs, zolmitriptan 5 mg is comparable with sumatriptan 100 mg . This is also the case in the well-known meta-analysis . Thus is seems reasonable to compare the systemic availability of these doses. Sumatriptan has an oral bioavailability of 14% [1, 3] and 100 mg thus results in sumatriptan 14 mg being available, whereas zolmitriptan 5 mg with an bioavailability of 39% [1, 3] results in zolmitriptan 1.95 mg being systemically available. The ratio between the systemically available doses is thus 7.2. In the animal study  of sumatriptan and zolmitriptan mentioned above, the dose ratio was 85/30 = 2.8. So either too little sumatriptan or too much zolmitriptan was used. The sumatriptan 85 μg/kg dose is near the subcutaneously used dose of 6 mg in man. So most likely a too high dose of zolmitriptan was used if the two drugs are equipotent.
The different results for sumatriptan in these animal models is most likely not a consequence of different doses of the drug used. Thus, in “negative” studies the dose range of sumatriptan was 85 μg/kg to 6 mg/kg, whereas in the “positive” studies the dose range was 100–1,000 μg/kg (Table 1). The results most likely depend on the animal model used. Whether an inhibitory CNS effect of sumatriptan is observed in an animal study is most likely the result of the ratio between stimulus used, electrical stimulation [5, 13] or inflammatory mediators [20, 21], and the inhibitory effect of sumatriptan. If the stimulus is very strong, such as superior sagittal stimulation (SSS), for 1 h in one study  and described in one study as a supramaximal stimulation  or trigeminal ganglion stimulation [13, 14] even “normal” levels of sumatriptan in the CNS are most likely unable to inhibit the response. In contrast, “more” physiological stimuli such as inflammatory mediators [21, 22] can probably be inhibited by “normal” levels of sumatriptan. It should be noted, however, that the more lipophilic triptans such as zolmitriptan , naratriptan , rizatriptan  and eletriptan  were effective in the SSS model without a breakdown of the BBB. This higher efficacy of these triptans than sumatriptan in this SSS model does not, however, result in increased effect of these triptans in the acute treatment of migraine [1, 2].
The presence of triptan binding sites and triptan receptor mRNA within the CNS leaves little doubt as to the potential for CNS effects of the triptans [67–69]. It is recognized that the triptan class of compounds do generally have poor penetration characteristics with brain/plasma partition coefficient (Kp,brain)  well below 1, when compared with typical CNS marketed drugs (e.g. diphenhydramine with a Kp,brain of 9) . The Kp,brain in P-glycoprotein-competent (mdrla +/+) mice were 0.13 (sumatriptan), 0.42 (naratriptan), 0.20 (rizatriptan),0.038 (zolmitriptan), and 0.30 (eletriptan) .
The extent of brain penetration is, however, a poor guide to central activity, especially with potent agonists such as the triptans, since they, in contrast to most other CNS agents that are antagonists, will require only low fractional receptor occupancy to exert central effects .
The original hypothesis when sumatriptan was developed was that the drug was a specific cranial vasoconstrictor [6, 7] and that it did not or only to a very minor extent penetrate across the BBB into the CNS [7, 19]. The best way to substantiate a hypothesis is to try to falsify it ad modum Popper . The intended falsifying experiment should have a suitable design and should be of high quality. In the present case the hypothesis was that sumatriptan cannot cross the BBB, and the falsifying experiment would be an investigation aimed at and demonstrating an effect in CNS of sumatriptan in an animal and if possible in man. Until 1996 the investigations failed to unequivocally falsify the hypothesis (Table 1). Thus in two studies [12, 13] the BBB had to be broken down by hyperosmolar mannitol before sumatriptan could exert an inhibitory effect in the trigeminal nucleus caudalis (TNC). There were two animal studies 1992  and 1993  which by the authors were interpreted as showing a peripheral inhibitory effect of sumatriptan on primary afferents of the trigeminovascular system but which, as mentioned above, could not exclude an inhibitory effect in the TNC . From 1996 on several high-quality animal studies, see Table 1, demonstrated a CNS effect of sumatriptan. In addition, it was shown that sumatriptan induced more CNS adverse events than placebo when used in the acute treatment of migraine . Among the studies, two investigations are the most convincing as falsifying experiments both in animals and man: in one study in rats sumatriptan blocked the induction of central sensitization after an inflammatory soup on dura most likely by presynaptic inhibition . In a recent PET investigation in six migraine patients during an actual attack, subcutaneous sumatriptan 6 mg normalizes the attack-related increase in brain serotonin synthesis .
There is a debate as to whether the anti-migraine action of triptans is solely through peripheral effects, cranial vasoconstriction [6, 7] and inhibition of release of neuropeptide from the trigeminovascular nerve endings, or whether antinociceptive activity within the brain stem is partly responsible .
Sumatriptan can most likely, in addition to a possible peripheral trigeminovascular effect, exert an effect in the brain stem when used for migraine treatment. The BBB is most likely intact during migraine attacks [22, 71] and there is therefore no need to consider a leakage of the BBB  for sumatriptan to exert a CNS effect in migraine.
Finally, it is noteworthy, that the increased activity during migraine attacks in the brain stem, as measured with PET [72, 73], still persisted after successful treatment of migraine attacks with subcutaneous sumatriptan. The drug was thus unable to “extinguish” the “migraine generator” and this is most likely the cause of headache recurrence after sumatriptan. This is likely also the case for other brain penetrating triptans with which recurrence also occurs [1, 2].
The study was supported by the Lundbeck Foundation via the Lundbeck Foundation Center for Neurovascular Signaling (LUCENS).
Conflict of interest
- Tfelt-Hansen P, De Vries P, Saxena PR (2000) Triptans in migraine. A comparative review of pharmacology, pharmacokinetics and efficacy. Drugs 60:1259–1287, 10.2165/00003495-200060060-00003, 1:CAS:528:DC%2BD3MXktFarsA%3D%3D, 11152011View ArticlePubMedGoogle Scholar
- Ferrari MD, Goadsby PJ, Roon KI, Lipton RB (2002) Triptans (serotonin, 5-HT1B/1D agonists) in migraine: detailed results and methods of a meta-analysis of 53 trials. Cephalalgia 22:633–658, 10.1046/j.1468-2982.2002.00404.x, 1:STN:280:DC%2BD38njtlehtw%3D%3D, 12383060View ArticlePubMedGoogle Scholar
- Saxena PR, Tfelt-Hansen P (2006) Triptans, 5HT1B/1D agonists in the acute treatment of migraine. In: Olesen J, Goadsby PJ, Ramadan NM, Tfelt-Hansen P, Welch KMA (eds) The headaches, 3rd edn. Lippincott Williams and Wilkins, Philadelphia, pp 469–503Google Scholar
- Tfelt-Hansen P (2008) Maximum effect of triptans in migraine? A comment. Cephalalgia 28:767–768, 10.1111/j.1468-2982.2007.01415.x, 1:STN:280:DC%2BD1cznvV2rsA%3D%3D, 18547214View ArticlePubMedGoogle Scholar
- Hoskin KL, Goadsby PJ (1998) Comparison of more and less lipophilic serotonin (5-HT 1B/1D) agonists in a model of trigeminovascular nociception in cat. Exp Neurol 150:45–51, 10.1006/exnr.1997.6749, 1:CAS:528:DyaK1cXitV2muro%3D, 9514827View ArticlePubMedGoogle Scholar
- Humphrey PP, Goadsby PJ (1994) The mode of action of sumatriptan is vascular? A debate. Cephalalgia 14:401–410, 10.1046/j.1468-2982.1994.1406401.x, 1:STN:280:DyaK2M3htFyiug%3D%3D, 7697699View ArticlePubMedGoogle Scholar
- Humphrey PPA, Feniuk W, Perren MJ, Beresford IJM, Skingle M, Whalley ET (1990) Serotonin and migraine. Ann N Y Acad Sci 600:587–598, 10.1111/j.1749-6632.1990.tb16912.x, 1:CAS:528:DyaK3MXks12gtbg%3D, 2252337View ArticlePubMedGoogle Scholar
- Buzzi MG, Moskowitz MA (1990) The antimigraine drug, sumatriptan (GR43175), selectively blocks neurogenic plasma extravasation from blood vessels in dura mater. Br J Pharmacol 99:202–206, 1:CAS:528:DyaK3cXptFOltw%3D%3D, 2158835PubMed CentralView ArticlePubMedGoogle Scholar
- Goadsby PJ, Charbit AR, Andreou AP, Akerman S, Holland PR (2009) Neurobiology of migraine. Neuroscience 161:327–341, 10.1016/j.neuroscience.2009.03.019, 1:CAS:528:DC%2BD1MXms1WjsLo%3D, 19303917View ArticlePubMedGoogle Scholar
- Goadsby PJ, Hoskin KL (1996) Inhibition of trigeminal neurons by intravenous administration of the serotonin (5HT)1B/1D receptor agonist zolmitriptan (311C90): are brain stem sites therapeutic target in migraine? Pain 67:355–359, 10.1016/0304-3959(96)03118-1, 1:CAS:528:DyaK28XnsVChsbk%3D, 8951929View ArticlePubMedGoogle Scholar
- Sleight AJ, Cervenka A, Peroutka SJ (1990) In vivo effects of sumatriptan (GR 43175) on extracellular levels of 5-HT in the guinea pig. Neuropharmacology 29:511–513, 10.1016/0028-3908(90)90061-U, 1:CAS:528:DyaK3cXksFansb0%3D, 2166920View ArticlePubMedGoogle Scholar
- Kaube H, Hoskin KL, Goadsby PJ (1993) Inhibition by sumatriptan of central trigeminal neurones only after blood–brain barrier disruption. Br J Pharmacol 109:788–792, 1:CAS:528:DyaK3sXltlWnsbw%3D, 8395298PubMed CentralView ArticlePubMedGoogle Scholar
- Shepheard SL, Williamson DJ, Williams J, Hill RG, Hargreaves RJ (1995) Comparison of the effects of sumatriptan and the NK1 antagonist CP-99, 994 on plasma extravasation in the dura mater and c-fos mRNA expression in the trigeminal nucleus caudalis of rats. Neuropharmacology 34:255–261, 10.1016/0028-3908(94)00153-J, 1:CAS:528:DyaK2MXlsFKrtb8%3D, 7630480View ArticlePubMedGoogle Scholar
- Knyihár-Csillik E, Tajti J, Samsam M, Sáry G, Slezák S, Vécsei L (1997) Effect of a serotonin agonist (sumatriptan) on the peptidergic innervation of the rat cerebral dura mater and on the expression of c-fos in the caudal trigeminal nucleus in an experimental migraine model. J Neurosci Res 48:449–464, 10.1002/(SICI)1097-4547(19970601)48:5<449::AID-JNR6>3.0.CO;2-E, 9185668View ArticlePubMedGoogle Scholar
- Goadsby PJ, Knight YE (1997) Direct evidence for central sites of action of zolmitriptan (311C90): an autoradiographic study in cat. Cephalalgia 17:153–158, 10.1046/j.1468-2982.1997.1703153.x, 1:STN:280:DyaK2szhtl2gtA%3D%3D, 9170337View ArticlePubMedGoogle Scholar
- Goadsby PJ, Knight Y (1997) Inhibition of trigeminal neurones after intravenous administration of naratriptan through an action at 5-hydroxytryptamine (5-HT (1B/1D) receptors. Br J Pharmacol 122:913–922, 10.1038/sj.bjp.0701456View ArticleGoogle Scholar
- Cumberbatch MJ, Hill RG, Hargreaves RJ (1997) Rizatriptan has central antinociceptive effects against durally evoked responses. Eur J Pharmacol 328:37–40, 10.1016/S0014-2999(97)83024-5, 1:CAS:528:DyaK2sXjsVKgsbg%3D, 9203565View ArticlePubMedGoogle Scholar
- Goadsby PJ, Hoskin KL (1999) Differential effects of low dose CP122, 288 and eletriptan on fos expression due to stimulation of the superior sagittal sinus in cat. Pain 82:15–22, 10.1016/S0304-3959(99)00025-1, 1:CAS:528:DyaK1MXksV2qur8%3D, 10422655View ArticlePubMedGoogle Scholar
- Dixon CM, Saynor DA, Andrew J, Oxford J, Bradbury A, Talbit MH (1993) Disposition of sumatriptan in laboratory animals and humans. Drug Metab Dispos 21:761–769, 1:CAS:528:DyaK2cXptg%3D%3D, 7902233PubMedGoogle Scholar
- Johnson DE, Rollema H, Schmidt AW, McHarg AD (2001) Serotonergic effects and extracellular brain levels of eletriptan, zolmitriptan and sumatriptan in rat brain. Eur J Pharmacol 425:203–210, 10.1016/S0014-2999(01)01151-7, 1:CAS:528:DC%2BD3MXmtV2ktr8%3D, 11513839View ArticlePubMedGoogle Scholar
- Levy D, Jakubowski M, Burstein R (2004) Disruption of communication between peripheral and central trigeminovascular neurons mediates the antimigraine action of 5-HT1B/1D receptor agonists. Proc Natl Acad Sci USA 101:4274–4279, 10.1073/pnas.0306147101, 1:CAS:528:DC%2BD2cXivFartLY%3D, 15016917PubMed CentralView ArticlePubMedGoogle Scholar
- Edelmayer RM, Vanderah TW, Majuta L, Zhang ET, Fioranvanti B, De Felice M et al (2009) Medullary pain facilitating neurons mediate allodynia in headache-related pain. Ann Neurol 65:184–193, 10.1002/ana.21537, 1:CAS:528:DC%2BD1MXktVynurc%3D, 19259966PubMed CentralView ArticlePubMedGoogle Scholar
- De Vries P, Villalon CM, Saxena PR (1999) Pharmacological aspects of experimental headache models in relation to acute antimigraine therapy. Eur J Pharmacol 375:61–74, 10.1016/S0014-2999(99)00197-1, 10443565View ArticlePubMedGoogle Scholar
- Skingle M, Birch PJ, Leighton GE, Humphrey PPA (1990) Lack of nociceptive activity of sumatriptan in rodents. Cephalalgia 10:207–212, 10.1046/j.1468-2982.1990.1005207.x, 1:STN:280:DyaK3M7gsFygsA%3D%3D, 2176936View ArticlePubMedGoogle Scholar
- Read SJ, Hirst WD, Upton N, Parssons AA (2001) Cortical spreading depression produces increased cGMP levels in cortex and brain stem that is inhibited by tonabersat (SB-220453) but not sumatriptan. Brain Res 891:69–77, 10.1016/S0006-8993(00)03191-7, 1:CAS:528:DC%2BD3MXnsVGhsw%3D%3D, 11164810View ArticlePubMedGoogle Scholar
- Pardutz A, Szatmári E, Vecsel L, Schoenen J (2004) Nitroglycerin-induced nNOS increase in rat trigeminal nucleus caudalis is inhibited by systemic administration of lysine acetylsalicylate but not of sumatriptan. Cephalalgia 24:439–445, 10.1111/j.1468-2982.2004.00699.x, 1:STN:280:DC%2BD2c3ls1yjtw%3D%3D, 15154853View ArticlePubMedGoogle Scholar
- Ingvardsen BK, Laursen H, Olsen UB, Hansen AJ (1997) Possible mechanism of c-fos expression in trigeminal nucleus caudalis following cortical spreading depression. Pain 72:407–415, 10.1016/S0304-3959(97)00069-9, 1:CAS:528:DyaK2sXlslersb0%3D, 9313281View ArticlePubMedGoogle Scholar
- Ghehardini C, Galeotti N, Figini M, Imperato A, Nicolodi M, Sicuteri F et al (1996) The central cholinergic system has a role in the antinociception induced in rodents and guinea pigs by the antimigraine drug sumatriptan. J Pharmacol Exp Ther 279:884–890Google Scholar
- Hoskin KL, Kaube H, Goadsby PJ (1996) Sumatriptan can inhibit trigeminal afferents by an exclusively neural mechanism. Brain 119:1419–1428, 10.1093/brain/119.5.1419, 8931567View ArticlePubMedGoogle Scholar
- Mitsikostas DD, Papadopoulou-Daifotis Z, Sfikakis A, Varonos D (1996) The effect of sumatriptan on brain monoamines in rats. Headache 36:29–31, 10.1046/j.1526-4610.1996.3601029.x, 1:STN:280:DyaK283nsVajuw%3D%3D, 8666533View ArticlePubMedGoogle Scholar
- Read SJ, Manning P, McNeil CJ, Hunter AJ, Parsons AA (1999) Effect of sumatriptan on nitric oxide and superperoxide balance during glyceryl trinitrate infusion in the rat. Implications for antimigraine mechanisms. Brain Res 847:1–8, 10.1016/S0006-8993(99)01985-X, 1:CAS:528:DyaK1MXntlentbg%3D, 10564729View ArticlePubMedGoogle Scholar
- Read SJ, Parsons AA (2000) Sumatriptan modifies cortical free radical release during cortical spreading depression. A novel antimigraine action for sumatriptan? Brain Res 870:44–53, 10.1016/S0006-8993(00)02400-8, 1:CAS:528:DC%2BD3cXktlKrsrY%3D, 10869500View ArticlePubMedGoogle Scholar
- Kayser V, Aubel B, Hamon M, Bourgoin S (2002) The antimigraine 5-HT1B/1D receptor agonists, sumatriptan, zolmitriptan and dihydroergotamine, attenuate pain-related behaviour in a rat model of trigeminal neuropathic pain. Br J Pharmacol 137:1287–1297, 10.1038/sj.bjp.0704979, 1:CAS:528:DC%2BD3sXktlWg, 12466238PubMed CentralView ArticlePubMedGoogle Scholar
- Dobson CF, Tohyama Y, Diksic M, Hamel E (2004) Effects of acute and chronic administration of anti-migraine drugs sumatriptan and zolmitriptan on serotonin synthesis in the rat brain. Cephalalgia 24:2–11, 10.1111/j.1468-2982.2004.00647.x, 1:STN:280:DC%2BD2c%2FhslSjsg%3D%3D, 14687006View ArticlePubMedGoogle Scholar
- Bates EA, Nikai T, Brennan KC, Fu Y-H, Charles AC, Basbaum AI et al (2009) Sumatriptan alleviates nitroglycerin induced mechanical and thermal allodynia in mice. Cephalalgia (in press)Google Scholar
- Nozaki K, Moskowitz MA, Boccalini P (1992) CP-93, 129, sumatriptan, dihydroergotamine block c-fos expression within rat trigeminal nucleus caudalis caused by chemical stimulation of the meninges. Br J Pharmacol 106:409–415, 1:CAS:528:DyaK38XksVSgsLs%3D, 1327382PubMed CentralView ArticlePubMedGoogle Scholar
- Moskowitz MA, Nozaki K, Kraig RP (1993) Neocortical spreading depression provokes the expression of C-fos protein-like immunoreactivity within trigeminal nucleus caudalis via trigeminovascular mechanisms. J Neurosci 13:1167–1177, 1:CAS:528:DyaK3sXhvVCisb0%3D, 8382735PubMed CentralPubMedGoogle Scholar
- Moskowitz MA, Kraig RP et al (1998) Comment on Invardesen et al, Pain 72 (1997) 407–415. Pain 76:265–266Google Scholar
- Millson DS, Tepper SJ, Rapoport AM (2000) Migraine pharmacotherapy with oral triptans: a rational approach to clinical management. Expert Opin Pharmacother 1:391–404, 10.1517/14656522.214.171.1241, 1:CAS:528:DC%2BD3cXit1Wlsbo%3D, 11249525View ArticlePubMedGoogle Scholar
- Evans DC, O’Connor D, Lake BG, Evers R, Allen C, Hargreaves R (2003) Eletriptan metabolism by human hepatic CYP450 enzymes and transport by human P-glycoprotein. Drug Metab Dispos 31:861–869, 10.1124/dmd.31.7.861, 1:CAS:528:DC%2BD3sXltFalu7Y%3D, 12814962View ArticlePubMedGoogle Scholar
- Kalvass JC, Maurer TS, Pollack GM (2007) Use of plasma and brain unbound fractions to assess the extent of brain distribution of 34 drugs: comparison of unbound concentration ratios to in vivo p-glycoprotein efflux ratios. Drug Metab Dispos 35:660–666, 10.1124/dmd.106.012294, 1:CAS:528:DC%2BD2sXktVOntb4%3D, 17237155View ArticlePubMedGoogle Scholar
- Pascual J, del Arco C, Romón T, del Olmo E, Castro E, Pazos A (1996) Autoradiographic distribution of [3H]sumatriptan-binding sites in post-mortem human brain. Cephalalgia 16:317–322, 10.1046/j.1468-2982.1996.1605317.x, 1:STN:280:DyaK2s%2FitlCjtA%3D%3D, 8869766View ArticlePubMedGoogle Scholar
- Castro ME, Pascual J, Romón T, del Arco C, del Olmo E, Pazos A (1997) Differential distribution of [3H]sumatriptan binding sites (5-HT1B, 5-HT1D and 5-HT1F) in the human brain: focus on brain stem and spinal cord. Neuropharmacology 36:535–542, 10.1016/S0028-3908(97)00061-0, 1:CAS:528:DyaK2sXktlShsrY%3D, 9225278View ArticlePubMedGoogle Scholar
- Gallagher RM, Kunkel R (2003) Migraine patient concerns affecting compliance: results from the NHF survey. Headache 43:36–43Google Scholar
- Goadsby PJ, Dodick D, Almas M, Diener H-C, Tfelt-Hansen P, Lipton RB, Parsson B (2007) Treatment emergent CNS symptoms following triptan therapy are part of the migraine attack. Cephalalgia 27:254–262, 10.1111/j.1468-2982.2007.01278.x, 1:STN:280:DC%2BD2s7otFKgtg%3D%3D, 17381558View ArticlePubMedGoogle Scholar
- Tfelt-Hansen P, Teall J, Rodriguez F, Giacovazzo M, Paz J, Malbecq W, Block GA, Reines SA, Visser WH, on behalf of the Rizatriptan 030 study Group (1998) Oral rizatriptan versus oral sumatriptan: a direct comparative study in the acute treatment of migraine. Headache 38:748–755, 10.1046/j.1526-4610.1998.3810748.x, 1:STN:280:DC%2BD3M3js1eiug%3D%3D, 11284463View ArticlePubMedGoogle Scholar
- Silberstein SD, Diener H-C, McCarrolll KA, Lines CR (2004) CNS effects of sumatriptan and rizatriptan. Cephalalgia 24:78–79, 10.1111/j.1468-2982.2004.t01-2-00610.x, 1:STN:280:DC%2BD2c%2FhslSisw%3D%3D, 14687019View ArticlePubMedGoogle Scholar
- Barbanti P, Fabbrini G, Berardelli A (2008) Acute pathological laughter induced by sumatriptan. Cephalalgia 28:92–93, 1:STN:280:DC%2BD2sjls1Krsw%3D%3D, 17868284PubMedGoogle Scholar
- Oterino A, Pascual J (1998) Sumatriptan-induced axial dystonia in a patient with cluster headache. Cephalalgia 18:360–361, 10.1046/j.1468-2982.1998.1806358-4.x, 1:STN:280:DyaK1cvgtVKqtg%3D%3D, 9731945View ArticlePubMedGoogle Scholar
- López-Alemany M, Ferrer-Tuset C, Bernácer-Alpera B (1997) Akathisia and acute dystonia induced by sumatriptan. J Neurol 244:131–133, 10.1007/s004150050062, 9120496View ArticlePubMedGoogle Scholar
- van der Post J, Schram MT, Schoemaker RC, Pieters MS, Fuseau E, Pereira A et al (2002) CNS effects of sumatriptan an rizatriptan in healthy female volunteers. Cephalalgia 22:271–281, 10.1046/j.1468-2982.2002.00344.x, 12100089View ArticlePubMedGoogle Scholar
- Proieletti-Cecchini P, Afra J, Schoenen J (1997) Intensity dependence of cortical auditory evoked potential as a surrogate marker of central nervous system serotonin transmission in man: demonstration of a central effect for the 5HT1B/1D agonist zolmitriptan (311C90, Zomig). Cephalalgia 17:849–854, 10.1046/j.1468-2982.1997.1708849.xView ArticleGoogle Scholar
- Sullivan JT, Preston KL, Testa MP, Busch M, Jasinski DR (1992) Psychoactivity and abuse potential of sumatriptan. Clin Pharmacol Ther 52:635–642, 1:STN:280:DyaK3s%2Fpt1Ghtg%3D%3D, 1333934View ArticlePubMedGoogle Scholar
- Sakai Y, Dobson C, Diksic M, Aubé M, Hamel E (2008) Sumatriptan normalizes the migraine attack-related increase in brain serotonin synthesis. Neurology 70:431–439, 10.1212/01.wnl.0000299095.65331.6f, 1:CAS:528:DC%2BD1cXhtFels7o%3D, 18250288View ArticlePubMedGoogle Scholar
- Göbel H, Krapat S, Dworschak M, Heuss D, Ensink FB, Soyka D (1994) Exteroceptive suppression of temporalis muscle activity during migraine attack and migraine interval before and after treatment with sumatriptan. Cephalalgia 14:143–148, 10.1046/j.1468-2982.1994.1402143.x, 8062353View ArticlePubMedGoogle Scholar
- Göbel H, Krapat S, Ensink FB, Soyka D (1993) Comparison of contingent negative variation between migraine interval and migraine attack before and after treatment with sumatriptan. Headache 33:570–572, 10.1111/j.1526-4610.1993.hed3310570.x, 8294198View ArticlePubMedGoogle Scholar
- Thomaides T, Tagaris S, Karageorgiou C (1996) EEG and topographic frequency analysis in migraine attack before and after sumatriptan infusion. Headache 36:111–114, 10.1046/j.1526-4610.1996.3602111.x, 1:STN:280:DyaK28zmt1Omuw%3D%3D, 8742685View ArticlePubMedGoogle Scholar
- Koran LM, Pallanti S, Quercioli L (2001) Sumatriptan, 5-HT(1D) receptors and obsessive-compulsive disorder. Eur J Neuropsychopharmacol 11:169–172, 10.1016/S0924-977X(01)00082-7, 1:CAS:528:DC%2BD3MXislGrsL0%3DView ArticleGoogle Scholar
- Pian KL, Westenberg HG, van Megen HJ, den Boer JA (1998) Sumatriptan (5-HT1D receptor agonists) does not exacerbate symptoms in obsessive compulsive disorder. Psychopharmacology (Berl) 140:365–370, 10.1007/s002130050777, 1:CAS:528:DyaK1MXitVOrtw%3D%3DView ArticleGoogle Scholar
- McCann GP, Cahill H, Knipe S, Muir DF, MacIntyre PD, Hillis WS (2000) Sumatriptan reduces exercise capacity in healthy males: a peripheral effect of 5-hydroxytryptamine agonism? Clin Sci (Lond) 98:643–648, 10.1042/CS19990249, 1:CAS:528:DC%2BD3cXltFOmt7s%3DView ArticleGoogle Scholar
- Dodick DW, Martin V (2004) Triptans and CNS-side effects: pharmacokinetic and metabolic mechanisms. Cephalalgia 24:417–424, 10.1111/j.1468-2982.2004.00694.x, 1:STN:280:DC%2BD2czhs12jtQ%3D%3D, 15154851View ArticlePubMedGoogle Scholar
- Fox AW (2000) Comparative tolerability of oral 5-HT1B/1D agonists. Headache 40:521–527, 10.1111/j.1526-4610.2000.00083.x, 1:STN:280:DC%2BD3M%2Fls1ahtQ%3D%3D, 10940090View ArticlePubMedGoogle Scholar
- Pascual J, Muñoz P (2005) Correlation between lipophilicity and triptan outcomes. Headache 45:3–6, 10.1111/j.1526-4610.2005.05003.x, 15663606View ArticlePubMedGoogle Scholar
- Cady RK, Wendt JK, Kirchner JR, Sargent JD, Rothrock JF, Skaggs H (1991) Treatment of acute treatment with subcutaneous sumatriptan. JAMA 265:2831–2835, 10.1001/jama.265.21.2831, 1:STN:280:DyaK3M3jsl2ntw%3D%3D, 1851894View ArticlePubMedGoogle Scholar
- Subcutaneous Sumatriptan International Study Group (1991) Treatment of migraine attacks with sumatriptan. N Eng J Med 325:316–321, 10.1056/NEJM199108013250504View ArticleGoogle Scholar
- Geraud G, Olesen J, Pfaffenrath V, Tfelt-Hansen P, Zupping R, Diener H-C, Sweet R, on behalf of the Study Group (2000) Comparison of the efficacy of zolmitriptan and sumatriptan: issues in migraine trial design. Cephalalgia 20:30–38, 10.1046/j.1468-2982.2000.00004.x, 1:STN:280:DC%2BD3c3nsFWntw%3D%3D, 10817444View ArticlePubMedGoogle Scholar
- Ahnn AH, Basbaum AI (2005) Where do triptans act in the treatment of migraine? Pain 115:1–4, 10.1016/j.pain.2005.03.008View ArticleGoogle Scholar
- Bonaventure P, Voorn P, Luyten WH, Leysen JE (1998) 5HT1B and 5HT1D receptor mRNA differential colocalization with peptide mRNA in the guinea pig trigeminal ganglion. Neuroreport 9:641–645, 10.1097/00001756-199803090-00015, 1:CAS:528:DyaK1cXitlCht7k%3D, 9559931View ArticlePubMedGoogle Scholar
- Lin H, Oksenberg D, Ashkanazi A, Peroutka S, Duncan A, Rozmahel R et al (1992) Characterization of the human 5-hydroxytryptamine1b receptor. J Biol Chem 267:5735–5738Google Scholar
- Popper K (1959) The logic of scientific discovery. Basic Books, New YorkGoogle Scholar
- Edvinsson L, Tfelt-Hansen P (2008) The blood–brain barrier in migraine treatment. Cephalalgia 28:1245–1258, 10.1111/j.1468-2982.2008.01675.x, 1:STN:280:DC%2BD1cjmslWnsQ%3D%3D, 18727638View ArticlePubMedGoogle Scholar
- Weiller C, May A, Limroth V, Jüpter M, Kaube H, Schayck RV et al (1995) Brain stem activation in spontaneous human migraine attacks. Nat Med 1:658–660, 10.1038/nm0795-658, 1:CAS:528:DyaK2MXms1Kgsbs%3D, 7585147View ArticlePubMedGoogle Scholar
- Afridi SK, Matharu MS, Lee L, Kaube H, Friston KJ, Frackowick RS et al (2005) A PET study exploring the laterality of brainstem activation in migraine using glyceryl trinitrate. Brain 128:932–939, 10.1093/brain/awh416, 1:STN:280:DC%2BD2M7lsV2jug%3D%3D, 15705611View ArticlePubMedGoogle Scholar