No contractile effect for 5‐HT<sub>1D</sub> and 5‐HT<sub>1F</sub> receptor agonists in human and bovine cerebral arteries: similarity with human coronary artery

Bouchelet, Isabelle; Case, Bruce W.; Olivier, André; Hamel, Edith

doi:10.1038/sj.bjp.0703081

Cited by 95 publications

(70 citation statements)

References 45 publications

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“…60,61 The 5-HT 1F mRNA receptor could only be detected in a very low amount in human coronary arteries. 33 The mRNA of all three receptors has been detected in the saphenous vein of the rabbit. 61,62 Although sumatriptan, zolmitriptan, rizatriptan, and naratriptan contracted the saphenous vein of the rabbit, no contraction could be achieved with high doses of the 5-HT 1F receptor agonist LY344864.…”

Section: -Ht 1f Receptor Agonists and Vascular Propertiesmentioning

confidence: 99%

“…8,32 Pharmacological activation of 5-HT 1F receptors through selective agonists does not lead to vasoconstriction of cerebral arteries. 26,33 Moreover, no vasoconstrictive activity of 5-HT 1F receptor agonists could be observed in peripheral arteries. 25,34,35 In conclusion, the 5-HT 1F receptor is very unlikely to be involved in the regulation of the vascular tone in the human brain.…”

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confidence: 99%

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5-HT1F Receptor Agonists: A New Treatment Option for Migraine Attacks?

2010

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Summary:Migraine is a debilitating disorder of the CNS. Although therapeutic options for migraine attacks have tremendously advanced with the development of triptans more than a decade ago, several conditions (such as vascular disease) restrict their use. Moreover, some patients do not respond to triptans and other currently available medications. Therefore, treatment alternatives are needed. Study data show that 5-HT 1F receptor agonists successfully abort migraine attacks. These data also suggest a favorable vascular side-effect profile of these substances, which could be beneficial for migraine treatment in subjects with cardiac or vascular disease. We discuss the current knowledge of 5-HT 1F receptor-mediated effects, in part by comparing them to triptans, and we also summarize data from basic research and clinical trials. Key Words: 5-HT 1F , serotonin receptor, migraine, treatment, triptans. CURRENT TREATMENT OPTIONSMigraine attacks can be treated effectively with nonsteroidal anti-inflammatory drugs, pain killers, the first generation triptan (sumatriptan), and newer triptans such as rizatriptan or almotriptan. To date, these 5-HT 1B/1D agonists represent the gold standard for the treatment of migraine attacks. A meta-analysis showed that 59% of all patients achieve a headache response with 100 mg sumatriptan orally. Approximately 29% of subjects are pain-free after 2 h, and 20% of subjects show sustained pain freedom (pain-free by 2 h after dosing and no headache recurrence or use of rescue medication through 24 h). With some of the newer triptans, higher success rates of as much as 40% for the 2 h pain-free endpoint can be seen.1 Despite the good efficacy of triptans, it has been estimated that approximately 25% of all migraine patients do not respond to triptan treatment, even when the drug is used correctly (i.e, according to prescribed dose, time, and route of administration).2 The reasons for treatment failure remain obscure.Triptans are supposed to have three important mechanisms of action: 1) vasoconstriction, 2) inhibition of neuropeptide release, and 3) inhibition of signal transmission to second order neurons within the trigeminal nucleus complex. 3 The inhibition of calcitonin generelated peptide and substance P release attenuates peripheral consequences of trigeminal stimulation (e.g., neurogenic inflammation) and also central pain transmission. However, it is still an unsolved question as to whether neuronal or vascular or both mechanisms are responsible for the anti-migraine effect of these compounds. 5-HT 1 RECEPTORS AND MIGRAINETriptans exert their function mainly through binding at the 5-HT 1B and 5-HT 1D receptor. The 5-HT 1B receptor can be found on smooth muscle cells in cerebral and coronary vessels, and this receptor mediates triptan induced vasoconstriction.4 -8 Experimentally, various isolated blood vessels from several species contract in response to triptans. The vascular effects of 5-HT 1B/1D agonists are more pronounced in cranial vessels than in peripheral arteries, probably ...

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Section: -Ht 1f Receptor Agonists and Vascular Propertiesmentioning

confidence: 99%

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confidence: 99%

5-HT1F Receptor Agonists: A New Treatment Option for Migraine Attacks?

2010

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“…Since vascular side effects of triptans are presumed to be mediated by 5-HT 1B receptors, a non-vascular drug with an improved therapeutic index may be discovered by targeting neuronal 5-HT 1D and 5-HT 1F receptor subtypes. In fact, studies on human cerebral arteries demonstrated that the triptan-induced contraction in brain vessels is mediated exclusively by the 5-HT 1B receptor, which is also present in a majority of human coronary arteries [4]. Selective 5-HT 1D and 5-HT 1F agonists may represent new drugs devoid of cerebrovascular and cardiovascular effects, thus offering a safer strategy for the treatment of migraine.…”

Section: Triptansmentioning

confidence: 99%

“…Binding sites for 5-HT 1F have been widely identified in the human brain, in particular at the higher brain centers involved in pain perception [8]. The 5-HT 1F receptor agonists block dural plasma extravasation in guinea pig without significant contraction activity on human cerebral and coronary vascular beds [4].…”

Section: Triptansmentioning

confidence: 99%

Seeking the best care for acute migraine

Fanciullacci

2002

J Headache Pain

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In recent years, we have seen exciting advances in the knowledge of mechanisms that underlie migraine. These have thus promoted investigations into new drugs for the management of acute migraine. The major goal in migraine research is to identify and study non-vascular targets for migraine therapy. The 5-HT 1F neuronal receptor is apparently not involved in the vascular effects of triptans. Clinical evaluation of LY33470, a potent agonist of 5-HT 1F receptors, has demonstrated that the drug is effective in ending a migraine attack. These results suggest that 5-HT 1F receptor agonists may represent new antimigraine drugs without cerebrovascular or cardiovascular effects. From the plasma extravasation model of migraine, potential therapeutic targets were identified, although in testing no effects were observed: endothelin and substance P antagonists and the specific serotonin agonist CP 122,288, potent inhibitors of neurogenic inflammation, were ineffective in the treatment of a migraine attack. Since a causative role of CGRP in migraine has been postulated, novel antimigraine drugs include CGRP antagonists. Molecules with highly selective antagonistic action on human CGRP receptors of cerebral circulation have been discovered. These CGRP antagonists are in preclinical and clinical trials and the results are awaited with great interest. In addition, a small pilot study found civamide, a capsaicin derivative which causes CGRP depletion from trigeminal sensory fibers, to be effective in the migraine attack. Both NMDA and non-NMDA receptors for glutamate and related excitatory aminoacids are found on trigeminal neurons; therefore excitatory aminoacid receptor antagonists may provide therapeutic action in migraine. Recently, a glutamate receptor antagonist (LY293558) that had not shown vascular effects in animal models demonstrated an antimigraine effect. More specific compounds are also warranted in confirming nitric oxide inhibition as a therapeutic approach in migraine. Thus, it is likely that in the near future emerging therapies will increasingly meet patients' and physicians' goals.

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“…A number of isolated blood vessels from several species contracts in response to triptans, but the contractile effect is more marked on cranial vessels. There is ample evidence that this effect is mediated by the 5-HT 1B receptor and not by 5-HT 1D or 5-ht 1F receptors [14][15][16].…”

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confidence: 99%