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

Abstract

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 ...

Where does a migraine attack originate? In the brainstem

“…The 5-HT 1F receptor is to be found in the trigeminal ganglion (mRNA) (Bouchelet et al 1996) and the TNC (mRNA and protein) (Bruinvels et al 1994;Waeber and Moskowitz 1995;Pascual et al 1996). 5-HT 1F receptor agonists successfully abort migraine attacks (Neeb et al 2010). The efficacy of 5-HT 1F agonists supports the .…”

“…The nociceptive second-order neurones in the TNC receive convergent synaptic input from the trigeminal innervated supratentorial dura mater, and from the cervical afferents of the C 2 spinal nerve, modulated by projections from the brainstem nuclei (PAG, NRM and LC) then convey the input to the thalamus. C 2 cervical 2 spinal nerve, DRG dorsal root ganglion, LC locus coeruleus, NRM nucleus raphe magnus, PAG periaqueductal grey matter, TRIG ganglion trigeminale, TNC trigeminal nucleus caudalis hypothesis that the TNC is one of the key elements in the pathomechanism of migraine (Neeb et al 2010). Functionally the second-order neurones are not merely single relays between the meningeal trigeminal central nerve terminal and the thalamus.…”

Identification of molecular genetic factors that influence migraine

“…Glutamate is believed to be required for CSD and to activate the TNS and central sensitization, thus inhibition of glutamate release culminates in an anti-nociceptive effect (Vikelis and Mitsikostas 2007;Neeb et al 2010). GRIA3 at Xq28 codes for 1 of 4 subunits for the AMPA receptor.…”

The pharmacological profile and clinical prospects of the oral 5-HT1F receptor agonist lasmiditan in the acute treatment of migraine

“…5-HT 1F receptor protein cannot be found on endothelial or smooth muscle cells of cerebral vessels, which leads to the conclusion that this serotonin receptor subtype is not involved in the regulation of the vascular tone in the human brain [Neeb et al 2010].…”