Editing Triptan (section)

===Mechanism of action===
{{further|Discovery and development of triptans|Serotonin receptor agonist}}
Their action is attributed to their [[receptor agonist|agonist]]<ref name="Tepper">{{Cite journal 
| last1 = Tepper | first1 = S. J. 
| last2 = Rapoport | first2 = A. M. 
| last3 = Sheftell | first3 = F. D. 
| title = Mechanisms of action of the 5-HT1B/1D receptor agonists 
| journal = Archives of Neurology 
| volume = 59 
| issue = 7 
| pages = 1084–1088 
| year = 2002 
| pmid = 12117355
 | doi=10.1001/archneur.59.7.1084
| doi-access = free 
}}</ref> effects on [[serotonin]] [[5-HT1B receptor|5-HT<sub>1B</sub>]] and [[5-HT1D receptor|5-HT<sub>1D</sub> receptors]] in blood vessels (causing their [[vasoconstriction|constriction]]) and nerve endings in the brain, and subsequent inhibition of pro-inflammatory [[neuropeptide]] release, including [[CGRP]] and [[substance P]]. Triptans are [[Ligand (biochemistry)#Receptor.2Fligand binding affinity|selective]] agents for 5-HT<sub>1B</sub> and 5-HT<sub>1D</sub><ref name="Tepper" /> and have low or even no [[Ligand (biochemistry)#Receptor.2Fligand binding affinity|affinity]] for other types of 5-HT receptors.<ref name="Goodman">{{cite book|author=Brunton, L. |author2=Lazo, J. |author3=Parker, K. |year=2006|title=Goodman & Gilman's The Pharmacological Basis of Therapeutics|edition=11th|publisher=McGraw-Hill Education|pages=305–308}}</ref>

5-HT receptors are classified into seven different families named 5-HT<sub>1</sub> to 5-HT<sub>7</sub>. All receptors are [[G protein coupled receptors]] with seven transmembrane domains with the one exception of  5-HT<sub>3</sub> receptor which is a [[ligand gated ion channel]]. There is a high [[homology (biology)|homology]] in the amino acid sequence within each family. Each family couples to the same [[second messenger systems]]. Subtypes of 5-HT<sub>1</sub> are the 5-HT<sub>1A</sub>, 5-HT<sub>1B</sub>, 5-HT<sub>1D</sub>, 5-HT<sub>1E</sub> and 5-HT<sub>1F</sub> receptors. All 5-HT<sub>1D</sub> receptors are coupled to inhibition of [[adenylate cyclase]]. 5-HT<sub>1B</sub> and 5-HT<sub>1D</sub> receptors have been difficult to distinguish on a pharmacological basis. After cloning two distinct genes for 5-HT<sub>1B</sub> and 5-HT<sub>1D</sub> receptors, a better insight into distribution and expression in different tissues was gained, except in brain tissue where they are overlapping in several areas.<ref name="Hamel, E. 1999">{{cite journal|author=Hamel, E.|year=1999|title=The biology of serotonin receptors: focus on migraine pathophysiology and treatment|journal=Can J Neurol Sci|at=26 Suppl 3:S2–6|pmid=10563226|volume=26 Suppl 3|issue=3|doi=10.1017/s0317167100000123|doi-access=free}}</ref>

{{Technical|section|date=October 2016}}

Most [[mammalian]] species, including humans, have 5-HT<sub>1D</sub> binding sites widely distributed throughout the [[central nervous system]]. 5-HT<sub>1D</sub> receptors are found in all areas of the brain but they differ in quantity at each area.<ref name="Lowther">{{cite journal|title=The distribution of 5HT<sub>1D</sub> and 5HT<sub>1E</sub> binding sites in human brain|author=Lowther, S.|journal=Eur J Pharmacol|year=1992|volume=222|issue=1|pages=137–42|pmid=1468490|doi=10.1016/0014-2999(92)90473-h}}</ref>
An important initiator of head pain is suggested to be the activation of [[trigeminovascular]] [[Afferent nerve fiber|afferent]] nerves which upon activation releases neuropeptides such as CGRP, substance P and [[neurokinin A]]. Also they are thought to promote neurogenic inflammatory response important for sensitization of [[sensory neuron|sensory]] afferents, and also transmission and generation of head pain centrally. 5-HT<sub>1D</sub> has been found responsible for inhibition of neurogenic inflammation upon administration with sumatriptan and other related compounds that act on prejunctional 5-HT<sub>1D</sub> receptors.<ref name="Hamel, E. 1999" />

All triptans, like the older drug [[dihydroergotamine]], have agonistic effects on the 5-HT<sub>1D</sub> receptor. Comparison of sumatriptan and dihydroergotamine showed that dihydroergotamine has high affinity and sumatriptan has medium affinity for 5-HT<sub>1D</sub>.<ref name="Tepper" />  Triptans have at least three modes of action. These antimigraine mechanisms are:

# [[vasoconstriction]] of pain producing intra cranial extracerebral vessels by a direct effect on vascular smooth muscle. Sumatriptan and rizatriptan have been shown to cause vasoconstriction in the human [[middle meningeal arteries]].
# inhibition of vasoactive neuropeptide release by trigeminal terminals innervating intracranial vessels and the dura mater. The trigeminocervical complex has 5-HT<sub>1D</sub> receptors that bind dihydroergotamine and triptans in humans. Rizatriptan has been shown to block dural vasodilation and plasma protein extravasation by inhibiting the release of CGRP via activation of receptors on preganglionic trigeminal sensory nerver terminals. Sumatriptan is shown to inhibit potassium stimulated CGRP secretion from cultured trigeminal neurons in a dose dependant manner and may also inhibit the release of substance P.
# inhibition of [[nociceptive]] [[neurotransmission]] within the trigeminocervical complex in the [[brainstem]] and upper cervical spinal column. Rizatriptan has central trigeminal antinociceptive activity.
Other possibilities of triptans in antimigraine effects are modulation of [[nitric oxide]] dependent [[signal transduction pathways]], nitric oxide scavenging in the brain, and sodium dependent cell metabolic activity.<ref>{{cite journal | last1 = Goadsby | first1 = P. J. | year = 1998 | title = Serotonin 5HT<sub>1B/1D</sub> receptor agonists in migraine - Comparative pharmacology and its therapeutic implications | journal = CNS Drugs | volume = 10 | issue = 4| pages = 271–286 | doi = 10.2165/00023210-199810040-00005 | s2cid = 68150076 }}</ref><ref name="Tepper" />