REFERAT MIGREN

PEMBIMBING : dr.H. Awaludin Noor Sp.S Oleh: Aga Haris S.Ked

LATAR BELAKANG :
90% penddk nyeri kepala/ th 9 dari 10 org/th 1 kali

NYERI KEPALA
mengganggu

aktivitas, produktiv. menghentikan keg.sehari-hari dampak sosial-ekonomi

Prevalensi tidak banyak, namun merugikan (AS, 13jt dolar)

MIGREN
Peny.neurologi yg kompleks

Vaskuler Neurovaskuler Sistem trigeminovaskuler

Pemahaman patof, teori blm jelas Tidak terdiagnosis, terapi kurang baik

CGRP

MASALAH
MIGREN : - Morbiditas sedikit dampak merugikan: - aktivitas terganggu - pe produktivitas pekerjaan/ sekolah (dampak sos-ek) - tdk terdx/ tx : - kurang dlm pemahaman patofisiologi - penyebab blm pasti - jrg yg periksa ke dokter - teori neurovaskuler: - sistem trigeminovaskuler pelepasanneuropeptida (CGRP)nyeri kepala migren?

PEMBAHASAN :
1.SEJARAH PERKEMBANGAN TEORI MIGREN:
Eber Papyrus (1200 SM) supranatural Hipocrates (400 SM) sesuatu dari perut menjalar ke kepala aura Gallen : hemikrania

Thomas Willis (1664) : migren ok dilatasi pemb.darah (I kali teori vasc.diajukan) tdp beberapa kelemahan

Edward Liveing (1873) : migren ok gangg. saraf di talamus (neurogenik)

Moebius (1898): disfungsi otak & PD.

DEFINISI :
MIGREN : Konsep klasik : gg. Fungs. otak dg manifest.nyeri kepala unilateral, bdenyut, mendadak disertai mual atau muntah (Marquardt et al.,2000). Lance (1998) : NK episodik, disertai mual, fotofobia, mgkn didahului aura cit Harsono,1999 Djoenaedi W (93): NK bulang, bdenyut, unilat, 2-72 jam, bebas nyeri ant. serangan dg gg.keprib,GIT, aura (Basjiruddin, 2004). Rapoport et al.,(2004) dokter umum : Migren: NK, intensitas sedang-berat, pola stabil, hilang timbul, kemampuan, normal 48 jam, perburukan (-), Sampai ada bukti bahwa itu bukan migren

The Research group on Migraine and Headache of the World Federation of Neurology: familial, serangan berulang, intensitas, frek,lama bervariasi. NK unilateral, disertai anoreksia, mual, muntah, bbrp diawali gejala neurologik, gangguan mood (Evan & Mathew, 1999)

Gambaran klinik

KRITERIA DIAGNOSTIK:
Klasifikasi formal

Fase prodromal/ premonitori F. serangan utama: aura & nyeri kepala F. postdromal ICHD th 2004: 1. MWO paling sering dijumpai 2. MWA 3. Childhood periodic syndromes that are commonly precursors of migraine 4. Retinal migraine 5. Complications of migraine 6. Probable migraine

Gambaran klinik:
Fase
Prodromal

karakteristik
Trigger 60% pend.migren Bbrp jam-hari

Gejala/ bukti penelitian

25%: Sensitif (mdh marah) Euforia, ngantuk, depresi,lapar, haus

Aura

30% pend.migren 5-20mnt (bakhir 60) Visual (V), sensorik (S), mtrk (M), g.btg otak, gg.bicara/afasia (A)

Thomsen (Denmark): 1881 sampel,72% ; 28% : VSMA : 70% pasien VS : 17% ; SMA : 7% SM : 4%; AM : 1%; VMA : 1% Nilai median memberatnya g/ aura: V 10(1-180); S 15(1-720); M 15(1-720); Nilai median lamanya aura: V 45 (1-1440) ; S 90 (10-2880) M 120 (10-4320); A 60 (5-1440)

Nyeri kepala

Onset unilat, bdenyut, Sedang Berat, aktiv. mbrt 4-72 j,Frek : 1-3 x/bln

postdromal

Lelah, iritabel, gg.mood, gg.konsentr, NT klt kpl.

Klasifikasi Formal (ICHD 2004):

Migren dengan aura
A. B. 1. Min.2 serangan yang sesuai kriteria B Min.3 dari 4 kriteris dibawah ini: Satu/ lebih gjl aura yg reversibel, mengarah ada kel.dikorteks serebri dan/ disf.otak Plg t tdp 1 gjl aura yg makin mbrt dlm 4 mnt, atau 2/ lbh gjl yg tjd bsamaan Aura < 60 menit NK tjd dlm wkt 60 mnt sth aura berakhir min.1 dari kriteria berikut: Ggn.NK sekunder (-), pd: p.neuro,fsk, r.peny. Pem.neuro, fsk, r.peny.mengarah NK sekunder, tp disimgkirkan oleh pem.yg teliti NK sekunder (+), tapi serangan migren yg pertama kali tdk bersamaan dengan timbulnya gangg.tersebut. A. B. C. 1. 2. 3.

Olesen et al., 2003)

Migren tanpa aura

Min. 5 serangan yg memenuhi kriteria B-D NK 4-72 jam (tidak membaik dengan tx) Karakter.NK plg tdk memenuhi 2 dibwh: Lokasi unilateral Nyeri berdenyut Intensitas sedang-brt (sedang: mengganggu aktiv.sehari-hari; berat: tdk dpt melaks.keg) Memberat bl jalan naik tangga/ aktiv.fisik Selama NK min.disertai: Mual dan atau muntah Fotofobi dan fonofobi Min.1 dari kriteria berikut: Ggn.NK sekunder (-),pd: p.neuro,fsk,r.peny. Pem.neuro, fsk, r.peny.mengarah NK sekunder, tp disimgkirkan oleh pem.yg teliti NK sekunder (+), tapi serangan migren yg pertama kali tdk bersamaan dengan timbulnya gangg.tersebut.

2. 3. 4. C. 1. 2.

4. D. 1. 2. E. 1. 2.

3.

3.

PREVALENSI KARAKTERISTIK NYERI KEPALA MIGREN MENURUT IHS

Migren tanpa aura Laki-laki (%) Wanita (%) N=197 N=145
Lokasi unilateral Memberat padaaktivitas fisik Nausea Vomiting Fotofobia Fonofobia 48,2 98,0 85,8 41,6 92,4 78,7 64,3 95,8 88,9 49,3 92,4 85,4

Migren dengan aura Laki-laki (%) Wanita (%) N=92 N=64

55,4 87,0 70,7 37,0 82,6 64,1 64,1 80,0 81,5 44,6 90,8 78,5

Sumber : Lipton et al., (2000)

TRIGGERS / PENCETUS MIGREN :

Bukti kuat pencetus migren Stres menstruasi caffeine withdrawal rangsang visual perubahan cuaca

Diduga pencetus migren nitrat perut kosong gangguan tidur alkohol monosodium glutamat

Sinclair, 1999; Lipton, 2000

PATOFISIOLOGI MIGREN :
A. FASE TRIGGER

Landy, 2003

B. FASE AURA:
CSD rCBF oligemia iskemik disfungsi neuronal aura

Olesen, 1991

C. FASE NYERI KEPALA :

DeVries et al., 1999

Lanjutan

MercMedicus Modules, 2001

CALCITONIN GENE-RELATED PEPTIDE (CGRP) :

1.Definisi dan karakteristik :

Kelomp.kalsit (5): kalsitonin, amilin,CGRP( dan ), adrenomedulin neuropeptida 37-asam amino hsl pengolahan/ penyambungan alternatif mRNA di kromosom 11 tdp 2 btk CGRP : : di sistem saraf sensorik : di sistem saraf enterik pertama kali ditemukan th 1983 (pd tikus) merupakan vasodilator poten.

CGRP

2. Molekuler genetik :

Ma, 2004

CGRP

3. Struktur CGRP dan hub. aktivitas

(Dikutip dari: Nimmagadda & Ghatta, 2004).

N-terminal loop (disulphide) memicu transduksi sinyal

dan aktivitas reseptor Struktur -helix interaksi molekul dg reseptor. Residu 19-27 daerah pengatur perlekatan dg reseptornya C-terminal memastikan interaksi yg sesuai dg reseptornya.
(Conner et al.,2002; Ma, 2004)

CGRP

4. DISTRIBUSI :

SUSUNAN

SARAF PERIFER: - Sel kornu post.ganglia sensorik - srg berhub.dg P.D. otot polos ( GIT, gld.parotis, sel endokrin duod, ileum, gangl.mienterik, paru, gld.tiroid, sinusoid dan vena lienalis, kulit manusia, kelj.pituitari.

KARDIOVASKULER: - Arteri > vena - Arteri: disambungan ant.T.adventisia dan T.media - atrium > ventrikel - otot jantung

RESEPTOR CGRP.

1. Klasifikasi :
CGRP1 dan CGRP2

2. struktur reseptor
CRLR RAMP(1,2,3) RCP: as.amino 148 + Prot.G

Transduksi sinyal

Department of Neurobiology & Anatomy Ian Dickerson's Lab

RESEPTOR CGRP.. 3. DISTRIBUSI DAN IKATAN ;

Afinitas tertinggi : serebelum dan medula spinalis diserebelum : - lap. Molekuler : CGRP densitas tinggi - lap. Purkinje : sedang - lap. Granuler : CGRP (-). Afinitas sedang- tinggi : korteks piriformis insula Af rendah-sedang : area preoptik medial. Di gangl.radiks dorsalis dan neuron lain CGRP bergab. dg reseptor lain sbg: Neurotransmiter dan neuromodulator

RESEPTOR CGRP.

4. MEKANISME TRANSDUKSI SINYAL :

Wimalawansa, 1996

Fungsi Fisiologis CGRP :

SISTEM SARAF

SISTEM PULMO

tersebar merata di jar. otak: sistem motorik & sensorik informasi auditorius Sist.trigeminovaskuler: letak resept=letak respt 5-HT

Degranulasi sel mast Vasodilatasi A-V pulmo,ok resept.tdp di endotel P.D pulmo -CGRP relaks. A.pulmo dilat.a.pulmo

Sistem kardiovaskuler

Fungsi lain

Kontrol tonus P.D perifer Vasorelaksasi kuat me kontraksi denyut jtg >> di jar perivask: dilat.mesenterium, ginjal, ot.skelet jlr endotel dependen/ indep Efek inotropik/ kronotopik positif

Sekresi hormon pertumb. Hipertermia Aktivitas motorik Respon nosiseptik Memodulasi Ach Tulang: hipokals, prolif.osteoklas, hbt resorpsi tlg intak mepermeab.mikrovask: hiperemia inflam, akumul. netrof, edema lokal Inflam neurogenik: kebocoran vaskuler

PERAN cgrp PADA NYERI KEPALA MIGREN:

A. CGRP dan MIGREN :

CGRP :
di prod.di ganglion saraf trigeminal

dilepas, sth terjadi aktivasi saraf vasodilator poten P.D.serebral dan dural punya peran ptg dlm pengaturan aliran drh ke otak dan meningen. P.D meningen vasodilat; sel mast :degranulasi inflam. steril nilai Normal : 2-35 pmol/L
Wimalawansa, 1996; Durham, 2004

TRIGGER / Pencetus Aktivasi btg otak/ migren generator CSD rCBF Oligemia iskemik Refleks vasodilatasi P.D.& anast.A-V vol.darah tiap denyut jtg

Dikutip dari: Olesen, 1991 Goadsby et al., 2002 Villalon et al., 2002 Durham, 2004

Aktivasi saraf trigeminal Pelepasan neuropeptida (CGRP)

rCBF <23ml ml Disfungsi neuronal (+) Aura (+)

rCBF >23ml ml Disfungsi neuronal (-) Aura (-)

pulsasi P.D Impuls nosiseptik talamus Nukl. saraf trigeminal yg lebih tinggi

meningen
p.darah Vasodilat. Sel mast

Pemb. Darah intraserebral

Degranulasi

Hipotalamus Foto/ fonofobia

CTZ korteks Nausea, vomiting

Inflamasi steril Vol.darah , Pengaliran cepat Vasodilatasi

NK migren

B. Penatalaksanaan farmakologis berdasarkan peran CGRP pada migren: Inhibisi pelepasan CGRP Antagonis reseptor CGRP
BIBN4096BS: Menghbt inflamasi neurogenik Menurunkan blood flow di P.D serebral Menghambat transmisi nyeri
(Durham, 2004).

Gol. Triptan:
(1) vasokonstriksi P.D arteri kranial dan anastomosis arteri-vena yang mengalami dilatasi melalui stimulasi reseptor 5-HT 1B (Villalon et
al., 2002)

1.

2.
3.

(2)

inhibisi pelepasan CGRP dan transmisi nosiseptif pada saraf sensorik trigeminal sentral dan perifer melalui reseptor 5-HT 1B/1D
(Bigal et al., 2002; Goadsby et al., 2002; Swidan, 2002; Tepper et al., 2002).

T A R G E T O B A T

RINGKASAN
Morbiditas rendah Dampak nyeri: - kualitas hdp - produktivitas kerja/ sklh

MIGREN
Klinis; sulit dx Pemahaman patof << penanganan krg Teori terbaru neurovaskuler sistem trigeminovaskuler pelepasan CGRP ke reseptor vasodilatasi, inflamasi neurogenik nyeri kepala migren

BIBN4096BS iv sbg antagonis reseptor CGRP efektif mengurangi NK migren, sbg obat alternatif gol.triptan

PREVALENSI MIGREN:

AstraZeneca Medicines (2005)

what do you do when you are in pain? You stop using that limb, which leads to decreased mobility and reduces your functional status. As you start to not do the things you used to do, there can be a loss of self-esteem and self-efficacy. You start to limit yourself, and this vicious cycle goes on and on. Another way that I like to try and describe it to clinicians is this: as an infant, you are born as this groping little thing trying to find your feet, putting everything into your mouth, getting sensory awareness. You then grow up as a member of a family; you get integrated into that family; you learn that you are not the only entity that exists. You develop into a mature adult and hopefully you become a viable, contributing member of your community and society. (Brennan, 2002)

Four Headache Questions that can help Diagnose Migraine

1. 2. Do you have headaches that interfere with work, social, or family functions? chronic, periodic, disabling headaches should be considered as migraine. Has your headache pattern been stable over the past six months? any headache pattern that changes over a six-month interval should be investigated as a possible secondary headache disorder. How frequently do you experience headaches? an increase in the frequency, intensity, and duration of headaches may indicate transformed migraine. Patients who at one time experienced an intermittent disabling headache and now suffer from near-daily headaches may be overusing symptomatic medications. The primary medical focus for these individuals should be headache prevention and avoidance of medication overuse. How effective is your current headache treatment? patients who successfully treat their headaches are rarely seen by physicians. Those who treat their headaches with symptomatic medication more than twice weekly may note that over time their analgesics become less effective. Headache education, lifestyle changes, and preventive medications are necessary to alleviate these headaches and restore normal daily function.

3.

4.

Unger et al, Emerg Med, 2003

Unger et al., 2003

Unger et al., 2003

The Calssification of Headache :

Characteristics of three common types of headaches

Secondary Headache Disorders :

Wagner, 2005

PATOGENESIS TENSION TYPE HEADACHE:

Schachter, 2004

Studies of Migraine Trigger Factors

From Headache, The Newsletter of ACHE. Spring 2002,

Menstrual migraine: terjadi 3 hr I fase mens estrogen + progesteron How so many different migraine triggers can produce such similar disabling headaches? A migraine trigger is any factor that can lead to the development of a migraine headache. How a specific trigger brings on a headache is becoming more clear, thanks to recent scientific studies on the subject. One leading theory suggests that migraine occurs because of an inherited hyperactivity of the nervous system. Individuals with migraine are genetically programmed to be more vulnerable to irritating stimuli such as flickering lights or sudden changes in weather. When one, two, or several of these irritating stimuli occur, their hyperactive nervous systems respond with a full-blown migraine attack.

Philip Bain, Wilkinson Medical Clinic

Diamond, www.Medscape.com

Diamond, www.Medscape.com

Falling Estrogen Theory Serotonin Theory

HO

CH3OH

Estrogen
+

Serotonin

Trigeminal Neuron

CGRP

Falling Estrogen Theory Serotonin Theory

HO

CH3OH

Menstruation
Serotonin

Estrogen

Serotonin

Trigeminal Neuron

CGRP, SP Pain & Inflammation

Vasodilation

One explanation for the onset of migraine when estrogen levels drop is that estrogen influences the serotonin receptors, which is believed to be an important part in headache pain. Other factors that may play a role in the development of menstrual migraine include: 1.the relative proportions of estrogen and progesterone; 2.dysfunction of platelets, a compenent of the blood which contains serotonin; 3.decreased levels of brain magnesium (which increases brain excitability); 4.decreased natural brain endorphines; and 5.increased secretion of prostaglandins (substances that sensitize pain receptors and cause inflammation around the cerebral blood vessels).

S E N S O R Y P A T H W A Y S

the trigeminal nucleus caudalis are the key relay neurons for nociceptive input in head and neck.

There is correlation between input from the trigeminal system and the cervical routes. So there are neurons in this complex that receive convergent input from the trigeminal cutaneous fibers, from the supratentorial dura, from the posterior routes in the deep musculature, or from the cutaneous dermatome served by the greater occipital nerve. It's sensitization of these neurons that have received convergent input that may result in the clinical syndromes of spread

Referred pain and perhaps hypersensitivity, central sensitization, and allodynia.

Goadsby et al., 2002

www.medscape.com

Trigeminal nerve activity during migraine and with the addition of a serotonin agonist. During a migraine, the trigeminal nerve releases CGRP, substance P, and neurokinin A, which are vasodilators. The addition of a serotonin agonist inhibits the release of these neuropeptides, inhibiting vasodilation and migraine pain

Trigeminal innervation of cranial structures. The ophthalmic division of the trigeminal nerve innervates meningeal, cerebral, and cranial vessels. It is the ophthalmic nerve that is thought to be responsible for the pain associated with migraines. The superior sagittal sinus runs between the meninges and is the primary vein draining the cranial vasculature

Algorithm for the symptomatic and prophylactic treatment of migraine headache (adapted from Capobianco13).

Rami Burstein uses a brush to check skin sensitivity.

www.ncbi.nlm.nih.gov/genemap

DNA to protein http://cellbio.utmb.edu/cellbio/ribosome.htm

Poly A site choice and alternative splicing produce either Calcitonin or CGRP (Calcitonin Gene Related Peptide) (hormones) in the calcitonin gene transcript from rats depending on tissue type:

Amino acid sequences of human and -CGRP

Endocrine Reviews; 1996

Endocrine Reviews; 1996

Endocrine Reviews; 1996

PENATALAKSANAAN MIGREN:

Terapi abortif

Terapi preventif

menghilangkan nyeri kepala serta gejala-gejala yang menyertai ketika serangan migren sedang berlangsung

(1)

(2)
(3)

mengurangi frekuensi, durasi, dan intensitas serangan; memperbaiki reaksi terhadap pengobatan akut; memperbaiki fungsi dan mengurangi disabilitas.

Silberstein, 2000; American Academy of Neurology

Obat
- asetaminofen - aspirin -Ergot (ergotamine tartrate, dihydroergotamine) -Opioid -triptans (sumatriptan, rizatriptan, zolmitriptan)

Mekanisme kerja

-steroid - beta bloker (propanolol, timolol) -Ca channel antagonis (nimodipin, flunarisin) -Antikonvulsan : - Asam divalproat - Gabapentin

Inhibisi sintesa prostaglandin di CNS, inhibisi aktifitas nosiseptif via reseptor 5HT - Inhibisi sintesa prostaglandin - Selektif arterial konstriktor yang kuat dan mempunyai daya ikat yang kuat pd otot dinding arteri - Stimulasi reseptor opioid endogen - Berikatan dengan reseptor 5HT1B, 5HT 1D, 5HT 1F, menginhibisi neuronal dengan cara blokade sensoris pada n. trigeminal, blokade pelepasan vasoaktif peptide dan juga proses inflamasi neurovaskuler di dura maupun meningen. - Anti inflamasi -Inhibisi pelepasan NE dg cara blokade prejunctional beta bloker reseptor, efek agonis pada 5HT1 reseptor, efek antagonis pada 5HT2 - Mempengaruhi Ca influks dalam mencegah vasokonstriksi dan pelepasan SP - Menambah kadar GABA di sinap, menghambat enzin GABA di otak, menambah konduktansi kalium yang memberi hiperpolarisasi neuronal, menghentikan letupan dari neuron 5HT dari nukleus raphe dorsalis. - Merubah aktivitas glutamic acid decarboxylase sehingga mampu meningkatkan GABA, menghambat pelepasan monoamin neurotransmiter (termasuk noradrenalin, dopamin dan serotonin)

Silberstein, 2001;Headache Council Philippne Neurological Association, 2000

Wagner, 2005

British Journal of Pharmacology (2000) 129, 420-423

(Olesen et al., 2004)

(Olesen et al., 2004)

(Olesen et al., 2004)

(Olesen et al., 2004)

Silberstein, 2000; American Academy of Neurology

Silberstein, 2000; American Academy of Neurology

Silberstein, 2000; American Academy of Neurology

Silberstein, 2000; American Academy of Neurology

Silberstein, 2000; American Academy of Neurology

Silberstein, 2000; American Academy of Neurology

Silberstein, 2000; American Academy of Neurology

Goadsby et al., 2002

Indications for Hospitalization When outpatient treatment has been unsuccessful, hospitalization may be necessary for: Severe dehydration, for which inpatient parenteral therapy may be necessary Diagnostic suspicion (confirmed by appropriate diagnostic testing) of organic etiology, such as: 1.infectious disorder involving the CNS (ie, brain abscess or meningitis) 2.acute vascular compromise (ie, aneurysm, subarachnoid hemorrhage) 3.structural disorder with accompanying symptoms (ie, brain tumor) Prolonged, unrelenting headache with associated symptoms, such as nausea and vomiting, which, if allowed to continue, would pose a further threat to the patient's welfare Status migraine, or dependence on analgesics, ergots, opiates, barbiturates, or tranquilizers Pain that is accompanied by serious adverse reactions or complications from therapy continued use of such therapy aggravates or induces further illness Pain that occurs in the presence of significant medical disease -- but appropriate treatment of headache symptoms aggravates or induces further illness Failed outpatient detoxification, for which inpatient pain and psychiatric management may be necessary Intractable and chronic cluster headache, for which inpatient administration of histamine or dihydroergotamine may be necessary Treatment requiring co-pharmacy with drugs that may cause a drug interaction, thus necessitating careful observation (monoamine oxidase inhibitors and blockers)
Drug Benefit Trends, 1999

Jenis migren
Typical aura with migraine headache

karakteristik
Migren dg aura spt tanda-tanda:

-aura visual :

(+):chy kilat, berkedip, bintik2/ garis2. (-) : gelap

-aura sensorik: (+) : spt ditusuk jarum, (-): parestesi Gradual > 5 mnt; < 1 jam, reversibel; diikuti NK yg memenuhi kriteria migren WO aura

Typical aura with nonmigraine headache

Familial hemiplegic migraine (FHM)

diikuti NK yg tidak memenuhi kriteria migren WO aura

-bersifat autosomal, dominan -Sergn.di t/ oleh NK jns migren dg foto/ fonopobia, N,V -Didahului/ disertai hemiparesis bbrp mnt-mgg, membaik tanpa g/ sisa. -Tjd sergn.awal masa kanak-kanak, atau < 30 th -20% keluarga dg FHM N,V, episodik, berulang, pucat, lethargi Nyeri di tengah abdomen, episodik, berulang, selama 1-72 jam, diikuti N,V, dg masa diantara serangan pasien dlm kead. Normal Sergn. Vertigo tiba2 saat interval anak sehat Multipel, tiba2, gangg.keseimb(+), nistagmus, muntah, Pem.Neuro(N), EEG (N)

Cyclical vomiting Abdominal migraine Benign paroxysmal vertigo of childhood

Chronic migraine Persistent aura without infarction Migrainous infarction Migraine-triggered seizure Probable migraine

NK migren t/ aura selama 15 hr/> per-bulan; selama 3 bln/ > tanpa ada tanda-tanda overdosis obat Gejala aura menetao selama > 1 minggu, tanpa ada kelainan infark pada rontgen Gjl aura 1 atau lebih sehubungan dg lesi iskemik otak sesuai dg teritori daerahnya pd pem. Imaging Timbulnya kejang yg dipicu oleh adanya aura migren

Serangan migren yg disertai/ tdk NK dimn tdk adanya salah satu gjl, shg tdk memenuhi kriteria migren yg sebenarnya; baik migren dg/ tanpa aura

Kaplan et.al., 1997

Kaplan et.al., 1997

Kaplan et.al .,1997

Serotonin Receptors
Class
5-HT1A
5-HT1B

Localization
Raphe nuclei Hippocampus
Cranial Blood Vessels

Synaptic Action
Inhibition ( K+)
Cerebral vasoconstriction

Signalling Mechanism
cAMP Direct K+ open
cAMP

5-HT1D

Cranial Blood Vessels

Autoreceptor-mediated 5- cAMP HT release

cAMP

5-HT1E/F Cortex Striatum

5-HT2A

Platelets Smooth Muscle Cerebral Cortex

Platelet aggregation Contraction Excitation ( K+)

IP3 production