Pharmacological aspects of experimental headache models in relation to acute antimigraine therapy

doi:10.1016/S0014-2999(99)00197-1

European Journal of Pharmacology

Volume 375, Issues 1–3, 30 June 1999, Pages 61-74

https://doi.org/10.1016/S0014-2999(99)00197-1 Get rights and content

Abstract

The last decade has witnessed a tremendous progress in the acute therapy of migraine, with sumatriptan, belonging to a new class of drugs, now known as 5-HT_1B/1D/1F receptor agonists, leading the way. The undoubted success of sumatriptan stimulated the development of new triptans as well as other suitable pharmacological tools and experimental models to probe into complex migraine mechanisms. In this review, we discuss the main experimental models for migraine, against the background of the disease pathophysiology and 5-HT receptors considered most important for migraine therapy. We believe that the use of these migraine models will provide even better treatment for migraine patients in the next millennium.

Introduction

Migraine is a syndrome that affects a substantial fraction of world's population, with a higher prevalence in females (15–18%) than in males (6%; Lipton and Stewart, 1997). Migraine is characterised by attacks of intense, pulsatile and throbbing headache, which is typically unilateral and is accompanied by anorexia, nausea, vomiting and photo- and/or phonophobia. In about one third of patients, the headache is preceded by aura symptoms, consisting of certain sensory (pins and needle feeling or numbness), motor (weakness or paralysis) and/or focal neurological (characteristically a homonymous, spreading, scintillating scotoma) symptoms (migraine with aura). The majority of patients, however, do not present with such symptoms (migraine without aura) (for review, see Ferrari, 1998).

In the last decade there has been a tremendous progress in the acute therapy of migraine, with sumatriptan belonging to a new class of drugs, now known as 5-HT_1B/1D/1F receptor agonists, providing the lead (Humphrey et al., 1988, Humphrey et al., 1990; The Subcutaneous Sumatriptan International Study Group, 1991). This seminal discovery by Humphrey and colleagues was based on the findings that a novel 5-HT (now 5-HT_1B; see below) receptor mediates selective carotid vasoconstriction, which is also observed following small doses of the well-known antimigraine drug ergotamine (Saxena, 1972; Saxena and De Vlaam-Schluter, 1974). The success of sumatriptan in migraine therapy undoubtedly resulted in heightened research interest in the field of migraine. This, in turn, led to a better understanding of the pathophysiological processes involved in migraine as well as the development of new triptans (for reviews, see Ferrari, 1998; Goadsby, 1998; De Vries et al., 1999a) and other prospective drugs (Fig. 1). This review is devoted to the pharmacological aspects of experimental migraine models recently employed in the development of acutely acting antimigraine drugs. To provide relevant background, the pathophysiology of migraine and 5-HT₁ receptor subtypes that are important in relation to antimigraine potential will also be discussed briefly.

Section snippets

Migraine pathophysiology

Based on the clinical features of migraine, three distinct phases can be discerned: an initiating trigger, an aura and, finally, the headache. Although limited information is available about the trigger phase, there is indeed now a better understanding of the pathophysiology of migraine (e.g., Goadsby, 1997; Ferrari, 1998). Some results indicate that the initiating trigger, involving the brainstem as `migraine generator' (Weiller et al., 1995), may be linked to a `familial' channelopathy (

5-HT₁ receptor subtypes relevant to migraine

At the time of its introduction, sumatriptan was regarded as a selective 5-HT₁-like receptor agonist (Humphrey et al., 1988, Humphrey et al., 1990). Indeed, sumatriptan-induced vasoconstrictor as well as the prejunctional neuronal inhibitory actions clearly exhibited the pharmacological profile of 5-HT₁-like receptors, which from the very outset were considered heterogeneous (Bradley et al., 1986; Hoyer et al., 1994). As recently argued (Saxena et al., 1998), the term `5-HT₁-like receptor' is

Models based on the involvement of cranial vasodilatation in migraine

These models are based on the view that cranial extracerebral vasodilatation is an integral part of the pathophysiology of migraine and that the ergot alkaloids and sumatriptan, which do not readily cross the blood–brain-barrier, owe their therapeutic efficacy primarily to constriction of dilated vessels (Saxena and Ferrari, 1989; Humphrey and Feniuk, 1991; Ferrari and Saxena, 1993). There are several ways to investigate the effects of antimigraine drugs on cranial blood vessels, both in vitro

Conclusions

The seminal discovery of sumatriptan led to the development of new triptans and selective ligands for 5-HT_1B, 5-HT_1D and 5-HT_1F receptors as well as a better understanding of the disease pathophysiology and a growing number of experimental models for migraine. These experimental models aim at achieving drugs that (i) counteract continued cranial extracerebral vasodilatation either by vasoconstriction or by decreasing neuropeptide release at neurovascular synapse; (ii) inhibit impulse

References (142)

W.A Bax et al.
5-HT receptors mediating contractions of the isolated human coronary artery
Eur. J. Pharmacol.
(1993)
M.S Beer et al.
Pharmacological characterisation of a cloned dog 5-HT_1B receptor cell line
Eur. J. Pharmacol.
(1998)
P.B Bradley et al.
Proposals for the classification and nomenclature of functional receptors for 5-hydroxytryptamine
Neuropharmacology
(1986)
P Brändli et al.
Role of endothelin in mediating neurogenic plasma extravasation in rat dura mater
Pain
(1996)
W.N Chan et al.
Identification of (−)-cis-6-acetyl-4S-(3-chloro-4-fluoro-benzoylamino)-3,4-dihydro-2,2-dimethyl-2H-benzo[b]pyran-3S-ol as a potential antimigraine agent
Bioorg. Med. Chem. Lett.
(1999)
H.E Connor et al.
5-Hydroxytryptamine contracts human coronary arteries predominantly via 5-HT₂ receptor activation
Eur. J. Pharmacol.
(1989)
M.J Cumberbatch et al.
Rizatriptan has central antinociceptive effects against durally evoked responses
Eur. J. Pharmacol.
(1997)
M.J Cumberbatch et al.
The effects of 5-HT_1A, 5-HT_1B and 5-HT_1D receptor agonists on trigeminal nociceptive neurotransmission in anaesthetized rats
Eur. J. Pharmacol.
(1998)
P De Vries et al.
The canine external carotid vasoconstrictor 5-HT₁ receptor: blockade by 5-HT_1B (SB224289), but not by 5-HT_1D (BRL15572) receptor antagonists
Eur. J. Pharmacol.
(1998)
R.M Eglen et al.
The 5-HT₇ receptor: orphan found
Trends Pharmacol. Sci.
(1997)

K.J Escott et al.

The modulation of the increase in rat facial skin blood flow observed after trigeminal ganglion stimulation

Eur. J. Pharmacol.

(1995)

K.J Escott et al.

Trigeminal ganglion stimulation increases facial skin blood flow in the rat: a major role for calcitonin gene-related peptide

Brain Res.

(1995)

M.D Ferrari

Migraine

Lancet

(1998)

M.D Ferrari et al.

Clinical and experimental effects of sumatriptan in humans

Trends Pharmacol. Sci.

(1993)

L Friberg et al.

Migraine pain associated with middle cerebral artery dilatation: reversal by sumatriptan

Lancet

(1991)

P.J Goadsby

Inhibition of calcitonin gene-related peptide by h-CGRP(8-37) antagonizes the cerebral dilator response from nasociliary nerve stimulation in the cat

Neurosci. Lett.

(1993)

P.J Goadsby

Current concepts of the pathophysiology of migraine

Neurol. Clin.

(1997)

P.J Goadsby et al.

Extracranial vasodilation mediated by vasoactive intestinal polypeptide (VIP)

Brain Res.

(1985)

P.J Goadsby et al.

Inhibition of trigeminal neurons by intravenous administration of the serotonin (5HT)_1B/D receptor agonist zolmitriptan (311C90): are brain stem sites therapeutic target in migraine?

Pain

(1996)

P.J Goadsby et al.

Stimulation of the trigeminal ganglion increases flow in the extracerebral but not the cerebral circulation of the monkey

Brain Res.

(1986)

P.J Goadsby et al.

Stimulation of an intracranial trigeminally-innervated structure selectively increases cerebral blood flow

Brain Res.

(1997)

P.J Goadsby et al.

Substance P blockade with the potent and centrally acting antagonist GR205171 does not effect central trigeminal activity with superior sagittal sinus stimulation

Neuroscience

(1998)

P Gupta et al.

Characterisation of the contractile activity of elebriptan at the canine vascular 5-HT_1B receptor

Eur. J. Pharmacol.

(1999)

J.J Hagan et al.

Stimulation of 5-HT_1B receptors causes hypothermia in the guinea pig

Eur. J. Pharmacol.

(1997)

P.R Hartig et al.

Alignment of receptor nomenclature with the human genome: classification of 5-HT_1B and 5-HT_1D receptor subtypes

Trends Pharmacol. Sci.

(1996)

P.P.A Humphrey et al.

Mode of action of the anti-migraine drug sumatriptan

Trends Pharmacol. Sci.

(1991)

G Lambert et al.

Effect of antimigraine drugs on dural blood flows and resistances and the responses to trigeminal stimulation

Eur. J. Pharmacol.

(1996)

R.B Lipton et al.

Prevalence and impact of migraine

Neurol. Clin.

(1997)

S.J MacLennan et al.

Cranial vascular effects of zolmitriptan, a centrally active 5-HT_1B/1D receptor partial agonist for the acute treatment of migraine

Eur. J. Pharmacol.

(1998)

A May et al.

Endothelin antagonist bosentan blocks neurogenic inflammation, but is not effective in aborting migraine attacks

Pain

(1996)

R.B McCall

Trigeminal ganglion elicited increases in nucleus trigeminal caudalis blood flow: a novel migraine model

Brain Res.

(1997)

A Mills et al.

[ $^{3} H$ ]311C90 binding sites in cat brain stem: implications for migraine treatment

Cephalalgia

(1995)

M.A Moskowitz

Neurogenic versus vascular mechanisms of sumatriptan and ergot alkaloids in migraine

Trends Pharmacol. Sci.

(1992)

J Olesen et al.

Nitric oxide is a key molecule in migraine and other vascular headaches

Trends Pharmacol. Sci.

(1994)

R.A Ophoff et al.

Familial hemiplegic migraine and episodic ataxia type-2 are caused by mutations in the Ca²⁺ channel gene CACNL1A4

Cell

(1996)

C.T O'Shaughnessy et al.

Investigation of the role of tachykinin NK1, NK2 receptors and CGRP receptors in neurogenic plasma protein extravasation in dura mater

Eur. J. Pharmacol.

(1994)

L.A Phebus et al.

Characterization of LY344864 as a pharmacological tool to study 5-HT_1F receptors: binding affinities, brain penetration and activity in the neurogenic dural inflammation model of migraine

Life Sci.

(1997)

N Adham et al.

The rat 5-hydroxytryptamine_1B receptor is the species homologue of the human 5-hydroxytryptamine_1Dβ receptor

Mol. Pharmacol.

(1992)

N Adham et al.

Cloning of another human serotonin receptor (5-HT_1F): a fifth 5-HT₁ receptor subtype coupled to the inhibition of adenylate cyclase

Proc. Natl. Acad. Sci. USA

(1993)

J.A Bard et al.

Differences in ligand binding profiles between cloned rabbit and human 5-HT_1Dα and 5-HT_1Dβ receptors: ketanserin and methiothepin distinguish rabbit 5-HT_1D receptor subtypes

Naunyn-Schmiedeberg's Arch. Pharmacol.

(1996)

D.T Beattie et al.

The influence of the trigeminal ganglion on carotid blood flow in anaesthetized guinea-pigs

Br. J. Pharmacol.

(1994)

J Bou et al.

Pharmacological profile of almotriptan, a novel antimigraine agent

Cephalalgia

(1997)

I Bouchelet et al.

Differential expression of sumatriptan-sensitive 5-hydroxytryptamine receptors in human trigeminal ganglia and cerebral blood vessels

Mol. Pharmacol.

(1996)

Branchek, T.A., Bard, J.A., Kucharewicz, S.A., Zgombick, J.M., Weinshank, R.L., Cohen, M.L., 1995. Migraine:...

A.T Bruinvels et al.

Autoradiographic characterisation and localisation of 5-HT_1D compared to 5-HT_1B binding sites in rat brain

Naunyn-Schmiedeberg's Arch. Pharmacol.

(1993)

J.F Caekebeke et al.

Antimigraine drug sumatriptan increases blood flow velocity in large cerebral arteries during migraine attacks

Neurology

(1992)

M.E Castro et al.

Identification and characterization of a new serotonergic recognition site with high affinity for 5-carboxamidotryptamine in mammalian brain

J. Neurochem.

(1997)

J.W Clitherow et al.

Evolution of a novel series of [(N,N-dimethylamino)propyl]- and piperazinylbenzanilides as the first selective 5-HT_1D antagonists

J. Med. Chem.

(1994)

Cohen, M.L., Johnson, K.W., Schenck, K.W., 1998. Lack of vasoconstriction to the selective 5-HT1F receptor agonists,...

Connor, H.E., Beattie, D.T., 1999. 5-Hydroxytryptamine receptor subtypes: relation to migraine. In: Edvinsson, L....

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ReviewPharmacological aspects of experimental headache models in relation to acute antimigraine therapy

Abstract

Introduction

Section snippets

Migraine pathophysiology

5-HT1 receptor subtypes relevant to migraine

Models based on the involvement of cranial vasodilatation in migraine

Conclusions

Eur. J. Pharmacol.

Eur. J. Pharmacol.

Neuropharmacology

Pain

Bioorg. Med. Chem. Lett.

Eur. J. Pharmacol.

Eur. J. Pharmacol.

Eur. J. Pharmacol.

Eur. J. Pharmacol.

Trends Pharmacol. Sci.

Eur. J. Pharmacol.

Brain Res.

Lancet

Trends Pharmacol. Sci.

Lancet

Neurosci. Lett.

Neurol. Clin.

Brain Res.

Pain

Brain Res.

Brain Res.

Neuroscience

Eur. J. Pharmacol.

Eur. J. Pharmacol.

Trends Pharmacol. Sci.

Trends Pharmacol. Sci.

Eur. J. Pharmacol.

Neurol. Clin.

Eur. J. Pharmacol.

Pain

Brain Res.

Cephalalgia

Trends Pharmacol. Sci.

Trends Pharmacol. Sci.

Cell

Eur. J. Pharmacol.

Life Sci.

The rat 5-hydroxytryptamine1B receptor is the species homologue of the human 5-hydroxytryptamine1Dβ receptor

Mol. Pharmacol.

Cloning of another human serotonin receptor (5-HT1F): a fifth 5-HT1 receptor subtype coupled to the inhibition of adenylate cyclase

Proc. Natl. Acad. Sci. USA

Differences in ligand binding profiles between cloned rabbit and human 5-HT1Dα and 5-HT1Dβ receptors: ketanserin and methiothepin distinguish rabbit 5-HT1D receptor subtypes

Naunyn-Schmiedeberg's Arch. Pharmacol.

The influence of the trigeminal ganglion on carotid blood flow in anaesthetized guinea-pigs

Br. J. Pharmacol.

Pharmacological profile of almotriptan, a novel antimigraine agent

Cephalalgia

Differential expression of sumatriptan-sensitive 5-hydroxytryptamine receptors in human trigeminal ganglia and cerebral blood vessels

Mol. Pharmacol.

Autoradiographic characterisation and localisation of 5-HT1D compared to 5-HT1B binding sites in rat brain

Naunyn-Schmiedeberg's Arch. Pharmacol.

Antimigraine drug sumatriptan increases blood flow velocity in large cerebral arteries during migraine attacks

Neurology

Identification and characterization of a new serotonergic recognition site with high affinity for 5-carboxamidotryptamine in mammalian brain

J. Neurochem.

Evolution of a novel series of [(N,N-dimethylamino)propyl]- and piperazinylbenzanilides as the first selective 5-HT1D antagonists

J. Med. Chem.

Review
Pharmacological aspects of experimental headache models in relation to acute antimigraine therapy

5-HT₁ receptor subtypes relevant to migraine

The rat 5-hydroxytryptamine_1B receptor is the species homologue of the human 5-hydroxytryptamine_1Dβ receptor

Cloning of another human serotonin receptor (5-HT_1F): a fifth 5-HT₁ receptor subtype coupled to the inhibition of adenylate cyclase

Differences in ligand binding profiles between cloned rabbit and human 5-HT_1Dα and 5-HT_1Dβ receptors: ketanserin and methiothepin distinguish rabbit 5-HT_1D receptor subtypes

Autoradiographic characterisation and localisation of 5-HT_1D compared to 5-HT_1B binding sites in rat brain

Evolution of a novel series of [(N,N-dimethylamino)propyl]- and piperazinylbenzanilides as the first selective 5-HT_1D antagonists