- Email: [email protected]
New vistas on 5-HT receptors and migraine
Prog. NewpRvchophnrmncol &EM Fs@la~1991,Vd. lS,pp.l9l-197 mnte!dInGnatEMta&Allligntsrrrvmd
NEW VISTAS
ON 5-HT
RECEPTORS
02785&46/91$0.00+.50 01991RrgamonF+emp1c
AND
MIGRAINE
STEPHEN J. PEROUTKA Department of Neurology, Stanford University Medical Center Stanford, CA, USA (Final form, June, 1990) Contents 1. 2. 3. 4. 5. 6.
191 191 191 193 194 194 194 195 195
Abstract Introduction 5-HTID Receptors 5-HT2 Receptor Agents 5-HTlC Receptor Agents 5-HT Receptor Agents Sums2 ry Acknowledgements References Abstract
Peroutka, Stephen J.: New vistas on 5-HT receptors and migraine . Neuro-Psychopharmacol. & Biol. Psychiat. 1991, -15:191-197.
Prog.
1.
A number of serotonergic agents have been shown to be effective in the treatment of migraine. At the present time, migraine drug interactions have been analyzed most extensively at 5-hydroxytryptaminelD (5-HTlD), 5-HT2 and 5-HT3 receptor subtypes.
2.
This review will summarize the current status of 5-HT receptor subtypes as they relate to anti-migraine agents.
3.
The available data suggest that drug interactions with specific 5-HT receptor subtypes may be the basis for their efficacy in both the acute and prophylactic treatment of migraine.
Keywords:
5-HT, migraine, serotonergic agents, headache.
Abbreviations:
S-hydroxytryptamine (5-HT), dihydroergotamine (DHE). 1.
Introduction
Since the demonstration in 1959 that methysergide was an effective migraine prophylactic agent, a number of serotonergic agents have been shown to be effective in the treatment of migraine (Peatfield et al. 1986). At the present time, a variety of molecular, biochemical and physiological observations suggest that multiple 5-hydroxytryptamine (5-HT) receptors exist in the central nervous system (Schmidt and Peroutka 1989). 5-HT receptors can be generally divided into 3 main "families": 5-HTl, 5-HT and 5-HT receptors. Within each of the 3 "families", receptor subtypes have bzen descrl.aed. Migraine drug interactions have been analyzed most extensively at 5-HTID, 5-HT and 5-HT receptor subtypes. Recent advances in this area are he present review. summ 2 rized in +? 2.
5-HTD Receptors
receptor was initially characterized in 1987 (Heuring and 7) and has been shown to be widespread in human brain (Waeber et 191
192
S. 1. Peroutka
receptors are the most In fact, 5-HT 1988, Peroutka et al. 1989). al. common of S-HT receptor subtypes observed in the'Ruman brain (Peroutka et al. At the same time, vascular studies have identified a "5-HTl-like" 1989). receptor in the cranial vasculature which may be identical to the 5-HT receptor (Humphrey et al. 1988, Feniuk et al. 1989, Parsons et al. 1984: Multiple vascular studies have implicated this "5-HT1Connor et al. 1989). In particular, of cerebral blood vessels. like" receptor in the constriction a novel serotonergic agent called sumatriptan (formerly called GR 43175) appears to be an extremely selective agonist of these vascular 5-HT receptors (Feniuk et al. 1989). Moreover, recent studies have indicated that sumatriptan receptor agent (Peroutka and McCarthy 1989, is a potent and selective 5-HT McCarthy and Peroutka 1989). +Rerefore, the "5-HT -like" receptor in certain cerebral vessels may, in fact, be the 5-HTID recep h or. Moreover, sumatriptan has been reported to be extremely effective in the acute treatment of migraine. Doenicke et al (19881 reported that 2 mg sumatriptan IV completely abolished migraine symptoms in 71% of 24 migraine attacks and significantly reduced headache symptoms in the remaining patients. Only minor side effects (transient pressure in the head, feeling of warmth or tingling).were observed. Sumatriptan is now in phase III trials and it continues to show promise as an acute migraine therapy with minimal side effects. Ergot compounds are the most common class of agents used currently in the acute treatment of severe migraine. Dihydroergotamine (DHE), for example, has been shown to relieve a migraine attack in approximately 70% of patients (Callahan and Raskin 1986, Raskin 1986). However, ergot compounds also possess significant side effects. For example, the drugs often induce nausea, a property which frequently exacerbates the underlying nausea and vomiting of a migraine attack. Chronic use and abuse of ergots is also associated with vasoconstrictive disorders such as ergotism. Despite these side effects, ergots are the most widely prescribed acute anti-migraine agents due to their documented efficacy. An attempt was made to determine if DHE and sumatriptan share a common site of action at the molecular level. The potencies of DHE and sumatriptan were determined by drug competition studies at 13 neurotransmitter receptors using radioligand binding techniques (McCarthy and Peroutka 1989). DHE is receptors (1.2 nM) and is approximately an order of ~~$~~~","~e~~ ;,::A# at 5-HTID receptors. DHE does display moderate ;f;;ni:;c:;;o;;HTIA and 5-HT$ receptors but is essentially inactive at s we repo ted recently, a different pharmacological profgle is obseived with sumatriptan (Peroutka and McCarthy 1989). The drug receptors and approximately 5-fold less potent at ;~H~~~tr~~~$&~? 'if&? riptan is also active at 5-HT not resent in human brain). other 5-HT receptor subtypes. DHE interactions with other biogenic amine receptor sites were also assessed. DHE displays high (i.e. nanomolarl affinity for both alpha - and alpha -adrenergic receptors. DHE displays moderate affinity for b & ta-adrenerg 2 c and dopamine receptors. In marked contrast, sumatriptan is totally inactive at each of these neurotransmitter receptor binding sites. Both DHE and sumatriptan are inactive at muscarinic cholinergic and benzodiazepine receptors. DHE and sumatriptan
are similar
in that they both display high affinity is also potent at a number of other ;::g:::C5,::@ ::::$::,, :::h ::w;Y;;;C, 5-HTg, dopamine2, alphalyadrenergic receptors. Therefore, sumatriptan is much m re selective agent in that it interacts most potently with 5-HT receptors, displays moderate affinity receptors and is essen hDially inactive at all other receptor sites
An unresolved issue is whether the anti-migraine effects of DHE and sumatriptan relate to their vascular and/or neuronal receptor actions. receptor(s) stimulated by both DHE and sumatriptan has been implicated
The in the
New vistas on 5-HT receptors andmigraine
193
constriction of arteriovenous anastomoses (Saxena and Ferrari 1989). Under the migraine model proposed by Heyck (19691, as yet unknown events lead to the opening of carotid arteriovenous anastomoses in the head. Blood is diverted from the capillary beds, and ischemia and hypoxia result. Based on this hypothesis of migraine, an effective migraine agent would close the shunts and restore blood flow. Indeed, Feniuk et al. (1989) *have shown that sumatriptan is a selective vasoconstrictor of the carotid circulation in the dog. An alternative hypothesis derives from the fact that the S-HT receptor functions as an "autoreceptor" which modulates neurotransmitter lpelease agonists like DHE and (Hoyer and Middlemiss 1989). Conceivably, 5-HT sumatriptan may act by blocking the release, at'ehe nerve terminal, of transmitters such as 5-HT, norepinephrine and/or acetylcholine. The agonists to antagonize endogenous transmitter ability of potent 5-HT release may, theoreticA!?ly, account for their efficacy in the acute treatment of migraine. In a recent study by Sleight et al. (1990), the effect of sumatriptan on extracellular levels of 5-HT in the guinea pig frontal cortex was easursq by intracerebral dialysis. A constant infusion of sumatriptan -pt - 10 M) dose-dependently reduced extrace+lular levels of 5-HT (e.g., (10 80 + 2% decrease from control 5-HT levels at 10 M). The effect of perTphera1 injections of sumatriptan (50 ug/kg i.p. and 500 ug/kg i-p.) on extracellular levels of 5-HT were also determined. Neither peripheral dose of sumatriptan had any effect on extracellular levels of 5-HT in the frontal cortex. These data suggest that sumatriptan, when infused into the brain, stimulates 5-HT autoreceptors and thereby inhibits release of the neurotransmitter. These data also suggest that the putative acute anti-migraine effects of sumatriptan are likely to be mediated by peripheral mechanisms. If the early clinical success of sumatriptan is confirmed in future clinical trials, then the 5-HT receptor is a likely candidate to play an important role in the acute re ID ief of a migraine attack. As a result, drugs which selectively interact with these sites may allow for the development of effective anti-migraine agents with minimal side effects. Analysis of such agents may also provide important insights into the pathophysiological basis of migraine. 5-HT Receptor Agents -2 The 5-HT receptor has been extensively characterized in vitro and a number of 6otent 5-HT antagonists have been marketed asprophylactic antimigraine agents (Perostka 1988). In comparison to their 5-HT potencies, methysergide, cyproheptadine, pizotifen and amitri~@y.?~dne5a~~1D even more potent agents at the 5-HT2 receptor in human brain. Methysergide, cyproheptadine and pizotifen display nanomolar affinity for this 5-HT receptor subtype. Amitriptyline is only slightly less potent (K. = 23 nM) whereas verapamil and nifedipine display apparent affinities of i40 nM and 320 nM, respectively. Diltiazem and the majority of beta-adrenergic agents are inactive at concentrations below 1,000 nM. In addition, other 5-HT antagonists such as metergoline and lisuride have also been shown, in limi.$ed clinical trials, to benefit migraine patients (Peatfield et al. 1986). These data demonstrate that a number of anti-migraine drugs display high or moderate affinity for the 5-HT2 receptor subtype in human brain. 3.
An hypothesis has been proposed which may explain the efficacy of 5-HT antagonists in the prophylactic treatment of migraine. The 5-HT recept a r has been shown to mediate contraction of smooth muscle in many v2 scular beds (Peroutka 1984). In addition, Moskowitz and colleagues have demonstrated that 5-HT can stimulate production of prostacyclin and other products of arachidonic acid metabolism in smooth muscle cells in vitro (Coughlin et al. 1981, Coughlin et al. 1984). This action of SzT-ars to be mediated by 5-HT receptors since methysergide, cryproheptadine and pizotifen potently pre 6 ent this effect. The significance of this finding is that modulation of prostacyclin and arachidonic acid metabolism may have important effects on vascular tone (Coughlin et al. 1981) and/or local
194
S.1.Peroutka
inflammation (Peatfield et al. 1986). In essence, 5-HT (via 5-HT receptors) sine attack could stimulate arachidonic acid metabolism at the onset of a mig $' which would be expected to lead to a "sterile inflammatory reaction" in the brain vasculature. Theoretically, 5-HT antagonists are able to inhibit 5-HT from inducing the inflammatory stage. 4.
5-HTlC Receptor Agents
receptor antagonists, Most recently, it has been suggested that 5-HTIC as opposed to the 5-HT2 receptor antagonists, may play an important role in the pathophysiology of migraine (Fozard and Gray 1989). This suggestion derives from the fact that 5-HT receptors share similar pharmacological characteristics to 5-HT recept&&s. Unfortunately, currently available prophylactic anti-migra tne agents do not differentiate between 5-HT2 receptors. Therefore, as noted below, selective 5-HT must be identified and developed before this interesting hyifgthesis can be tested in clinical trials. 5.
5-HT3 Receptor Agents
5-HT also has a number of potent effects which are not affected by 5-HTl and/or 5-HT2 selective drugs but which can often be blocked with drugs such as MDL 12222, metoclopramide and ICS 205-930 (Richardson et al. 1985). These sites have been designated 5-HT receptors. 5-HT receptor antagonists such as ICS 205-930, MDL 32222, BRL 24924 ai?d odansetron (formerly called GR 38032F) appear to possess unique and potent anti-emetic effects in both animals and man (Miner et al. 1987). Recent radioligand binding studies have revealed a high density of 5-HT receptors in the area postrema, which contains the emetic centers of the c2 ntral nervous system (Barnes et al. 1988). These data are therefore consistent with a possible central site of anti-emetic activity for 5-HT3 antagonists. One selective 5-HT antagonist, MDL 72222, was reported to be effective in the acute treatme ;1 t of migraine (Loisy et al. 1985). An intravenous dose of the drug was given during the acute migraine phase in a total of 24 patients. Compared to the 23 placebo patients, individuals who received MDL 72222 reported that the migraine pain was significantly alleviated. However, no further data have been reported on the efficacy of other selective 5-HT 3 antagonists in migraine. Interestingly, metoclopramide is a 5-HT antagonist as well as a dopamine D receptor antagonist (Hamik and Peroutk 2 1989). Metoclopramide has been u 3ed both alone and in combination with other medications, such as ergotamine, in the acute treatment of migraine (Hakkarainen and Allonen 1982). Metoclopramide was found to be effective in both conditions, although the patients reported a preference for the combination therapy. Conceivably, the anti-migraine efficacy of metoclopramide may derive from its ability to block S-HT3 receptors. More likely, the beneficial effect of metoclopramide may derive from its anti-emetic properties. 6.
Summary
Since a satisfactory animal model for migraine does not exist, attempts to determine a common mechanism of action for effective anti-migraine agents may be of benefit in elucidating the pathogenesis of this neurological syndrome. A large number of both acute and prophylactic anti-migraine agents share an ability to interact with 5-HT receptor subtypes in human brain. Specifically, acute anti-migraine drugs (e.g., ergots, sumatriptanf share high affinity for S-HT receptors and somewhat lower affinity for receptors. These ret bD ptors are present in certain intracranial blood 2::&*S. receptors are also located on nerve terminals where they act to inhibit "-""?he relea se of 5-HT and other neurotransmitters. Theoretically, 5-HTlD receptor agonists may acutely inhibit the release of vasoactive and/or pain-inducing substances in the perivascular space. Conceivably, drugs acting at this receptor would stop the progression of
New vistas on S-HT receptors and migraine
this perivascular
195
process.
drugs display a In addition, a number of prophylactic anti-migraine relatively high affinity for both 5-HT, and/or 5-HTlr receptors in human Although these receptors are aIso found in Eertain blood vessels, brain. The receptors appear to they are present throughout the nervous system. Moreover, the mediate neuronal depolarizations at the cellular level. 5-HT2 receptor appears to play a key role in the development of inflammation in certain smooth muscle systems (Coughlin et al. 1984). Theoretically, the ability of :-HT$ antagonists . to protect perivascular inflammation may account for their e ficacy in the prophylactic treatment of migraine. These data offer a novel approach to the analysis of anti-migraine Drugs could be selected for use in clinical migraine studies based agents. on their selectivity for a specific 5-HT receptor subtype. For example, an agent which displays both high affinity and selectivity for 5-HT receptors could be clinically evaluated.' Its effectiveness, or lack there019 , would indicate the importance of the specific 5-HT receptor site in the pathogenesis of migraine. Future attempts to determine a common mechanism of action for effective anti-migraine agents should facilitate the elucidation of the pathogenesis of this neurological syndrome. Acknowledgements I thank Mary Keller for editorial assistance. This work was supported part by the Stanley Foundation and NIH Grant NS 12151-15.
in
References BARNES, N. M., COSTALL. B., NAYLOR, R. J. and TATTERSALL, Identification of 5-HT Recognition Sites in the Ferret J. Pharm. Pharmacol. -43: 586-588. CALLAHAN, M. and RASKIN, N. (1986) A Controlled in the Treatment of Acute Migraine Headache.
F. D. (1988) Area Postrema.
Study of Dihydf;;qT;amine Headache -26: .
CONNOR, H. E., FENIUK, W. and HUMPHREY, P. P. A. (1989) Characterization of 5-HT Receptors Mediating Contraction of Canine and Primate Basilar Artery Br. J. by Use of GR 43175, a Selective 5-HTl-like Receptor Agonist. Pharmacol. -96: 379-387. COUGHLIN, S. R., MOSKOWITZ, M. A., ANTONIADES, H. N. and LEVINE, L. (1981) Serotonin Receptor-Mediated Stimulation of Bovine Smooth Muscle Cell Prostacyclin Synthesis and Its Modulation by Platelet-derived Growth Proc. Natl. Acad. Sci. USA -78: 7134-7138. Factor. COUGHLIN, S. R., MOSKOWITZ, M. A. and LEVINE, L. (1984) Identification of a Serotonin Type 2 Receptor Linked to Prostacyclin Synthesis in Vascular Smooth Muscle Cells. Biochem. Pharmacol. -33: 692-695. DOENICKE, A., BRAND, J. and PERRIN, V. L. (1988) Possible Benefit a Novel of 5-HT -like Receptor Agonist, for the Acute Treatment Lanckt i: 1309-1311. Migraine.
of GR 43175, of Severe
FENIUK, W., HUMPHREY, P. P. A. and PERREN, M. J. (1989) The Selective Carotid Arterial Vasoconstrictor Action of GR 43175 in Anesthetized 83-90. Br. J. Pharmacol. -96: FOZARD, J. R. and GRAY, J. a. (1989) 5-HT TI% Step in the Initiation of Migraine? H. and ALLONEN, HAKKARAINEN, Their Combination in Acute HAMIK,
A. and PEROUTKA,
Receptor Activation: 307-309.
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H. (1982) Ergotamine vs. Metoclopramide 10-12. Headache -22: Migraine Attacks.
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and Novel Anti-emetics with Dopamine D2 and 5-Hydroxytryptamine3 Can. Chemother. Pharmacol. -24: 307-310.
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HEYRING, R. E. and PEROUTKA, S. J. (1987) Characterization of a Novel H-5-hydroxytryptamine Binding Site Subtype in Bovine Brain Membranes. J. Neurosci. 1: 894-903. HEYCK, H. (1969) Pathogenesis l-28.
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HOYER, D. and MIDDLEMISS, D. N. of Terminal 5-HT Autoreceptors
Rs. Clin.
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(1989) Species Differe;;;; in Mammalian Brain.
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i; the Pharmacology 130-132.
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HUMPHREY, P. P. A., FENIUK, W., PERREN, M. J., CONNOR, H. E., OXFORD, A. W., COATES, I. H. and BUTINA, D. (1988) GR 43175, a Selective Agonist for the 5-HTl-like Receptor in Dog Isolated Saphenous Vein. Br. J. Pharmacol. 1123-1132. -94: LOISY, C., BEORCHIA, S., CENTONZE, V., FOZARD, J. R., SCHECHTER, P. J. and TELL, G. P. (1985) Effects on Migraine Headache of MDL 72222, An Antagonist at Neuronal 5-HT Receptors. Double-blind, Placebo-controlled Study. Cephalalgia 2: 79-82. MCCARTHY, B. G. and PEROUTKA, S. J. (1989) Comparative Neuropharmacology Dihydroergotamine and Sumatriptan (GR 43175). 420-422. Headache -29: MINER, W. D., SANGER, G. J. and TURNER, 5-Hydroxytryptamine receptors Mediate Emesis. Br. J. Cancer -56: l-5.
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D. H. (1987)'Evidence that Cytotoxic Drug and Radiation-evoked
PARSONS, A. A., WHALLEY, E. T., FENIUK, W., CONNOR, H. E. and HUMPHREY, P. A. (1989) 5-HT -like R eceptors Mediate 5-Hydroxytryptamine-induced Contraction of Hu l?i an Isolated Basilar Artery. Br. J. Pharmacol. -96: 434-449.
P.
PEATFIELD, R. C., FOZARD J. R. and ROSE, F. C. (1986) Drug Treatment of Migraine. In: Handbook of Clinical Neurology, Rose, F. C. (Ed.), pp 4173-4216, Raven Press, New York. PEROUTKA, S. J. (1984) Vascular Serotonin Receptors: and 5-HT2 Binding Sites. Biochem. Pharmacol. -33:
Correlation 2349-2353.
Drug Interactions with PEROUTKA, S. J. (1988) Antimigraine Subtypes in Human Brain. Ann. Neurol. -23: 500-504.
with
Serotonin
5-HT1
Receptor
(GR 43175) Interacts PEROUTKA, S. J. and MCCARTHY, B. G. (1989) Sumpatriptan and-5THTlD Bihdjng Sites. Eur,.J. Bharmacol. ~~~fc"~~~'~,~"t"-51"Tl~
. PEROUTKA, S. J., SWITZER, J. A. and HAMIK, A. (1989) Identification of 5Binding Sites in Human Brain Membranes. Synapse Hydr;;y;;yptaminelD 2: . Intravenous RASKIN, N. H. (1986) Repetitive for Intractable Migraine. Neurology -36:
Dihydroergotamine 995-997.
as Therapy
RICHARDSON, B. P., ENGEL, G., DONATSCH, P. and STADLER, P. A. (1985) Identification of Serotonin M-receptor Subtypes and Their Specific 126-131. Nature 316: Blockade by a New Class of Drugs. SAXENA, P. R. and FERRARI, M. D. (1989) 5-HTl-like Receptor the Pathophysiology of Migraine. TIPS -10: 200-204. SCHMIDT, A. W. and PEROUTKA, S. J. (1989) "Families". 2242-2249. FASEB 2:
5-Hydroxytryptamine
Agonists
and
Receptor
New vistas on 5-HT receptors and rni~rain~
197
SLEIGHT, A. J., CERVENKA, A. and PEROUTKA, S. J. (1990) In vivo Effects of Sumatriptan (GR 43175) on Extracellular Levels of S-HT?nx Guinea Pig. Neuropharmacol. 2: 511-513. WAESER, C., DIETL, M. M., HOYER, D. R., PROBST, A. and PALACIOS, J. M. (1988) Visualization of a Novel Serotonin Recognition Site (S-HTlD) in the Human Brain by Autoradiography. Neurosci Letters -88: 11-16. Inquiries and reprint requests should be addressed to: Stephen J. Peroutka, M.D., Ph.D. Genentech, Inc. 460 Point San Bruno Boulevard South San Francisco, CA 94080
NEW VISTAS
ON 5-HT
RECEPTORS
02785&46/91$0.00+.50 01991RrgamonF+emp1c
AND
MIGRAINE
STEPHEN J. PEROUTKA Department of Neurology, Stanford University Medical Center Stanford, CA, USA (Final form, June, 1990) Contents 1. 2. 3. 4. 5. 6.
191 191 191 193 194 194 194 195 195
Abstract Introduction 5-HTID Receptors 5-HT2 Receptor Agents 5-HTlC Receptor Agents 5-HT Receptor Agents Sums2 ry Acknowledgements References Abstract
Peroutka, Stephen J.: New vistas on 5-HT receptors and migraine . Neuro-Psychopharmacol. & Biol. Psychiat. 1991, -15:191-197.
Prog.
1.
A number of serotonergic agents have been shown to be effective in the treatment of migraine. At the present time, migraine drug interactions have been analyzed most extensively at 5-hydroxytryptaminelD (5-HTlD), 5-HT2 and 5-HT3 receptor subtypes.
2.
This review will summarize the current status of 5-HT receptor subtypes as they relate to anti-migraine agents.
3.
The available data suggest that drug interactions with specific 5-HT receptor subtypes may be the basis for their efficacy in both the acute and prophylactic treatment of migraine.
Keywords:
5-HT, migraine, serotonergic agents, headache.
Abbreviations:
S-hydroxytryptamine (5-HT), dihydroergotamine (DHE). 1.
Introduction
Since the demonstration in 1959 that methysergide was an effective migraine prophylactic agent, a number of serotonergic agents have been shown to be effective in the treatment of migraine (Peatfield et al. 1986). At the present time, a variety of molecular, biochemical and physiological observations suggest that multiple 5-hydroxytryptamine (5-HT) receptors exist in the central nervous system (Schmidt and Peroutka 1989). 5-HT receptors can be generally divided into 3 main "families": 5-HTl, 5-HT and 5-HT receptors. Within each of the 3 "families", receptor subtypes have bzen descrl.aed. Migraine drug interactions have been analyzed most extensively at 5-HTID, 5-HT and 5-HT receptor subtypes. Recent advances in this area are he present review. summ 2 rized in +? 2.
5-HTD Receptors
receptor was initially characterized in 1987 (Heuring and 7) and has been shown to be widespread in human brain (Waeber et 191
192
S. 1. Peroutka
receptors are the most In fact, 5-HT 1988, Peroutka et al. 1989). al. common of S-HT receptor subtypes observed in the'Ruman brain (Peroutka et al. At the same time, vascular studies have identified a "5-HTl-like" 1989). receptor in the cranial vasculature which may be identical to the 5-HT receptor (Humphrey et al. 1988, Feniuk et al. 1989, Parsons et al. 1984: Multiple vascular studies have implicated this "5-HT1Connor et al. 1989). In particular, of cerebral blood vessels. like" receptor in the constriction a novel serotonergic agent called sumatriptan (formerly called GR 43175) appears to be an extremely selective agonist of these vascular 5-HT receptors (Feniuk et al. 1989). Moreover, recent studies have indicated that sumatriptan receptor agent (Peroutka and McCarthy 1989, is a potent and selective 5-HT McCarthy and Peroutka 1989). +Rerefore, the "5-HT -like" receptor in certain cerebral vessels may, in fact, be the 5-HTID recep h or. Moreover, sumatriptan has been reported to be extremely effective in the acute treatment of migraine. Doenicke et al (19881 reported that 2 mg sumatriptan IV completely abolished migraine symptoms in 71% of 24 migraine attacks and significantly reduced headache symptoms in the remaining patients. Only minor side effects (transient pressure in the head, feeling of warmth or tingling).were observed. Sumatriptan is now in phase III trials and it continues to show promise as an acute migraine therapy with minimal side effects. Ergot compounds are the most common class of agents used currently in the acute treatment of severe migraine. Dihydroergotamine (DHE), for example, has been shown to relieve a migraine attack in approximately 70% of patients (Callahan and Raskin 1986, Raskin 1986). However, ergot compounds also possess significant side effects. For example, the drugs often induce nausea, a property which frequently exacerbates the underlying nausea and vomiting of a migraine attack. Chronic use and abuse of ergots is also associated with vasoconstrictive disorders such as ergotism. Despite these side effects, ergots are the most widely prescribed acute anti-migraine agents due to their documented efficacy. An attempt was made to determine if DHE and sumatriptan share a common site of action at the molecular level. The potencies of DHE and sumatriptan were determined by drug competition studies at 13 neurotransmitter receptors using radioligand binding techniques (McCarthy and Peroutka 1989). DHE is receptors (1.2 nM) and is approximately an order of ~~$~~~","~e~~ ;,::A# at 5-HTID receptors. DHE does display moderate ;f;;ni:;c:;;o;;HTIA and 5-HT$ receptors but is essentially inactive at s we repo ted recently, a different pharmacological profgle is obseived with sumatriptan (Peroutka and McCarthy 1989). The drug receptors and approximately 5-fold less potent at ;~H~~~tr~~~$&~? 'if&? riptan is also active at 5-HT not resent in human brain). other 5-HT receptor subtypes. DHE interactions with other biogenic amine receptor sites were also assessed. DHE displays high (i.e. nanomolarl affinity for both alpha - and alpha -adrenergic receptors. DHE displays moderate affinity for b & ta-adrenerg 2 c and dopamine receptors. In marked contrast, sumatriptan is totally inactive at each of these neurotransmitter receptor binding sites. Both DHE and sumatriptan are inactive at muscarinic cholinergic and benzodiazepine receptors. DHE and sumatriptan
are similar
in that they both display high affinity is also potent at a number of other ;::g:::C5,::@ ::::$::,, :::h ::w;Y;;;C, 5-HTg, dopamine2, alphalyadrenergic receptors. Therefore, sumatriptan is much m re selective agent in that it interacts most potently with 5-HT receptors, displays moderate affinity receptors and is essen hDially inactive at all other receptor sites
An unresolved issue is whether the anti-migraine effects of DHE and sumatriptan relate to their vascular and/or neuronal receptor actions. receptor(s) stimulated by both DHE and sumatriptan has been implicated
The in the
New vistas on 5-HT receptors andmigraine
193
constriction of arteriovenous anastomoses (Saxena and Ferrari 1989). Under the migraine model proposed by Heyck (19691, as yet unknown events lead to the opening of carotid arteriovenous anastomoses in the head. Blood is diverted from the capillary beds, and ischemia and hypoxia result. Based on this hypothesis of migraine, an effective migraine agent would close the shunts and restore blood flow. Indeed, Feniuk et al. (1989) *have shown that sumatriptan is a selective vasoconstrictor of the carotid circulation in the dog. An alternative hypothesis derives from the fact that the S-HT receptor functions as an "autoreceptor" which modulates neurotransmitter lpelease agonists like DHE and (Hoyer and Middlemiss 1989). Conceivably, 5-HT sumatriptan may act by blocking the release, at'ehe nerve terminal, of transmitters such as 5-HT, norepinephrine and/or acetylcholine. The agonists to antagonize endogenous transmitter ability of potent 5-HT release may, theoreticA!?ly, account for their efficacy in the acute treatment of migraine. In a recent study by Sleight et al. (1990), the effect of sumatriptan on extracellular levels of 5-HT in the guinea pig frontal cortex was easursq by intracerebral dialysis. A constant infusion of sumatriptan -pt - 10 M) dose-dependently reduced extrace+lular levels of 5-HT (e.g., (10 80 + 2% decrease from control 5-HT levels at 10 M). The effect of perTphera1 injections of sumatriptan (50 ug/kg i.p. and 500 ug/kg i-p.) on extracellular levels of 5-HT were also determined. Neither peripheral dose of sumatriptan had any effect on extracellular levels of 5-HT in the frontal cortex. These data suggest that sumatriptan, when infused into the brain, stimulates 5-HT autoreceptors and thereby inhibits release of the neurotransmitter. These data also suggest that the putative acute anti-migraine effects of sumatriptan are likely to be mediated by peripheral mechanisms. If the early clinical success of sumatriptan is confirmed in future clinical trials, then the 5-HT receptor is a likely candidate to play an important role in the acute re ID ief of a migraine attack. As a result, drugs which selectively interact with these sites may allow for the development of effective anti-migraine agents with minimal side effects. Analysis of such agents may also provide important insights into the pathophysiological basis of migraine. 5-HT Receptor Agents -2 The 5-HT receptor has been extensively characterized in vitro and a number of 6otent 5-HT antagonists have been marketed asprophylactic antimigraine agents (Perostka 1988). In comparison to their 5-HT potencies, methysergide, cyproheptadine, pizotifen and amitri~@y.?~dne5a~~1D even more potent agents at the 5-HT2 receptor in human brain. Methysergide, cyproheptadine and pizotifen display nanomolar affinity for this 5-HT receptor subtype. Amitriptyline is only slightly less potent (K. = 23 nM) whereas verapamil and nifedipine display apparent affinities of i40 nM and 320 nM, respectively. Diltiazem and the majority of beta-adrenergic agents are inactive at concentrations below 1,000 nM. In addition, other 5-HT antagonists such as metergoline and lisuride have also been shown, in limi.$ed clinical trials, to benefit migraine patients (Peatfield et al. 1986). These data demonstrate that a number of anti-migraine drugs display high or moderate affinity for the 5-HT2 receptor subtype in human brain. 3.
An hypothesis has been proposed which may explain the efficacy of 5-HT antagonists in the prophylactic treatment of migraine. The 5-HT recept a r has been shown to mediate contraction of smooth muscle in many v2 scular beds (Peroutka 1984). In addition, Moskowitz and colleagues have demonstrated that 5-HT can stimulate production of prostacyclin and other products of arachidonic acid metabolism in smooth muscle cells in vitro (Coughlin et al. 1981, Coughlin et al. 1984). This action of SzT-ars to be mediated by 5-HT receptors since methysergide, cryproheptadine and pizotifen potently pre 6 ent this effect. The significance of this finding is that modulation of prostacyclin and arachidonic acid metabolism may have important effects on vascular tone (Coughlin et al. 1981) and/or local
194
S.1.Peroutka
inflammation (Peatfield et al. 1986). In essence, 5-HT (via 5-HT receptors) sine attack could stimulate arachidonic acid metabolism at the onset of a mig $' which would be expected to lead to a "sterile inflammatory reaction" in the brain vasculature. Theoretically, 5-HT antagonists are able to inhibit 5-HT from inducing the inflammatory stage. 4.
5-HTlC Receptor Agents
receptor antagonists, Most recently, it has been suggested that 5-HTIC as opposed to the 5-HT2 receptor antagonists, may play an important role in the pathophysiology of migraine (Fozard and Gray 1989). This suggestion derives from the fact that 5-HT receptors share similar pharmacological characteristics to 5-HT recept&&s. Unfortunately, currently available prophylactic anti-migra tne agents do not differentiate between 5-HT2 receptors. Therefore, as noted below, selective 5-HT must be identified and developed before this interesting hyifgthesis can be tested in clinical trials. 5.
5-HT3 Receptor Agents
5-HT also has a number of potent effects which are not affected by 5-HTl and/or 5-HT2 selective drugs but which can often be blocked with drugs such as MDL 12222, metoclopramide and ICS 205-930 (Richardson et al. 1985). These sites have been designated 5-HT receptors. 5-HT receptor antagonists such as ICS 205-930, MDL 32222, BRL 24924 ai?d odansetron (formerly called GR 38032F) appear to possess unique and potent anti-emetic effects in both animals and man (Miner et al. 1987). Recent radioligand binding studies have revealed a high density of 5-HT receptors in the area postrema, which contains the emetic centers of the c2 ntral nervous system (Barnes et al. 1988). These data are therefore consistent with a possible central site of anti-emetic activity for 5-HT3 antagonists. One selective 5-HT antagonist, MDL 72222, was reported to be effective in the acute treatme ;1 t of migraine (Loisy et al. 1985). An intravenous dose of the drug was given during the acute migraine phase in a total of 24 patients. Compared to the 23 placebo patients, individuals who received MDL 72222 reported that the migraine pain was significantly alleviated. However, no further data have been reported on the efficacy of other selective 5-HT 3 antagonists in migraine. Interestingly, metoclopramide is a 5-HT antagonist as well as a dopamine D receptor antagonist (Hamik and Peroutk 2 1989). Metoclopramide has been u 3ed both alone and in combination with other medications, such as ergotamine, in the acute treatment of migraine (Hakkarainen and Allonen 1982). Metoclopramide was found to be effective in both conditions, although the patients reported a preference for the combination therapy. Conceivably, the anti-migraine efficacy of metoclopramide may derive from its ability to block S-HT3 receptors. More likely, the beneficial effect of metoclopramide may derive from its anti-emetic properties. 6.
Summary
Since a satisfactory animal model for migraine does not exist, attempts to determine a common mechanism of action for effective anti-migraine agents may be of benefit in elucidating the pathogenesis of this neurological syndrome. A large number of both acute and prophylactic anti-migraine agents share an ability to interact with 5-HT receptor subtypes in human brain. Specifically, acute anti-migraine drugs (e.g., ergots, sumatriptanf share high affinity for S-HT receptors and somewhat lower affinity for receptors. These ret bD ptors are present in certain intracranial blood 2::&*S. receptors are also located on nerve terminals where they act to inhibit "-""?he relea se of 5-HT and other neurotransmitters. Theoretically, 5-HTlD receptor agonists may acutely inhibit the release of vasoactive and/or pain-inducing substances in the perivascular space. Conceivably, drugs acting at this receptor would stop the progression of
New vistas on S-HT receptors and migraine
this perivascular
195
process.
drugs display a In addition, a number of prophylactic anti-migraine relatively high affinity for both 5-HT, and/or 5-HTlr receptors in human Although these receptors are aIso found in Eertain blood vessels, brain. The receptors appear to they are present throughout the nervous system. Moreover, the mediate neuronal depolarizations at the cellular level. 5-HT2 receptor appears to play a key role in the development of inflammation in certain smooth muscle systems (Coughlin et al. 1984). Theoretically, the ability of :-HT$ antagonists . to protect perivascular inflammation may account for their e ficacy in the prophylactic treatment of migraine. These data offer a novel approach to the analysis of anti-migraine Drugs could be selected for use in clinical migraine studies based agents. on their selectivity for a specific 5-HT receptor subtype. For example, an agent which displays both high affinity and selectivity for 5-HT receptors could be clinically evaluated.' Its effectiveness, or lack there019 , would indicate the importance of the specific 5-HT receptor site in the pathogenesis of migraine. Future attempts to determine a common mechanism of action for effective anti-migraine agents should facilitate the elucidation of the pathogenesis of this neurological syndrome. Acknowledgements I thank Mary Keller for editorial assistance. This work was supported part by the Stanley Foundation and NIH Grant NS 12151-15.
in
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