Neurogenic versus vascular mechanisms of sumatriptan and ergot alkaloids in migraine

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Neurogenic versus vascular mechanisms of sumatriptan and ergot alkaloids in migraine Michael A. Moskowitz Sumatriptan and the ergot alkaloids are useful tools for deciphering drug mechanisms in migraine and related headaches. Both neuronal and vascular mechanisms have been proposed on the basis of actions of 5HT at receptors resembling the 5HTrv subtype. In this Viewpoint article, Michael A. Moskowitz argues that blockade of neural transmission and the neurogenic inflammatory response provides a mechanism by which sumatriptan and ergot alkaloids alleviate vascular headaches. He postulates, with similar arguments, that sumatriptan and ergot alkaloids may block headaches that develop from meningovascular inflammatory disorders such as from viral and bacterial meningitis and from the sequelae of head injury. accounted for its reliefr. As is discussed later, Wolff’s explanation for the headache and for the mechanism of ergot action has not been validated in man or laboratory animal, despite 60 years of investigation5s8. In the past ten years, it has become clear that meningeal blood vessels possess anatomical and physiological properties shared by other tissues that can be the source of pain. For example, neuropeptide-containing unmyelinated C fibers originating from the trigeminal ganglion innervate meningeal blood vessels’,“. Trigeminovascular fibers terminate, in part, within the trigeminal The meninges as a source of pain nucleus caudalis. Activation of The most likely source for the trigeminovascular fibers triggers pain of migraine headaches is the neuronal responses within brain meninges - the dura mater, arachregions associated previously noid and pia maters. Wolff and his with the transmission of nocicepcolleagues determined that stimutive informatiorP. Stimulation of lation of meningeal vessels causes intrinsic inhibitory brainstem aching, throbbing and penetratpathways such as the periaqueing headache&. All other intraductal gray modulates the activity cranial tissues, including the brain, of responding neurons within are relatively insensate. On the trigeminal nucleus caudalis. basis of clinical experiments, Wolff In many ways, headaches are postulated that vasodilation caused the cranial equivalent of pain from migraine headache and that other visceral organsi’. As such, vasoconstriction ergot-induced headaches may reflect an underlying disturbance in organ funcM. A. Moskowifz is Professor of Neurology, tion. In both instances, polymodal HarvardMedical School, ond Director of the nociceptors are more dense withStroke Research Laboratory, Neurosurgery in the organ capsule (or the and Neurology Service, Massachusetts meninges) than within the parenGeneralHospital, 32 Fruit St, Boston, MA chyma. Within this capsule, poly02114, USA.

Sumatriptan is effective for the treatment of migraine and cluster headaches. Like the ergot alkaloids, sumatriptan constricts intracranial vascular smooth muscle and was developed for migraine treatment based on this mechanismr. More recent data, however, indicate that headaches occur independently of changes in vessel diametes, and that ergot alkaloids (and sumatriptan) exhibit important actions on trigeminovascular fibers that are distinct from their postjunctional effects on vascular smooth muscle (Fig. 1)3,4.

307 modal nociceptors mediate the development of plasma extravasat-ion and vasodilation, components of the neurogenic inflammatory responseis. Drugs showing some selectivity for the 5-HTio receptor (or a closely related receptor subtype - see Box) suppress both the neurogenic inflammatory response and vascular headaches. The debate as to sumatriptan’s primary mode of action relates to the presence of receptor-mediated actions on pre- as well as postjunctional elements within the vessel wall.

Evidence supporting neurogenic action

Evidence from two models neurogenic inflammation and cfos expression - supports a neurogenie action of sumatriptan and ergot alkaloids.

Blockade of neurogenic inflammation In 1987, Markowitz and colleagues developed a model to study neurogenic inflammation in the dura mater based on electrical and chemical stimulation of the trigeminovascular systemis. There are several reasons why this model is relevant to headache: l the tissue is an important source of head pain l the sterile inflammatory process that accompanies neurogenic edema is thought to sensitize nerve fibers to respond to previously innocuous stimuli (e.g. vessel pulsations or venous pressure changes) and sustain pain long after the initial trigger (see Ref. 14 for review) l the levels of calcitonin generelated peptide (CGRP) in venous blood increase in migraine patients15 and during trigeminal stimulationf6, probably reflecting neuropeptide release from activated sensory fibers l the elevated CGRP levels in both patients” and animals16 become reduced after administering sumatriptan l acute treatments of migraine headaches (i.e. ergot alkaloids’, and nonsteroidal sumatriptan* anti-inflammatory agents’*) decrease the neurogenic inflammatory response, in dosages that in most instances approximate the amounts required to treat humans.

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As in other tissues, neurogenic inflammation within the dura mater involves the release of vasodilating neuropeptides from capsaicin-sensitive nerve fibers. Released neuropeptides then initiate a cascade of events resulting in the formation of endo~e~~ microvilli, endothelial vesicles and vacuoles specifically within postcapillary dural venules, degranulation of mast cells and platelet aggregationlg. Sumatriptan and the ergot alkaloids reduce the uktstructural changes in endothelium, platelets and mast cells caused by sensory fiber stimuIatioxP. Only intracranial tissues innervated by the trigeminal nerve seem to possess the relevant receptor, since edema and the

The 5-HTm receptor subtype is used here to refer to a family of receptors including the rodent 5HTxsreceptor [see Hartig, P. R. ef al. (1992) Tips 13,152-159]. At least two binding sites and two distinct proteins have been identified. One site may constrict cerebral vessels mediated by sumatriptan. A phamxacoIogically distinct site that may or may not belong to the 5-HTIo family mediates the effects of surnatriptan and dihydroergotamine on the trigeminovascular system.

ultrastructural consequences of neurogenic stimulation within the tongue, eyelid or lip are unaffected by sumatriptan administration3n4,**. Hence, sumatriptan’s effects appear to derive from receptor-mediated actions that are specific to intracranial vascular tissues.

Prejunctional

mechanisms The following evidence indicates that sumatriptan and related compounds inhibit neurogenic inflammation via prejunctional mechanisms: l dihydroergotamine or sumatriptan pretreatment attenuated the elevated plasma CGRP levels within draining venous effluent during tigeminal stimulation, presumably reflecting decreased sensory neu~~~~~~ release16 * plasma leakage in the dura mater induced by exogenous substance P or neurokinin A administration, in contrast to that evoked by nerve stimulation, was not blocked by sumatriptan, dihydroergotamine or ergotamine tartrate, or by CP93129, a selective 5-HT1s receptor agonis@S4Z21.(The 5-l-ITIs receptor subtype in rats and mice subserves the same physiological functions as the 5-HTIo receptor subtype in guinea-pig and human. CP93129 blocks neurogenie plasma extravasation selectively in rat but not guinea-pig dura mater, whereas sumatriptan

is somewhat more potent at the 5-l-lTID than 5-HTIs receptor subtype and blocks plasma extravasation in both species21) o sumatriptan or dihydroergotamine significantly attenuate or abolish the mast cell, platelet and endo~eli~ cell changes accomneurogenic inflampanying mation. The existence of sumatriptan or dihydroergotamine receptors on each of these cell types seems most unlikely * the local anesthetic lidocaine blocks neurogenic plasma extravasation in dura mater with a time-course and effect similar to sumatriptan, CP93129 and neutral endopeptidase 24.11 (Moskowitz, M. A. et al., unpublished). All four drugs significantly reduce the when response administered intravenously either .before or after trigeminal stimulation * 5-HTIs/5-HT~~ receptors mediate inhibition of neurotransmitter release in other regions of the peripheral and central nervous systemz2. Prejunctional receptors on trigeminovascular fibers have also been identified for other receptor ar2-Adrenoceptors, histtypes. amine H3 receptors, p-opioid receptors and possibly somatostatin receptors have been implicated in prejunctional mechanisms recently on the basis of the effects of their respective ligands UKl~3~ and idazoxan, R-ar-methylhistamine and thioper-

TiPS -August 1992 /Vol. 131 azide, morphine and naloxone, and octreotide (a synthetic somatostatin analog) on the dural neuroinflammatory process. To this extent, the trigeminovascular system is similar to afferent fibers innervating the lung and other visceral organs. Inhibition of transmitter release mediated by such prejunctional receptors may explain the anecdotal success of somatostatin, adrenaline or narcotic analgesics in headache relief, and suggest novel avenues for treatments (Matsubara, T. et al., unpublished). The prejunctional receptor A previously unrecognized receptor that differs from the ~-HT~D receptor constricting vascular smooth muscle may mediate the blockade of neurogenic dural inflammation. This conclusion is based on three findings: the exquisite sensitivity of neurogenic inflammation to the effects of 5-carboxamidotryptamine; the failure of metitepine, a 5-I-IT1 antagonist that blocks sumatriptanmediated vasoconstriction, to block the actions of sumatriptan or 5-carboxamidotryptamine in the electrical stimulation model; and the failure of 5-I-IT itself to inhibit neurogenic inflammation. The differences may be exploitable in the development of antimigraine drugs that decrease pain but lack the ability to activate those 5-HT1* receptors that constrict coronary artery and intracranial vascular smooth muscle=. The capability of putative 5HTID receptor agonists that lack inherent analgesic properties to prevent neurogenically mediated responses adds further weight to the notion that dural inflammation may be relevant to headache pathogenesis. However, plasma leakage, neuropeptide levels, tissue ultrastructural appearance and especially blood vessel diameters are poor predictors of pain per se, thus conclusions about the likely presence or absence of pain based on these parameters can only be inferred in the most general terms.

Inhibition oft-fos expression

Expression of c-fos within trigeminal nucleus caudalis is useful for studying the brain’s responses to noxious stimulation. Hunt and colleagues found c-fos-like im-

309 munoreactivity within the superficial laminae I and II,, of the lumbar spinal cord after delivery of a noxious stimulus to the peripheti4. Basbaum and colleagues determined that the number of cfos-labeled cells in laminae I and II, was related to stimulus intensity, and that morphine pretreatment reduced this numbed. Sumatriptan, dihydroergotamine, Cl’93129 and morphine were also shown to attenuate the expression of c-fos-like immunoreactivity within laminae I and II, of the trigeminal nucleus caudalis caused by noxious meningeal stimulationX. Effective dosages of sumatriptan and related compounds were approximately equal to the amounts required to block neurogenic plasma extravasation within the dura mater. Meningeal afferents were stimulated by injecting an algesic substance, blood, into the subarachnoid space. The number of labeled cells was related to the amount of blood injected, and this number was reduced by chronic surgical or chemical denervation of primary afferent fibers terminating within laminae I and IL. As expected, cfos expression after noxious stimulation of the nasal mucosa (topical formalin) was not suppressed by administering sumatriptan. The expression and suppression of c-fos-like immunoreactivity in our model suggests the importance of primary afferent fibers to the actions of sumatriptan, and raises serious questions about the therapeutic role of drug-induced vasoconstriction. Blood is a potent vasoconstrictor when placed in the subarachnoid space, and in the experiments described, cerebral blood flow was reduced by 50%. The nature of the stimulus (both painful and vasoconstricting) and the actions of the drug on the c-fos response suggest that vasoconstriction is not the primary mechanism for c-fos attenuation in this model, nor is dilation a necessary substrate. If the assumptions concerning pain and c-fos expression are correct in trigeminal nucleus caudalis, then it follows that either sumatriptan possesses a second mechanism of action, or that one of the postulated mechanisms (neuronal or vascular) may not be correct. The clinical evidence discussed below favors the latter interpretation.

Evidence against the dilation/ constriction theory

By itself, receptor-mediated blockade of neural transmission and neurogenic inflammation does not exclude the possible importance of vasodilation/vasoconstriction to the genesis of migraine pain and its treatment. The challenge to this theory is based primarily on the limitations of Wolff’s data and emerging clinical information that clearly refutes Wolff’s, and more recently Humphrey’s’, contentions. First, Wolff’s data showing exaggerated temporal artery pulsations in migraineurs have not been replicated. Heyck’ could not reproduce the findings and, in fact, Wolff’s original pulse-wave tracings do not show the purported differences in pulse amplitude before and during pain5. Secondly, the temporal artery, the vessel Wolff studied most intensively and upon which he based his theory, is an extracranial cephalic vessel and therefore unlikely to possess the receptor that mediates the therapeutic effects of sumatriptan and ergot alkaloidsa’. Hence, the ergot-induced constriction reported by Wolff was probably mediated by a receptor other than 5-I-R+ It follows that Wolff% formulation of the vascular hypothesis was based on what we now know to be epiphenomena and unsubstantiated data. The Wolff hypothesis is also not supported by recent clinical studies measuring vessel caliber and blood flow during headache. Simple vasodilation is not usually painful. In seven preliminary studies examining more than 120 transcranial patients using Doppler flow velocity (an indirect vessel diameter measure of assuming that flow remains constant), consistent differences in vessel caliber were not detected between the pain-free interval and the attacks. When changes did occur, they often did not correspond to the side of headache or neurological aura. One notable report documented an association between vasodilation and headache in 10 classical migraine patients29, but the findings were not confirmed in studies of 40 other patients28*30. These discrepancies cannot be reconciled entirely by technical considerations, since consistent changes

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310 reflecting dilation were observed in cluster headaches and also in response to glyceryl trinitrate Of note, the administration. cluster headaches that were pmvoked by glyceryl trinitrate adnot developed ministration during peak vasodilation but during the waning period3*. Hence, it appears that vessel caliber alone does not determine the presence or absence of headache. Ti-imcranial Doppler studies from patients or normal subjects treated with sumatriptan or dihydmergotamine do not support a vascular mechanism of action either. Diener reported that increases in blood flow velocity lasted less than two minutes or did not accompany relief of headache pain in 16 drug-treated patients=, whereas Friberg et al. noted vasoconstriction in 10 ~thers~~. In 20 normal subjects, flow velocity did not change within the middle or basilar arteries cerebral after sumatriptan administration. Hence, obvious discrepancies are now recognized between the in viuo and in vitro actions of surnatriptan and ergot alkaloids in humans. Convincing data to support the role of drug-induced vasoconstriction even as a minor or secondary mechanism in migraine are lacking at present. Clearly, additional reports will be necessary to further establish vessel caliber as an important parameter in the pathophysiology and treatment of this condition. Data from blood flow studies also do little to strengthen the cause-and-effect relationship between vasodilation and pain. Blood flow, more a reflection of events within small resistance vessels, is typically low during the aura and during the initial headache phase of classical migraine. Only later may hyperemia develop and, most typically, the flow elevations sustain well beyond the headache phase. Hence, vasodilation of small as well as large cerebral vessels in migraineurs seems, at best, to be an inconsistent finding that in some instances may be associated with migraine pain. It is proposed that vessels may dilate sometimes during migraine headache, not as the source of pain, but as a component of both neurogenic inflammation and

central activation coupled to increases in brain metabolism2. In the former, vasodilation does not trigger pain but occurs pari ~USSU with neuropeptide release from perivascular fibers. Changes in blood levels of neuropeptides in migraine and after sumatriptan treatment are consistent with this interpretation. Because the determinants of vessel diameter are complex, vasodilation need not always accompany neuropeptide release. Algesic agents implicated in migraine (such as K+, prostaglandins, leukotrienes, bradykinin, histamine, H+) modulate vascular smooth muscle tone independently of their ionic or effects on receptor-mediated axonal membranes. Some cause constriction, and others dilation. To complicate matters, central transmission of impulses from trigeminal nerve elevates brain blood flow globallyss. The coupling mechanism may involve cortical activation and secondary flow changes mediated by increases in brain metabolism. Perhaps such a mechanism contributes to the bilateral elevations in brain blood flow in some unilateral cluster headaches. Additional arguments have been marshalled to support the vascular hypothesis1*27, and three examples are given below. l Proponents point to the association between pain and vasodilation after drug administration (e.g. nitrates). However, evidence is accumulating that direct neuronal and not vascular actions may cause headaches in this instance%. At low concentrations, glyceryl trinitrate and sodium nitroprusside release the vasodilator peptide CGRP from trigemr!ovascular fibers to mediate vasodilation within the pial circulation. Nitrateinduced vasodilation was markedly attenuated in the presence of CGRP%sr, a competitive CGRP receptor antagonist, or in the presence of trigeminal denervation, whereas the vasodilatory response to acetylcholine was unaffected=. It may turn out that headacheinducing agents such as alcohol or other vasodilator drugs stimulate perivascular nociceptive fibers directly as well. Of note, some drugs that are recommended for the treatment of headaches actually

promote vasodilation (e.g. Ca2+ channel blockers). l Stretching of vessels following angioplasty or balloon catheterization can be intensely painful. But pain of this type probably results from real or threatened vessel wall injury and underscores Sherrington’s notions about the pathophysiological basis for pain. Hence, the relevance of headache after balloon catheterization to obscure, esmigraine seems pecially since vasodilation is not invariant in migraineurs. l Some have suggested that the beneficial effects of noradrenaline and 5-HT in migraineurs argue for the importance of smooth muscle mechanisms. The observation, if true, is also consistent with neuronal effects at prejunctional receptors, as described above. On the basis of a neuronal mechanism, it is proposed that sumatriptan and the ergot alkaloids may be indicated for the treatment of headaches complicating meningeal inflammation. As evidence, it was observed that the drugs blocked c-fos expression in trigeminal nucleus caudalis caused by intracistemal carrageenan, a potent inflammatory ageng6. Moreover, it was recently shown (Moskowitz, M. A. et al., unpublished) that sumatriptan inhibits the expression of c-fos-like immunoreactivity within trigeminal nucleus caudalis induced by neocortical spreading depression, a neurophysiological event that others have postulated to underlie the ‘aura’ characteristic of migraine headaches. In this model, sumatriptan did not block spreading depression itself. We now know that sumatriptan and dihydroergotamine decrease headaches with diverse (albeit unknown) pathogeneses and clinical expression (e.g. cluster headache, classic and common migraine, drug withdrawal), and that headaches unrelated to migraine or cluster headaches respond as we1132*35.Along these lines, headaches associated with meningovascular irritation such as from AIDS or other viral and bacterial infections and from subarachnoid hemorrhage may be treated by sumatriptan and the ergot alkaloids. Post-traumatic headaches may also fall into this

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category. The absence of hypnotic effects and low addictive potential suggests that this strategy could be a useful adjunct to primary therapy, provided that the potential development of vasoconstriction is not a medical contraindication.

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Vasodilatorlvasoconstrictor mechanisms of vascular head pain have received exaggerated emphasis over the past 60 years, in part due to confusion arising from the prominent vasoconstricting actions of ergot alkaloids. Results to date do not support the enduring concepts of Wolff and his disciples that suggested a simple relationship between dilation and pain, and constriction and pain relief. Instead, the evidence favors a neurogenic mechanism of drug action based on blockade of neural transmission and neurogenic inflammation. It follows from these arguments that pharmacological strategies aimed at selectively activating prejunctional trigeminoinhibitory vascular receptors should clarify the relative importance of pre- and postjunctional receptors as well as promote the development of more selective headache medications with fewer side-effects.

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Moskowitz, M. A. (1987) I. Neurosci, 7, 4129-4136 Cline, M. A., Ochoa, J. and Torebjork, H. E. (1989) Brain 112.621-647 Goadsby, .P. J., Edvinsson, L. and Ekman, R. (1990) Ann. Neural. 28. 183-187 Buzzi, M. G., Moskowitz, M A., Shimizu. T. and Heath. H. H.. III 119911 Neuropharmacology 30,~11931200 I~ -’ Goadsby, P. J. and Edvinsson, L. (1991) Cephalalgia II (Suppl. II), 3 Buzzi, M. G., Sakas, D. E. and Moskowitz, M. A. (1989) Eur. J. Pharmacol. 165,251-258 Dimitriadou. V.. Buzzi. M. G.. Theoharides] T. C. and .Moskowitz; M. A. (1992) Neuroscience 48,187-203 Buzzi, M: G., Dimitriadou, V., Theoharides, T. and Moskowitz, M. A. Brain Res. (in press) Matsubara, T., Moskowitz, M. A. and Byun, B. J. (1991) Br. I. Pharmacol. 104, 3-4 Middlemiss, D. and Hutson, P. H. (1990) in The Neuropharmacalagy of Serofonin (Whitaker-Azmitia, P. M. and Pemutka, S. J., eds), pp. 132-148, NY Academy of Science _ Buzzi, M. G., Moskowitz, M. A., Pemutka, S. J. and Byun, B. (1991) Br. J. Pharmacol. 103,1421-1428 Hunt, S. P., Pini, A. and Evan, G. (1987) Nature 328,632-634 Presley, R. W., Menetrey, D., Levine, J. D. and Basbaum, A. I. (1990)

1. Neurosci. 10, 323-335 26 Nozaki, K., Moskowitz, M. A. and Boccalini, P. (1992) Br. 1. Pharmncol. 106, 405-41s 27 Humohrev. P. P. A.. Feniuk. W.. Perren. M. J.,-Be&ford, I. J: M. and Ski&e, M. (1990) in 7he Neuropharmacolopv of Serotonin (Whitaker-Azmitia, P. Mrand Peroutka, S. J., eds), pp. 587-600, NY Academy of Science 28 Zwetsloot, C. P., Caekebeke, J. F. V., Jansen, J. C., Odink, J. and Ferrari, M. D. (1991) Cephalaigia 11,103-107 29 Friberg, L., Olesen, J., Iversen, H. K. and Speding, B. (1991) Lancet 338,1%17 30 Thie, A. (1991) in Migruine und Other Headaches: Vascular Mechunisms (Olesen, J., ed.), pp 263-274, Raven Press 31 Dahl, E., Russell D., Nyberg-Hansen, R. and Rootwelt, K. (1990) Cephulnlgin 10,87-94 32 Diener, J. C. et UL (1991) Headache 31, 205-209 33 Lang, R. and Zimrner, R. (1974) Exp. Neural. 43,143-161 34 Wei, E. P.. Moskowitz, M. A., Boccalini, P. and Kontos, H. A. (1992) Circ. Res. 70, 13x%1319 35 Ferrari, M. D. et al. (1991) New Engl. J. Med. 325,316-321 CP93l29: 3-(1,2,5,6-tetrahydropyrid-4-yl)pyrrolo[3,2-bJpyrid-5-one UK14304:5-bromo-6-(2-imidazoline-2-ylamino)quinoxaline

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of GABAA and glutamate receptors’ will be given at the

15th Annual Meeting of the European Neuroscience Association 13-17 September 1992, Munich

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