Migraine: A Chronic Sympathetic Nervous System Disorder

Stephen J. Peroutka

Disclosures

Headache. 2004;44(1) 

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The major finding of the present study is that a wide variety of diagnostic tests and clinical signs indicate that migraine shares many features with other chronic SNS disorders. Indeed, the fact that sympathetic dysfunction is present in migraine has been noted by many investigators for more than 150 years and has been confirmed in a recent population study.[39] In the mid-19th century, the vasoconstrictive aspect of migraine was attributed to an "irritation" of the cervical sympathetic system whereas the vasodilatation component of migraine was attributed to a "paralysis" of the cervical sympathetic system.[40,41] More recently, migraine was suggested to result from a dysautonomia involving principally the central noradrenergic system and its cortical connections.[42] Numerous other investigators have suggested that a disturbance of the autonomic nervous system is a primary characteristic of migraine.[43,44,45,46,47,48]

In comparison to PAF and MSA, however, migraine clearly represents a distinct subtype of sympathetic hypofunction. Despite the many overlapping symptoms between these 3 clinical entities, the throbbing, often unilateral, headache of migraine has rarely been reported to be present in either PAF or MSA. Therefore, an important issue that must be addressed is how SNS dysfunction might induce migraine in some individuals but not in others (including most of those with MSA and PAF). One possible explanation is that MSA and PAF differ from migraine in that they are characterized by the anatomical absence of the entire sympathetic neuron (or nerve terminal) as a result of central sympathetic lesions in MSA and peripheral sympathetic lesions in PAF. By contrast, there is no known evidence that an anatomical loss of central or peripheral sympathetic neurons exists in migraine.

How, then, could a migraine attack occur as a result of SNS dysfunction if the SNS in migraineurs is anatomically intact? Although NE is the neurotransmitter most frequently associated with the sympathetic nervous system, it is only one of many cotransmitters. Dopamine (the immediate chemical precursor of NE), adenosine triphosphate (ATP), neuropeptide Y, dynorphin, and prostaglandins are other neurotransmitters released from sympathetic neurons.[49,50,51] Moreover, physiological studies have demonstrated variations in the relative amounts of NE versus the other sympathetic cotransmitters that are released from the SNS at different levels of activation.[49,50] For example, following 30 minutes of superior cervical ganglion stimulation, salivary gland dopamine levels increase 1700% while NE levels drop 67%.[52] Thus, prolonged stimulation of the SNS depletes NE stores rapidly and leads to an increase in the neuronal release of dopamine (the immediate chemical precursor of NE), adenosine triphosphate (ATP), adenosine, and prostaglandins.

The effect of prolonged stimulation of the SNS on cotransmitter release from the SNS is shown schematically in Figure 2. Many of the symptoms of an acute migraine attack can be attributed to elevations in the three cotransmitters shown as well as to a deficiency of norepinephrine. For example, nausea, vomiting, and yawning have been related to excessive dopamine levels,[53] an increase in pain sensitivity and inflammation is clearly induced by prostaglandins and sedation has been associated with elevated adenosine levels. Lack of norepinephrine, as described in this report, would lead directly to vasodilatation, ptosis, and other orthostatic symptoms.

Figure 2.

The effect of prolonged or "excessive" stimulation of sympathetic nervous system co-transmitter release

It is therefore proposed that the primary symptoms of migraine are caused by the differential release, following "excessive" SNS stimulation, of sympathetic cotransmitters. Sympathetic activation is a primary component of the physiological stress response. Stress is the most commonly cited cause of migraine. Thus, the SNS offers an unequivocal link between known causes of migraine and a specific biological system. Specifically, it is proposed that a migraine attack may occur when NE release from sympathetic terminals is decreased by prolonged or excessive SNS stimulation at the same time as the concurrent release of dopamine, adenosine, and prostaglandin is increased from the SNS.

This hypothesis is consistent with the observations of Wolff and colleagues. Approximately 24 hours prior to a headache, vasoconstriction is the predominate vascular state of the extracranial vasculature and was noted by Wolff to be "frequently maximal during the minutes preceding the onset of the headache."[54] The vascular theory of Wolff attributed the vasoconstrictor phase of the migraine prodrome to neuronal release of NE, which than acted on vascular α-adrenergic receptors and caused the vasoconstriction. By contrast, the painful phase of migraine was attributed to a painful vasodilatation of extracranial arteries.[55]

However, an adequate physiological explanation was never developed by Wolff to account for the transition from the nonpainful vasoconstriction phase of migraine to the subsequent painful vasodilatation phase. The hypothesis summarized in Figure 2 could provide a pathophysiological explanation for this vascular transition. Specifically, at some point in the process of prolonged or excessive SNS stimulation (shown along the x-axis), the relative synaptic concentrations of sympathetic cotransmitters that cause vasoconstriction (ie, norepinephrine) and that cause vasodilatation (ie, dopamine, adenosine, prostaglandins) change so that the net effect of SNS stimulation on the extracranial circulation is no longer vasoconstriction but vasodilatation.

Furthermore, this hypothesis is also consistent with a major role for the trigeminovascular system in migraine. The direct relationship that exists between the SNS and the trigeminovascular system is underappreciated in the medical literature. The sympathetic system, both peripherally via the superior cervical ganglia and centrally via the locus coeruleus, provides a major inhibitory input to the trigeminal system.[56,57] At the vasculature level, activation of the trigeminal system causes a net vasodilatation in the extraparenchymal cranial circulation. By contrast, activation of the SNS in the same vascular distribution causes a net vasoconstriction (under normal conditions). Thus, the vasoactive roles of the SNS and trigeminal system are normally in opposition. Therefore, loss of SNS function, specifically NE, would lead to extracranial vasodilatation and trigeminal activation (as a result of the normal inhibitory effect of the sympathetic system). The probable role of trigeminal activation in migraine has been well described.[58]

Therapeutically, this hypothesis is consistent with current acute pharmacological approaches to migraine. For example, the "decrease" in the vasoconstrictive effect of NE can be replaced by vasoconstrictors such as ergots and triptans. In addition, it is well established that migraine can also be treated effectively by blocking the "increase" in the vasodilatory effects of dopamine, prostaglandins, and adenosine. Of note is the fact each of these effective, yet mechanistically distinct, therapeutic approaches can be related directly to the current pathophysiological hypothesis shown in Figure 2.

Conceivably, genetically-based differences in the population could result in variations in an individual's ability to synthesize, store, release, and/or re-accumulate NE within the SNS nerve terminals, both centrally and peripherally. Variations in degrees of SNS activation could also cause central and/or peripheral depletion of NE in certain individuals. Future studies are needed to more clearly determine the roles of SNS cotransmitters in the pathophysiology of migraine. Ultimately, an improved understanding of the role of sympathetic function and dysfunction in migraine may help to prevent and/or more effectively treat migraine and other headache attacks.

The amount of objective diagnostic data and clinical information indicating that migraineurs have a chronic sympathetic hypofunction is overwhelming. An important issue that remains unclear, however, is whether the SNS dysfunction is a primary cause of migraine or is secondary to some other pathophysiological feature of migraine. Conceivably, genetically based variations in the population could result in variations in an individual's ability to synthesize, store, release, and/or re-accumulate NE within the postsynaptic SNS nerve terminal. Alternatively, more central variations in SNS outflow could cause peripheral depletion of NE. Future studies are needed to more clearly determine the cause of the SNS hypofunction in migraineurs.

Sympathetic activation is a primary component of the physiological stress response. Stress is the most commonly cited cause of migraine. Thus, the SNS offers an unequivocal link between known causes of migraine and a specific biological system. An increased appreciation of the role of SNS dysfunction in migraineurs might lead to enhanced diagnostic precision and clinical management. Ultimately, an improved understanding of the role of sympathetic dysfunction in migraine may help to prevent or more effectively treat migraine and other types of headache.


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