7.1 Introduction

7.2 Background on Migraine Headache

Migraine headache is a spectrum of cerebrovascular disorders that result in widespread su ering and long has been a challenge to medical therapeutics.2,3 If the pain and distress itself is not enough, in the United States alone the economic impact for lost work productivity and treatment is estimated to be billions of dollars annually.4 While for many years the genesis of migraine pathophysiology was largely unknown, by the 1960s, mostly due to the presence of anti-migraine ergot alkaloids (e.g. ergotamine, ergonovine, methysergide and dihydro-ergotamine) with complicated tryptamine structures, serotonin (5-hydroxytryptamine; 5HT) began to take a lead in mechanistic speculation.5 Although 5HT may now be recognized more in a modulatory role rather than a central position in the pathogenesis of migraine headache, in the context of multi-faceted signaling networks, which are the theme of this chapter, 5HT is involved in a number of the pathways common to migraine and other related disorders. 5HT may be a crucial integrative factor with respect to these diverse networks.

Serotonin is widely active in nature as a regulator and modulator of physiological systems via nervous, hormonal and autacoidal means.6–10 Of the seven known classes of 5HT receptors (R), receptors from G protein-coupled categories (5HT1 and 7; especially 5T1a, 1d, 1e and 1f; and 5HT2; especially 5HT2a) have been particularly prominent in ideas underlying headache disorders and in drug development.11 G protein coupling of these receptors is an important characteristic in that these transducers are common to many other non-serotonin receptors and thus keys to shared communication. To date, the lone category of 5HTR ionophores (5HT3) has not been implicated other than in the nausea and vomiting that often accompanies migraine, but that issue will be addressed later in this discussion (see astrocyte section 7.4; 5HT3R is mentioned there in the context of cultured astrocytes).

Development of the triptan 5HT1d receptor agonists (such as sumatriptan) from knowledge of the actions of the semi-synthetic ergot derivative methysergide5 led to substantial improvements in treatment of acute migraine. Although drugs like methysergide (a 5HT2aR antagonist) have considerable e cacy as migraine prophylactics, toxicity is a definite concern, and preventative treatment remains problematic. A serious problem with the ergot drugs, especially in the past, when they were used much more in migraine than they are today, was the inability of some patients to adhere to dose and time constraints considering the drugs’ toxicities (this was especially true of methysergide in which ‘‘drug vacations’’ were absolutely necessary for safe utilization of the drug for long-term use).

Ethnopharmacologic approaches to migraine and related headaches have been employed both culturally and in a more systematic and recent scientific vein.12 An example would be the migraine prophylactic, feverfew, which has been studied in vitro13 as well as in clinical studies that support its e cacy. While the overall scientific vigor of studies analyzing alternative versus ‘‘conventional’’ approaches to migraine therapy is still controversial,14 the use of

multi-faceted (a crude or semi-crude mixture of compounds from a natural product) herbal drugs to treat interconnected regulatory pathways in headache is appealing, and, at the very least, justifies considerably more research e ort to validate the putative e cacies (see the brief discussion of this topic using cannabis as an example in the introductory chapter of this book).

An interesting development in this regard is increasing evidence that serotonin15 as well as dopamine (DA) plays a role in the brain’s reward system. This may be at least partially explanatory for abuse potential of the ergot drugs, which interact with multiple receptors, including those for both 5HT and DA. The observation that 5HT is involved with reward may play a role in future drug development. Possibly related to this reward e ect is the demonstration that corticotrophin releasing factor (CRF; CRH) applied to the dorsal raphe nuclei di erentially dose-regulates serotonin in the nucleus accumbens (a brain area suggested to be of great importance to reward events and drug dependency).16 This stress-related connection is a potential example of how looking at uncommonly considered networks could produce unexpected results in chronic treatment of migraine (which is the area of greatest need in migraine drug development), much as it has in previously non-responsive disorders such as obesity.17 Similar thoughts on interacting signaling pathways in schizophrenia are now under consideration in developing new anti-psychotics.18

While many hypotheses have been advanced as to migraine pathophysiology, the only firmly established mechanism is for the rare form of headache known as familial hemiplegic migraine.19 In this case, a mutation results in a defective calcium channel, and much mechanistic speculation currently surrounds socalled channelopathies.2 The mechanistic theme of channelopathies goes far beyond migraine to a number of neurological disorders, some of which are mentioned in relation to migraine in this chapter.

Amongst the many ideas that have been advanced to explain migraine occurrence, some of the more interesting and diverse examples include: migraine as dysfunction of the autonomic nervous system20 and migraine as a disorder of mitochondria.21 Recently, it has also been speculated that migraine pathophysiology may be associated with energy balance metabolism. There is a high rate of comorbidity between migraine and the eating disorders anorexia nervosa and bulimia nervosa.22 Interestingly, there is a correlation between serotonergic regulation and hypothalamic physiology and pathology.23 Specifically, the adipocyte hormone, leptin, influences melanocyte-stimulating hormone (MSH) in the hypothalamic arcuate nucleus. Further, the MSH system is under serotonergic control. Beyond these considerations, neuroendocrine dys-regulation, energy intake and the sleep disorder known as night eating syndrome are correlated.24 Another hypothalamic-based connection that is worth exploring in the migraine area is adiponectin.25 Adiponectin receptor type 1 (AdipoR1) in the hypothalamus triggers the insulin (see discussion under the section 7.5: Adipokine signaling) and leptin (see the next paragraph) pathways following activation by adiponectin.

Migraine is known to be triggered by a wide variety of factors, and the observation that hypothalamic involvement, such as via autonomic

regulation, may be one of an interrelated set of triggers that may fit the adipokine signaling pathways emphasized in this chapter.26 Specific adipokines that are known to exert e ects because of interactions with discrete hypothalamic nuclei include: leptin (arcuate nucleus; and after NPY release, the paraventricular nucleus) and ghrelin (arcuate nucleus); and both ghrelin and the orexins regulate growth hormone release.27 There may be an interesting connection between ghrelin, metabolic dysfunction and the brain’s reward system (noted earlier with respect to serotonin). Another neurotransmitter/neuropeptide connection that could have relevance to migraine is the synergistic and complementary role that the orexins and histamine have in weight regulation and sleep.28 These hypothalamic e ects may tie in to migraine, as we will discuss later in the chapter, via a larger theme of sleep, metabolic regulation and migraine pathogenesis.

Ghrelin binds to and activates receptors in the substantia nigra, ultimately increasing dopamine in the corpus striatum.29 This neuroprotective e ect is most directly related to neurodegenerative disorders such as Parkinson’s disease; however, the potential to re-regulate metabolic problems in the neurodegenerative setting may have relevance to metabolic dys-regulation in migraine and perhaps also to related dopamine reward pathways, although this is an area that requires research exploration.

Clearly, adipokines such as leptin and visfatin have been shown to play a role in the pathophysiology of diabetes and obesity.30 It is noteworthy that in this diabetic/obesity realm, adipokines may be secreted not only by adipocytes but also by macrophages that have moved into adipose tissue. This inflammatory connection could be of relevance to migraine headache, in which there are known inflammatory components which are at least modestly accessible in a pharmacotherapeutic sense by NSAIDs such as ibuprofen and aspirin. Additionally, the hypothalamic hormones, Orexin A and B, mentioned above as appetite regulators, have been directly implicated in pain processing, including that found in migraine.3

7.3 Migraine and Neuropathic Pain

Broadly speaking, there are some common characteristics31 between certain types of migraine and another highly refractory disorder known as neuropathic pain.32 In migraine, the fifth cranial nerve system (trigeminal) has come under increasing scrutiny as being central to the sensory and pain processing phenomena leading to migraine headache. Painful stimuli associated with trigeminal pathology may produce pain via the nearby superior sagittal sinus.3 Overall, ‘‘normal’’ stimuli such as light and sound may produce pain much as in general neuropathic pain; that is, there is pain production that exceeds the amount expected from the sensory input. Additionally, the long-recognized phenomenon of cortical-spreading depression (CSD) may trigger trigeminal dys-regulation, and the complicated factors leading to CSD may be related to other upstream signaling complications, only now being identified as the initial causes of migraine.

One interesting example that could have parallels to headache pain involves injury to the mouse sciatic nerve (SCN). Such injury activates macrophages in the vicinity, which results from upregulation of leptin in adipocytes.33 This type of mechanism has potential for broad spread implications. Leptin is overproduced in obesity-related metabolic disorders like diabetes. Accordingly, metabolic pathology may leave subjects prone to neuropathic pain. This spectrum of dys-regulatory events may be reversible via weight control and subsequent lowering of leptin production, and fits the lifestyle themes promoted in this book.

Seemingly, these unsuspected metabolic signaling connections may have similar applications to other disorders such as headache. Adipoonectin has also been linked to migraine,34 and it is relevant to note that abnormalities in feeding behavior (both overand under-eating may be relevant) suggest that metabolic dys-regulation itself may be the trigger. Both anorexia nervosa and bulimia nervosa are potentially related to migraine via biogenic amine action and metabolism,35 and the trace amines tyramine, octopamine and synephrine may tie this association to the neuroendocrine system. Trace amine associated receptors are found in particular brain regions regulating hormones such as the hypothalamus and amygdala.36

Traditional di culties with reducing neuropathic pain have slowly been addressed in recent years.37 Systematic and highly organized schema have been developed and tested for guiding both conceptualization as well as therapeutic strategies for handling this puzzling set of disorders. From a pharmacotherapeutic standpoint, current state-of-the-art treatment utilizes a diverse array of drugs, either alone or more likely in combination, for reducing the severity and frequency of neuropathic pain. Specific calcium channel inhibitors, anti-depressants, GABA agents, anti-seizure agents, opioids and cannabinoids, amongst others, constitute the e ective list. As of yet, the exact mechanisms for e cacy are not known or at best are incompletely understood. Despite this ignorance, the multiplicity of useful drugs suggests involvement of many underlying hormonal, neurotransmitter and ionic systems, and very likely complex interactive signaling networks, much as is suspected in migraine headache.

One historical problem in understanding migraine pathophysiology and appropriately targeted therapy is that the label migraine represents a number of related, yet unique, disorders. Thus, at least some of the underlying mechanisms should di er from one migraine subtype to another. Nevertheless, whether considering subtypes or the general disorder, there is substantial evidence to support multiple interacting mechanisms. For example, migraine and depression are comorbid, and the presence of pain during pharmacological treatment of depression has been recognized as an interfering factor.38

Additionally, fibromyalgia and chronic headache are comorbid,39 and in both cases disruption of sleep mechanisms is associated with the disorder. Since adipokines under consideration in this chapter are so highly correlated with sleep behavior, it is tempting to hypothesize that adipokine signaling provides an underlying template for these related disorders. Attempts to study this