Targeting the Trigeminocervical Complex in Migraine

Abstract and Introduction

Abstract

Migraine is one of the most severe and debilitating brain disorders. Most scientists accept that it involves activation and sensitization of the trigeminovascular system, which includes the sensory peripheral projections to the pain-producing dura mater, and a central projection to the trigeminal nucleus caudalis and its cervical extension, the trigeminocervical complex (TCC). The development of the anti-migraine therapeutics, triptans-5-HT_1B/1D receptor agonists, had originally targeted the craniovasculature to exert therapeutic effects, and this locus of action seemed to predict efficacy in the clinic. However, subsequent development of novel targets, using the same strategy failed to replicate this early success and as a consequence central mechanisms of action away from the dural vasculature were thought to be responsible for these therapeutic effects. Coupled to this, migraine has been hypothesized to involve a dysfunction of areas of the brainstem and diencephalon, which seem to mediate the activation, or perception of activation, of the trigeminovascular system as well as sensitization of neuronal pathways that drive trigeminovascular activation. Therefore, drug targets that act in the brain, specifically on the central component of the trigeminovascular system, the TCC, would seem to be ideally placed to modulate this nociceptive pathway and relieve migraine, but particularly the headache phase. This review will discuss how the TCC, rather than other more craniovascular sites, may be the anatomical target of some of the current and emerging therapies to relieve migraine symptoms, and why this should prove to be a fruitful area for drug development for the treatment of migraine.

Introduction

Migraine is a chronic and disabling disorder of the brain that affects at least 15% of the population,^[1,2] and is estimated to cost the USA and European economies US$19.6 billion and €27 billion a year in lost personnel hours, respectively.^[3,4] The exact pathophysiology of migraine is not fully understood, but it is now widely accepted that it involves activation and sensitization of the trigeminovascular system,^[5,6] as well as nuclei of the brainstem and diencephalon.^[7] Detailed reviews of the anatomy and physiology of the trigeminovascular system and its role in migraine can be found elsewhere.^[7,8] However, briefly, it includes the pseudounipolar trigeminal ganglion that has central afferent projections to the trigeminal nucleus caudalis in the medullary spinal cord, and a peripheral projection, largely from the ophthalmic division of the trigeminal ganglion, which innervates the cranial blood vessels and other cranial structures, including the pain-sensitive dura mater, via meningeal nociceptors. In animal models, it has been demonstrated that the central afferent projection to the trigeminal nucleus, using stimulation of the dura mater, also extends to the C2 and C3 regions of the cervical spinal cord,^[9–13] which have been collectively described as the trigeminocervical complex (TCC). The TCC also receives inputs from the greater occipital nerve that converge with inputs from the dura mater.^[14,15] It is thought that the anatomical transition from the trigeminal nucleus to the cervical spinal cord represents a functional continuum and it is likely that inputs to the TCC can explain the common distribution of pain in migraine in frontal, temporal, parietal, occipital and higher cervical regions.^[16]

It is known that the TCC is a key relay center for conveying sensory and visceral information, particularly nociceptive, from the head and orofacial region, including the cranial vasculature, to higher pain processing centers in the brain, along the trigeminohypothalamic tract to the hypothalamus,^[17–20] and trigeminothalamic (or quintothalamic) tract^[21–23] to the thalamus. The TCC also receives and makes projections to key areas of the brainstem involved in the processing of nociceptive information from the head, including the superior salivatory nucleus, the ventrolateral periaqueductal gray and rostral ventromedial medulla.^[24–27] The TCC is therefore ideally situated, receiving inputs and projecting to all areas of the central nervous system thought to play a part in the generation of symptoms of migraine. It is clear from preclinical studies that neurons in the TCC are activated and modulated by various pathways thought to be involved in and contribute to migraine pathophysiology. In the periphery, it is known that electrical or mechanical stimulation of the trigeminal nociceptive innervation of dural blood vessels causes neuronal activation in the TCC.^[9,10,28] Furthermore, activation of meningeal nociceptors with pro-inflammatory mediators sensitizes first-order neurons in the trigeminal ganglion^[29] and second-order central trigeminovascular neurons in the TCC.^[11] This causes an increase in basal firing of TCC neurons, but also hypersensitive response of TCC neurons to intracranial stimulation of the dura mater and extracranial stimulation of cutaneous facial receptive fields, that extends beyond the ophthalmic dermatome. Peripheral facial inflammatory mechanisms in the orofacial region affecting both maxillary and mandibular divisions of the trigeminal nerve also alter firing of TCC neurons.^[30] These neuronal responses in the TCC are also modulated by manipulation of brainstem and diencephalic structures, reviewed recently^[7] but summarized briefly here. Activation of the superior salivatory nucleus causes neuronal activation in the TCC.^[31,32] Manipulation of the ventrolateral periaqueductal gray,^[33–35] rostral ventromedial medulla^[27] and nucleus raphe magnus,^[26] can all modulate basal and/or dural-evoked nociceptive firing in the TCC, some of these responses are mediated by known anti-migraine drugs. Finally, it is known that biochemical manipulation of the posterior hypothalamus can similarly modulate basal and/or dural-evoked nociceptive firing in the TCC.^[36,37] Therefore, various peripheral and central mechanisms are involved in activating and modulating trigeminovascular nociceptive pathways thought to be involved in migraine pathophysiology, and each of these pathways also has the potential to be a therapeutic target in migraine.

In the last 20–30 years, theories of migraine have moved from more vascular hypotheses to the current thinking that migraine is a disorder of the brain, and it has been hypothesized to be caused by a dysfunction of neural mechanisms that mediate trigeminovascular activation,^[6,7] as well as sensitization of pathways that project to the dural vasculature,^[6] and to and from brainstem and diencephalic structures. Taken together, these ideas would suggest that the TCC is well suited as a therapeutic anatomical target in the CNS for the treatment of migraine, or targets that effect neuronal inputs to the TCC. Indeed, it is thought that not only do pharmacological approaches help inhibit trigeminovascular activation to relieve migraine it is likely that device-based therapies also ultimately help by reducing the level of trigeminovascular nociceptive traffic.^[38] However, the remainder of this review will concentrate specifically, using examples of current and emerging pharmacological approaches, on how we believe many anti-migraine drugs target the TCC to abort or prevent migraine, and may even modulate neuronal projections to the TCC to alter its ability to fire, rather than more peripheral vascular mechanisms, and that this is a fruitful area for drug development for the treatment of migraine.