Migraine
Pathogenesis
Meninges & Vasoconstriction
The trigeminal nerve has a substantial sensory area that includes the face, the oronasal mucous membranes, the teeth, the dura matter and the major intracranial blood vessels. It has both motor and sensory components, which are particularly important to the muscles involved in mastication (chewing). The motor root lies medial to the sensory root, which is larger, and they project to the pons (the sensory root terminates in the principal pontine nucleus of the upper pons). These sensory projections send second-order (post-synaptic) neurones across the pons midline, where they join the trigeminothalamic tract; the two neurones join above this level and are then referred to as the ‘Trigeminal Lemniscus’. Dorsal to this principal sensory nucleus lies the mesencephalic tract of the trigeminal nerve, with the parent nucleus being located in the midbrain. [6, 40]
Sensory Nuclei
There are three trigeminal nerve associated sensory nuclei: the mesencephalic, the pontine (principal) and the spinal.
- The Mesencephalic nucleus
- This is the only CNS located nucleus that contains the cell bodies of primary sensory neurones. Peripheral neurone processes enter the sensory root via the mesencephalic tract of the trigeminal. Some processes travel in a mandibular division – to supply the stretch receptors in the masticatory muscles. The others travel in maxillary and mandibular divisions to supply stretch receptors in the suspensory, periodontal teeth ligaments.
- The Pontine Nucleus
- The Pontine Nucleus is the primary trigeminal sensory nucleus and is homologous to the posterior column nuclei. It processes discriminative tactile information from the face and oronasal cavity.
- Spinal Nucleus
- This extends from the lower segment of the pons down to the third cervical
segment of the spinal cord. The main spinal nucleus (there are two minor
ones that receive afferent from the mouth), the pars caudalis, receives
nociceptive and thermal information from the whole of the trigeminal area
and some beyond that as well.
The spinal nucleus is effectively an extension of the outer laminae of the posterior horn of the spinal cord (laminae I-III) and this can be seen when sectioned. The inner laminae (IV-VI) are largely compressed and not relevant in comparison to the outer laminae (laminae III & IV are known as the magnocellular portion of the nucleus. In animals only laminae I contains nociceptive-specific internuncials. Polymodal neurones are located in the magnocellular nucleus and they correspond to neurones found in laminae V; these polymodal neurones respond to tactile stimuli in the trigeminal area and also to noxious mechanical stimuli (Nociceptive-specific neurones, by contrast, have very small receptive fields). Arrangements for pain modulation appear to be the same as in the spinal cord, including GABAergic inhibition and Serotinergic stimulation. Afferents come from three sources, the Trigeminal Afferents, the Vagal Afferents and the Cervical Afferents.
The Trigeminal afferents are the main processes of the trigeminal ganglion;
peripheral processes terminate in tactile and nociceptive endings in the territory
of the nerves three divisions. One of the clinically important nerve terminals
are those in the dura matter of the anterior and meddle cranial fossae; tension
of these areas, due to vasoconstriction or other factors, results in headache
and hence contributes to migraine pain. [6,
40]
The internal carotid artery in the cavernous sinus lies close to the ophthalmic division of the trigeminal nerve; this branch of the trigeminal nerve gives rise to afferents that accompany the artery to its bifurcation with anterior and middle cerebral branches. Nerve fibres remain with these arteries and reach the posterior cerebral artery too. Neuropeptides, particularly the nociceptive related Substance P, have been identified in these neurones. Collectively known as the trigeminovascular neurones their role is not fully understood but their presence accounts for frontal headache and cerebral artery distortion associated with space-occupying lesions; this may also be significant in migraine.
It is the Vth Cranial nerve and the trigeminal ganglia that are thought to be involved in the pathogenesis of migraine and hence important in considering the role of bradykinin in this situation.
Neurogenic Inflammation
Moskowitz, some years ago, suggested the role of neurogenic inflammation in migraine; since then the theory has been developed and defined. The main features of neurogenic inflammation are vascular dilatation, enhanced leakage or extravasation of plasma proteins across the endothelium with resulting oedema. A complicated chain of chemical and physiological events causes the changes that excite, sensitise and lower the threshold of the neurones affected. In migraine the neurones in question are the trigeminal neurones, in particular their nociceptive terminals. Neurogenic inflammation is developed by activation of trigeminal nociceptive fibres in the region of the dura’s blood vessels.
The main substances and processes involved are outlined in the diagram.
Bradykinin (BK) is known to be involved in the genesis of peripheral inflammation, causing arteriole relaxation through an EDRF (endothelium-derived relaxing factor) mediated process. It also has significant effects on vascular permeability and it can also elicit pain through direct stimulation and sensitisation of neurones. Some animal studies have shown BK to be active in exciting nociceptive endings of intracranial vascular neurones but the mechanisms of which have not been investigated in relation to migraine. BKs effects may also be mediated by prostaglandins, but again this has not been clarified in the trigeminal neurones involved in migraine. [8, 11, 19, 20]
For further information see the bradykinin section.
Serotonin
Serotonin (5-HT) is a chemical mediator that often acts as a neurotransmitter (NT) within the central nervous system. It is also present in the intestinal wall and in the blood platelets. The platelets contain high concentrations of 5-HT transported actively from the plasma and released when platelets aggregate at tissue damage sites. It is synthesised from the amino acid tryptophan via enzymic reactions. 5-HT has an important role as a NT and also as a co-transmitter. It acts on 5-HT receptors, of which there are numerous subtypes, to elicit cellular responses. Actions include stimulating nerve endings, to cause platelet aggregation, to affect blood vessels and to affect smooth muscle cells in the intestine to cause gastrointestinal motility.
The release of serotonin by platelets and also by neurones has been implicated in the pathogenesis of migraine. Not only may it be involved in the central and prominent features of migraine (such as aura, pain and vascular dilatation) it may also have an effect on other symptoms such as vomiting.
The evidence for the involvement of 5-HT rests on two key factors. Firstly the concentration of the 5-HT metabolite 5-HIAA is found to dramatically increase in the urine during a migraine attack and the blood levels of 5-HT fall. The falling blood levels can probably be attributed to the depletion of platelet 5-HT and hence a rapid reuptake by the platelets will express itself in a decrease in plasma levels. Secondly the drugs that are predominately effective in the treatment of migraine are 5-HT receptor agonists or antagonists. (Rang Dale & Ritter)
The receptors that are involved in 5-HTs actions in migraine are not fully identified but the 5-HT related drugs used to treat migraine do target specific receptors; these are covered in the treatment section. [8, 13, 35, 48, 52]
Summary
There are four main threads of concept in the theories of the pathogenesis of migraine, these are:
- The trigeminovascular system acts as a protective system to the brain against tissue damage and insults such as ischaemia and toxins, much like peripheral tissues.
- The trigeminal nerve can be stimulated both electrically and chemically, by such as Serotonin, prostaglandins and neuropeptides. Migraine triggers either act to alter these chemical mediators, either by directly changing levels or through neural routes.
- Substance P and CGRP are released by the trigeminal nerve, on stimulation, into the dural and meningal blood vessels. This stimulates the processes of inflammation, with the degranulation of mast cells and attraction of leukocytes. This results in the release of histamine and platelet release of Serotonin, which leads to vasodilation and exudation of plasma into the surrounding tissues. The resultant swelling and inflammation of blood vessels are consistent with Wolff’s proposed ‘sterile arteritis’.
- Neurogenic inflammation and the release of Substance P cause cranial arterial distension and headache pain. The mediator of this vasodilation is likely to be nitric oxide and it may have a dual role in acting as a nociceptive neurotransmitter. Other neuropeptides may also be involved in the development of neurogenic inflammation and the possibly vital production of nitric oxide.
Whilst the probable processes of how the arterial dilation and other effects
are known it is not known what stimulates these. Chemicals known to be released
by the trigeminal sensory neurones in migraine, such as Substance P and CGRP,
lead to vasodilation etc, but what precipitates their release is unclear.
Release of such substances is directly due to neuronal activation but obviously
the neurone must be stimulated in the primary instance in order to trigger
the migraine-causing cascade of events. This stimulatory factor has been linked
to many external factors, such as diet, but what internal factor is created
by these probable causes is not known. This website asks the question whether
bradykinin, the neuropeptide, may fill that role. [23,
24, 43,
59]
