Personal ViewOrigin of pain in migraine: evidence for peripheral sensitisation
Introduction
Great progress has been made in migraine research during the past few decades:1 migraine has been better classified and defined;2 imaging studies have shown that cortical spreading depression is most probably the phenomenon that underlies the migraine aura;3, 4, 5 the neurobiology of the trigeminal vascular system has been delineated;6, 7, 8, 9, 10, 11, 12, 13 several messenger molecules have been strongly implicated in the initiation and triggering mechanisms of migraine;14, 15, 16, 17, 18 the importance of central sensitisation (increased excitability of neurons in the CNS) of pain pathways has been documented;19, 20 and novel classes of selective antimigraine drugs, such as triptans and calcitonin gene-related peptide antagonists, have been developed.21, 22, 23, 24
Despite this progress, there is little or no evidence that shows with certainty which pain fibres are activated or what activates them. Most investigators currently believe that a migraine attack starts in the brain, as is suggested by the premonitory symptoms. However, there is ongoing debate about the origin of the headache pain; some argue for a central origin of headache pain, whereas others, including us, believe that the headache phase begins with the activation of peripheral nociceptors. In this Personal View, we will not discuss the mechanisms of onset of a migraine attack, but rather focus on the origin of the headache. We will describe evidence that suggests that the input that causes the headache is abnormal (peripheral sensitisation) and discuss the origin of this input. In particular, we focus on the possible role of cerebral, dural, or extracranial perivascular nociceptors in the headache phase of a migraine attack.
Section snippets
Anatomy and physiology of head pain
More than half a century ago, Penfield and McNaughton25 reported that the dura mater is innervated by three nerves (the tentorial, spinosus, and ethmoidal), and the cell somas of these are found in the trigeminal ganglion. The trigeminal nerve conveys sensory information from most extracranial and intracranial structures to the spinal trigeminal nucleus. To investigate the site of nociception in migraine, the structures of the head that are sensitive to pain must first be identified. Figure 1
Dysfunctional modulatory pathways versus activation of nociceptors
During the past decade, CNS mechanisms have again come into focus as primary drivers of migraine. Several researchers,43, 44 led by the findings of Raskin and co-workers,45 have adopted the hypothesis that the headache phase of migraine could be triggered from the periaqueductal grey matter (ie, without nociceptor activation). Raskin and colleagues investigated 175 patients with pain who had stimulating electrodes placed in the periaqueductal grey matter. In 160 patients, stimulation of the
Nociception from veins or arteries
With the exception of the great sinuses, veins are much less sensitive to noxious stimulation than are arteries, indicating a minor role for perivenous nociception in migraine.35 Compression of the jugular veins to cause substantially increased venous distension, both intracranially and extracranially, during a migraine attack was done in three studies. There was no aggravation of the headache when the patients were in the sitting position;69 however, other authors have reported aggravation
What to tell patients with migraine
In this Personal View, we have summarised the available data on the origin of migraine pain, but we cannot draw firm conclusions. Any explanation to patients should therefore be carefully worded. If the patient has symptoms of aura, these definitely originate in the brain. With regard to migraine without aura, a reasonable explanation is that unknown mechanisms activate deep-brain structures that, in turn, activate the sensory nerve endings around the arteries of the head, which include the
Conclusions
In recent years, some groups have questioned whether there is any peripheral activation of sensory nerve terminals (nociception) in migraine; rather, they suggest that migraine pain is caused by abnormal central interpretation of normal sensory input in the trigeminal sensory system. We discussed this view, which would make migraine different from all other pain syndromes, and have concluded that it is unlikely to be true. We then discussed where and how activation of nociceptors might take
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