Elsevier

The Lancet Neurology

Volume 8, Issue 7, July 2009, Pages 679-690
The Lancet Neurology

Personal View
Origin of pain in migraine: evidence for peripheral sensitisation

https://doi.org/10.1016/S1474-4422(09)70090-0Get rights and content

Summary

Migraine is the most common neurological disorder, and much has been learned about its mechanisms in recent years. However, the origin of painful impulses in the trigeminal nerve is still uncertain. Despite the attention paid recently to the role of central sensitisation in migraine pathophysiology, in our view, neuronal hyperexcitability depends on activation of peripheral nociceptors. Although the onset of a migraine attack might take place in deep-brain structures, some evidence indicates that the headache phase depends on nociceptive input from perivascular sensory nerve terminals. The input from arteries is probably more important than the input from veins. Several studies provide evidence for input from extracranial, dural, and pial arteries but, likewise, there is also evidence against all three of these locations. On balance, afferents are most probably excited in all three territories or the importance of individual territories varies from patient to patient. We suggest that migraine can be explained to patients as a disorder of the brain, and that the headache originates in the sensory fibres that convey pain signals from intracranial and extracranial blood vessels.

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

References (140)

  • G Holstege et al.

    The anatomy of brain stem pathways to the spinal cord in cat. A labeled amino acid tracing study

    Prog Brain Res

    (1982)
  • YE Knight et al.

    The periaqueductal grey matter modulates trigeminovascular input: a role in migraine?

    Neuroscience

    (2001)
  • F Porreca et al.

    Chronic pain and medullary descending facilitation

    Trends Neurosci

    (2002)
  • Z Katsarava et al.

    Symptomatic migraine and sensitization of trigeminal nociception associated with contralateral pontine cavernoma

    Pain

    (2003)
  • AP Friedman

    Current concepts in the diagnosis and treatment of chronic recurring headache

    Med Clin North Am

    (1972)
  • V Dimitriadou et al.

    Ultrastructural evidence for neurogenically mediated changes in blood vessels of the rat dural mater and tongue following antidromic trigeminal stimulation

    Neuroscience

    (1992)
  • HK Iversen et al.

    Arterial responses during migraine headaches

    Lancet

    (1990)
  • HK Iversen et al.

    Intravenous nitroglycerin as an experimental model of vascular headache. Basic characteristics

    Pain

    (1989)
  • A May et al.

    Endothelin antagonist bosentan blocks inflammation, but is not effective in aborting migraine attacks

    Pain

    (1996)
  • D Levy et al.

    Mast cell degranulation activates a pain pathway underlying migraine headache

    Pain

    (2007)
  • Classification and diagnostic criteria for headache disorders, cranial neuralgias and facial pain, 2nd edn

    Cephalalgia

    (2004)
  • J Olesen et al.

    Focal hyperemia followed by spreading oligemia and impaired activation of rCBF in classic migraine

    Ann Neurol

    (1981)
  • J Olesen et al.

    Timing and topography of cerebral blood flow, aura, and headache during migraine attacks

    Ann Neurol

    (1990)
  • N Hadjikhani et al.

    Mechanism of migraine aura revealed by functional MRI in the visual cortex

    Proc Natl Acad Sci USA

    (2001)
  • MA Moskowitz

    The neurobiology of vascular head pain

    Ann Neurol

    (1984)
  • MA Moskowitz

    The visceral organ brain: implications for the pathophysiology of vascular head pain

    Neurology

    (1991)
  • MA Moskowitz

    The 2006 Thomas Willis lecture: the adventure of a translational researcher in stroke and migraine

    Stroke

    (2007)
  • D Levy et al.

    Disruption of communication between peripheral and central trigeminovascular neurons by a 5HT1B/1D receptor agonist: implications for migraine therapy with triptans

    Proc Nat Acad Sci USA

    (2004)
  • AM Strassman et al.

    Sensitization of meningeal sensory neurons and the origin of headache

    Nature

    (1996)
  • R Burstein et al.

    Chemical stimulation of the intracranial dura induces enhanced responses to facial stimulation in brain stem trigeminal neurons

    J Neurophysiol

    (1998)
  • PJ Goadsby

    Migraine pathophysiology

    Headache

    (2005)
  • LH Lassen et al.

    Histamine induces migraine via the H1-receptor. Support for the NO hypothesis of migraine

    Neuroreport

    (1995)
  • J Olesen et al.

    Nitric oxide supersensitivity: a possible molecular mechanism of migraine pain

    Neuroreport

    (1993)
  • LH Lassen et al.

    CGRP may play a causative role in migraine

    Cephalalgia

    (2002)
  • HW Schytz et al.

    PACAP38 induces migraine-like attacks in patients with migraine without aura

    Brain

    (2009)
  • R Burstein et al.

    An association between migraine and cutaneous allodynia

    Ann Neurol

    (2000)
  • R Burstein et al.

    Defeating migraine pain with triptans: a race against the development of cutaneous allodynia

    Ann Neurol

    (2004)
  • PP Humphrey

    The discovery of a new drug class for the acute treatment of migraine

    Headache

    (2007)
  • P Tfelt-Hansen et al.

    Triptans in migraine. A comparative review of pharmacology, pharmacokinetics and efficacy

    Drugs

    (2000)
  • J Olesen et al.

    Calcitonin gene-related peptide receptor antagonist BIBN 4096 BS for the acute treatment of migraine

    N Engl J Med

    (2004)
  • TW Ho et al.

    Randomized controlled trial of an oral CGRP antagonist, MK-0974, in acute treatment of migraine

    Neurology

    (2008)
  • W Penfield et al.

    Dural headache and innervation of the dura mater

    Arch Neurol Psychiatry

    (1940)
  • HG Wolff

    Headache and other head pain

    (1963)
  • L Edvinsson et al.

    Anatomy of muscles, tendons, joints, blood vessels and meninges

  • K Messlinger et al.

    Anatomy and physiology of pain-sensitive cranial structures

  • K Messlinger et al.

    Anatomy and physiology of head pain

  • R Burstein et al.

    Peripheral and central sensitization related to headache

  • R Dubner et al.

    The neural basis of oral and facial function

    (1978)
  • JC Hinsey

    Observations on the innervation of blood vessels in skeletal muscles

    J Comp Neurol

    (1928)
  • Cited by (444)

    • Migraine headache pathophysiology

      2023, Handbook of Clinical Neurology
    View all citing articles on Scopus
    View full text