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The Immune System and Headache: A Review
Lawrence D. Robbins, M.D., Assistant Professor of Neurology,
Rush Medical College, Chicago
with Joseph Maides, D.O., Dmitriy Shmaryan
Posted: June 2009  
To be presented at the October 2009 meeting of the American Academy of Pain Management

Background:   Various immunologic cells have been implicated in the pathophysiology of headache. Early research focused on mast cells, while cytokines have been the subject of many papers since 1987. Recently the focus has been on the role of calcitonin gene-related peptide (CGRP)
in migraine.

Objective:   To review the role of the immune system in headache.

Methods:   This is based upon a literature review from 1980 through 2009.

Results:   HEADACHE AND IMMUNOLOGIC DISORDERS: Studies have revealed conflicting results as to the prevalence of headache in SLE. Controlled trials indicate that the prevalence of headache with SLE may be somewhat more than in controls. Severity of headache does not correlate with SLE severity. MAST CELLS: Degranulation of mast cells prolong nociceptor excitation. This may propagate the cascade of neuronal activation via CGRP release. CYTOKINES: Cytokines play a role in inflammation, and modulate pain. CGRP triggers the release of cytokines. Both pro- and anti-inflammatory cytokines increase during migraine. The injection of certain cytokines will trigger migraine. The presence of cytokines in the CSF during migraine has unclear significance. TUMOR NECROSIS FACTOR (TNF): TNF is a pro-inflammatory cytokine involved in pain initiation. Elevated levels of TNF have been found in those with New Daily Persistent Headache, as well as migraine and tension headache. TNF probably plays a role in pathogenesis of migraine. ADIPONECTIN: a cytokine released by adipose tissue; obesity is a risk factor for chronic headache. Adiponectin is anti-inflammatory, possibly decreasing the number of migraine attacks. CGRP: This inflammatory peptide is primarily released via trigeminocervical neurons. CGRP is involved at every level of migraine generation, from the meninges to the cortex, via neurogenic inflammation. Triptans inhibit CGRP release. Migraine relief corresponds to a reduction of CGRP levels. CGRP antagonists may be effective for preventing and aborting migraine.

Conclusions:   Various components of the immune system may play a vital role in initiating and propagating headache pain.