Triptan-induced latent sensitization: a possible basis for medication overuse headache.
OBJECTIVE
Identification of the neural mechanisms underlying medication overuse headache resulting from triptans.


METHODS
Triptans were administered systemically to rats by repeated intermittent injections or by continuous infusion over 6 days. Periorbital and hind paw sensory thresholds were measured to detect cutaneous allodynia. Immunofluorescent histochemistry was employed to detect changes in peptidic neurotransmitter expression in identified dural afferents. Enzyme-linked immunoabsorbent assay was used to measure calcitonin gene-related peptide (CGRP) levels in blood.


RESULTS
Sustained or repeated administration of triptans to rats elicited time-dependent and reversible cutaneous tactile allodynia that was maintained throughout and transiently after drug delivery. Triptan administration increased labeling for CGRP in identified trigeminal dural afferents that persisted long after discontinuation of triptan exposure. Two weeks after triptan exposure, when sensory thresholds returned to baseline levels, rats showed enhanced cutaneous allodynia and increased CGRP in the blood following challenge with a nitric oxide donor. Triptan treatment thus induces a state of latent sensitization characterized by persistent pronociceptive neural adaptations in dural afferents and enhanced responses to an established trigger of migraine headache in humans.


CONCLUSIONS
Triptans represent the treatment of choice for moderate and severe migraine headaches. However, triptan overuse can lead to an increased frequency of migraine headache. Overuse of these medications could induce neural adaptations that result in a state of latent sensitization, which might increase sensitivity to migraine triggers. The latent sensitization could provide a mechanistic basis for the transformation of migraine to medication overuse headache.
De Felice
Milena
M
Department of Pharmacology, University of Arizona College of Medicine, Tucson, AZ, USA.
Ossipov
Michael H
MH
Wang
Ruizhong
R
Lai
Josephine
J
Chichorro
Juliana
J
Meng
Ian
I
Dodick
David W
DW
Vanderah
Todd W
TW
Dussor
Gregory
G
Porreca
Frank
F
D000818:Animals; D015740:Calcitonin Gene-Related Peptide / Q000032:analysis / Q000097:blood; D004334:Drug Administration Schedule; D004388:Dura Mater / Q000503:physiopathology; D004797:Enzyme-Linked Immunosorbent Assay; D005455:Fluorescent Antibody Technique; D051271:Headache Disorders, Secondary / Q000503:physiopathology*; D006930:Hyperalgesia / Q000139:chemically induced / Q000503:physiopathology; D008297:Male; D008881:Migraine Disorders / Q000188:drug therapy*; D020030:Nitric Oxide Donors / Q000494:pharmacology; D009619:Nociceptors / Q000187:drug effects / Q000502:physiology; D010147:Pain Measurement; D017288:Pain Threshold / Q000187:drug effects / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D011930:Reaction Time / Q000187:drug effects / Q000502:physiology; D011984:Sensory Receptor Cells / Q000187:drug effects / Q000502:physiology; D013997:Time Factors; D014276:Trigeminal Nerve / Q000187:drug effects / Q000503:physiopathology; D014363:Tryptamines / Q000009:adverse effects / Q000633:toxicity*
D020030:Nitric Oxide Donors; D014363:Tryptamines; D015740:Calcitonin Gene-Related Peptide