Medullary pain facilitating neurons mediate allodynia in Headache-Related pain

Rebecca M. Edelmayer, Todd W. Vanderah, Lisa Majuta, Zhang En-Tan, Beatriz Fioravanti, Milena De Felice, Juliana G. Chichorro, Michael H. Ossipov, Tamara King, Josephine Lai, Shashi H. Kori, Andrew C. Nelsen, Keri E. Cannon, May M. Heinricher, Frank Porreca

    Research output: Contribution to journalArticlepeer-review

    162 Scopus citations


    Objective: To develop and validate a model of cutaneous allodynia triggered by dural inflammation for pain associated with headaches. To explore neural mechanisms underlying cephalic and extracephalic allodynia. Methods: inflammatory mediators (IM) were applied to the dura of unanesthetized rats via previously implanted cannulas, and sensory thresholds of the face and hind-paws were characterized. Results: IM elicited robust facial and hind-paw allodynia, which peaked within 3 hours. These effects were reminiscent of cutaneous allodynia seen in patients with migraine or other primary headache conditions, and were reversed by agents used clinically in the treatment of migraine, including sumatriptan, naproxen, and a calcitonin gene - related peptide antagonist. Consistent with clinical observations, the allodynia was unaffected by a neurokinin-1 antagonist. Having established facial and hind-paw allodynia as a useful animal surrogate of headache-associated allodynia, we next showed that blocking pain-facilitating processes in the rostral ventromedial medulla (RVM) interfered with its expression. Bupivacaine, destruction of putative pain-facilitating neurons, or block of cholecystokinin receptors prevented or significantly attenuated IM-induced allodynia. Electrophysiological studies confirmed activation of pain-facilitating RVM "on" cells and transient suppression of RVM "off" cells after IM. Interpretation: Facial and hind-paw allodynia associated with dural stimulation is a useful surrogate of pain associated with primary headache including migraine and may be exploited mechanistically for development of novel therapeutic strategies for headache pain. The data also demonstrate the requirement for activation of descending facilitation from the RVM for the expression of cranial and extracranial cutaneous allodynia, and are consistent with a brainstem generator of allodynia associated with headache disorders.

    Original languageEnglish (US)
    Pages (from-to)184-193
    Number of pages10
    JournalAnnals of Neurology
    Issue number2
    StatePublished - Feb 2009

    ASJC Scopus subject areas

    • Neurology
    • Clinical Neurology


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