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Medullary pain facilitating neurons mediate allodynia in headache‐related pain
Author(s) -
Edelmayer Rebecca M.,
Vanderah Todd W.,
Majuta Lisa,
Zhang EnTan,
Fioravanti Beatriz,
De Felice Milena,
Chichorro Juliana G.,
Ossipov Michael H.,
King Tamara,
Lai Josephine,
Kori Shashi H.,
Nelsen Andrew C.,
Can Keri E.,
Heinricher Mary M.,
Porreca Frank
Publication year - 2009
Publication title -
annals of neurology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.764
H-Index - 296
eISSN - 1531-8249
pISSN - 0364-5134
DOI - 10.1002/ana.21537
Subject(s) - allodynia , medicine , rostral ventromedial medulla , anesthesia , hyperalgesia , migraine , sumatriptan , nociceptor , neurogenic inflammation , nociception , neuropeptide , substance p , receptor , agonist
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. Ann Neurol 2009;65:184–193