PAIN FACILITATING NEURONS IN THE BRAINSTEM MEDIATE CUTANEOUS ALLODYNIA IN AN EXPERIMENTAL MODEL OF HEADACHE-RELATED PAIN

Persistent Link:
http://hdl.handle.net/10150/195707
Title:
PAIN FACILITATING NEURONS IN THE BRAINSTEM MEDIATE CUTANEOUS ALLODYNIA IN AN EXPERIMENTAL MODEL OF HEADACHE-RELATED PAIN
Author:
Edelmayer, Rebecca M.
Issue Date:
2009
Publisher:
The University of Arizona.
Rights:
Copyright © is held by the author. Digital access to this material is made possible by the University Libraries, University of Arizona. Further transmission, reproduction or presentation (such as public display or performance) of protected items is prohibited except with permission of the author.
Abstract:
Migraine patients often demonstrate cutaneous allodynia, defined as a hypersensitivity of the skin to touch or mechanical stimuli that is considered non-noxious under normal circumstances. The allodynia sometimes begins intracranially and spreads, via unknown mechanisms, to extracranial regions. The goal of the study was to develop and validate a model of cutaneous allodynia triggered by dural inflammation for pain associated with headaches, and to explore neuronal and glial mechanisms underlying generalized allodynia. Inflammatory mediators (IM) were applied to the dura of unanesthetized rats via previously implanted cannulas and sensory thresholds of the face and hindpaws were characterized. IM elicited robust and time-related facial and hindpaw allodynia which peaked after approximately three hours as well as FOS expression in the trigeminal nucleus caudalis (TNC), indicative of central sensitization. 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, CGRP-antagonist, and morphine. Consistent with clinical observations, the allodynia was unaffected by an NK-1 antagonist. Having established facial and hindpaw allodynia as a useful animal surrogate of headache-associated allodynia, we next showed that blocking pain-facilitating processes from the rostral ventromedial medulla (RVM) interfered with its expression. Inactivation of the RVM with local anesthetic, destruction of putative pain-facilitation cells, and blockade of cholecystokinin receptors all prevented or significantly attenuated IM-induced allodynia. Electrophysiological studies confirmed activation of pain-facilitating "ON" cells and transient suppression of "OFF" cells in the RVM following IM. Additionally, microinjection of the RVM with a microglial inhibitor or sumatriptan also inhibited the expression of IM-induced cutaneous allodynia as well as microglial activation. Facial and hindpaw allodynia associated with dural stimulation is a useful surrogate of pain associated with primary headache including migraine and may be exploited mechanistically for the development of novel therapeutic strategies for headache pain. The data also demonstrate a requirement for activation of descending facilitation from the RVM, likely reliant on neuronal-glial interactions, for the expression of cranial and extracranial cutaneous allodynia. Consequently, the findings are consistent with a brainstem generator of allodynia associated with headache disorders.
Type:
text; Electronic Dissertation
Keywords:
Allodynia; Headache; Migraine; Pain; RVM
Degree Name:
Ph.D.
Degree Level:
doctoral
Degree Program:
Medical Pharmacology; Graduate College
Degree Grantor:
University of Arizona
Advisor:
Porreca, Frank

Full metadata record

DC FieldValue Language
dc.language.isoENen_US
dc.titlePAIN FACILITATING NEURONS IN THE BRAINSTEM MEDIATE CUTANEOUS ALLODYNIA IN AN EXPERIMENTAL MODEL OF HEADACHE-RELATED PAINen_US
dc.creatorEdelmayer, Rebecca M.en_US
dc.contributor.authorEdelmayer, Rebecca M.en_US
dc.date.issued2009en_US
dc.publisherThe University of Arizona.en_US
dc.rightsCopyright © is held by the author. Digital access to this material is made possible by the University Libraries, University of Arizona. Further transmission, reproduction or presentation (such as public display or performance) of protected items is prohibited except with permission of the author.en_US
dc.description.abstractMigraine patients often demonstrate cutaneous allodynia, defined as a hypersensitivity of the skin to touch or mechanical stimuli that is considered non-noxious under normal circumstances. The allodynia sometimes begins intracranially and spreads, via unknown mechanisms, to extracranial regions. The goal of the study was to develop and validate a model of cutaneous allodynia triggered by dural inflammation for pain associated with headaches, and to explore neuronal and glial mechanisms underlying generalized allodynia. Inflammatory mediators (IM) were applied to the dura of unanesthetized rats via previously implanted cannulas and sensory thresholds of the face and hindpaws were characterized. IM elicited robust and time-related facial and hindpaw allodynia which peaked after approximately three hours as well as FOS expression in the trigeminal nucleus caudalis (TNC), indicative of central sensitization. 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, CGRP-antagonist, and morphine. Consistent with clinical observations, the allodynia was unaffected by an NK-1 antagonist. Having established facial and hindpaw allodynia as a useful animal surrogate of headache-associated allodynia, we next showed that blocking pain-facilitating processes from the rostral ventromedial medulla (RVM) interfered with its expression. Inactivation of the RVM with local anesthetic, destruction of putative pain-facilitation cells, and blockade of cholecystokinin receptors all prevented or significantly attenuated IM-induced allodynia. Electrophysiological studies confirmed activation of pain-facilitating "ON" cells and transient suppression of "OFF" cells in the RVM following IM. Additionally, microinjection of the RVM with a microglial inhibitor or sumatriptan also inhibited the expression of IM-induced cutaneous allodynia as well as microglial activation. Facial and hindpaw allodynia associated with dural stimulation is a useful surrogate of pain associated with primary headache including migraine and may be exploited mechanistically for the development of novel therapeutic strategies for headache pain. The data also demonstrate a requirement for activation of descending facilitation from the RVM, likely reliant on neuronal-glial interactions, for the expression of cranial and extracranial cutaneous allodynia. Consequently, the findings are consistent with a brainstem generator of allodynia associated with headache disorders.en_US
dc.typetexten_US
dc.typeElectronic Dissertationen_US
dc.subjectAllodyniaen_US
dc.subjectHeadacheen_US
dc.subjectMigraineen_US
dc.subjectPainen_US
dc.subjectRVMen_US
thesis.degree.namePh.D.en_US
thesis.degree.leveldoctoralen_US
thesis.degree.disciplineMedical Pharmacologyen_US
thesis.degree.disciplineGraduate Collegeen_US
thesis.degree.grantorUniversity of Arizonaen_US
dc.contributor.advisorPorreca, Franken_US
dc.contributor.committeememberVanderah, Todd W.en_US
dc.contributor.committeememberFrench, Edward D.en_US
dc.contributor.committeememberOssipov, Michael H.en_US
dc.contributor.committeememberSherman, Scott J.en_US
dc.identifier.proquest10245en_US
dc.identifier.oclc659750844en_US
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