Behavioral and Neurochemical Consequences of Cortical Spreading Depression in Freely Moving Rats

Persistent Link:
http://hdl.handle.net/10150/193852
Title:
Behavioral and Neurochemical Consequences of Cortical Spreading Depression in Freely Moving Rats
Author:
Lindstrom, Beatriz Fioravanti
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:
Cortical Spreading Depression (CSD) is characterized by a wave of neuronal and glial depolarization followed by depression of bioelectrical activity that slowly propagates through the cortex of many species, including humans. CSD is associated with brain disorders such as stroke, head trauma and migraine. Many earlier studies have provided compelling evidence that CSD is the underlying mechanism of aura in migraine; however, whether CSD can elicit headache associated with migraine is not fully understood. Cutaneous allodynia is highly prevalent in the peri-orbital area and extracephalic sites of migraine patients, suggesting that sensitization of primary afferents and central trigeminovascular neurons in these patients could be initiated by the underlying mechanism of aura.Unlike previous reports on the interaction between CSD and the trigeminal system, in which nociceptive behavior could not be measured since they employed anesthetized animals, we designed a model in which freely moving rats could be monitored for both CSD events and behavior responses due to pinprick plus KCl injection to the occipital cortex. We show that significant tactile hypersensitivity of the periorbital region of the face and hindpaws develop in a time-dependent manner following CSD. Enhanced expression of Fos protein and increased mRNA levels of the inflammatory cytokines IL-1beta and IL-6 are found within the trigeminal nucleus caudalis (TNC) two hours following cortical injection. We further show that systemic administration of anti-migraine drugs such as sumatriptan, naproxen and CGRP(8-37) (a CGRP antagonist) attenuate the generalized allodynia that ensue following cortical stimulation by KCl. Microinjection of bupivacaine in the ipsilateral trigeminal ganglion or in the rostral ventromedial medulla (RVM) prior to cortical pinprick plus KCl injection reversibly diminishes tactile hypersensitivity, suggesting that RVM pain-facilitating cells become activated by a trigeminal-RVM pathway following CSD. In addition we demonstrate that cortical pinprick plus KCl injection induced CSD events in 24/28 (85%) rats, among which 66% and 87% developed allodynia in the face and hindpaw, respectively.These studies suggest a potential association between CSD and development of hypersensitivity in rats, indicating that this model can be used to investigate the role of CSD-evoked migraine-related pain and to explore novel therapeutic strategies.
Type:
text; Electronic Dissertation
Keywords:
Allodynia; Migraine; Rat; Spreading Depression
Degree Name:
Ph.D.
Degree Level:
doctoral
Degree Program:
Medical Pharmacology; Graduate College
Degree Grantor:
University of Arizona
Advisor:
Vanderah, Todd W.

Full metadata record

DC FieldValue Language
dc.language.isoENen_US
dc.titleBehavioral and Neurochemical Consequences of Cortical Spreading Depression in Freely Moving Ratsen_US
dc.creatorLindstrom, Beatriz Fioravantien_US
dc.contributor.authorLindstrom, Beatriz Fioravantien_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.abstractCortical Spreading Depression (CSD) is characterized by a wave of neuronal and glial depolarization followed by depression of bioelectrical activity that slowly propagates through the cortex of many species, including humans. CSD is associated with brain disorders such as stroke, head trauma and migraine. Many earlier studies have provided compelling evidence that CSD is the underlying mechanism of aura in migraine; however, whether CSD can elicit headache associated with migraine is not fully understood. Cutaneous allodynia is highly prevalent in the peri-orbital area and extracephalic sites of migraine patients, suggesting that sensitization of primary afferents and central trigeminovascular neurons in these patients could be initiated by the underlying mechanism of aura.Unlike previous reports on the interaction between CSD and the trigeminal system, in which nociceptive behavior could not be measured since they employed anesthetized animals, we designed a model in which freely moving rats could be monitored for both CSD events and behavior responses due to pinprick plus KCl injection to the occipital cortex. We show that significant tactile hypersensitivity of the periorbital region of the face and hindpaws develop in a time-dependent manner following CSD. Enhanced expression of Fos protein and increased mRNA levels of the inflammatory cytokines IL-1beta and IL-6 are found within the trigeminal nucleus caudalis (TNC) two hours following cortical injection. We further show that systemic administration of anti-migraine drugs such as sumatriptan, naproxen and CGRP(8-37) (a CGRP antagonist) attenuate the generalized allodynia that ensue following cortical stimulation by KCl. Microinjection of bupivacaine in the ipsilateral trigeminal ganglion or in the rostral ventromedial medulla (RVM) prior to cortical pinprick plus KCl injection reversibly diminishes tactile hypersensitivity, suggesting that RVM pain-facilitating cells become activated by a trigeminal-RVM pathway following CSD. In addition we demonstrate that cortical pinprick plus KCl injection induced CSD events in 24/28 (85%) rats, among which 66% and 87% developed allodynia in the face and hindpaw, respectively.These studies suggest a potential association between CSD and development of hypersensitivity in rats, indicating that this model can be used to investigate the role of CSD-evoked migraine-related pain and to explore novel therapeutic strategies.en_US
dc.typetexten_US
dc.typeElectronic Dissertationen_US
dc.subjectAllodyniaen_US
dc.subjectMigraineen_US
dc.subjectRaten_US
dc.subjectSpreading Depressionen_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.advisorVanderah, Todd W.en_US
dc.contributor.committeememberPorreca, Franken_US
dc.contributor.committeememberFrench, Edward D.en_US
dc.contributor.committeememberLai, Josephineen_US
dc.contributor.committeememberMalan, Philen_US
dc.identifier.proquest10236en_US
dc.identifier.oclc659750834en_US
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