Attenuation of morphine tolerance, reward, and spinal gliosis in neuropathic pain by ultra-low dose alpha2-adrenergic antagonists

dc.contributor.authorGrenier, Patricken
dc.contributor.departmentPharmacology and Toxicologyen
dc.contributor.supervisorCahill, Catherine M.en
dc.contributor.supervisorOlmstead, Mary C.en
dc.date2016-04-28 15:14:43.102
dc.date.accessioned2016-04-28T22:17:43Z
dc.date.available2016-04-28T22:17:43Z
dc.date.issued2016-04-28
dc.degree.grantorQueen's University at Kingstonen
dc.descriptionThesis (Ph.D, Pharmacology & Toxicology) -- Queen's University, 2016-04-28 15:14:43.102en
dc.description.abstractAims: To determine the effects of ULD α2-AR antagonists on: i) sensory responses in morphine tolerant and nerve injured rats, ii) chronic morphine and nerve-injury induced spinal gliosis and neuronal activation, iii) morphine conditioned place preference (CPP), a paradigm that assesses the affective or emotional component of pain processing. Methods & Results: In a model of opioid tolerance, ULD atipamezole attenuated the loss of morphine antinociception in pain naïve rats, consistent with the literature. Next, a model of neuropathic pain (chronic constriction injury (CCI)) was employed and changes in responses to mechanical and thermal nociceptive stimuli were tracked over time. This was the first study to show positive effects of ULD α2-AR antagonists in alleviating pain hypersensitivity associated with nerve injury and attenuation of morphine tolerance in neuropathic animals. Using immunohistochemistry, tissue collected from all the animals was labeled to determine if molecular changes correlated with the behavior induced by ULD atipamezole. Morphine and CCI-induced gliosis in the spinal dorsal horn were attenuated in animals chronically administered ULD atipamezole. Neuronal activity inferred by c-Fos cell counts was likewise attenuated in neuropathic animals. Finally, through the use of the CPP paradigm, it was shown ULD atipamezole is neither rewarding nor aversive on its own, but disrupts the development of morphine CPP in CCI animals, but not the sham or pain naïve animals. Currently, experimental evidence suggests a reduction in opioid reward in the neuropathic rats. Conclusion: ULD α2-AR antagonist atipamezole inhibits morphine tolerance and enhances opioid analgesia in pain naïve and chronic pain states, alleviates the mechanical hypersensitivity following nerve injury, inhibits chronic morphine and nerve injury-induced glial and neuronal activation in the spinal dorsal horn, and disrupts opioid reward in chronic pain states.en
dc.description.degreePhDen
dc.identifier.urihttp://hdl.handle.net/1974/14318
dc.language.isoengen
dc.relation.ispartofseriesCanadian thesesen
dc.rightsQueen's University's Thesis/Dissertation Non-Exclusive License for Deposit to QSpace and Library and Archives Canadaen
dc.rightsProQuest PhD and Master's Theses International Dissemination Agreementen
dc.rightsIntellectual Property Guidelines at Queen's Universityen
dc.rightsCopying and Preserving Your Thesisen
dc.rightsThis publication is made available by the authority of the copyright owner solely for the purpose of private study and research and may not be copied or reproduced except as permitted by the copyright laws without written authority from the copyright owner.en
dc.subjectUltra-low doseen
dc.subjecttoleranceen
dc.subjectNeuropathic painen
dc.subjectRewarden
dc.subjectOpioiden
dc.subjectGliosisen
dc.subjectAdrenergic antagonistsen
dc.titleAttenuation of morphine tolerance, reward, and spinal gliosis in neuropathic pain by ultra-low dose alpha2-adrenergic antagonistsen
dc.typethesisen
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