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The Role of Kappa Opioid Receptor Signaling in Injury-Free Pain
Başlık:
The Role of Kappa Opioid Receptor Signaling in Injury-Free Pain
Yazar:
Nation, Kelsey, author.
ISBN:
9780355942422
Yazar Ek Girişi:
Fiziksel Tanımlama:
1 electronic resource (128 pages)
Genel Not:
Source: Dissertation Abstracts International, Volume: 79-10(E), Section: B.
Advisors: Frank Porreca Committee members: Stephen Cowen; Edward French; Rajesh Khanna; Edita Navratilova.
Özet:
Kappa opioid receptor (KOR) signaling has been shown to be involved in the production of negative affective states. We hypothesized that KOR signaling in the brain may also be important in promoting pain states in the absence of injury, such as in functional pain syndromes (FPS), which are difficult to study in rodents due to our current lack of understanding of the etiology underlying these disorders. In order to study FPS we developed an injury-free hyperalgesic priming model that utilizes a loss of diffuse noxious inhibitory controls (DNIC), an endogenous mechanism of pain modulation that is diminished in patients with FPS, as the output measure. After establishing the model we used it to study the contribution of KOR signaling to the loss of DNIC and found that blocking endogenous KOR signaling with a KOR antagonist was sufficient to restore the DNIC response when the KOR antagonist was administered either subcutaneously or directly into the right central nucleus of the amygdala (right CeA), but not when given into the left central nucleus of the amygdala (left CeA) or into the rostral ventromedial medulla (RVM). The loss of DNIC was accompanied by elevated levels of dynorphin, the endogenous KOR agonist, in the right CeA.
Further experiments designed to study the contribution of signaling from KOR-expressing cells in various brain regions to the production of pain in the absence of an injury were performed using KOR-Cre mice and Cre-dependent designer receptors exclusively activated by designer drugs (DREADDs). When Gi-coupled DREADDs were activated in the KOR-expressing cells in the right CeA a loss of DNIC was observed in male and female mice and this was accompanied by decreases in static pain thresholds in female mice. Activation of Gi-coupled DREADDs in KOR-expressing cells in the anterior cingulate cortex (ACC) produced conditioned place aversion, suggesting a negative affective state that is relevant to pain conditions, and this aversion was not accompanied by changes in sensory thresholds.
These results establish that lateralized KOR signaling in the CeA is sufficient to produce changes in static and dynamic sensory measures of pain and that blockade of this KOR signaling is sufficient to restore DNIC in our model of FPS. Additionally, these results establish that ACC KOR signaling contributes to the development of a negative affective state. These results suggest that KOR signaling plays a critical role in the development of pain in the absence of injury and that increased levels of endogenous KOR signaling may be a relevant piece of the biology that underlies the development of FPS.
Notlar:
School code: 0009
Tüzel Kişi Ek Girişi:
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Yer Numarası | Demirbaş Numarası | Shelf Location | Lokasyon / Statüsü / İade Tarihi |
---|---|---|---|
XX(680206.1) | 680206-1001 | Proquest E-Tez Koleksiyonu | Arıyor... |
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