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The role of microglia in morphine to...

Horvath, Ryan Joseph.

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The role of microglia in morphine tolerance.

Record Type:	Language materials, printed : Monograph/item
Title/Author:	The role of microglia in morphine tolerance./
Author:	Horvath, Ryan Joseph.
Description:	272 p.
Notes:	Source: Dissertation Abstracts International, Volume: 71-06, Section: B, page: 3491.
Contained By:	Dissertation Abstracts International71-06B.
Subject:	Biology, Neurobiology. -
Online resource:	http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=3404441
ISBN:	9781124014838

The role of microglia in morphine tolerance.
Horvath, Ryan Joseph.

The role of microglia in morphine tolerance. - 272 p.

Source: Dissertation Abstracts International, Volume: 71-06, Section: B, page: 3491.

Thesis (Ph.D.)--Dartmouth College, 2010.

Chronic pain is a debilitating condition which exacts severe emotional, physical and economic tolls on the millions of people who suffer from it worldwide. Opioids are a mainstay of acute, postoperative and cancer pain therapy, however, their use for the treatment of chronic pain is limited by side effects including analgesic tolerance. Although the mechanisms driving analgesic tolerance are not fully understood, we propose that spinal cord glial cells have a fundamental role in this phenomenon. We hypothesize that acutely, morphine binds to abundant neuronal mu opioid receptors, producing analgesia. Chronically, morphine binds to less abundant microglial mu opioid receptors, enhancing intracellular pathway signaling, protein expression and cell migration, causing proinflammatory factor mediated neuronal sensitization and ultimately analgesic tolerance. In Chapter 3, we demonstrated that in vitro ADP dependent microglial migration can be inhibited by glial modulating agents. In Chapter 4, we showed that in vitro morphine treatment enhanced mu opioid receptor dependent microglial migration towards ADP via P2X4 receptor activation and PI3K/Akt signaling. In Chapter 5, we showed that antisense oligonucleotide-mediated inhibition of microglial P2X 4 receptor expression attenuated the development of morphine tolerance in vivo. In Chapter 6, we showed that morphine tolerance attenuated the resolution of postoperative allodynia and enhanced microglial p38 and ERK phosphorylation in vivo. In Chapter 7, we explored the mechanism of morphine-induced microglial migration. We showed that in vitro morphine treatment enhances cytosolic beta-catenin expression in microglia and that microglial migration is enhanced towards organotypic spinal cord slices harvested from animals treated in vivo or ex vivo with morphine. This thesis describes the following major contributions to the opioid tolerance field: (1) Identification of cellular migration as a significant functional response of microglia to morphine stimulation; (2) Identification of the modulatory role of microglial P2X4 receptors in the development of morphine tolerance; (3) Introduction of the idea that prior morphine tolerance can prime microglia to respond more robustly to subsequent stimuli; (4) Development of the ex vivo organotypic slice culture technique to allow for the evaluation of the molecular and cellular changes associated with microglial migration and chemoattractant production in morphine tolerant states.

ISBN: 9781124014838Subjects--Topical Terms:

1681328
Biology, Neurobiology.

The role of microglia in morphine tolerance.
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100 1 $a Horvath, Ryan Joseph. $3 1683874
245 1 4 $a The role of microglia in morphine tolerance.
300 $a 272 p.
500 $a Source: Dissertation Abstracts International, Volume: 71-06, Section: B, page: 3491.
500 $a Adviser: Joyce A. DeLeo.
502 $a Thesis (Ph.D.)--Dartmouth College, 2010.
520 $a Chronic pain is a debilitating condition which exacts severe emotional, physical and economic tolls on the millions of people who suffer from it worldwide. Opioids are a mainstay of acute, postoperative and cancer pain therapy, however, their use for the treatment of chronic pain is limited by side effects including analgesic tolerance. Although the mechanisms driving analgesic tolerance are not fully understood, we propose that spinal cord glial cells have a fundamental role in this phenomenon. We hypothesize that acutely, morphine binds to abundant neuronal mu opioid receptors, producing analgesia. Chronically, morphine binds to less abundant microglial mu opioid receptors, enhancing intracellular pathway signaling, protein expression and cell migration, causing proinflammatory factor mediated neuronal sensitization and ultimately analgesic tolerance. In Chapter 3, we demonstrated that in vitro ADP dependent microglial migration can be inhibited by glial modulating agents. In Chapter 4, we showed that in vitro morphine treatment enhanced mu opioid receptor dependent microglial migration towards ADP via P2X4 receptor activation and PI3K/Akt signaling. In Chapter 5, we showed that antisense oligonucleotide-mediated inhibition of microglial P2X 4 receptor expression attenuated the development of morphine tolerance in vivo. In Chapter 6, we showed that morphine tolerance attenuated the resolution of postoperative allodynia and enhanced microglial p38 and ERK phosphorylation in vivo. In Chapter 7, we explored the mechanism of morphine-induced microglial migration. We showed that in vitro morphine treatment enhances cytosolic beta-catenin expression in microglia and that microglial migration is enhanced towards organotypic spinal cord slices harvested from animals treated in vivo or ex vivo with morphine. This thesis describes the following major contributions to the opioid tolerance field: (1) Identification of cellular migration as a significant functional response of microglia to morphine stimulation; (2) Identification of the modulatory role of microglial P2X4 receptors in the development of morphine tolerance; (3) Introduction of the idea that prior morphine tolerance can prime microglia to respond more robustly to subsequent stimuli; (4) Development of the ex vivo organotypic slice culture technique to allow for the evaluation of the molecular and cellular changes associated with microglial migration and chemoattractant production in morphine tolerant states.
590 $a School code: 0059.
650 4 $a Biology, Neurobiology. $3 1681328
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790 1 0 $a Hwa, John $e committee member
790 1 0 $a Ji, Ru-Rong $e committee member
790 1 0 $a Martin, Kathleen A. $e committee member
790 $a 0059
791 $a Ph.D.
792 $a 2010
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