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Opioid-Induced Side Effects in Beta-arrestin2 adn G Protein-Coupled Receptor Kinase Knockout Mice

Raehal, Kirsten Michele

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2009, Doctor of Philosophy, Ohio State University, Integrated Biomedical Sciences.
Opioid drugs are potent analgesics; however, they also produce several adverse side effects including constipation, antinociceptive tolerance, and physical dependence by activating the mu opioid receptor, a G protein-coupled receptor (GPCR). There is a substantial literature that suggests that the GPCR regulatory proteins G protein-coupled receptor kinases (GRKs) and beta-arrestins play a key role in regulating mu opioid receptor signaling and responsiveness. In vivo, the loss of beta-arrestin2 significantly alters morphine-induced analgesia, antinociceptive tolerance, respiratory suppression, and reward. Moreover, distinct opioid agonists have been shown to differ in their propensity to promote interactions between the mu opioid receptor and beta-arrestins and such agonist directed events may ultimately determine the functional response of the receptor to a particular drug. Therefore, we hypothesize that GRK and beta-arrestin2-mediated mu opioid receptor regulation may determine the extent of opioid-induced side effects including constipation, antinociceptive tolerance, and physical dependence, in a manner that is specifically influenced by different opioid agonists and cellular environments. Using mice genetically lacking individual GRKs and beta-arrestin2, we evaluated distinct opioid agonists (morphine, methadone, and fentanyl) for their ability to elicit constipation, antinociceptive tolerance, and physical dependence. We find that beta-arrestin2 is important in determining the expression of morphine-induced constipation, antinociceptive tolerance, and physical dependence, even more so than GRKs. However, while all responses evaluated in response to morphine were affected by the loss of beta-arrestin2, only methadone-induced physical dependence was altered in the beta-arrestin2-knockout mice, suggesting that beta-arrestin2 differentially affects these opioid-mediated responses in an agonist-dependent manner. Collectively, these results provide evidence that distinct opioid agonists can influence mu opioid receptor regulation and responsiveness and that the contribution of a particular regulatory factor to receptor function can differ based upon the specific cell composition and physiology assessed.
Laura Bohn, PhD (Advisor)
John Oberdick, PhD (Committee Member)
Wolfgang Sadee, Dr.rer.nat (Committee Member)
Jackie Wood, PhD (Committee Member)
139 p.

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Citations

  • Raehal, K. M. (2009). Opioid-Induced Side Effects in Beta-arrestin2 adn G Protein-Coupled Receptor Kinase Knockout Mice [Doctoral dissertation, Ohio State University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=osu1236884585

    APA Style (7th edition)

  • Raehal, Kirsten. Opioid-Induced Side Effects in Beta-arrestin2 adn G Protein-Coupled Receptor Kinase Knockout Mice. 2009. Ohio State University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=osu1236884585.

    MLA Style (8th edition)

  • Raehal, Kirsten. "Opioid-Induced Side Effects in Beta-arrestin2 adn G Protein-Coupled Receptor Kinase Knockout Mice." Doctoral dissertation, Ohio State University, 2009. http://rave.ohiolink.edu/etdc/view?acc_num=osu1236884585

    Chicago Manual of Style (17th edition)