Opioid-Induced Side Effects in Beta-arrestin2 adn G Protein-Coupled Receptor Kinase Knockout Mice
Year: 2009
Type: article
Abstract: 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 (μOR), a G protein-coupled receptor (GPCR).There is a substantial literature that suggests that the GPCR regulatory proteins G proteincoupled receptor kinases (GRKs) and beta-arrestins (β-arrestins) play a key role in regulating μOR signaling and responsiveness.In vivo, the loss of β-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 μOR and β-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 β-arrestin2-mediated μOR 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 β-arrestin2, we evaluated distinct opioid agonists (morphine, methadone, and fentanyl) for their ability to elicit constipation, antinociceptive tolerance, and physical dependence.We find that β-arrestin2 is important in determining the expression of morphine-induced constipation, iii 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 β-arrestin2, only methadone-induced physical dependence was altered in the β-arrestin2-knockout mice, suggesting that β-arrestin2 differentially affects these opioid-mediated responses in an agonist-dependent manner.Collectively, these results provide evidence that distinct opioid agonists can influence μOR 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.ivIn loving memory of my mother,
Author: Kirsten M. Raehal
Institution: The Ohio State University
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: green
OpenAlex ID: W2519838443