Abstract
Opioids are the most effective analgesic drugs for the management of moderate or severe pain, yet their clinical use is often limited because of the onset of adverse side effects. Drugs in this class produce most of their physiological effects through activation of the μ opioid receptor; however, an increasing number of studies demonstrate that different opioids, while presumably acting at this single receptor, can activate distinct downstream responses, a phenomenon termed functional selectivity. Functional selectivity of receptor-mediated events can manifest as a function of the drug used, the cellular or neuronal environment examined, or the signaling or behavioral measure recorded. This review summarizes both in vitro and in vivo work demonstrating functional selectivity at the μ opioid receptor in terms of G protein coupling, receptor phosphorylation, interactions with β-arrestins, receptor desensitization, internalization and signaling, and details on how these differences may relate to the progression of analgesic tolerance after their extended use.
Footnotes
This article is available online at http://pharmrev.aspetjournals.org.
doi:10.1124/pr.111.004598.
1 Abbreviations:
- CaMKII
- calcium/calmodulin kinase II
- CaV
- voltage-gated calcium channel
- CHO
- Chinese hamster ovary
- DAMGO
- [d-Ala2,N-Me-Phe4,Gly5-ol]-enkephalin
- DRG
- dorsal root ganglion
- ERK1/2
- extracellular regulated kinase 1/2
- FRET
- fluorescence resonance energy transfer
- GF109203X
- 3-[1-[3-(dimethylaminopropyl]-1H-indol-3-yl]-4-(1H-indol-3-yl)-1H-pyrrole-2,5-dione monohydrochloride
- Gö6976
- 12-(2-cyanoethyl)-6,7,12,13-tetrahydro-13-methyl-5-oxo-5H-indolo(2,3-a)pyrrolo(3,4-c)-carbazole
- GPCR
- G protein-coupled receptor
- GRIN1
- glutamate receptor subunit ζ 1
- GRK
- G protein-coupled receptor kinase
- GTPγS
- guanosine 5′-O-(3-thio)triphosphate
- HA
- hemagglutinin
- HEK
- human embryonic kidney
- JNK
- c-jun N-terminal kinase
- Kir3
- G protein-coupled inwardly rectifying potassium channel
- KO
- knockout
- μOR
- μ opioid receptor
- MOR
- μ opioid receptor
- MEF
- mouse embryonic fibroblast
- PKA
- protein kinase A
- PKC
- protein kinase C
- Ro32-0432
- 3-[(8S)-8-[(dimethylamino)methyl]-6,7,8,9-tetrahydropyrido[1,2-a]indol-10-yl[-4-(1-methyl-1H-indol-3-yl)-1H-pyrrole-2,5-dione hydrochloride
- siRNA
- small interfering RNA
- WT
- wild type.
- © 2011 by The American Society for Pharmacology and Experimental Therapeutics
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In this issue
Jump to section
- Article
- Abstract
- I. Introduction
- II. Biased Agonism with Respect to G Protein Coupling
- III. Biased Agonism with Respect to Activation of Second Messengers
- IV. Biased Agonism with Respect to μOR Phosphorylation
- V. Biased Agonism with Respect to Recruitment of β-Arrestin2
- VI. Biased Agonism with Respect to Receptor Desensitization
- VII. Biased Agonism with Respect to Receptor Internalization
- VIII. Biased Agonism with Respect to β-Arrestin-Mediated Signaling
- IX. Biased Agonism and Antinociceptive Tolerance
- X. Conclusions
- Acknowledgments
- Authorship Contributions
- Footnotes
- References
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