title: Evidence that behavioral phenotypes of morphine in β-arr2-/- mice are due to the unmasking of JNK signaling.
abstract: The altered behavioral effects of morphine, but not most other mu agonists, in mice lacking β-arrestin 2, suggest that this scaffolding protein regulates the signaling cascade of this commonly used analgesic. One of the cascades that could be regulated by β-arrestin 2 is cJun-N-terminal kinase (JNK), which binds with β-arrestin 2 and modulates the analgesic effects of morphine. Using neurons lacking β-arrestin 2 (β-arr2-/-) to examine this interaction, we found that β-arr2-/- neurons show altered intracellular distribution of JNK and cJun, and that morphine, but not fentanyl, increased the nuclear localization of the phosphorylated, therefore activated, form of cJun, a JNK target in dorsal root ganglia neurons. This suggests that deleting β-arrestin 2 affects the JNK cascade. We therefore examined whether some of the behavioral phenotypes of mice lacking β-arrestin 2 could be a result of altered JNK signaling. Indeed, two different JNK inhibitors reversed the enhanced analgesic effect of morphine, a known phenotype of β-arr2-/- mice, to +/+ levels. Both the reduced locomotor effect of morphine and the psychomotor sensitization to repeated morphine administration in β-arr2-/- mice were also returned to +/+ levels by inhibiting JNK. In contrast, the behavioral effects of fentanyl were neither genotype-dependent nor affected by JNK inhibition. Furthermore, a PKC inhibitor had a similar effect as inhibiting JNK in reducing the enhanced analgesic effect of morphine in β-arr2-/- mice to +/+ levels. In summary, removing β-arrestin 2 reveals mu receptor activation of the JNK cascade in a ligand-specific manner explaining several behavioral phenotypes of β-arr2-/- mice.
authors.affiliation: Department of Psychology, California State University, San Bernardino, CA, USA.
authors.forename: Nitish
authors.initials: N
authors.lastname: Mittal
authors.forename: Miao
authors.initials: M
authors.lastname: Tan
authors.forename: Onyemachi
authors.initials: O
authors.lastname: Egbuta
authors.forename: Nina
authors.initials: N
authors.lastname: Desai
authors.forename: Cynthia
authors.initials: C
authors.lastname: Crawford
authors.forename: Cui-Wei
authors.initials: CW
authors.lastname: Xie
authors.forename: Christopher
authors.initials: C
authors.lastname: Evans
authors.forename: Wendy
authors.initials: W
authors.lastname: Walwyn
mesh_terms: D000818:Animals; D019390:Arrestins / Q000235:genetics*; D002478:Cells, Cultured; D005260:Female; D005283:Fentanyl / Q000494:pharmacology; D005727:Ganglia, Spinal / Q000187:drug effects / Q000378:metabolism / Q000502:physiology; D048031:JNK Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009020:Morphine / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D009043:Motor Activity / Q000187:drug effects*; D010147:Pain Measurement / Q000187:drug effects*; D010766:Phosphorylation; D011493:Protein Kinase C / Q000037:antagonists & inhibitors; D016755:Proto-Oncogene Proteins c-jun / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D000071560:beta-Arrestin 2; D000071557:beta-Arrestins
chemical_list: C000605258:Arrb2 protein, mouse; D019390:Arrestins; D016755:Proto-Oncogene Proteins c-jun; D000071560:beta-Arrestin 2; D000071557:beta-Arrestins; D009020:Morphine; D011493:Protein Kinase C; D048031:JNK Mitogen-Activated Protein Kinases; D005283:Fentanyl