| First Author | Mittal N | Year | 2012 |
| Journal | Neuropsychopharmacology | Volume | 37 |
| Issue | 8 | Pages | 1953-62 |
| PubMed ID | 22491351 | Mgi Jnum | J:318118 |
| Mgi Id | MGI:6858319 | Doi | 10.1038/npp.2012.42 |
| Citation | Mittal N, et al. (2012) Evidence that behavioral phenotypes of morphine in beta-arr2-/- mice are due to the unmasking of JNK signaling. Neuropsychopharmacology 37(8):1953-62 |
| abstractText | The altered behavioral effects of morphine, but not most other mu agonists, in mice lacking beta-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 beta-arrestin 2 is cJun-N-terminal kinase (JNK), which binds with beta-arrestin 2 and modulates the analgesic effects of morphine. Using neurons lacking beta-arrestin 2 (beta-arr2-/-) to examine this interaction, we found that beta-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 beta-arrestin 2 affects the JNK cascade. We therefore examined whether some of the behavioral phenotypes of mice lacking beta-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 beta-arr2-/- mice, to +/+ levels. Both the reduced locomotor effect of morphine and the psychomotor sensitization to repeated morphine administration in beta-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 beta-arr2-/- mice to +/+ levels. In summary, removing beta-arrestin 2 reveals mu receptor activation of the JNK cascade in a ligand-specific manner explaining several behavioral phenotypes of beta-arr2-/- mice. |
