b-Arrestins in the Central Nervous System - Progress in Molecular Biology and Translational Science - page 274

morphine, the responses of b -arrestin 2 knockout mice after etorphine,
methadone, and fentanyl administration are similar to wild-type animals.
This discrepancy between drugs is likely due to the efficiency with which
the ligands stimulate receptor phosphorylation. While etorphine, metha-
done, and fentanyl induce a robust phosphorylation, morphine stimulation
induces a weaker response. In the latter case, recruitment of b -arrestin 1 may
permit near normal MOR desensitization and provide compensatory
regulation. 137 Nonetheless, these data suggest that “biased” MOR ligands
with reduced ability to stimulate b -arrestin recruitment might exhibit the
desirable clinical properties of prolonged analgesia and diminished opiate
tolerance.
The reinforcing and psychomotor effects of morphine involve MOR
stimulation of the dopaminergic system. b -Arrestin 2-mediated MOR
desensitization also appears to negatively regulate these effects in vivo. 57
Whereas the ability of cocaine to affect locomotor activity, behavioral sen-
sitization, conditioned place preference, and striatal DA release is very sim-
ilar between wild-type and b -arrestin 2 knockout mice, all of these responses
to morphine are significantly reduced in the knockouts, indicating the
b -arrestin 2 plays a more important role in modulating the dopaminergic
effects of morphine than those produced by cocaine.
5.3. Alternative pathways
Some evidence supports a role for b -arrestin 1 in nuclear signaling by
d -opioid receptors (DOR). In transfected HEK cells and neuronal
SK-N-SH cells, DOR activation causes b -arrestin 1 to translocate to the
nucleus, where it is selectively enriched at specific promoters, such as p27
and c-fos [147A]. Once there, it facilitates recruitment of the histone
acetyltransferase, p300, leading to increased local histone H4 acetylation
and gene transcription ( Fig. 11.2 ). This novel form of GPCR signaling to
the nucleus via signal-dependent histone modification may underlie some
of the transcriptional effects of opioid receptors in the brain.
6. ARRESTINS AND CORTICOTROPIN RECEPTORS
6.1. Generalities
Stress events are characterized by a release of corticotropin-releasing factor
(CRF) from the hypothalamic paraventricular nucleus, which activates pitu-
itary CRF receptors to promote adrenocorticotropic hormone (ACTH)