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of MOR by
b
-arrestin 2.
125,126
Thus,
in vivo
studies demonstrate that the
absence of
b
-arrestin 2 delays the onset of MOR desensitization and
amplifies its G protein coupling efficacy.
130
Furthermore,
b
-arrestin 2
knockout mice are resistant to opiate tolerance following repeated admin-
istration. After chronic exposure, MOR in wild-type animals are des-
ensitized to the antinociceptive effect of morphine, but this phenomenon
fails to occur in
b
-arrestin 2 knockout mice. The knockout mice do not
develop antinociceptive tolerance to morphine in the hot plate test, as
the lack of
b
-arrestin 2 allows MOR to engage in persistent G protein
coupling.
126
The tail flick test can be used to assess the role of
b
-arrestin 2 in
nociception at the spinal cord level. In
b
-arrestin 2 knockout mice, results
in this test are consistent with those obtained with the hot plate studies.
Mutant mice exhibit enhanced and prolonged morphine-induced antino-
ciception.
131
These results, and the role of
b
-arrestin 2 as a negative
MOR regulator, have been confirmed by intrathecal injection of
b
-arrestin
2 antisense mRNA in rats. This selective
b
-arrestin 2 knockdown also
enhances the response to morphine in the tail flick test.
132
After 7 days of
morphine treatment,
b
-arrestin 2 knockout mice retain two-fold higher
sensitivity to morphine as compared to wild-type mice but do develop some
tolerance to morphine-induced analgesia in the tail flick test.
131
The toler-
ance develops by
b
-arrestin 2 knockout mice is less dramatic and delayed in
onset when compared with wild-type animals and can be reversed by injec-
tion of chelerythrine, a PKC inhibitor. Thus,
b
-arrestin 2 also plays a signif-
icant role in morphine tolerance in at the spinal cord level, but in the absence
of
b
-arrestin 2-mediated desensitization, other MOR effectors, such as
PKC, are able to mediate a degree of tolerance.
133
Thus, regulation of
MOR by
b
-arrestin 2 differs between the brain and the spinal cord indicat-
ing that the capacity of
b
-arrestins to modulate different aspects of MOR
signaling varies depending on the cellular context.
MOR stimulation by different agonists such as morphine, etorphine,
methadone, and fentanyl induces G protein coupling and analgesia in
mice. Consistent with the concept that structurally distinct agonists can
effect different downstream pathways with different efficacy, MOR regula-
tion differs from one agonist to another. Morphine is a relatively weak acti-
vator of MOR desensitization. In contrast, etorphine, methadone, and
fentanyl are very efficient at inducing MOR phosphorylation,
b
-arrestin
2 recruitment, and MOR internalization.
134-136
Thus, while knocking
out
b
-arrestin 2 dramatically enhances the antinociceptive response to
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