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Sedation can be induced in mice by stimulation of a 2 AR with com-
pounds such as UK14304 [5-bromo-6-(2-imidazolin-2-ylamino)
quinoxaline]. This sedation effect can be assessed in mice with the rotarod
test, which determines performance in motor coordination. While a 2 AR
stimulation using UK14304 decreases performance on this test in wild-type
animals, b -arrestin 2 knockout animals are more resistant. To assess if this
sedation resistance in b -arrestin 2 knockout animals is specific to a 2 AR,
the test has been performed using R(
)N6-(2-phenylisopropyl)adenosine
(R-PIA), an adenosine 1 receptor agonist. R-PIA-induced sedation is pre-
served in b -arrestin 2 knockout mice, demonstrating that these mice are not
resistant to adenosine 1 receptor-mediated sedation, and that unlike the
adenosine receptor, a 2 AR responsiveness is b -arrestin 2-dependent. 124
5. ARRESTINS IN OPIOID RECEPTOR SIGNALING
5.1. Generalities
Mu-opioid receptors (MOR) are coupled to G proteins, and their activity
in periaqueductal gray matter and brainstem is associated with analgesic
effects. MOR signaling in the CNS is complex, and its effects on such
diverse processes as analgesia, constipation, respiratory depression, thermal
regulation, locomotor activity, and narcotic addiction, dependence, and tol-
erance indicate that MOR signaling is highly context dependent. Among
the physiological effects induced by morphine treatment, DA release in
the striatum, drug reinforcement, and hypothermia, but not physical depen-
dence, is affected in b -arrestin 2 knockout mice. 44,125,126 Furthermore,
opiate-induced constipation, respiratory suppression, and hyperlocomotor
activity are diminished in b -arrestin 2 knockout animals. 44,127 These data
suggest that b -arrestin 2 can act as both a negative and a positive MOR
regulator.
5.2. Arrestins and MOR internalization
Among the behavioral responses induced by b -arrestin 2 deletion, the first
one reported is related to morphine-induced analgesia. When wild-type and
b -arrestin 2 knockout mice are challenged in a hot plate test after morphine
administration, the mutant mice exhibit prolonged latency. 125 This reveals
defects in nociceptive perception of a thermal stimulus mediated by
MOR. 128,129 MOR-G protein coupling is enhanced in b -arrestin 2 knock-
out mice as compared to wild-type animals, indicating a negative regulation
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