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Received for publication April 1, 2005.
Revised May 18, 2005.
Accepted for publication May 23, 2005.
-ARRESTIN-2 KNOCKOUT MICEMorphine is a potent analgesic, yet, like most opioid narcotics, it exerts unwanted side effects such as constipation and respiratory suppression thereby limiting its clinical utility. Pharmacological approaches taken to preserve the analgesic properties, while eliminating the unwanted sided effects, have met with very limited success. Here we provide evidence that altering mu opioid receptor regulation may provide a novel approach to discriminate morphine's beneficial and deleterious effects in vivo. We have previously reported that mice lacking the G protein-coupled receptor regulatory protein, beta-arrestin-2, display profoundly altered morphine responses. Beta-arrestin-2 knockout mice have enhanced and prolonged morphine analgesia with very little morphine tolerance. In this report we examine whether the side-effects of morphine treatment are also augmented in this animal model. Surprisingly, the genetic disruption of opioid receptor regulation, while enhancing and prolonging analgesia, dramatically attenuates the respiratory suppression and acute constipation caused by morphine.
Key words:
Arrestin, Desensitization, GPCR, GPCR Kinases (GRK), Opioid, Regulation
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