Abstract
Morphine 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 side effects, have met with very limited success. Here, we provide evidence that altering μ 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, β-arrestin 2, display profoundly altered morphine responses. β-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.
Footnotes
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This work was supported by National Institutes of Health, National Institute on Drug Abuse Grants DA-14600 and DA-018860 (to L.M.B). K.M.R. is a student in the Integrated Biological Sciences Graduate Program of the Ohio State University. J.K.L.W. is supported by the Veterans Administration.
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Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
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doi:10.1124/jpet.105.087254.
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ABBREVIATIONS: GPCR, G protein-coupled receptor; GRK, GPCR kinase; KO, knockout; βarr, β-arrestin; μOR, μ opioid receptor; WT, wild type; GI, gastrointestinal; ANOVA, analysis of variance.
- Received March 31, 2005.
- Accepted May 23, 2005.
- The American Society for Pharmacology and Experimental Therapeutics
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