Abstract
Previously, we reported minimal opioid receptor occupancy following a clinical dose of the μ-opioid agonist, methadone, measured in vivo using positron emission tomography (PET) with [11C]diprenorphine and subsequently used rats to obtain experimental data in support of a high receptor reserve hypothesis (Melichar et al., 2005). Here, we report on further preclinical studies investigating opioid receptor occupancy with oxycodone (μ- and κ-receptor agonist), morphine (μ-receptor agonist), and buprenorphine (partial agonist at the μ-receptor and antagonist at the δ- and κ-receptors), each given at antinociceptive doses. In vivo binding of [11C]diprenorphine was not significantly reduced after treatment with the full agonists but was reduced by ∼90% by buprenorphine. In addition, given that [11C]diprenorphine is a non-subtype-specific PET tracer, there was no regional variation that might feasibly be interpreted as due to differences in opioid subtype distribution. The data support minimal competition between the high-efficacy agonists and the non-subtype-selective antagonist radioligand and highlight the limitations of [11C]diprenorphine PET to monitor in vivo occupancy. Alternative means may be needed to address clinical issues regarding opioid receptor occupancy that are required to optimize treatment strategies.
Footnotes
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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.107.121749.
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ABBREVIATIONS: PET, positron emission tomography; SBI, specific binding index; ANOVA, analysis of variance.
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↵1 Current affiliation: Department of Palliative Medicine, Royal Marsden National Health Science Foundation Trust, Surrey, United Kingdom.
- Received February 20, 2007.
- Accepted May 7, 2007.
- The American Society for Pharmacology and Experimental Therapeutics
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