Supersensitivity to opioid analgesics following chronic opioid antagonist treatment: Relationship to receptor selectivity

Supersensitivity to opioid analgesics following chronic opioid antagonist treatment: Relationship... The effect of chronic opioid antagonist treatment on the analgesic potency of six opioid agonists was compared to changes in opioid receptor density and the selectivity of each agonist for μ (DAMGO), δ (DPDPE) and κ (U69,593) opioid receptors. Mice were implanted SC with a 15-mg naltrexone or placebo pellet for 8 days. The pellets were removed and 24 h later, mice were sacrificed and binding studies were conducted, or mice were tested in analgesia (tail-flick) dose-response studies. All six analgesics acted as full agonists for both placebo and naltrexone-treated mice. Naltrexone increased the analgesic potency of methadone, etorphine, fentanyl, meperidine, and oxycodone by 1.9–3.2-fold. The analgesic potency of propoxyphene was not increased significantly (1.3-fold). In saturation binding studies in brain homogenate, naltrexone increased the B max of μ, δ, and κ opioid receptors by 86,43, and 33%, respectively, without altering K d . Competition binding studies for each receptor type were conducted in brains from untreated mice, and K I s were determined for each agonist. All agonists had greatest selectivity toward μ compared with δ and κ receptors. There did not appear to be an obvious relationship between receptor selectivity and the magnitude of Supersensitivity. These studies indicate that Supersensitivity occurs for a broad range of opioid analgesics following chronic opioid antagonist treatment in the mouse. However, the selectivity of these agonists for μ, δ, and κ receptors does not appear to correlate with differences in Supersensitivity. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Pharmacology Biochemistry and Behavior Elsevier

Supersensitivity to opioid analgesics following chronic opioid antagonist treatment: Relationship to receptor selectivity

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Publisher
Elsevier
Copyright
Copyright © 1995 Elsevier Ltd
ISSN
0091-3057
eISSN
1873-5177
DOI
10.1016/0091-3057(94)00375-S
Publisher site
See Article on Publisher Site

Abstract

The effect of chronic opioid antagonist treatment on the analgesic potency of six opioid agonists was compared to changes in opioid receptor density and the selectivity of each agonist for μ (DAMGO), δ (DPDPE) and κ (U69,593) opioid receptors. Mice were implanted SC with a 15-mg naltrexone or placebo pellet for 8 days. The pellets were removed and 24 h later, mice were sacrificed and binding studies were conducted, or mice were tested in analgesia (tail-flick) dose-response studies. All six analgesics acted as full agonists for both placebo and naltrexone-treated mice. Naltrexone increased the analgesic potency of methadone, etorphine, fentanyl, meperidine, and oxycodone by 1.9–3.2-fold. The analgesic potency of propoxyphene was not increased significantly (1.3-fold). In saturation binding studies in brain homogenate, naltrexone increased the B max of μ, δ, and κ opioid receptors by 86,43, and 33%, respectively, without altering K d . Competition binding studies for each receptor type were conducted in brains from untreated mice, and K I s were determined for each agonist. All agonists had greatest selectivity toward μ compared with δ and κ receptors. There did not appear to be an obvious relationship between receptor selectivity and the magnitude of Supersensitivity. These studies indicate that Supersensitivity occurs for a broad range of opioid analgesics following chronic opioid antagonist treatment in the mouse. However, the selectivity of these agonists for μ, δ, and κ receptors does not appear to correlate with differences in Supersensitivity.

Journal

Pharmacology Biochemistry and BehaviorElsevier

Published: Jun 1, 1995

References

  • Probit analysis
    Finney, D.J

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