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

• Published in: Pharmacology, biochemistry and behavior biochemistry and behavior, 1995-06, Vol.51 (2), p.535-539
• Main Authors: Yoburn, Byron C, Shah, Sukrut, Chan, Kawa, Duttaroy, Alokesh, Davis, Trong
• Format: Article
• Language: English
• Subjects: Analgesia; Analgesics; Analgesics - pharmacology; Animals; Biological and medical sciences; Dose-Response Relationship, Drug; Drug Implants; Enkephalin, Ala-MePhe-Gly; Enkephalin, D-Penicillamine (2,5); Enkephalins - pharmacology; Etorphine; Fentanyl; Male; Medical sciences; Meperidine; Methadone; Mice; Naltrexone; Naltrexone - administration & dosage; Naltrexone - pharmacology; Narcotic Antagonists - administration & dosage; Narcotic Antagonists - pharmacology; Neuropharmacology; Opioid Peptides - administration & dosage; Opioid Peptides - pharmacology; Opioid receptor; Oxycodone; Pain Measurement - drug effects; Pharmacology. Drug treatments; Propoxyphene; Receptors, Opioid - drug effects; Receptors, Opioid, delta - agonists; Receptors, Opioid, delta - drug effects; Receptors, Opioid, kappa - agonists; Receptors, Opioid, kappa - drug effects; Receptors, Opioid, mu - agonists; Receptors, Opioid, mu - drug effects; Supersensitivity; Up-Regulation - drug effects; Upregulation
• ISSN: 0091-3057; 1873-5177
• DOI: 10.1016/0091-3057(94)00375-S

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.