In vivo pharmacological resultant analysis reveals noncompetitive interactions between opioid antagonists in the rat tail‐withdrawal assay

• Published in: British journal of pharmacology Vol. 149; no. 8; pp. 1071 - 1082
• Main Author: Walker, E A
• Format: Journal Article
• Language: English
• Published: Oxford, UK Blackwell Publishing Ltd 01.12.2006; Nature Publishing
• Subjects: Algorithms; Animals; antinociception; Biological and medical sciences; CTAP; CTOP; Dose-Response Relationship, Drug; Drug Interactions; Injections, Intraventricular; Injections, Subcutaneous; Male; Medical sciences; morphine; Morphine - antagonists & inhibitors; Morphine - pharmacology; naltrexone; Naltrexone - pharmacology; Narcotic Antagonists - pharmacology; Narcotics - pharmacology; Pain Measurement - drug effects; Peptide Fragments; Peptides - pharmacology; pharmacologic resultant; Pharmacology. Drug treatments; Rats; Rats, Sprague-Dawley; Reaction Time - drug effects; Research Papers; Schild regressions; Somatostatin - analogs & derivatives; Somatostatin - pharmacology; Morphinan derivatives; Narcotic antagonist; Rat; antinociception; Interaction; Rodentia; Morphine; Opiates; Narcotic analgesic; Naltrexone; Opioid peptide; CTOP; Analgesia; In vivo; Schild regressions; Vertebrata; Mammalia; pharmacologic resultant; Animal; rats; CTAP
• ISSN: 0007-1188; 1476-5381
• DOI: 10.1038/sj.bjp.0706946

Background and purpose: Pharmacological resultant analysis is a technique that can detect secondary effects of competitive antagonists in vitro. The utility of pharmacological resultant analysis as a potential tool for the investigation of antagonist interactions in vivo was examined in the present study using two opioid antagonists, naltrexone and CTAP. Experimental approach: Using the experimental design of pharmacological resultant analysis, the well‐characterized opioid antagonist naltrexone was examined in the presence of multiple doses of CTAP to block the antinociceptive effects of morphine in the rat warm‐water (55oC), tail‐withdrawal assay. Key results: Alone, all doses of naltrexone, CTAP, and CTOP examined blocked the antinociceptive effects of morphine. In the presence of fixed doses of 1 or 10 μg CTAP, increasing doses of naltrexone produced dose‐dependent shifts to the right in the morphine dose‐response curve. However, a lower dose of naltrexone in combination with 1 or 10 μg CTAP failed to alter the morphine dose‐response curve. In the presence of a fixed dose of 0.1 mg kg−1 naltrexone, CTAP doses produced irregular shifts to the right in the morphine dose‐response curves. Conclusions and implications: Resultant analysis was applied and an apparent pKC value for CTAP was found to be one log unit higher than the apparent pA2 value for CTAP, evidence that CTAP may have secondary actions or that a signal transducer function may be altered by the combinations of these antagonists. Taken together, these data suggest pharmacological resultant analysis can reveal novel interactions between antagonists in vivo. British Journal of Pharmacology (2006) 149, 1071–1082. doi:10.1038/sj.bjp.0706946