Abstract
Pentazocine is a widely used mixed agonist-antagonist opioid. Previous animal studies have demonstrated that pentazocine-induced antinociception displayed a ceiling effect characterized by biphasic dose response with a increasing and then descending analgesia like a bell-shaped curve. This study attempted to clarify the mechanisms underlying such dose-response relationships. ddY and C57BL/6J mice received subcutaneous injection of saline or pentazocine (3, 10, 30, 56, or 100 mg · kg−1), at 120 min after subcutaneous injection of saline, a μ-opioid receptor antagonist clocinnamox mesylate (C-CAM) (5 mg · kg−1), a κ-opioid receptor antagonist nor-binaltorphimine (nor-BNI) (10 mg · kg−1), or the combination of C-CAM and nor-BNI. The antinociceptive effects of pentazocine were evaluated using tail pressure, hot plate, tail flick, and acetic acid writhing tests. Without pretreatment with an opioid receptor antagonist, the antinociceptive effects of pentazocine exhibited biphasic bell-shaped dose-response curves peaking at 30 mg · kg−1. C-CAM completely and partly antagonized the antinociception induced by pentazocine at low (3–30 mg · kg−1) and high (56–100 mg · kg−1) doses, respectively. nor-BNI enhanced the antinociception by pentazocine at high doses and turned the later descending portion of the biphasic dose-response curves into a sigmoid curve. The combination of C-CAM and nor-BNI completely abolished the antinociception by pentazocine at all doses. Our results suggest pentazocine produces antinociception primarily via activation of μ-opioid receptors, but at high doses, this μ-opioid receptor-mediated antinociception is antagonized by concomitant activation of κ-opioid receptors. This provides the first reasonable hypothesis to explain the ceiling effects of pentazocine analgesia characterized by a biphasic dose response.
Footnotes
This work was supported in part by the Scientific Research Foundation for Returned Scholars, Ministry of Education of China [Grant 2008890]; and the Research Fund for the Doctoral Program of Higher Education of China [Grant 200805581110].
Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
doi:10.1124/jpet.111.179879.
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ABBREVIATIONS:
- PZ
- pentazocine
- C-CAM
- clocinnamox mesylate
- nor-BNI
- nor-binaltorphimine
- KOR
- κ-opioid receptor
- MOR
- μ-opioid receptor
- AUC
- area under the response-versus-time curve
- PLSD
- protected least significance difference test
- Sal
- saline.
- Received January 26, 2011.
- Accepted May 3, 2011.
- Copyright © 2011 by The American Society for Pharmacology and Experimental Therapeutics
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