Pentazocine is a widely used mixed agonist-antagonist opioid. Previous animal studies demonstrated that pentazocine-induced antinociception displayed a ceiling effect characterized by biphasic dose response with a increasing and then descending analgesia which like a bell-shaped curve. This study attempted to clarify the mechanisms underlying such dose-response relationships. ddY or C57BL/6J Mice received subcutaneous injection of saline or pentazocine 3, 10, 30, 56 or 100 mgkg-1, respectively, at 120 min after subcutaneous injection of saline, a mu-opioid receptor antagonist clocinnamox mesylate (C-CAM) 5 mgkg-1, a kappa-opioid receptor antagonist nor-binaltorphimine (nor-BNI) 10 mgkg-1, or the combination of C-CAM and nor-BNI, respectively. The antinociceptive effects of pentazocine were evaluated with 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 mgkg-1. C-CAM completely and partly antagonized the antinociception induced by pentazocine at low doses (3-30 mgkg-1) and high doses (56-100 mgkg-1), 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 mu-opioid receptors, but at high doses, this mu-opioid receptor mediated antinociception is antagonized by concomitant activation of kappa-opioid receptors. This provides the first reasonable hypothesis to explain the ceiling effects of pentazocine analgesia characterized by a biphasic dose-response.
- Received January 26, 2011.
- Revision received May 3, 2011.
- Accepted May 3, 2011.
- The American Society for Pharmacology and Experimental Therapeutics