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Journal of Pharmacology And Experimental Therapeutics Fast Forward
First published on January 12, 2007; DOI: 10.1124/jpet.106.113290

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Received for publication September 8, 2006.
Revised January 9, 2007.
Accepted for publication January 10, 2007.

Thienorphine: receptor binding and behavioral effects in rhesus monkeys

Jun-Xu Li 1, Ginger L Becker 1, John R. Traynor 2, Ze-Hui Gong 3, Charles P. France 1*

1 Department of Pharmacology, the University of Texas Health Science Center at San Antonio 2 Department of Pharmacology, University of Michigan Medical School 3 Department of Pharmacology, Beijing Institute of Pharmacology and Toxicology

* Address correspondence to: E-mail: france{at}uthscsa.edu

Abstract

Thienorphine is an oripavine with long-lasting antinociceptive effects in mice that are thought to be mediated by µ-opioid receptors. These studies examined the receptor binding of thienorphine in cell membrane homogenates and its behavioral effects in rhesus monkeys. Affinity and potency were determined using radioligand displacement and stimulation of 5'-(3-[35S]thio)triphosphate ([35S]GTP{gamma}S) binding in C6 (µ, {delta}) and CHO ({kappa}) cell membranes. Thienorphine displayed high affinity for {kappa}-, µ- and {delta}-opioid receptors with Ki values of 0.14, 0.22, and 0.69 nM, respectively. Thienorphine partially stimulated {kappa}-opioid (75%) and µ-opioid (19%) receptors and not {delta}-opioid receptors. Thienorphine dose-dependently increased tail-withdrawal latency for 50°C water and not 55°C water with effects lasting for more than 7 days. The {kappa}-opioid receptor antagonist nor-BNI (3.2 mg/kg) and a large dose (1.0 mg/kg) of naltrexone prevented thienorphine-induced antinociception. Thienorphine enhanced the antinociceptive effects of morphine and U50,488 with 50°C water; with 55°C water thienorphine enhanced the effects of morphine and attenuated the effects of U50,488. In other monkeys, thienorphine decreased responding in both components of a multiple schedule of food presentation and stimulus shock termination for up to 8 days; naltrexone and nor-BNI partially prevented these rate-decreasing effects. In morphine-treated monkeys discriminating naltrexone, thienorphine and U50,488 neither substituted for nor modified the naltrexone discriminative stimulus. Thienorphine and U50,488 produced the same directly observable signs. These results show that thienorphine has long-lasting effects that appear to be mediated by low efficacy agonism at {kappa}-opioid receptors, both in vitro and in vivo.


Key words: Antinociception, Behavior, Opioid receptor, Receptor binding, Rhesus monkey, Thienorphine




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