PT  - JOURNAL ARTICLE
AU  - Wang, Yu-Jun
AU  - Tao, Yi-Min
AU  - Li, Fu-Ying
AU  - Wang, Yu-Hua
AU  - Xu, Xue-Jun
AU  - Chen, Jie
AU  - Cao, Ying-Lin
AU  - Chi, Zhi-Qiang
AU  - Neumeyer, John L.
AU  - Zhang, Ao
AU  - Liu, Jing-Gen
TI  - Pharmacological Characterization of ATPM [(-)-3-Aminothiazolo[5,4-<em>b</em>]-<em>N</em>-cyclopropylmethylmorphinan hydrochloride], a Novel Mixed κ-Agonist and μ-Agonist/-Antagonist That Attenuates Morphine Antinociceptive Tolerance and Heroin Self-Administration Behavior
AID  - 10.1124/jpet.108.142802
DP  - 2009 Apr 01
TA  - Journal of Pharmacology and Experimental Therapeutics
PG  - 306--313
VI  - 329
IP  - 1
4099  - http://jpet.aspetjournals.org/content/329/1/306.short
4100  - http://jpet.aspetjournals.org/content/329/1/306.full
SO  - J Pharmacol Exp Ther2009 Apr 01; 329
AB  - ATPM [(-)-3-amino-thiazolo[5,4-b]-N-cyclopropylmethylmorphinan hydrochloride] was found to have mixed κ- and μ-opioid activity and identified to act as a full κ-agonist and a partial μ-agonist by in vitro binding assays. The present study was undertaken to characterize its in vivo effects on morphine antinociceptive tolerance in mice and heroin self-administration in rats. ATPM was demonstrated to yield more potent antinociceptive effects than (-)U50,488H (trans-3,4-dichloro-N-methyl-N-[2-(1-pyrrolidinyl)cyclohexyl]benzeneacetamide). It was further found that the antinociceptive effects of ATPM were mediated by κ- and μ-, but not δ-opioid, receptors. In addition to its agonist profile on the μ-receptor, ATPM also acted as a μ-antagonist, as measured by its inhibition of morphine-induced antinociception. It is more important that ATPM had a greater ratio of the ED50 value of sedation to that of antinociception than (-)U50,488 (11.8 versus 3.7), indicative of a less sedative effect than (-)U50,488H. In addition, ATPM showed less potential to develop antinociceptive tolerance relative to (-)U50,488H and morphine. Moreover, it dose-dependently inhibited morphine-induced antinociceptive tolerance. Furthermore, it was found that chronic treatment of rats for 8 consecutive days with ATPM (0.5 mg/kg s.c.) produced sustained decreases in heroin self-administration. (-)U50,488H (2 mg/kg s.c.) also produced similar inhibitory effect. Taken together, our findings demonstrated that ATPM, a novel mixed κ-agonist and μ-agonist/-antagonist, could inhibit morphine-induced antinociceptive tolerance, with less potential to develop tolerance and reduce heroin self-administration with less sedative effect. κ-Agonists with some μ-activity appear to offer some advantages over selective κ-agonists for the treatment of heroin abuse. The American Society for Pharmacology and Experimental Therapeutics