Effects of ATPM-ET, a novel K agonist with partial μ activity, on morphine-induced physical dependence and behavior sensitization in mice  

作　　者：Jian-feng SUN Yu-hua WANG Fu-ying LI Gang LU Yi-min TAO Yun CHENG Jie CHEN Xue-jun XU Zhi-qiang CHI John L NEUMEYER Ao ZHANG Jing-gen LIU 

机构地区：[1]State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 201203, China [2]School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing 210046, China [3]Alcohol & Drug Abuse Research Center, McLean Hospital, Harvard Medical School, MA 02478, USA

出　　处：《Acta Pharmacologica Sinica》2010年第12期1547-1552,共6页中国药理学报（英文版）

摘　　要：Aim： To investigate the effects of ATPM-ET [（-）-3-N-Ethylaminothiazolo [5,4-b]-N-cyclopropylmethylmorphinan hydrochloride] on physical dependence and behavioral sensitization to morphine in mice. Methods： The pharmacological profile of ATPM-ET was characterized using competitive binding and GTPyS binding assays. We then examined the antinociceptive effects of ATPM-ET in the hot plate test. Morphine dependence assay and behavioral sensitization assay were used to determine the effect of ATPM-ET on physical dependence and behavior sensitization to morphine in mice. Results： The binding assay indicated that ATPM-ET ATPM-ET exhibited a high affinity to both K- and p-opioid receptors with K1 values of 0.15 nmol/L and 4.7 nmoVL, respectively, indicating it was a full K-opioid receptor agonist and a partial p-opioid receptor agonist. In the hot plate test, ATPM-ET produced a dose-dependent antinociceptive effect, with an ED50 value of 2.68 （2.34-3.07） mg/kg. Administration of ATPM-ET （1 and 2 mg/kg, sc） prior to naloxone （3.0 mg/kg, sc） injection significantly inhibited withdrawal jumping of mice. In addition, ATPM-ET （1 and 2 mg/kg, sc） also showed a trend toward decreasing morphine withdrawal-induced weight loss. ATPM-ET （1.5 and 3 mg/kg, sc） 15 min before the morphine challenge significantly inhibited the morphine-induced behavior sensitization （P〈0.05）. Conclusion： ATPM-ET may have potential as a therapeutic agent for the treatment of drug abuse.Aim： To investigate the effects of ATPM-ET [（-）-3-N-Ethylaminothiazolo [5,4-b]-N-cyclopropylmethylmorphinan hydrochloride] on physical dependence and behavioral sensitization to morphine in mice. Methods： The pharmacological profile of ATPM-ET was characterized using competitive binding and GTPyS binding assays. We then examined the antinociceptive effects of ATPM-ET in the hot plate test. Morphine dependence assay and behavioral sensitization assay were used to determine the effect of ATPM-ET on physical dependence and behavior sensitization to morphine in mice. Results： The binding assay indicated that ATPM-ET ATPM-ET exhibited a high affinity to both K- and p-opioid receptors with K1 values of 0.15 nmol/L and 4.7 nmoVL, respectively, indicating it was a full K-opioid receptor agonist and a partial p-opioid receptor agonist. In the hot plate test, ATPM-ET produced a dose-dependent antinociceptive effect, with an ED50 value of 2.68 （2.34-3.07） mg/kg. Administration of ATPM-ET （1 and 2 mg/kg, sc） prior to naloxone （3.0 mg/kg, sc） injection significantly inhibited withdrawal jumping of mice. In addition, ATPM-ET （1 and 2 mg/kg, sc） also showed a trend toward decreasing morphine withdrawal-induced weight loss. ATPM-ET （1.5 and 3 mg/kg, sc） 15 min before the morphine challenge significantly inhibited the morphine-induced behavior sensitization （P〈0.05）. Conclusion： ATPM-ET may have potential as a therapeutic agent for the treatment of drug abuse.

关 键 词：behavioral sensitization mu opioid receptors MORPHINE kappa opioid receptors physical dependence ADDICTION 

分 类 号：Q593.2[生物学—生物化学] Q426