Cavun Sinan, Göktalay Gökhan, Millington William R
Department of Basic and Pharmaceutical Sciences, Albany College of Pharmacy, Union University, NY 12208, USA.
J Pharmacol Exp Ther. 2005 Nov;315(2):949-58. doi: 10.1124/jpet.105.091553. Epub 2005 Aug 3.
Glycyl-glutamine (Gly-Gln; beta-endorphin(30-31)) is an endogenous dipeptide synthesized from beta-endorphin(1-31). Previous investigations have shown that Gly-Gln inhibits the cardiovascular and respiratory depression caused by morphine and beta-endorphin(1-31), but it does not interfere with opioid analgesia. In this study, we tested whether Gly-Gln administration would influence morphine-induced conditioned place preference, tolerance, dependence, or withdrawal. For place preference experiments, rats were conditioned with morphine sulfate (2.5 mg/kg i.p.) or saline on alternate days for 6 days and tested on day 7. Glycyl-glutamine (1-100 nmol i.c.v.) pretreatment inhibited acquisition of a conditioned place preference to morphine significantly. Glycyl-glutamine (100 nmol i.c.v.) also blocked expression of a pre-established morphine place preference, but it did not interfere with acquisition of a conditioned place preference to palatable food, and it did not produce place preference or aversion when given alone to morphine-naive animals. To induce antinociceptive tolerance, rats were treated with morphine (10 mg/kg i.p.) twice daily for 7 days, and morphine antinociception was evaluated with the tail-flick test. Glycyl-glutamine (100 nmol i.c.v.) pretreatment delayed the onset of morphine tolerance significantly and partially reversed pre-established tolerance. Morphine dependence and withdrawal were assessed by measuring naloxone-precipitated withdrawal symptoms. Glycyl-glutamine inhibited the development of morphine dependence when given to rats twice daily immediately before they received morphine (10 mg/kg i.p.) and suppressed withdrawal symptoms of rats with subcutaneously implanted morphine pellets when administered 5 min before withdrawal was induced with naloxone. Glycyl-glutamine thus attenuates morphine-induced conditioned place preference, tolerance, dependence, and withdrawal without compromising morphine analgesia.
甘氨酰谷氨酰胺（Gly-Gln；β-内啡肽(30 - 31)）是一种由β-内啡肽(1 - 31)合成的内源性二肽。先前的研究表明，Gly-Gln可抑制吗啡和β-内啡肽(1 - 31)引起的心血管和呼吸抑制，但不干扰阿片类镇痛作用。在本研究中，我们测试了给予Gly-Gln是否会影响吗啡诱导的条件性位置偏爱、耐受性、依赖性或戒断反应。对于位置偏爱实验，大鼠每隔一天分别用硫酸吗啡（2.5 mg/kg腹腔注射）或生理盐水进行条件化处理，持续6天，并在第7天进行测试。甘氨酰谷氨酰胺（1 - 100 nmol脑室内注射）预处理显著抑制了对吗啡的条件性位置偏爱的形成。甘氨酰谷氨酰胺（100 nmol脑室内注射）也阻断了预先建立的吗啡位置偏爱表达，但不干扰对美味食物的条件性位置偏爱的形成，且单独给予未接触过吗啡的动物时不会产生位置偏爱或厌恶。为诱导抗伤害感受耐受性，大鼠每天两次腹腔注射吗啡（10 mg/kg），持续7天，并通过甩尾试验评估吗啡的抗伤害感受作用。甘氨酰谷氨酰胺（100 nmol脑室内注射）预处理显著延迟了吗啡耐受性的出现，并部分逆转了预先建立的耐受性。通过测量纳洛酮诱发的戒断症状来评估吗啡依赖性和戒断反应。当在大鼠接受吗啡（10 mg/kg腹腔注射）前每天两次立即给予甘氨酰谷氨酰胺时，可抑制吗啡依赖性的发展；当在皮下植入吗啡丸剂的大鼠用纳洛酮诱导戒断前5分钟给予甘氨酰谷氨酰胺时，可抑制其戒断症状。因此，甘氨酰谷氨酰胺可减轻吗啡诱导的条件性位置偏爱、耐受性、依赖性和戒断反应，而不影响吗啡镇痛作用。
