Rawls Scott M, Tallarida Ronald J, Zisk Jacob
Department of Pharmaceutical Sciences, Temple University School of Pharmacy, 3307 North Broad Street, Philadelphia, PA, 19140, USA.
Eur J Pharmacol. 2006 Dec 28;553(1-3):89-98. doi: 10.1016/j.ejphar.2006.08.038. Epub 2006 Aug 26.
Agmatine blocks morphine withdrawal symptoms and enhances morphine analgesia in rats. Yet, the role of agmatine in the pharmacological effects of other abused drugs has not been investigated. The present study investigates the effect of agmatine administration on the hypothermic response to cannabinoids. Hypothermia is an effective endpoint because cannabinoid agonists produce a rapid, reproducible, and significant decrease in body temperature that is abolished by cannabinoid CB(1) receptor antagonists. WIN 55212-2, a cannabinoid agonist, was administered to rats by itself and with agmatine. WIN 55212-2 (1, 2.5, 5 and 10 mg/kg, i.m.) caused a significant hypothermia. Agmatine (10, 25 and 50 mg/kg, i.p.) was ineffective. For combined administration, agmatine (50 mg/kg, i.p.) enhanced the hypothermic effect of WIN 55212-2 (1, 2.5, 5 and 10 mg/kg, i.m.). The enhancement was strongly synergistic, indicated by a 2.7-fold increase in the relative potency of WIN 55212-2. The central administration of agmatine (25 and 50 mug/rat, i.c.v.) significantly increased the hypothermic effect of WIN 55212-2 (2.5 mg/kg, i.m.). This indicates that agmatine acts through a central mechanism to augment cannabinoid-evoked hypothermia. Idazoxan (2 mg/kg, i.p.), an imidazoline antagonist, blocked the enhancement by agmatine, thus suggesting that imidazoline receptor activation is required for agmatine to enhance cannabinoid-evoked hypothermia. The present data reveal that agmatine and a cannabinoid agonist interact to produce a hypothermic synergy in rats. These results show that agmatine acts in the brain and via imidazoline receptors to enhance cannabinoid-evoked hypothermia.
胍丁胺可阻断大鼠吗啡戒断症状并增强吗啡镇痛作用。然而，胍丁胺在其他滥用药物药理作用中的角色尚未得到研究。本研究考察了胍丁胺给药对大麻素所致体温降低反应的影响。体温降低是一个有效的终点指标，因为大麻素激动剂可使体温迅速、可重复且显著下降，而这种下降可被大麻素CB(1)受体拮抗剂消除。大麻素激动剂WIN 55212-2单独及与胍丁胺联合给予大鼠。WIN 55212-2（1、2.5、5和10毫克/千克，肌肉注射）可引起显著体温降低。胍丁胺（10、25和50毫克/千克，腹腔注射）无效。对于联合给药，胍丁胺（50毫克/千克，腹腔注射）增强了WIN 55212-2（1、2.5、5和10毫克/千克，肌肉注射）的体温降低作用。这种增强具有强烈的协同性，WIN 55212-2的相对效价增加了2.7倍。胍丁胺中枢给药（25和50微克/只大鼠，脑室内注射）显著增强了WIN 55212-2（2.5毫克/千克，肌肉注射）的体温降低作用。这表明胍丁胺通过中枢机制增强大麻素诱发的体温降低。咪唑啉拮抗剂伊达唑啉（2毫克/千克，腹腔注射）可阻断胍丁胺的增强作用，因此提示胍丁胺增强大麻素诱发的体温降低需要激活咪唑啉受体。目前的数据表明，胍丁胺与大麻素激动剂相互作用可在大鼠中产生体温降低的协同作用。这些结果表明，胍丁胺在脑内通过咪唑啉受体发挥作用以增强大麻素诱发的体温降低。
