Craft Rebecca M, Lee Darla A
Department of Psychology, Washington State University, Box 644820, Pullman, WA 99164-4820, USA.
Pharmacol Biochem Behav. 2005 Apr;80(4):639-49. doi: 10.1016/j.pbb.2005.02.003.
NMDA antagonists may be useful for their potential to increase or prolong opioid analgesia while attenuating the development of opioid tolerance and dependence. The purpose of this study was to determine whether there are sex differences in NMDA antagonist modulation of morphine antinociception. Adult female and male Sprague-Dawley rats were injected s.c. with saline or one dose of MK-801 (0.005, 0.01, 0.02, or 0.04 mg/kg), dextromethorphan (5, 10, or 20 mg/kg), or LY235959 (0.5, 1.0, or 2.0 mg/kg) in combination with saline or one dose of morphine (1.8, 3.2, or 5.6 mg/kg), and tested on the 50 degrees C hotplate and tail withdrawal assays 15-120 min post-injection. At the doses examined, only LY235959 produced any antinociception when administered alone. MK-801 attenuated morphine antinociception on both assays, but only at sporadic (inconsistent) dose-combinations. Dextromethorphan increased morphine antinociception on the hotplate but not tail withdrawal assay, at all three morphine doses in males, but only the higher morphine doses in females. In contrast, LY235959 modulated morphine antinociception on both assays; the lowest dose attenuated, and higher doses enhanced morphine antinociception, but the particular morphine doses and assay in which these effects occurred depended on the sex of the subject. Thus, all three NMDA antagonists modulated morphine antinociception in female and male rats, but the direction of this modulation depended on the particular antagonist examined, the nociceptive test, the dose of antagonist and of morphine, and time post-injection.
N-甲基-D-天冬氨酸（NMDA）拮抗剂可能因其具有增强或延长阿片类药物镇痛作用、同时减轻阿片类药物耐受性和依赖性形成的潜力而发挥作用。本研究的目的是确定NMDA拮抗剂对吗啡镇痛作用的调节是否存在性别差异。成年雌性和雄性Sprague-Dawley大鼠皮下注射生理盐水或一剂MK-801（0.005、0.01、0.02或0.04毫克/千克）、右美沙芬（5、10或20毫克/千克）或LY235959（0.5、1.0或2.0毫克/千克），并联合注射生理盐水或一剂吗啡（1.8、3.2或5.6毫克/千克），在注射后15 - 120分钟进行50摄氏度热板法和甩尾试验。在所检测的剂量下，单独给药时只有LY235959产生了任何镇痛作用。MK-801在两种试验中均减弱了吗啡的镇痛作用，但仅在偶发（不一致）的剂量组合下出现。在雄性大鼠中，所有三个吗啡剂量下右美沙芬均增强了热板法试验中的吗啡镇痛作用，但甩尾试验中未增强；在雌性大鼠中，仅在较高吗啡剂量下右美沙芬增强了热板法试验中的吗啡镇痛作用。相比之下，LY235959在两种试验中均调节了吗啡的镇痛作用；最低剂量减弱了吗啡镇痛作用，较高剂量增强了吗啡镇痛作用，但这些作用出现时的特定吗啡剂量和试验取决于受试动物的性别。因此，所有三种NMDA拮抗剂均调节了雌性和雄性大鼠的吗啡镇痛作用，但这种调节的方向取决于所检测的特定拮抗剂、伤害性感受试验、拮抗剂和吗啡的剂量以及注射后的时间。
