Chen X H, Geller E B, DeRiel J K, Liu-Chen L Y, Adler M W
Department of Pharmacology, Temple University School of Medicine, Philadelphia, PA 19140, USA.
Drug Alcohol Depend. 1996 Dec 11;43(3):119-24. doi: 10.1016/s0376-8716(96)01295-1.
Previous studies showed that parenterally administered morphine at 4-16 mg/kg markedly increased body temperature in the rat, but higher doses of morphine (> or = 30 mg/kg, subcutaneously, sc) caused a profound decrease in body temperature. Based on the use of selective opioid agonists and antagonists, we postulated that these effects were due to morphine's actions on mu and kappa receptors, respectively. In the present study, we sought to determine whether an antisense (AS) oligodeoxynucleotide (oligo) against cloned mu or kappa opioid receptors could affect morphine-induced body temperature changes. AS oligos were directed against nucleotides 1-18 of the coding region of the mu receptor and 4-21 of the coding region of the kappa receptor. Male SD rats were surgically implanted with intracerebroventricular (icv) cannulae. Rats received icv injections of vehicle or oligo in the animal colony room on days 1, 3 and 5. Either AS oligo or missense (MS) oligo was infused in a volume of 5 microliters over 30 s to freely moving animals. On day 6, the rats were tested. The results showed that icv treatment with an AS oligo against mu opioid receptors, but not an MS oligo against the mu opioid receptor or an AS oligo against the kappa opioid receptor, significantly attenuated the hyperthermia normally produced by a relatively low dose of morphine administered sc. In addition, treatment with an AS oligo against kappa receptors, but not an MS oligo against kappa opioid receptor or an AS oligo against the mu opioid receptor, significantly blocked the hypothermia induced by a high dose of morphine. This study confirms our earlier postulate that morphine at 4 mg/kg, sc, induces an increase in body temperature primarily via mu opioid receptors in the brain and a high dose (30 mg/kg) of morphine administered sc produces a decrease primarily through kappa opioid receptors in the brain.
先前的研究表明，经肠胃外给予大鼠4 - 16毫克/千克的吗啡会显著升高其体温，但更高剂量的吗啡（皮下注射≥30毫克/千克）会导致体温大幅下降。基于对选择性阿片样物质激动剂和拮抗剂的使用，我们推测这些效应分别是由于吗啡对μ和κ受体的作用。在本研究中，我们试图确定针对克隆的μ或κ阿片样受体的反义（AS）寡脱氧核苷酸（oligo）是否会影响吗啡诱导的体温变化。AS寡核苷酸针对μ受体编码区的1 - 18位核苷酸以及κ受体编码区的4 - 21位核苷酸。雄性SD大鼠通过手术植入脑室内（icv）套管。在第1、3和5天，大鼠在动物饲养室接受icv注射载体或寡核苷酸。将AS寡核苷酸或错义（MS）寡核苷酸以5微升的体积在30秒内注入自由活动的动物体内。在第6天，对大鼠进行测试。结果表明，用针对μ阿片样受体的AS寡核苷酸进行icv处理，但不是针对μ阿片样受体的MS寡核苷酸或针对κ阿片样受体的AS寡核苷酸，能显著减弱皮下注射相对低剂量吗啡通常产生的体温过高现象。此外，用针对κ受体的AS寡核苷酸进行处理，但不是针对κ阿片样受体的MS寡核苷酸或针对μ阿片样受体的AS寡核苷酸，能显著阻断高剂量吗啡诱导的体温过低现象。这项研究证实了我们先前的推测，即皮下注射4毫克/千克的吗啡主要通过脑内的μ阿片样受体诱导体温升高，而皮下注射高剂量（30毫克/千克）的吗啡主要通过脑内的κ阿片样受体导致体温下降。
