Vanderah T W, Lai J, Yamamura H I, Porreca F
Department of Pharmacology, University of Arizona Health Science Center, Tucson 85724.
Neuroreport. 1994 Dec 20;5(18):2601-5. doi: 10.1097/00001756-199412000-00049.
Cholecystokinin (CCK) has been shown to attenuate, while CCK antagonists enhance, the antinociceptive activity of morphine, suggesting that this peptide may act as an endogenous modulator of the opioid system. Here, we have investigated the effects of administration of a synthetic oligodeoxynucleotide (oligo) complementary to the 5' coding region of the cloned mouse CCKB receptor (antisense), or a mismatch oligo, on the antinociceptive effects of morphine. Intracerebroventricular (i.c.v.) treatment of mice with CCKB antisense, but not mismatch, oligo for 3 days resulted in an enhancement of the antinociceptive potency of i.c.v. morphine, as indicated by an approximately 6-fold leftward shift of the dose-effect curve. The antinociceptive effects of morphine in control and CCKB antisense-treated animals were investigated in the presence or absence of naltrindole, an opioid delta receptor antagonist, as well as in the presence or absence of antisera directed against either [Leu5]- or [Met5]enkephalin. The enhanced potency of morphine in mice pretreated with CCKB antisense oligo was blocked by a delta-selective dose of naltrindole and antisera to [Leu5]enkephalin, but not [Met5]enkephalin; naltrindole, or antisera towards [Leu5]enkephalin or [Met5]enkephalin did not produce antinociceptive effects when given alone and did not alter the antinociceptive actions of morphine in control mice. These data suggest that CCK may act via CCKB receptors to tonically inhibit the release of [Leu5]enkephalin, or a [Leu5]enkephalin-like peptide. The enhancement of morphine antinociception seen in the presence of blockade of the CCKB receptor may be the result of the well-known enhancement of morphine antinociception by opioid delta agonists.
胆囊收缩素（CCK）已被证明可减弱吗啡的抗伤害感受活性，而CCK拮抗剂则增强其活性，这表明该肽可能作为阿片系统的内源性调节剂发挥作用。在此，我们研究了给予与克隆的小鼠CCKB受体5'编码区互补的合成寡脱氧核苷酸（oligo）（反义）或错配oligo对吗啡抗伤害感受作用的影响。脑室注射（i.c.v.）CCKB反义oligo而非错配oligo处理小鼠3天，导致i.c.v.吗啡的抗伤害感受效力增强，剂量效应曲线向左约6倍移位表明了这一点。在存在或不存在阿片δ受体拮抗剂纳曲吲哚以及存在或不存在针对[Leu5]-或[Met5]脑啡肽的抗血清的情况下，研究了吗啡在对照和CCKB反义处理动物中的抗伤害感受作用。用CCKB反义oligo预处理的小鼠中吗啡效力的增强被纳曲吲哚的δ选择性剂量和针对[Leu5]脑啡肽的抗血清阻断，但未被针对[Met5]脑啡肽的抗血清阻断；单独给予纳曲吲哚或针对[Leu5]脑啡肽或[Met5]脑啡肽的抗血清不会产生抗伤害感受作用，也不会改变对照小鼠中吗啡的抗伤害感受作用。这些数据表明CCK可能通过CCKB受体发挥作用，以持续抑制[Leu5]脑啡肽或[Leu5]脑啡肽样肽的释放。在CCKB受体被阻断的情况下观察到的吗啡抗伤害感受增强可能是阿片δ激动剂对吗啡抗伤害感受的众所周知的增强作用的结果。
