Kest B, Hopkins E, Palmese C A, Chen Z P, Mogil J S, Pintar J E
Department of Psychology and Center for Developmental Neuroscience, The College of Staten Island, City University of New York, Staten Island 10314 USA.
Neuroscience. 2001;104(1):217-22. doi: 10.1016/s0306-4522(01)00037-9.
It has been hypothesized that morphine tolerance and dependence in mice following chronic exposure may reflect increased compensatory activity of antiopioid systems. The endogenous peptide nociceptin/orphanin FQ has been shown to have anti-opioid effects, for example antagonizing morphine analgesia. Moreover, chronic morphine administration increases synthesis of the peptide, and morphine tolerance and dependence can be attenuated or reversed by antagonists and agonists of the nociceptin/orphanin FQ receptor, respectively. The present study seeks to confirm a role for nociceptin/orphanin FQ in opioid tolerance and dependence by comparing morphine ED(50) values and naloxone-precipitated withdrawal jumping in mice homozygous (knock-out) and heterozygous for a null mutation of the Npnc1 gene encoding the nociceptin/orphanin FQ propeptide, and their wild type littermates, following chronic morphine exposure. Relative to morphine-naive control mice, significant rightward shifts in the morphine dose-response curve, resulting in increased morphine ED(50) values (approximately two to three-fold), was observed for all genotypes following three days of repeated systemic morphine injections. However, no differences between genotypes in the magnitude of tolerance were observed. In contrast, knock-out mice displayed significantly increased naloxone-precipitated withdrawal jumping relative to heterozygous and wild-type mice following implantation with a morphine pellet (25mg) for 72h. Use of nociception/orphaninFQ transgenic knock-out mice thus demonstrate the differential involvement of nociceptin/orphanin FQ in morphine tolerance and dependence.
据推测，小鼠长期接触吗啡后的耐受性和依赖性可能反映了抗阿片系统代偿性活动的增强。内源性肽痛敏肽/孤啡肽FQ已被证明具有抗阿片作用，例如拮抗吗啡镇痛。此外，长期给予吗啡可增加该肽的合成，而痛敏肽/孤啡肽FQ受体的拮抗剂和激动剂可分别减弱或逆转吗啡耐受性和依赖性。本研究旨在通过比较慢性吗啡暴露后，编码痛敏肽/孤啡肽FQ前体肽的Npnc1基因纯合（敲除）和杂合突变小鼠及其野生型同窝仔鼠的吗啡ED(50)值和纳洛酮诱发的戒断跳跃，来证实痛敏肽/孤啡肽FQ在阿片耐受性和依赖性中的作用。相对于未接触过吗啡的对照小鼠，在重复全身注射吗啡三天后，所有基因型的吗啡剂量-反应曲线均显著右移，导致吗啡ED(50)值增加（约两到三倍）。然而，未观察到各基因型在耐受性程度上的差异。相反，在植入25mg吗啡丸72小时后，敲除小鼠相对于杂合和野生型小鼠表现出纳洛酮诱发的戒断跳跃显著增加。因此，使用痛觉感受/孤啡肽FQ转基因敲除小鼠证明了痛敏肽/孤啡肽FQ在吗啡耐受性和依赖性中的不同参与情况。
