Ritzmann R F, Steece K A, Lee J M, DeLeon-Jones F A
Neuropeptides. 1985 Jun;6(3):255-8. doi: 10.1016/0143-4179(85)90096-4.
Two different forms of tolerance to morphine were shown to develop. One form, environment dependent (ED), was associated with cues paired with the arrival of the drug. The second form of tolerance, environment independent (EI), was not dependent on any cues. ED tolerance was induced using a multiple injection model in which a cue (orange scent) preceeded each morphine injection (ip). After 12 days the animals were tolerant to the i.p. injection. However if morphine was injected i.c.v. tolerance was no longer evident. EI tolerance was induced by a pellet implant method. These animals were tolerant to morphine regardless of the route of administration. Peptides arginine vasopressin (AVP) and cyclo (Leu-Gly) (cLG) were tested for their ability to alter tolerance. AVP was found to facilitate the development of ED tolerance but had no effect on EI tolerance. On the other hand cLG blocked the development of EI tolerance without affecting ED tolerance. The determination of brain morphine levels indicated that the ED tolerance produced by this method is dispositional while EI tolerance is functional.
研究表明，吗啡耐受性会以两种不同形式产生。一种形式是环境依赖性（ED）耐受性，它与药物到来时配对的线索有关。第二种耐受性形式是环境独立性（EI）耐受性，它不依赖于任何线索。ED耐受性是使用多次注射模型诱导产生的，在该模型中，每次吗啡注射（腹腔注射）之前都有一个线索（橙子气味）。12天后，动物对腹腔注射产生了耐受性。然而，如果进行脑室内注射吗啡，耐受性就不再明显。EI耐受性是通过植入丸剂的方法诱导产生的。这些动物无论给药途径如何，都对吗啡产生耐受性。对精氨酸加压素（AVP）和环（亮氨酸 - 甘氨酸）（cLG）这两种肽改变耐受性的能力进行了测试。发现AVP促进了ED耐受性的发展，但对EI耐受性没有影响。另一方面，cLG在不影响ED耐受性的情况下，阻止了EI耐受性的发展。脑内吗啡水平的测定表明，通过这种方法产生的ED耐受性是处置性的，而EI耐受性是功能性的。
