@article{2b6f0ba85b3e412fa0c2b8c35c12917d,
title = "Estimation in vivo of the receptor constants of morphine in naive and morphine-tolerant rats",
abstract = "The efficacy and dissociation constant of morphine in naive and morphine-tolerant rats were estimated by the method of partial irreversible blockade of a fraction of the receptor population with buprenorphine. The dissociation constant (KA) of morphine increased from 3.3×10-5 M in naive to 1.4×10-4 M in morphine-tolerant animals, indicating a decrease in the affinity of morphine for its receptor in the tolerant state. The efficacy of morphine (KA/A50 + 1) was constant in naive and tolerant animals (4.23 and 4.46, respectively). When the data were recalculated following conversion of administered dose to brain morphine concentration, the value of KA was 1.7×10-7 M in naive and 7.7×10-7 M in morphine-tolerant rats, while the efficacy was 2.5 and 3.4, respectively. In addition, the stimulus-effect relationship varied in the two states, with the curve in the tolerant animal being of different shape and broader range than in the naive rat. The present results suggest that (a) tolerance to opiate agonists may involve affinity changes and (b) post-receptor events leading to the measured effect may also be affected.",
author = "Frank Porreca and Alan Cowan and Raffa, {Robert B.} and Tallarida, {Ronald J.}",
note = "Funding Information: It is also interesting that Blasig et al (15), reported a K D for morphine of approximately 25 mg/kg. The K value reported in the present study for naive animals (22 mg/kg) is similar. A However, unlike the findings of Blasig et al (15) who determined K~ using brain concentration and found no change between naive and morphine-Tolerant rats, the present work suggests that there is a fourfold difference between the two groups. The reason for the discrepancy between the two results may be attributable to the difference between the dissociation constant and the A50. While such an approximation can sometimes be true, it does not appear to apply for morphine (8,9,10). This distinction could only recently be made as a result of our use of buprenorphine as an irreversible antagonist of opiate agonists. It must be emphasized that the use of buprenorphine in an in vivo model leads to an estimation of K A. The results presented await verification following the development and availability of more selective irreversible antagonists that may be applied to in vitro bioassays. Such studies will increase the accuracy of these determinations and allow for a clearer understanding of the role of affinity changes in tolerance. Acknowledsement_s We thank Remus Berretta for his excellent technical assistance. study was supported by Grant DA 02322 from NIDA. References In Developments in Opiate Research (A. Herz, ed.) Inc., New York (1978) TAKEMORI, J. Pharmacol. Exp. Ther. 207, 494-503",
year = "1982",
doi = "10.1016/0024-3205(82)90155-2",
language = "English (US)",
volume = "31",
pages = "2355--2358",
journal = "Life Sciences",
issn = "0024-3205",
publisher = "Elsevier Inc.",
number = "20-21",
}