Estimation in vivo of the receptor constants of morphine in naive and morphine-tolerant rats.

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 x 10(-5) M in naive to 1.4 x 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 x 10(-7) M in naive and 7.7 x 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.