Elsevier

Neuropharmacology

Volume 18, Issue 5, May 1979, Pages 473-481
Neuropharmacology

Non-competitive nature of the antagonistic mechanism responsible for tolerance development to opiate-induced analgesia

https://doi.org/10.1016/0028-3908(79)90073-XGet rights and content

Abstract

The mechanism responsible for development of tolerance to opiate-induced analgesia was investigated by means of an analysis of a series of dose-response curves in groups of rats which had developed different degrees of tolerance. Increasing tolerance was reflected in the curves by an increasingly large shift to the right and depression of the maximum effect. When the responses produced by morphine were plotted against the concentrations of the drug in the brain, instead of against the doses applied, and the curves analysed with a double reciprocal (Lineweaver-Burk) plot, it became evident that the KD value of morphine was not changed during tolerance development. The KD value obtained with this behavioral method was close to that obtained with receptor binding studies performed under identical conditions in vivo. The data implies that the mechanism(s) responsible for tolerance development to opiate-induced analgesia does not involve a qualitative change in the opiate binding sites. Instead, tolerance seems to be due to non-competitive changes in the transduction process between receptor occupation and response.

References (27)

  • J. Dum et al.

    Lack of alteration in the analgesic receptor-antagonist interaction during the development of tolerance to morphine

    Eur. J. Pharmac.

    (1978)
  • P.E. Gilbert et al.

    Changes in the precipitated abstinence syndrome in chronic spinal dogs made physically dependent upon increasing doses of morphine (M)

  • A. Goldstein et al.

    Morphine-tolerant longitudinal muscle strip from guinea-pig ileum

    Br. J. Pharmac.

    (1973)
  • Cited by (33)

    • Onset of tolerance to discriminative stimulus effects of morphine

      1991, Pharmacology, Biochemistry and Behavior
    View all citing articles on Scopus
    View full text