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Vol. 60, Issue 1, 53-62, July 2001
Department of Pharmacology and Toxicology, University of Arkansas
for Medical Sciences, Little Rock, Arkansas
Chronic morphine treatment has been shown to produce constitutive
activation of µ-opioid receptors, and this transition might contribute to the development of tolerance and dependence. The apparent
ability of chronic morphine to increase the spontaneous, agonist-independent activation of µ-opioid receptors may be unique, due to its distinct partial agonist properties of possessing a relatively high intrinsic activity coupled with a poor ability to
produce desensitization and down-regulation. Therefore, the present
study tested the hypothesis that prolonged exposure to morphine would
produce greater constitutive activity of µ-opioid receptors than
exposure to the full agonist
[D-Ala2,N-MePhe4,Gly-ol5]enkephalin
(DAMGO). GH3 cells expressing µ-opioid
receptors were exposed to chronic morphine, DAMGO, or no opioid under
conditions determined to produce maximal desensitization,
down-regulation, and cAMP rebound. After chronic treatment, the
µ-opioid antagonists naloxone and 
-chlornaltrexamine (-CNA)
were evaluated in two assays predictive of inverse agonist activity.
Both antagonists produced a concentration-dependent inhibition of
[35S]GTP
S binding only in membranes prepared
from cells chronically exposed to opioids. This effect was reversed by
the neutral µ-opioid antagonist CTAP. Additionally, conditions known
to uncouple G protein-coupled receptors from G proteins produced a
leftward shift in the competition curve of -CNA for
[3H]DAMGO binding only in membranes prepared
from chronically treated cells. In contrast, these conditions produced
no shift in the competition curve by the neutral antagonist CTAP in
cells exposed to chronic DAMGO. Therefore, prolonged exposure of
GH3MOR cells to opioids produced constitutive
activation of µ-opioid receptors. Surprisingly, chronic treatment
with the more efficacious agonist DAMGO produced greater increases in
both measures of inverse agonist activity than did morphine. These
observations may lend novel insight into the mechanisms of opioid
tolerance and dependence.
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