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Vol. 286, Issue 2, 855-862, August 1998
Subunit
Institute of Pharmacology, Toxicology and Pharmacy, University of
Munich, Königinstrasse, München, Germany
On the cellular level, opioid dependence is characterized by a
significant elevation of adenylyl cyclase (AC) activity after drug
withdrawal, a regulatory phenomenon termed "AC supersensitivity" or
"cAMP overshoot." The present study examines the role of the stimulatory G protein (Gs) in the expression of naloxone
precipitated opioid withdrawal in chronically morphine (10 µM; 3 days) treated neuroblastoma X glioma (NG108-15) hybrid cells.
Determination of high-affinity [3H]forskolin binding to
intact cells, which provides a direct parameter for the binding of the
activated 
-subunit of Gs (Gs) to AC, revealed that the enhancement of AC activity after opioid withdrawal is
not caused by an increased stimulation of effector activity by
Gs. Although not a direct function of Gs,
the expression of AC supersensitivity required
Gs-mediated stimulation of AC, because 1) the
enhancement of AC activity after opioid withdrawal was observed only in
the presence of low, but not of high concentrations of forskolin,
and 2) chemical inactivation of Gs by low pH
pretreatment abolished the induction of AC supersensitivity. Moreover,
the regulatory mechanism underlying AC supersensitivity not only
required the presence of activated Gs per
se, but functional intact stimulatory signal transduction
pathways. Indeed, blockade of prostaglandin E1
receptor/Gs interaction in situ with a
site-specific anti-Gs antibody, as well as uncoupling of
prostaglandin E1 receptor signaling by cholera
toxin-catalyzed ADP-ribosylation of Gs, prevented the
expression of AC supersensitivity in membranes from opioid-withdrawn cells. These results suggest that the enhancement of AC activity in
opioid-dependent cells, triggered by drug withdrawal, is not a direct
Gs effect, but involves a secondary regulatory event that requires costimulation of AC by acutely receptor-activated Gs.
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