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Vol. 292, Issue 3, 1127-1134, March 2000
Department of Psychiatry and Biobehavioral Sciences, University of
California-Los Angeles, Los Angeles, California (P.A.Z., D.E.K.,
C.J.E.) and Chemistry and Life Sciences, Research Triangle Institute,
Research Triangle Park, North Carolina (G.A.B., F.I.C.)
In this study, we explored the relationship between regulation of
surface µ-opioid receptor number, ligand-induced G protein activation
{measured by
[35S]guanosine-5'-O-(3-thio)triphosphate
(GTP
S) binding} and second messenger signaling (measured by the
inhibition of cAMP accumulation). Etorphine and two isomers of
cis-
-hydroxy-3-methylfentanyl (RTI-1a and RTI-1b),
which were full agonists for G protein activation and signaling, caused
approximately a 50% loss of surface receptors after 1 h of
treatment. Fentanyl and morphine were full agonists for inhibiting cAMP
accumulation and partial agonists for stimulating [35S]GTPS binding and internalization. Although both
agonists were ~80% as efficacious as etorphine in stimulating
[35S]GTPS binding, fentanyl induced a 35% loss of
surface receptors, whereas morphine only caused a 10% loss.
Additionally, both long- and short-term treatment with the opioid
antagonist naloxone caused increases in surface receptors.
Unexpectedly, the weak partial agonists buprenorphine and one isomer of
cis--hydroxy-3-methylfentanyl (RTI-1d) also were
found to cause an increase in surface receptors. Treatment with
pertussis toxin (PTX) diminished agonist-induced loss of surface
receptors. Furthermore, the abilities of morphine and fentanyl to cause
internalization were more impaired after PTX treatment than that of
etorphine. PTX treatment also significantly enhanced the increase in
surface receptor number caused by 18-h treatment with naloxone and
buprenorphine. The results of this study suggest that disruption of G
protein coupling by PTX treatment affects ligand-regulated µ-receptor
trafficking and that partial agonists for signaling can vary greatly in
the ability to regulate the number of surface µ-opioid receptors.
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