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-Opioid Receptor Expressed in
Human Embryonic Kidney 293 Cells
Department of Pharmacology, University of Pennsylvania School of
Medicine, Philadelphia, Pennsylvania 19104
Opioid analgesics are used extensively in the management of pain.
Although the clinically effective opioids bind with high affinity to
the µ-opioid receptor, studies have suggested that the 
-opioid
agonists might represent more ideal analgesic agents, with fewer side
effects. A limitation to opiate effectiveness is the development of
tolerance, an event that has been linked to opioid receptor
desensitization. To gain a better understanding of -receptor agonist
regulation, the cloned mouse receptor was stably expressed in human
embryonic kidney 293 cells, and the functional effects of agonist
pretreatment were examined. With a 3-hr pretreatment protocol, the
-selective agonists
[D-Pen2,D-Pen5]enkephalin,
[D-Ala2,D-Leu5]enkephalin,
and
[D-Ser2,Leu5]enkephalin-Thr
and the nonselective opioids levorphanol, etorphine, and
ethylketocyclazocine were found to desensitize receptors. [DPen2,D-Pen5]enkephalin,
[D-Ser2,Leu5]enkephalin-Thr,
[D-Ala2,D-Leu5]enkephalin,
and etorphine treatments also caused a pronounced internalization of
the epitope-tagged receptor, suggesting that the desensitization
and internalization may be related. In contrast, levorphanol
pretreatment did not internalize the receptor but still resulted in a
400-fold reduction in potency, suggesting that prolonged treatment with
levorphanol only uncoupled the receptor from adenylyl cyclase. In
contrast to the desensitization induced by peptide-selective agonists, pretreatment with the -selective nonpeptide agonist
7-spiroindanyloxymorphone and morphine sensitized the opioid inhibition
of forskolin-stimulated cAMP accumulation. This differential regulation
of the receptor may be due to variations in the ability of agonists
to bind to the receptor. This hypothesis was supported by the finding
that a point mutation that converted Asp128 to Asn128 (D128N)
diminished the ability of -selective agonists to inhibit cAMP
accumulation while increasing the potency of morphine to reduce cAMP
accumulation. In particular, a lack of desensitization of the receptor by morphine may contribute to our understanding of the
molecular basis of development of morphine-induced tolerance and
dependence.
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