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JA Clark, R Houghten and GW Pasternak
Cotzias Laboratory of Neuro-Oncology, Memorial Sloan-Kettering Cancer Center, New York, New York.
In the present study, we examined the binding of [3H][D-Ala2,D- Leu5]enkephalin ([ 3H]DADL) to bovine thalamic membranes. Scatchard plots were linear with a KD of 0.7 nM. However, competition experiments suggested binding heterogeneity. Approximately 20% of [3H]DADL binding was easily inhibited by [D-Pen2,D-Pen5]enkephalin (DPDPE) and was insensitive to morphine, implying labeling of delta receptors. The remaining 80% of binding was quite sensitive to both morphine and [D- Ala2,MePhe4,Gly(ol)5]enkephalin (DAGO) and insensitive to DPDPE, consistent with a mu receptor. However, this binding did not correspond to classical morphine-selective mu receptors. Unlike morphine-selective receptors, this binding had similar affinities for morphine, DAGO, DADL and [D-Ser2,Leu5]enkephalin-Thr6 (DSLET). In addition, it was far more sensitive to naloxonazine's wash-resistant inhibition and magnesium- induced enhancement of binding than either the morphine-selective (mu 2) or delta sites. [3H]DSLET binding yielded results very similar to those using [3H]DADL. In conclusion, approximately 80% of [3H]DADL binding in thalamus corresponds to a mu receptor distinct from the classical morphine-selective site. Based upon the results of our studies, we feel that this binding represents mu 1 receptors. DPDPE (10 nM) can effectively inhibit the binding of [3H]DADL to delta receptors, leaving a relatively homogeneous labeling of mu 1 sites. The availability of this selective binding assay should facilitate additional studies of mu 1 receptors.
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