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Vol. 286, Issue 2, 1007-1013, August 1998
The Cotzias Laboratory of Neuro-Oncology, Memorial Sloan-Kettering
Cancer Center, New York, New York
The recently isolated peptides endomorphin-1 and endomorphin-2 have
been suggested to be the endogenous ligands for the mu receptor. In traditional opioid receptor binding assays in mouse brain
homogenates, both endomorphin-1 and endomorphin-2 competed both
mu1 and mu2
receptor sites quite potently. Neither compound had appreciable
affinity for either delta or
kappa1 receptors, confirming an earlier
report. However, the two endomorphins displayed reasonable
affinities for kappa3 binding sites, with
Ki values between 20 and 30 nM. Both
endomorphins competed
3H-[D-Ala2,MePhe4,Gly(ol)5] enkephalin
binding to MOR-1 receptors expressed in CHO cells with high affinity.
In mouse brain homogenates 125I-endomorphin-1 and
125I-endomorphin-2 binding was selectively competed
by mu ligands. I-Endomorphin-1 and
125I-endomorphin-2 also labeled MOR-1 receptors expressed
in CHO cells with high affinity. Autoradiography of the two
125I-labeled endomorphins demonstrated regional patterns in
the brain similar to those previously observed for mu
drugs. Pharmacologically, the endomorphins were potent analgesics.
Although they were equipotent supraspinally, endomorphin-1 was more
potent spinally. Endomorphin analgesia was effectively blocked by
naloxone, as well as the mu-selective antagonists
-funaltrexamine and naloxonazine. In CXBK mice, which are
insensitive to supraspinal morphine, neither endomorphin was active,
consistent with a mu mechanism of action. Finally, the
endomorphins inhibited gastrointestinal transit. In conclusion, these
results support the mu selectivity of these agents.
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