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Vol. 280, Issue 3, 1235-1240, 1997
Departments of
Pharmacology (S.A.T., T.J.A., T.P.D.) and
Chemistry
(V.J.H.), University of Arizona, Tucson, Arizona
The delta opioid receptor-selective, enzymatically stable
peptide [D-Penicillamine2,5]enkephalin (DPDPE)
has recently acquired special significance with the identification of a
saturable uptake system for this analgesic into the CNS. The aim of the
present study was to characterize further the entry of
[3H]DPDPE into the brain and CSF by means of a bilateral
in situ brain perfusion method. Initial experiments revealed
a saturable [3H]DPDPE uptake into the brain that followed
Michaelis-Menten type kinetics with a Km value
of 45.5 ± 27.6 µM, a Vmax value of
51.1 ± 13.2 pmol · min
1 · g1 and
a Kd value of 0.6 ± 0.3 µl · min1 · g1. Uptake of
[3H]DPDPE into the CSF could not be inhibited
(Kd = 0.9 ± 0.1 µl · min1 · g1). Entry of
[3H]DPDPE into the CNS was not inhibited in the presence
of 10 mM 2-aminobicyclo-[2,2,1]-heptane-2-carboxylic acid (BCH) or 50 µM ICI 174,864, which suggests that the saturable mechanism does not
involve the large neutral amino acid transporter or binding to opioid
receptors. It would also appear that [3H]DPDPE is not in
competition with either poly-L-lysine or insulin to enter
the CNS. However, both of these substances significantly increased the
CNS entry of [3H]DPDPE but not that of the vascular space
marker [14C]sucrose, and this may have valuable clinical
implications. It is not known at present which saturable uptake
mechanism is responsible for the CNS entry of [3H]DPDPE,
but overall the results suggest a carrier-mediated transport system.
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