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Effects of NMDA receptor antagonists on delta1- and delta2-opioid receptor agonists-induced changes in the mouse
Y J Cao1, J T Bian, H N Bhargava
1Department of Pharmaceutics and Pharmacodynamics, The University of Illinois at Chicago, Health Sciences Center, 60612, USA.
Abstract:
Male Swiss-Webster mice were injected intracerebroventricularly (i.c.v.) with [D-Pen2,D-Pen5]enkephalin (20 microg/mouse) twice a day for 2 days. This procedure resulted in down-regulation of binding sites for [3H][D-Pen2,D-Pen5]enkephalin as evidenced by a 52% decrease in the Bmax value. Twice daily injections of (+)-5-methyl-10,11-dihydro-5H-dibenzo-[a,d]-cyclohepten-5,10-imine (MK-801) (0.1 mg/kg, i.p.) or [(-)3-SR,4a-RS,8a-SR-6-(phosphonomethyl)-1,2,3,4,4a,5,6,7,8,8a-decahy droisoquinoline-3-carboxylic acid] (LY 235959) (2 mg/kg, i.p.), the noncompetitive and competitive antagonist of the N-methyl-D-aspartate (NMDA) receptor, respectively, for 2 days did not alter the Bmax or Kd value of [3H][D-Pen2,D-Pen5]enkephalin binding to the mouse brain. Concurrent treatment of MK-801, but not of LY 235959 with [D-Pen2,D-Pen5]enkephalin, reversed the decreases in Bmax value of [3H][D-Pen2,D-Pen5]enkephalin. Twice daily injections of [D-Ala2,Glu4] deltorphin II (20 microg/mouse) for 2 days caused an increase in the Kd value, but not the Bmax value of [3H][D-Pen2,D-Pen5]enkephalin to bind to brain membranes. Concurrent treatment of [D-Ala2,Glu4]deltorphin II with LY 235959 reversed the increase in Kd value of [3H][D-Pen2,D-Pen5]enkephalin binding induced by multiple injections of [D-Ala2,Glu4]deltorphin II, but MK-801 had no effect. The results suggest that multiple injections of delta1- and delta2-opioid receptor agonists down-regulate delta1-opioid receptors of the brain by modifying Bmax and Kd values of [3H][D-Pen2,D-Pen5]enkephalin binding, respectively. MK-801 and LY 235959 reverse delta1- and delta2-opioid receptor agonists-induced down-regulation of brain delta1-opioid receptor, respectively, apparently by different mechanisms. It is concluded that short term treatment of mice with delta1-opioid receptor agonist down-regulates brain delta1-opioid receptors by decreasing Bmax of the ligand which is partially reversed by concurrent treatment with MK-801 but not by LY 235959. On the other hand, short term treatment of mice with delta2-opioid receptor agonist down-regulates brain delta1-opioid receptors by increasing Kd of the ligand which is partially reversed by concurrent treatment with LY 235959 but not by MK-801.