• H N Bhargava, G A Matwyshyn, and K P Gudehithlu.
• Department of Pharmaceutics and Pharmacodynamics (M/C 865), University of Illinois at Chicago 60612, USA.
• Pharmacology. 1995 Nov 1; 51 (5): 323-30.

AbstractIn male Sprague-Dawley rats, acute and chronic effects of dizocilpine (MK-801), a noncompetitive antagonist of the N-methyl-D-aspartate (NMDA) receptor, were determined on the analgesic and hypothermic actions of U-50,488H, a kappa-opioid receptor agonist. In addition, the in vitro effects of MK-801 on the binding of [3H]ethylketocyclazocine ([3H]EKC) to kappa-opioid receptors in brain and spinal cord of the rat were determined. A single injection of MK-801 given 10 min prior to U-50,488H or given twice a day for 4 days dose-dependently enhanced the analgesic action of U-50,488H. The enhancement of the analgesic response was much greater in rats injected chronically with MK-801 as compared with those injected acutely. Both single and multiple injections of MK-801 failed to affect the hypothermic action of U-50,488H. In vitro, MK-801 inhibited the binding of [3H]EKC to brain and spinal cord membranes with IC50 values of 9.80 +/- 1.7 and 1.37 +/- 0.58 microM, respectively. Chronic administration of MK-801 twice a day for 4 days increased the Bmax value of [3H]EKC binding in the brain, but had no effect on Kd. On the other hand, chronic treatment with MK-801 decreased the Kd of [3H]EKC binding in spinal cord without affecting Bmax. It is concluded that blockade of NMDA receptor enhances the analgesic response to a kappa-opioid receptor agonist and upregulates brain and spinal cord kappa-opioid receptors. Finally, the results suggest that the NMDA receptor may have a role in the regulation of kappa-opioid systems.

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