title: Effects of acute and chronic administration of dizocilpine on the pharmacological responses to U-50,488H and brain and spinal cord kappa-opioid receptors in the rat.
abstract: In 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.
authors.affiliation: Department of Pharmaceutics and Pharmacodynamics (M/C 865), University of Illinois at Chicago 60612, USA.
authors.forename: H N
authors.initials: HN
authors.lastname: Bhargava
authors.forename: G A
authors.initials: GA
authors.lastname: Matwyshyn
authors.forename: K P
authors.initials: KP
authors.lastname: Gudehithlu
mesh_terms: D019900:3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; D000700:Analgesics / Q000494:pharmacology*; D000701:Analgesics, Opioid / Q000494:pharmacology; D000818:Animals; D001831:Body Temperature / Q000187:drug effects; D001835:Body Weight / Q000187:drug effects; D001923:Brain Chemistry / Q000187:drug effects*; D016291:Dizocilpine Maleate / Q000494:pharmacology*; D016314:Ethylketocyclazocine / Q000494:pharmacology; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology*; D066298:In Vitro Techniques; D007700:Kinetics; D008297:Male; D011759:Pyrrolidines / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D017473:Receptors, Opioid, kappa / Q000187:drug effects*; D013116:Spinal Cord / Q000187:drug effects / Q000378:metabolism*
chemical_list: D000700:Analgesics; D000701:Analgesics, Opioid; D018691:Excitatory Amino Acid Antagonists; D011759:Pyrrolidines; D017473:Receptors, Opioid, kappa; D016314:Ethylketocyclazocine; D019900:3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; D016291:Dizocilpine Maleate