Effect of dizocilpine (MK-801) on analgesia and tolerance induced by U-50,488H, a kappa-opioid receptor agonist, in the mouse.
The effect of dizocilpine (MK-801), an N-methyl-D-aspartate (NMDA) receptor antagonist, on the analgesic response to U-50,488H, a kappa-opioid receptor agonist, and tolerance to the analgesic effect of U-50,488H was determined in mice. The doses of MK-801 used were 0.03-0.30 mg/kg, whereas U-50,488H was administered at a dose of 25 mg/kg. Intraperitoneal (i.p.) administration of U-50,488H (25 mg/kg) produced analgesia as evidenced by the delay in the tail-flick latency in the mouse and lasted for a period of 240 min. MK-801 (0.03-0.30 mg/kg, i.p.) given 30 min prior to the injection of U-50,488H did not modify U-50,488H-induced analgesia. Twice daily administration of U-50,488H (25 mg/kg) for 9 days produced tolerance to its analgesic action. Administration of MK-801 (0.03 and 0.10 mg/kg) injected 30 min before each injection of U-50,488H prevented the development of tolerance to its analgesic effect. The higher dose, 0.3 mg/kg, of MK-801 had a minimal effect on U-50,488H tolerance. It is concluded that MK-801 in doses which do not affect U-50,488H-induced analgesia blocks the development of tolerance to its analgesic action in mice. These studies suggest that NMDA receptors play a crucial role in the development of tolerance to kappa-opioid agonist in mice.
Department of Pharmaceutics and Pharmacodynamics (m/c 865), University of Illinois at Chicago 60612.
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Bhargava
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Thorat
D019900:3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; D000700:Analgesics / Q000494:pharmacology*; D000818:Animals; D016291:Dizocilpine Maleate / Q000494:pharmacology*; D004361:Drug Tolerance; D008297:Male; D051379:Mice; D010147:Pain Measurement / Q000187:drug effects; D011759:Pyrrolidines / Q000494:pharmacology*; D017473:Receptors, Opioid, kappa / Q000819:agonists*
D000700:Analgesics; D011759:Pyrrolidines; D017473:Receptors, Opioid, kappa; D019900:3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; D016291:Dizocilpine Maleate