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BEHAVIORAL PHARMACOLOGY

The Competitive N-Methyl-D-aspartate Receptor Antagonist (-)-6-Phosphonomethyl-deca-hydroisoquinoline-3-carboxylic Acid (LY235959) Potentiates the Antinociceptive Effects of Opioids That Vary in Efficacy at the µ-Opioid Receptor

Departments of Psychology (R.M.A., A.L.G., L.A.D.) and Pharmacology (L.A.D.), University of North Carolina at Chapel Hill, Chapel Hill, North Carolina

(-)-6-Phosphonomethyl-deca-hydroisoquinoline-3-carboxylic acid (LY235959) is a competitive N-methyl-D-aspartate receptor antagonist shown to prevent the development of tolerance to the antinociceptive effects of morphine in rodents. Although administration of LY235959 alone generally does not produce antinociception, LY235959 potentiates the antinociceptive effects of morphine in squirrel monkeys. The present study was designed to determine whether LY235959 would potentiate the acute antinociceptive effects of morphine as well those of the opioid receptor agonists l-methadone, levorphanol, butorphanol, and buprenorphine. A squirrel monkey titration procedure was used in which shock (delivered to the tail) increased in intensity every 15 s (0.01-2.0 mA) in 30 increments. Five lever presses during any given 15-s shock period (fixed ratio 5) produced a 15-s shock-free period after which shock resumed at the next lower intensity. Morphine (0.3-3.0 mg/kg i.m.), l-methadone (0.1-0.56 mg/kg i.m.), levorphanol (0.1-1.0 mg/kg i.m.), butorphanol (1.0-10 mg/kg i.m.), and buprenorphine (0.01-0.03 mg/kg i.m.), but not LY235959 (0.1-1.0 mg/kg i.m.), dose and time dependently increased the intensity below which monkeys maintained shock 50% of the time (median shock level, MSL). LY235959 dose dependently potentiated the effect of each opioid agonist on MSL when concurrently administered to monkeys. Although LY235959 potentiated the antinociceptive effect of each opioid examined in a statistically significant manner, LY235959 seemed more potent and effective when combined with higher efficacy opioids. The present data suggest that the N-methyl-D-aspartate antagonist, LY235959, can potentiate the antinociceptive effects of a range of opioid receptor agonists independently of nonspecific motor effects.

Address correspondence to: Dr. Linda A. Dykstra, Department of Psychology, CB# 3270 Davie Hall, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599-3270. E-mail: ldykstra{at}unc.edu

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				B. D. Fischer and L. A. Dykstra Interactions between an N-Methyl-D-aspartate Antagonist and Low-Efficacy Opioid Receptor Agonists in Assays of Schedule-Controlled Responding and Thermal Nociception J. Pharmacol. Exp. Ther., September 1, 2006; 318(3): 1300 - 1306. [Abstract] [Full Text] [PDF]

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