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 -Opioid Receptor

( )-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.), lmethadone (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. An important goal of research in opioid pharmacology is to develop medications with the therapeutic effects of -opioid receptor (MOR) agonists (e.g., analgesia) without untoward effects, such as respiratory suppression and abuse potential. To this end, low-efficacy and/or mixed action opioids have been studied extensively in humans and in various animal models that assess the analgesic and abuse-related effects of opioid agonists. Several low-efficacy and/or mixed action opioids, such as butorphanol, seem to have a lower potential for abuse than drugs such as morphine (for review, see Preston and Jasinski, 1991). However, some have argued that there exists a limited effective dose range for these compounds relative to morphine (for review, see Hoskins and Hanks, 1991). In preclinical evaluations, these opioids tend to be less effective than morphine in rodent and primate models of antinociception (Dykstra, 1990; Walker et al., 1993; Morgan