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

Abstract

ABSTRACT(Ϫ)-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 et al., 1999).In addition to having lower antinociceptive efficacy, preclinical data show that chronic administration of drugs with lower efficacy at the MOR tend to produce more tolerance than drugs with higher efficacy at the MOR. For example, rats administered equieffective doses of morphi...

Interactions between an N-Methyl-D-aspartate Antagonist and Low-Efficacy Opioid Receptor Agonists in Assays of Schedule-Controlled Responding and Thermal Nociception

“…In agreement with these findings, LY235959 produced a synergistic interaction with each of the opioids, regardless of efficacy, in the assay of thermal nociception. These findings agree with data obtained in squirrel monkeys (Allen et al, 2003), suggesting efficacy is not an important determinant of interactions between NMDA and opioid receptors on the endpoint of antincoception.…”

“…Previous research has demonstrated that NMDA antagonists can increase the antinociceptive effects of morphine (Allen and Dykstra, 2003;Nemmani et al, 2004;Fischer et al, 2005;Grisel et al, 2005). Although the interactive effects of morphine and NMDA receptor antagonists have been investigated in various antinociceptive measures, the first purpose of the current study was to assess these interactions using a formally quantitative approach.…”

“…For example, behavioral evidence suggests that pretreatment or coadministration of an NMDA receptor antagonist can increase the acute effects of morphine in animal models of thermal nociception (Allen and Dykstra, 2003;Nemmani et al, 2004;Fischer et al, 2005;Grisel et al, 2005). In addition, NMDA antagonists can increase morphine-induced analgesia in humans under certain conditions (Javery et al, 1996;Bossard et al, 2002;Suzuki et al, 2005).…”

“…To date, a single study has assessed these interactions, showing that coadministration with the competitive NMDA antagonist LY235959 can increase the antinociceptive activity of the low-efficacy opioids buprenorphine and butorphanol in monkeys responding under a schedule of shock titration, suggesting NMDA receptor involvement in these effects (Allen et al, 2003). This latter finding is particularly intriguing because the enhancement of the antinociceptive effects of low-efficacy opioids may increase their clinical utility.…”

Discriminative Stimulus Effects of Acute Morphine Followed by Naltrexone in the Squirrel Monkey: A Further Characterization

“…Buprenorphine and meperidine paired with naltrexone occasioned little or no responding on the MOR 3 NTX-appropriate lever, even at doses that were behaviorally active and were well within the range of doses shown to be effective in other behavioral models using squirrel monkeys (Schaefer and Holtzman, 1977;Dykstra, 1983Dykstra, , 1985DeRossett and Holtzman, 1984;Negus et al, 1991;Dykstra et al, 2002;Allen et al, 2003). Likewise, pretreatment with the partial -opioid receptor agonist nalbuphine in combination with 0.1 mg/kg naltrexone failed to elicit criterion levels of responding, even at a dose 10 times higher than that of the training dose of morphine.…”