Ly235959

D-CPPene

Mouse Rat

Others

NMDA-R1 antisense Rat

Jumping

Teeth chattering

Teeth chattering, writhing

Hyperalgesia

Jumping

Elicited vocalization, spontaneous vocalization, abnormal posture, ejaculation, jumping Rearing, teeth chattering, hippocampal norepinephrine release

Hyperalgesia, teeth chattering, jumping, wet-dog shakes Micturition, running, diarrhea, piloerection, paw tremors, body shakes, jumping, convulsions Jumping (acute dependence) Chewing, irritibility, stretching, tremor

Hyperalgesia (acute dependence)

Hyperalgesia

Hyperalgesia

Suppression of operant responding Hyperalgesia (acute dependence) Weight loss Hyperalgesia

Micturition, running, diarrhea, piloerection, paw tremors, body shakes, jumping, convulsions Hyperalgesia

Hyperalgesia, teeth chattering, jumping, wet-dog shakes Teeth chattering, jumping Chewing, irritibility, stretching, tremor

Trujillo and Akil, 1991 (2S) Ben-Eliyahu et al., 1992 (101) Fundytus and Coderre, 1994 (102) Mao et al., 1994 (3S) Verma and Kulkarni, 1995 (3S) Dunbar and Yaksh, 1996 (40)

Makimura et al., 1996 (103)

Manning et al., 1996 (42) Gonzalez et al., 1997 (4S)

McLemore et al., 1997 (46) Shoemaker et al., 1997 (104)

Larcher et al., 1998 (49) Laulin et al., 1998 (10S) Mao et al., 1998 (S1) Bespalov et al., 1999 (77) Celerier et al., 1999 (106) Koyuncuoglu et al., 1999 (S3) Laulin et al., 1999 (S4) Gonzalez et al., 1997 (4S)

Celerier et al., 2000 (107) Manning et al., 1996 (42)

Micturition, running, diarrhea, piloerection, paw tremors, body shakes, jumping, convulsions Jumping (acute, not chronic dependence)

Suppression of operant responding Bespalov et al., 1999 (77)

Jumping, rearing, teeth chattering, Zhu and Ho, 1998 (108) stretching

Table 6

Reversal of Opiate Tolerance and Dependence by NMDA Receptor Antagonists

NMDA receptor antagonist0

Species

Observed effect

Citation

LY274614 (comp) Rat

Dextromethorphan Mouse

(noncomp)

ACPC (glycine) Mouse

LY274614 (comp) Rat

Memantine (noncomp) Mouse NPC 17742 (comp)

Ketamine (noncomp) Rat

MRZ 2/579 (noncomp) Mouse MRZ 2/570 (glycine) L-701,324 (glycine)

LY235959 (comp) Rat

MK-801 (noncomp) Mouse

Ketamine (noncomp)

ACEA-1328 (glycine) Mouse Memantine (noncomp) Mouse MRZ 2/579 (noncomp)

Reversal of tolerance to morphine analgesia Reversal of tolerance to morphine analgesia

Reversal of tolerance to morphine analgesia Reversal of tolerance to morphine analgesia Reversal of morphine physical dependence (jumping) Reversal of tolerance to morphine analgesia Reversal of morphine physical dependence (jumping)

Reversal of tolerance to morphine analgesia Reversal of tolerance to morphine analgesia

Mouse Reversal of tolerance to morphine analgesia

Reversal of tolerance to morphine analgesia Reversal of tolerance to morphine analgesia

Tiseo and Inturrisi, 1993 (SS) Elliott et al., 1994 (S4)

Kolesnikov et al., 1994 (66) Tiseo et al., 1994 (6S) Popik et al., 1996 (118)

Shimoyama et al., 1996 (55) Popik et al., 1998 (120)

Allen and Dykstra, 1999 (64) Kolesnikov and Pasternak,

1999a (52) Kolesnikov and Pasternak,

1999b (56) Lutfy et al., 1999 (68) Popik et al., 2000 (127)

a noncomp = noncompetitive antagonist; comp = competitive antagonist; glycine = glycine-site antagonist. For the present purposes, "reversal" refers to the ability of NMDA receptor antagonists to slowly diminish tolerance and/or physical dependence with repeated administration.

suggests that these drugs may be able to slowly reverse tolerance and physical dependence under certain experimental circumstances. This effect is different than the acute blockade of the expression of tolerance or dependence, in that it does not occur immediately but takes days of administration to develop. The phenomenon was first reported by Tiseo and Inturrisi (33) in studies on morphine tolerance. These investigators found that the competitive NMDA receptor antagonist LY274614 had the ability to restore morphine analgesia if administered over several days to tolerant animals. Interestingly, this effect occurred whether LY274614 was administered in the presence or the absence of continued administration of morphine. These findings led the authors to suggest that NMDA receptors may be involved, not only in the development of morphine tolerance but also in the maintenance of this phenomenon. The ability of NMDA receptor antagonists to slowly reverse tolerance has since been replicated in several different studies, using several different NMDA receptor antagonists and different experimental approaches (Table 6). This ability does not appear to be isolated to opiate tolerance, as similar findings have been obtained with opiate physical dependence. Popik and co-workers (118,120) have demonstrated that competitive, noncompetitive, and glycine-site NMDA receptor antagonists will reverse physical dependence when administered over several days to physically dependent mice (Table 6).

The implications of the ability to reverse tolerance and dependence are self-evident. If NMDA receptor antagonists had the ability to simply prevent the development of these phenomena, they would be of little use in the treatment of addiction. Individuals seeking treatment for opiate addiction would presumably already be tolerant and dependent, and NMDA receptor antagonists would, therefore, be of little use (see refs. 2 and 126). However, the ability to reverse these phenomena suggests that NMDA receptor antagonists may be useful in detoxification, perhaps speeding up the process and lessening the impact of withdrawal.

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