Effects of NMDA Receptor Antagonists Jianren Mao, MD, PhD
1. NMDA RECEPTORS AND OPIOID TOLERANCE/DEPENDENCE
The N-methyl-d-asparate (NMDA) receptor is a complex subtype of the glutamatergic receptor system. Glutamate and aspartate are endogenous ligands binding to NMDA receptors. Activation of NMDA receptors can be blocked at either the glutamate-binding site or the regulatory sites. Although the role of NMDA receptors in opioid tolerance and dependence was initially examined using ^-opioid agonists, studies have been carried out to investigate the effects of NMDA receptor antagonists on tolerance and dependence induced by k- and o-opioid agonists.
Morphine has been used primarily as a |-opioid agonist in a number of studies investigating ||-opioid-induced tolerance and dependence. Coadministration of morphine with MK-801, a noncom-petitive NMDA receptor antagonist, was initially shown to be effective in preventing the development of antinociceptive tolerance in rats, mice, and guinea pigs (1-4). Since these initial reports, a large number of studies have consistently shown the same results (5-24). NMDA receptor antagonists and Zn2+ also have been shown to block the development of acute tolerance to morphine (25). The methodologies employed in these studies are rather diversified with regard to the route of drug administration, tolerance-inducing regimens, and the choice of NMDA receptor antagonists (see above-cited references):
1. Morphine has been given via the route of subcutaneous (sc), intravenous (iv), intrathecal (it), intracere-broventricular (icv), intraperitoneal (ip), and oral administration. The treatment regimens have included daily boluses for 5-8 d or continuous infusion through an osmotic pump for 3-7 d.
2. The behavioral tests employed in these studies have included the hot-plate, tail-flick, and formalin tests. Different species of laboratory animals (mice, rats, guinea pigs, etc.) have been used in these studies and no reliable differences in species were observed with regard to the effect of NMDA receptor antagonists on morphine tolerance.
3. The NMDA receptor antagonists used in these studies have included the competitive agents AP-5, LY235959, CGP 39551, and LY274614, the noncompetitive channel blockers MK-801, dextromethorphan (DM), MRZ 2/579, ketamine, d-methadone, and memantine, and the glycine-binding-site NMDA receptor antagonists MRZ 2/576, ACEA-1328, and HA966. NMDA receptor antagonists were given via the sc, it,
From: Contemporary Clinical Neuroscience: Glutamate and Addiction Edited by: Barbara H. Herman et al. © Humana Press Inc., Totowa, NJ
and ip routes. There were no reliable differences between competitive and noncompetitive NMDA receptor antagonists in preventing the development of morphine tolerance. Collectively, these data indicate a broad generality of the NMDA receptor involvement in the development of morphine tolerance across species, behavioral tests, and tolerance-inducing regimens.
It is of significance to point out that low-affinity, clinically available NMDA receptor antagonists such as DM, d-methadone, and memantine may have a role in preventing the development of tolerance to and dependence on opioid analgesics in clinical settings (6,12,19,26,27). For instance, DM, commonly known as an antitussive drug, has been shown to be effective in preventing the development of opioid tolerance (6,12,27). In a rat model of morphine tolerance, DM prevented or attenuated the development of tolerance to the antinociceptive effects of morphine (15,24, or 32 mg/kg) when DM was coadministered orally with morphine (ratios from 4 : 1 to 1 : 2). This combined oral treatment regimen also reduced naloxone-precipitated signs (teeth chattering, wet-dog shaking, or jumping) of physical dependence on morphine in the same rats. The data reveal a constant ratio range of the morphine/DM combination effective for preventing the development of morphine tolerance and dependence (12). These results indicate that the combined treatment with clinically available NMDA receptor antagonists and morphine may be a useful approach for preventing morphine tolerance and dependence in humans.
1.1.2. Selective ¡i-Opioid Agonists
Although a prototypical |-agonist, morphine does have interactions with other opioid receptor subtypes. In a recent study, the role of NMDA receptors in the antinociceptive tolerance induced by highly selective ^-opioids was examined (5). It was reported that 0.1 mg/kg MK-801 given intraperitoncally did not prevent tolerance induced by the highly selective |-opioid agonists DAMGO and fentanyl in mice, although the same dose of MK-801 prevented the development of tolerance to morphine in the same study. Because autoradiographic studies have shown that morphine also binds to 8- and K-opioid receptors (28-30), these results could imply that interactions among subtypes of opioid receptors would be important in determining the involvement of NMDA receptors in mechanisms of opioid tolerance. Although in another study the development of tolerance resulting from repeated it administration of either 6 |g or 1.5 |g DAMGO was prevented dose dependently by the it coadministration of DAMGO and MK801 (31), it would be of interest to interest to further elucidate similarities and differences between the NMDA receptor-mediated mechanisms of tolerance induced by highly selective | -opioids or morphine.
The noncompetitive NMDA receptor antagonists (MK-801, memantine, DM, HA966) have been shown to prevent the development of dependence on morphine as assessed by naloxone-precipitated withdrawal signs (jumping, teeth chattering, diarrhea, wet-dog shakes, vocalization) in both mice and rats (6,9,12-14,32,33). Consistent with these findings, it has been shown that the occurrence of nalox-one-precipitated withdrawal signs in tolerant rats was associated with spinal cord release of glutamate (9). In addition, daily transient blockade of morphine with naloxone resulted in greater tolerance than that from continuous chronic morphine administration, presumably due to an increased release of glutamate in the naloxone treatment group (34). It would be of interest to examine differences in glutamate release, in the absence of naloxone precipitation, in animal models of opioid tolerance using daily bolus treatment versus continuous infusion with osmotic pumps.
Tolerance may involve both associative (constant presence of a cue) and nonassociative (lack of a cue) components. The role of NMDA receptors in associative versus nonassociative tolerance to morphine was examined (4,8). The blockade of NMDA receptors with MK-801 was particularly effective for preventing nonassociative tolerance as opposed to associative tolerance. In contrast, spinal cord neurotensin appeared to be contributory to the development of associative tolerance (8). Although mechanisms of such a distinction remain to be determined, these data indicate the importance of distinguishing these two processes in investigating the NMDA receptor-mediated mechanisms of opioid tolerance.
Although there is ample evidence indicating a critical role of NMDA receptors in the development of ^-opioid tolerance, the expression of tolerance as assessed by a behavioral test is not determined by the activity of NMDA receptors. The acute blockade of NMDA receptors with either MK-801 or LY274614 in animals already made tolerant to morphine did not reverse the tolerance status (1,16). The shifted dose-response relationship in morphine-tolerant rats appears to be directly related to the status of opioid receptors, because naloxone, but not MK-801, altered the antinociceptive response in these rats (11). However, NMDA receptors are contributory to the maintenance of an established tolerance status, because coadministration of morphine with a competitive NMDA receptor antagonist, LY274614, gradually (over days) reversed morphine tolerance in mice (16). These concepts support a combined use of opioids and NMDA receptor antagonists in clinical settings even in those patients who are already tolerant to opioid analgesics.
The data on the effects of NMDA receptor activation on S-opioid tolerance remain inconclusive. In a mouse model of tolerance induced by repeated icv administration of 20 nmol DELT II (S-2 agonist) twice daily for 3 d, neither MK-801 (0.1 mg/kg, ip) nor LY235959 (3 mg/kg) pretreatment before each DELT II dose prevented the development of tolerance (5). MK-801 in the dose used in that study also failed to prevent tolerance to antinociception induced by cold-water swim stress, a process presumably mediated by endogenous S-opioids (5).
In direct contrast, in a similar experimental paradigm in which DELT II (20 |g) was given intrac-erebroventricularly twice daily for 4 d, MK-801 (0.03 and 0.1 mg/kg, ip) or LY235959 (4 mg/kg, ip) pretreatment effectively inhibited the development of antinociceptive tolerance to DELT II (35). In addition, MK-801 (0.1 mg/kg, ip) or LY235959 (1, 2, or 4 mg/kg, ip) prevented the antinociceptive tolerance induced by twice daily icv administration of the S-1 agonist DPDPE (20 |g) in mice (36). The inhibition of DPDPE-induced tolerance also was observed when 1-aminocyclopropane carboxylic acid (ACPC) (150 mg/kg, sc, a competitive NMDA receptor antagonist) was coadministered with DPDPE (0.5 |g, it) in mice (37). Collectively, it appears that antagonism of NMDA receptors may prevent the development of tolerance to selective S-opioid agonists.
Similar to S-opioid-induced tolerance, mixed results have been reported concerning the role of NMDA receptors in K-opioid tolerance. Coadministration with the K-agonist U-50488H (5 mg/kg, sc, once daily for 5 d) of MK-801 (0.3 mg/kg, ip) or LY274614 (6 mg/kg, ip, or 24 mg/kg/24 h pump infusion) did not prevent the development of antinociceptive tolerance to U-50488H as assessed by the tail-flick test (38). Likewise, ACPC (150 mg/kg, sc) also failed to prevent tolerance induced by repeated administration of U-50488H (5 mg/kg, sc) (37). In addition, MK-801, LY274614, or ACPC in the doses described was ineffective in preventing the development of tolerance to the K-3 agonist naloxone benzoylhydrazone (50 mg/kg, sc) given once daily for 5 d (37,38).
In separate studies, MK-801 (0.01-0.3 mg/kg, ip) prevented the development of the antinociceptive tolerance induced by twice daily ip injection of 25 mg/kg U-50488H (4 d for rats and 9 d for mice) using the tail-flick test in both mice and rats (39). One confounding factor to the assessment of these data is that K-opioids may interact with both NMDA and K-opioid receptors (40,41). It is possible that the mixed results from these studies may be, in part, the dual functions of K-opioids interacting with both NMDA and K-opioid receptors. Little has been known with regard to the role of NMDA receptors in the development of dependence on S- or K-opioids.
It has been demonstrated in numerous studies that NMDA receptors play a significant role in tolerance to and dependence on opioid antinociceptive effects. Several important points may be drawn from these studies: (1) Coadministration of NMDA receptor antagonists with morphine prevents tolerance and dependence, indicating that NMDA receptors are crucial for the development of both tolerance to and dependence on morphine. (2) Although repeated application of NMDA receptor antagonists reverses tolerance over time, a single treatment with an NMDA receptor antagonist does not restore the antinociceptive effects of opioids in tolerant animals. Thus, activation of NMDA receptors is not required for the expression of opioid tolerance. (3) Except for morphine-induced tolerance and dependence, in which studies consistenly show the effectiveness of NMDA receptor antagonists, the role of NMDA receptors in tolerance induced by selective opioid agonists (particularly 8- and K-opioids) remains controversial. (4) Clinically available agents with NMDA receptor antagonist properties (such as DM, d-methadone, memantine) are generally as effective as MK-801 in preventing tolerance and dependence in preclinical trials.
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