Peripherally acting NMDA receptor/glycine site receptor antagonists inhibit morphine tolerance (original) (raw)
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Effects of short-acting NMDA receptor antagonist MRZ 2/576 on morphine tolerance development in mice
Naunyn-schmiedebergs Archives of Pharmacology, 2000
The present study sought to evaluate the ability of a short-acting glycineB site NMDA receptor antagonist, MRZ 2/576, to affect morphine tolerance development in mice. It was found that MRZ 2/576 (10 mg/kg, i.p.) significantly retarded development of morphine analgesic tolerance (20 mg/kg, s.c., 8 days, once a day; tail-flick test) when administered 120 min or 150 min after each daily morphine injection. MRZ 2/576 did not affect the development of morphine tolerance when administered immediately, 15, 30, 60, 90, 180, 240, 300 or 360 min after the daily morphine injections. Thus, short-acting NMDA receptor antagonists may be useful in exploring the temporal characteristics of opioid tolerance (i.e., periods after morphine injection that are critical for tolerance induction) and the present study suggests that after morphine administration there is a period of NMDA receptors activation crucial for the development of tolerance.
Modulation of Morphine Analgesia and Tolerance in Rats by NMDA Receptor Antagonists
Neurophysiology, 2012
The efficacy of opioids in chronic pain treatment is limited because of the development of opioid tolerance. We investigated the role of N-methyl-D-aspartate (NMDA) receptor antagonists (NMDAR Ants) in morphine analgesia and tolerance in rats. To induce the morphine tolerance, experimental rats received morphine (50 mg/kg; subcutaneously) once daily for 3 days. After the last dose of morphine was injected on day 4 and morphine tolerance was evaluated, analgesic effects of ketamine, dizocilpine (MK-801, a non-competitive NMDAR Ant), LY235959 (a competitive NMDAR Ant), cis-2,3-piperidinedicarboxylic acid (PDA, an NMDAR agonist), and morphine were estimated with 30-min-long intervals (0, 30, 60, 90, and 120 min) by the tail-flick and hot-plate algesia tests (n = 6 in each studied group). As was found, ketamine, MK-801, and LY235959 significantly attenuated the development of morphine tolerance (P < 0.05). On the other hand, PDA somewhat increased the development of this tolerance, but the difference was not statistically significant (P > 0.05). Our data indicate that NMDAR Ants attenuate the development of morphine tolerance, significantly affecting the effects of morphine analgesia in rats.
Naunyn-Schmiedeberg's Archives of Pharmacology, 2000
The tail-flick test was used to investigate the effects of chronic administration of the N-methyl-D-aspartate (NMDA) receptor antagonists, dextromethorphan, memantine and MRZ 2/579, on the development and reversal of morphine tolerance in mice in three separate experiments. Experiment 1 investigated the effects of NMDA receptor antagonists on the development of tolerance. Morphine (10 mg/kg for 6 days, twice daily) produced a 5.9-fold rightward shift of the cumulative dose-response curves. Co-administration of dextromethorphan, memantine or MRZ 2/579 between tests 1 and 2 dose-dependently (5-10 mg/kg) inhibited the development of morphine tolerance. In experiment 2, in which the effects on the reversal were investigated, morphine-tolerant mice were treated b.i.d. for an additional 6 days (between tests 2 and 3) with vehicle+vehicle, NMDA receptor antagonist+vehicle, ve-hicle+morphine or NMDA receptor antagonist+morphine. Morphine-tolerant mice treated with vehicle+vehicle remained morphine tolerant, whereas this residual morphine tolerance was inhibited by administration of all three NMDA antagonists (each 10 mg/kg). Morphine-tolerant mice receiving vehicle+morphine injections demonstrated an unchanged degree of antinociceptive tolerance. In these mice, the co-administration of memantine and MRZ 2/579, but not dextromethorphan, resulted in the reversal of morphine tolerance. In experiment 3, memantine and MRZ 2/579 (10 mg/kg) inhibited the acute antinociceptive effect of morphine, but dextromethorphan did not. These data indicate that low-affinity, clinically available and/or therapeutically promising NMDA receptor antagonists may be used to inhibit ongoing morphine tolerance.
Pharmacological Research, 1999
Opiate or NMDA receptor antagonists given during andror after the development of tolerance and dependence have been reported to prevent these developments. In the Ž . Ž . present study, MK801 dizolcipine and naltrexone NX , two antagonists of NMDA and opiate receptors, respectively were used in rats to find any correlations between changes in NMDA receptor kinetics, and the intensity of tolerance and dependence. Thus, six different Ž . groups of rats were formed. The rats in the groups were given saline S q S, Sq morphine Ž . M , NXq S, NXq M, MK801q S and MK801q M, respectively, once per day for 8 days. On day 9, the rats from each group were divided into four subgroups. The rats of the first subgroup were subjected to the determination of tail-flick latency. The rats of the second y1 Ž . subgroup were administered 1 mg kg naloxone NL 2 h after administration of 3 mg kg y1 M. The rats of the third subgroup were implanted with two M pellets and after 72 h they were challenged with NL. The remaining rats received drugs also on day 9 according to the previous administration paradigm. Two hours after the administrations, their brains w 3 x were utilised for the determination of NMDA receptor kinetics, employing H glutamate. The measurement of tail-flick latency showed the prevention by NX or MK801 of the development of tolerance to M. The rats, which were administered 3 mg kg y1 M 2 h before 1 mg kg y1 NL injection, on day 9 showed that only NX given previously along with M attenuated the intensity of the development of M dependence. NX administered alone intensified the development of dependence on a single dose of M. The development of M dependence upon the M pellet implantation was intensified by the previous administration of NX or MK801 concomitantly with M. The administration of M or MK801 alone, or NX together with M, caused significant upregulation of NMDA receptors. NX alone, and MK801 given concurrently with M led to a significant downregulation. So, in light of the Ž . previous findings and the present experimental data it can be said that: 1 supersensitivity to opioids may be a downregulation of NMDA as well as an upregulation of the opioid Ž . receptor; 2 either upregulation or downregulation of NMDA receptors may facilitate Ž . subsequent development of opioid dependence; 3 tolerance to opioid may necessitate Ž . both upregulation of NMDA receptors and downregulation of opioid receptors; and 4 beneficial effects of opioid antagonists in the treatment of opiate dependence and CNS injuries may be strongly related to the down regulation of NMDA receptors.
Neuropharmacology, 2006
N-methyl-D-aspartate (NMDA) receptors are widely involved in opioid tolerance. However, it is less clear whether NMDA receptor antagonists reverse already-established tolerance and whether the intensity of the nociceptive stimulus influences morphine tolerance. Three days after implantation of morphine or control pellets the effects of i.v. morphine and pre-administration of saline or (+)-HA966 (a glycine site-specific NMDA receptor antagonist), were studied on the C-fibre reflex elicited by a wide range of stimulus intensities. Morphine both increased the threshold and decreased the slope of the recruitment curve in the "non-tolerant" group of animals. In the "morphine-tolerant" group, the threshold did not change but the gain of the stimulus-response curve decreased. The expression of tolerance to morphine depended on the intensity of the stimulus, being maximal when threshold stimulus intensities were used but considerably less with supra-threshold stimulation. As expected, a single treatment with (+)-HA966, potentiated morphine antinociception in "non-tolerant" rats. However, in "morphine-tolerant" rats (+)-HA966 reversed established morphine tolerance and increased the antinociceptive effects of morphine. These results suggest that (+)-HA966 interfered with expression of morphine tolerance, and offered an encouraging therapeutic approach for pain management in opioid abusers.
European Journal of Pharmacology, 2000
The actual time-course of morphine antinociception is shorter than what would be predicted from its elimination kinetics, suggesting the presence of an acute tolerance phenomenon. Since antagonists acting at NMDA subtype of glutamate receptors were repeatedly shown to prolong acute morphine antinociception, acute tolerance may be attributed to hyperactivity of NMDA receptors. The ability of various site-selective NMDA receptor antagonists to affect morphine antinociception (tail-flick test) was assessed in mice 30 and 120 min after acute morphine challenge. Competitive NMDA receptor antagonist 3-(2-carboxypiperazin-4-yl)-1-propenyl-1-phosphonic acid (d-CPPene) (SDZ EAA 494; 0.1–1 mg/kg), low-affinity channel blockers 1-amino-3,5-dimethyl adamantane (memantine) (1–10 mg/kg) and 1-amino-1,3,3,5,5-pentamethyl-cyclohexan hydrochloride (MRZ 2/579) (1–10 mg/kg), glycine site antagonists 5-nitro-6,7-dichloro-1,4-dihydro-2,3-quinoxalinedione (ACEA-1021) (5 or 10 mg/kg) and 8-chloro-4-hydroxy-1-oxo-1,2-dihydropyridaliono(4,5-b)quinoline-5-oxide choline salt (MRZ 2/576) (1–10 mg/kg) were administered intraperitoneally (i.p.) 15 or 30 min prior to the tail-flick test (i.e., interval between injections of morphine and NMDA receptor antagonist was either 0–15 or 90–105 min). ACEA-1021, MRZ 2/576 and to the lesser extent, memantine and MRZ 2/579 enhanced morphine antinociception when tests were conducted 120 but not 30 min post-morphine. d-CPPene potentiated morphine antinociception irrespective of the interval between morphine administration and the tail-flick test. The results suggest that NMDA receptor antagonists may restore analgesic activity of morphine in acutely tolerant mice.
Neuropharmacology, 2008
Using the C-fibre reflex as a nociceptive response elicited by a wide range of stimulus intensities in the rat, we recently reported that a single treatment with (þ)-HA966, a glycine site-specific NMDA receptor antagonist: (1) potentiates morphine antinociception; and (2) reverses an established morphine tolerance. We presently aimed at determining whether our observation was likely to result from a direct effect on the spinal cord or an indirect effect of supraspinal origin. In a 2 2 2 experimental design, we compared the effects of 5 mg/kg morphine in: (1) shamoperated rats or animals whose brainstems had been transected at the level of the obex; (2) rats that were implanted with pellets, either 150 mg morphine or placebo; and (3) animals injected either with saline or 10 mg/kg (þ)-HA966. The control C-fibre reflexes were similar in all groups of animals. As compared to ‘‘non-tolerant’’ rats, the depressive effect of morphine was weaker in ‘‘morphine-tolerant’’ animals where the threshold did not change following morphine but the gain of the stimulus-response curve decreased, albeit to a significantly lesser extent than in the ‘‘non-tolerant’’ group. Whether in ‘‘non-tolerant’’ or ‘‘tolerant’’ groups, the effects of morphine were stronger in ‘‘obex-transected’’ than in ‘‘sham-operated’’ animals. In all groups, the effects of morphine were potentiated by the preliminary administration of (þ)-HA966. However, in the ‘‘morphine-tolerant’’ group, the preliminary administration of (þ)-HA966 was more potent in the ‘‘sham-operated’’ than in the ‘‘obextransected’’ groups. Since overall effects were very similar in ‘‘sham-operated’’ and ‘‘obex-transected’’ animals, we concluded for our model that the critical site for the expression of the neuronal plastic changes associated with morphine tolerance lies in the spinal cord.
Blockade of morphine tolerance by ACEA-1328, a novel NMDA receptor/glycine site antagonist
European Journal of Pharmacology, 1995
Recent studies indicate that competitive and non-competitive NMDA receptor antagonists can block the development of morphine tolerance. Since glycine is considered to be a co-agonist for activation of NMDA receptors we examined the effect of a novel bioavailable NMDA receptor/glycine site antagonist, 5-nitro-6,7-dimethyl-l,4-dihydro-2,3-quinoxalinedione (ACEA-1328), on the development of morphine tolerance. Administration of ACEA-1328 (20 mg/kg) completely blocked tolerance to morphine-induced antinociception in the tail flick test in CD-1 mice, without affecting the basal nociceptive response or potentiating morphine-induced antinociceptive effects. These data suggest that inhibition of NMDA receptor activity via blockade of the glycine co-agonist site is potentially viable as a therapeutic approach for preventing development of morphine tolerance.
European Journal of Pharmacology, 2001
We investigated the effects of pretreatment with low-affinity, uncompetitive NMDA receptor antagonists on morphine-induced antinociception in rats using the same intensity of thermal stimulus applied to the tail and the paws. Similar baseline responses to thermal stimuli of the same intensity were recorded from tails and hind paws. However, morphine produced equal antinociception from the tail and hind paw when used at doses of 2.5 and 6 mgrkg, respectively. These doses were used in further experiments. Thirty minutes before Ž . Ž . morphine, rats were administered the NMDA receptor antagonists dextromethorphan 2.5-30 mgrkg , memantine 2.5-15 mgrkg and Ž . Ž . MRZ 2r579 1-amino-1,3,3,5,5-pentamethyl-cyclohexane HCl 1.25-10 mgrkg . All three compounds significantly and dose-dependently potentiated morphine-induced antinociception recorded from the tail. However, none of these NMDA receptor antagonists affected morphine antinociception recorded from the paw. These findings suggest that low-affinity NMDA receptor antagonists modulate differently morphine antinociceptive activity recorded from the tail and hind paws. q
Pharmacology Biochemistry and Behavior, 1999
Mice were subjected to two successive treatment protocols: first with NMDA receptor channel blockers (14 days, once a day) and second with morphine (5 mg/kg, 8 days, once a day). Treatment with the higher doses of dizocilpine (1 mg/kg), memantine (30 mg/kg), and MRZ 2/576 (30 mg/kg) upon discontinuation revealed only minor behavioral abnormalities attributable to the state of withdrawal. Following repeated administration of low-dose morphine, tolerance to morphine analgesia developed in mice preexposed to dizocilpine (1 mg/kg but not 0.3 mg/kg) but not memantine (10 and 30 mg/kg), MRZ 2/579 (10 and 30 mg/kg), or saline. There were no signs of morphine dependence in any treatment group. Overall, the present study found only minor effects of the subchronic administration of high doses of NMDA receptor channel blockers, suggesting that clinical use of NMDA receptor channel blockers such as memantine will not be accompanied by increased propensity to induction of morphine tolerance and dependence.