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PubMed2006

Chronic morphine drinking establishes morphine tolerance, but not addiction in Wistar rats.

OBJECTIVE: Some animal models apply morphine in the drinking water to generate addiction, but related reports are not free of conflicting results. Accordingly, this study aimed to figure out if chronic consumption of morphine in the drinking water can induce morphine addiction in Wistar rats. METHODS: For 3 weeks, the animals received a daily morphine dose of 35 mg/kg by offering a calculated volume of sugar water (5% sucrose) with morphine (0.1 mg/ml) to each rat; animals receiving just sugar water served as controls. Immediately after the treatment phase, the tail immersion test was used to check for morphine tolerance, and all animals were then kept on tap water for one week (withdrawal phase). Afterwards, all rats were allowed to choose their drinking source by offering two bottles, containing sugar water without and with morphine, simultaneously for two days (preference phase). RESULTS: While the chronic consumption of morphine led to a reduction in body weight and to morphine tolerance, the morphine-treated Wistar rats did not show any preference for the opiate-containing sugar water. CONCLUSION: Body weight loss and tolerance do not reveal a condition of drug craving, and current animal models should be re-evaluated regarding their potential to establish morphine addicted animals.

Animals↗

PubMed1989

Stereospecific effects of a kappa-opiate antagonist on the actions of morphine in morphine-tolerant rats.

The effects of kappa-opiate receptor antagonist, MR 2266 and its dextro isomer, MR 2267 on morphine-induced analgesia and changes in colonic temperature were determined in morphine-naive and morphine-tolerant male Sprague-Dawley rats. Intraperitoneal administration of morphine (8 mg/kg) produced analgesia and hyperthermia in morphine-naive rats. MR 2266 (0.3-3.0 mg/kg) antagonized morphine-induced analgesia and hyperthermia in morphine-naive rates but MR 2267 was inactive. Subcutaneous implantation of six morphine pellets during a 7 day period induced tolerance to the analgesic and hyperthermic effects of morphine in the rat. MR 2266 also antagonized morphine analgesia and hyperthermia in morphine-tolerant rats, however, MR 2267 had no effect. A high dose (3 mg/kg) of MR 2266 produced an intense hypothermic response in morphine-tolerant rats. Previously we have shown that kappa-opiate receptor agonists antagonize morphine analgesia in morphine-naive rats but potentiate it in morphine-tolerant rats. The results of the present studies indicate that the antagonist of kappa-opiate receptors, on the other hand, antagonize morphine effects in both morphine-naive and morphine-tolerant rats in a stereospecific manner.

Analgesia↗

PubMed1999

Peripheral blockade of topical morphine tolerance by ketamine.

Repeated topical administration of morphine daily produces tolerance within three days. Ketamine alone has little effect in the radiant heat tailflick assay. However, with administered with morphine, topical ketamine prevented the development of morphine tolerance in a dose-dependent manner. Furthermore, topical ketamine also slowly reversed pre-existing morphine tolerance. These observations imply that topical morphine tolerance is mediated, at least in part, through peripheral N-methyl-D-aspartate (NMDA) receptors and raises the possibility of the use of topical NMDA receptor antagonists clinically.

Administration, Topical↗

PubMed1988

Inversion of the alpha-2 and alpha-1 noradrenergic control of the cortical release of acetylcholine and gamma-aminobutyric acid in morphine-tolerant guinea pigs.

In normal guinea pigs the adrenergic agonists clonidine and norepinephrine are known to inhibit directly the cortical outflow of acetylcholine (ACh) through alpha-2 receptors and to increase the cortical outflow of gamma-aminobutyric acid (GABA) through alpha-1 receptors. GABA, in turn, contributes to inhibit ACh through GABAA receptors. This scheme is changed drastically by morphine tolerance. In morphine-tolerant guinea pigs, clonidine at 7.5, 18.7 and 112 nmol/kg i.p. stimulates the cortical release of ACh through alpha-1 receptors. This effect is prevented by prazosin, 35.8 nmol/kg i.p. Clonidine reduces ACh release at high doses only (374 and 1122 nmol/kg i.p.). Furthermore, electrical stimulation of locus ceruleus also gives rise to a prazosin-sensitive increase in ACh release. In addition, locus ceruleus stimulation often causes behavioral activation rather than sedation. In morphine-tolerant guinea pigs, clonidine at 7.5 and 18.7 nmol/kg i.p. reduces GABA efflux through alpha-2 receptors, as the drug effect is prevented by idazoxan, 84 nmol/kg i.p. Clonidine increases GABA efflux at high doses only (112 and 374 nmol/kg i.p.). Locus ceruleus stimulation also gives rise to an idazoxan-sensitive reduction in GABA outflow. This new condition, evident after 7 days of morphine treatment, can be defined as inversion of the physiological norepinephrine control over ACh and GABA outflow and can represent a major part of the neurochemical derangement associated with opioid tolerance.

Acetylcholine↗

PubMed1992

The effect of morphine tolerance dependence and abstinence on immunoreactive dynorphin (1-13) levels in discrete brain regions, spinal cord, pituitary gland and peripheral tissues of the rat.

The effect of morphine tolerance dependence and protracted abstinence on the levels of dynorphin (1-13) in discrete brain regions, spinal cord, pituitary gland and peripheral tissues was determined in male Sprague-Dawley rats. Of all the tissues examined, the highest level of dynorphin (1-13) was found to be in the pituitary gland. Among the brain regions and spinal cord examined, the levels of dynorphin (1-13) in descending order were: hypothalamus, spinal cord, midbrain, pons and medulla, hippocampus, cortex, amygdala and striatum. The descending order for the levels of dynorphin (1-13) in peripheral tissues was: adrenals, heart and kidneys. In morphine tolerant rats, the levels of dynorphin (1-13) increased in amygdala but were decreased in pons and medulla. In morphine abstinent rats, the levels of dynorphin (1-13) were increased in amygdala, hypothalamus and hippocampus. The levels of dynorphin (1-13) were increased in pituitary but decreased in spinal cord and remained so even during protracted abstinence. The levels of dynorphin (1-13) in the peripheral tissues of morphine tolerant rats were unaffected. However, in the heart and kidneys of morphine abstinent rats, the levels of dynorphin (1-13) were increased significantly. It is concluded that both morphine tolerance and abstinence modify the levels of dynorphin (1-13) in pituitary, central and peripheral tissues. Morphine abstinence differed from non-abstinence process in that there were additional changes (increases) in the levels of dynorphin (1-13) in brain regions (hypothalamus and hippocampus) and peripheral tissues (heart and kidneys) and may contribute to the symptoms of the morphine abstinence syndrome.(ABSTRACT TRUNCATED AT 250 WORDS)

Adrenal Glands↗

PubMed2005

Increased glutamate synaptic transmission in the nucleus raphe magnus neurons from morphine-tolerant rats.

Currently, opioid-based drugs are the most effective pain relievers that are widely used in the treatment of pain. However, the analgesic efficacy of opioids is significantly limited by the development of tolerance after repeated opioid administration. Glutamate receptors have been reported to critically participate in the development and maintenance of opioid tolerance, but the underlying mechanisms remain unclear. Using whole-cell voltage-clamp recordings in brainstem slices, the present study investigated chronic morphine-induced adaptations in glutamatergic synaptic transmission in neurons of the nucleus raphe magnus (NRM), a key supraspinal relay for pain modulation and opioid analgesia. Chronic morphine significantly increased glutamate synaptic transmission exclusively in one class of NRM cells that contains mu-opioid receptors in a morphine-tolerant state. The adenylyl cyclase activator forskolin and the cAMP analog 8-bromo-cAMP mimicked the chronic morphine effect in control neurons and their potency in enhancing the glutamate synaptic current was significantly increased in neurons from morphine-tolerant rats. MDL12330a, an adenylyl cyclase inhibitor, and H89, a protein kinase A (PKA) inhibitor, reversed the increase in glutamate synaptic transmission induced by chronic morphine. In addition, PMA, a phorbol ester activator of protein kinase C (PKC), also showed an increased potency in enhancing the glutamate synaptic current in these morphine-tolerant cells. The PKC inhibitor GF109203X attenuated the chronic morphine effect. Taken together, these results suggest that chronic morphine increases presynaptic glutamate release in mu receptor-containing NRM neurons in a morphine-tolerant state, and that the increased glutamate synaptic transmission appears to involve an upregulation of both the cAMP/PKA pathway and the PKC pathway. This glutamate-mediated activation of these NRM neurons that are thought to facilitate spinal pain transmission may contribute to the reduced opioid analgesia during opioid tolerance.

Analgesics, Opioid↗

PubMed1999

d-Methadone blocks morphine tolerance and N-methyl-D-aspartate-induced hyperalgesia.

Previous in vitro and in vivo studies have determined that the d isomer of methadone has N-methyl-D-aspartate (NMDA) receptor antagonist activity. The present studies examined the ability of d-methadone to attenuate the development of morphine tolerance in mice and rats and to modify NMDA-induced hyperalgesia in rats. A decrease in the percentage of mice analgesic (tail-flick response) after 5 days of once-daily morphine (7 mg/kg s.c.) was completely blocked by coadministration of d-methadone given s.c. at 10 mg/kg. Morphine given s.c. to mice on an escalating three times per day dosing schedule resulted in a nearly 3-fold increase in the tail-flick ED50 dose of morphine which was prevented by s.c. coadministered d-methadone at 15 mg/kg. In rats, intrathecal (i.t.) morphine produced a 38-fold increase in the ED50, which was completely prevented by the coadministration of i.t. d-methadone at 160 micrograms/rat. A decrease in thermal paw withdrawal latency induced by the i.t. administration of 1.64 micrograms/rat NMDA was completely blocked by pretreatment with 160 micrograms/rat d-methadone. Thus, systemically coadministered d-methadone prevents systemically induced morphine tolerance in mice, i.t. d-methadone attenuates tolerance produced by i.t. morphine in rats, and i.t. d-methadone, at the same dose which modulates morphine tolerance, blocks NMDA-induced hyperalgesia. These results support the conclusion that d-methadone affects the development of morphine tolerance and NMDA-induced hyperalgesia by virtue of its NMDA receptor antagonist activity.

Analgesics, Opioid↗

PubMed1998

Inhibition of morphine tolerance and dependence by diazepam and its relation to mu-opioid receptors in the rat brain and spinal cord.

We have recently observed that concomitant administration of diazepam to morphine pellet implanted rats results in the inhibition of the development of morphine tolerance and dependence. We have now analyzed mu-opioid receptors in rats treated with morphine and diazepam for 5 days by using [3H]-DAMGO for binding studies. Male Sprague-Dawley rats were made tolerant and dependent by subcutaneous (s.c.) implantation of six morphine pellets (two pellets on the first day, and four on the second day). Diazepam (0.25 mg/kg b.wt) was injected once daily intraperitoneally (i.p.) for 5 days. Control rats were implanted with placebo pellets and injected once daily with saline or diazepam (i.p.). Animals were administered s.c. naloxone (10 mg/kg) to induce naloxone-precipitated withdrawal syndrome on the final day of the experiment (day 5). There was an up-regulation of mu-receptor (Bmax increased) in the spinal cord of morphine tolerant (+139%) and dependent (+155%) rats compared to saline treated animals. Diazepam treatment abolished the up-regulation of mu-receptors in spinal cord of morphine treated rats. In the cortex, Bmax was not affected in morphine tolerant or dependent rats but it decreased by 38% in morphine tolerant and 65% in morphine dependent rats treated with diazepam. The Kd of mu-receptors increased in the cortex, striatum and hypothalamus of morphine dependent rats. Diazepam treatment decreased the Kd of mu-receptors in the cortex of morphine tolerant and hypothalamus of morphine-dependent rats. These results suggest that diazepam treatment antagonizes the up-regulation of CNS mu-receptors observed in morphine tolerant rats. In addition, morphine tolerance and dependence may be associated with conversion of mu-opioid receptors to mu-constitutive opioid receptors that are less active, and this conversion is prevented in the brain of animals treated with diazepam.

Analgesics, Opioid↗

PubMed2001

Morphine tolerance and dependence in nociceptin/orphanin FQ transgenic knock-out mice.

It has been hypothesized that morphine tolerance and dependence in mice following chronic exposure may reflect increased compensatory activity of antiopioid systems. The endogenous peptide nociceptin/orphanin FQ has been shown to have anti-opioid effects, for example antagonizing morphine analgesia. Moreover, chronic morphine administration increases synthesis of the peptide, and morphine tolerance and dependence can be attenuated or reversed by antagonists and agonists of the nociceptin/orphanin FQ receptor, respectively. The present study seeks to confirm a role for nociceptin/orphanin FQ in opioid tolerance and dependence by comparing morphine ED(50) values and naloxone-precipitated withdrawal jumping in mice homozygous (knock-out) and heterozygous for a null mutation of the Npnc1 gene encoding the nociceptin/orphanin FQ propeptide, and their wild type littermates, following chronic morphine exposure. Relative to morphine-naive control mice, significant rightward shifts in the morphine dose-response curve, resulting in increased morphine ED(50) values (approximately two to three-fold), was observed for all genotypes following three days of repeated systemic morphine injections. However, no differences between genotypes in the magnitude of tolerance were observed. In contrast, knock-out mice displayed significantly increased naloxone-precipitated withdrawal jumping relative to heterozygous and wild-type mice following implantation with a morphine pellet (25mg) for 72h. Use of nociception/orphaninFQ transgenic knock-out mice thus demonstrate the differential involvement of nociceptin/orphanin FQ in morphine tolerance and dependence.

Analgesics, Opioid↗

PubMed1983

Effect of clonidine on the chronic morphine tolerance and on the sensitivity of the smooth muscles in mice.

Clonidine, when administered for prolonged period showed no tolerance to its analgesic activity. Prior exposure to clonidine attenuated the tolerance development to morphine-induced analgesia and the supersensitivity to acetylcholine (ACh) in ileum during chronic morphine treatment. Further, acute administration of lower doses of clonidine (upto 1 mg) produced supersensitivity in ileum to Ach while the higher dose (10 mg) induced subsensitivity. In vas deferens, clonidine in all the concentrations tested induced dose and time dependent supersensitivity to norepinephrine (NE) similar to that produced by morphine. Chronic clonidine treatment failed to alter the ACh responses in ileum while it produced supersensitivity to NE in vas deferens. The results suggest that clonidine and morphine possess comparable properties and the antagonism of chronic morphine tolerance by clonidine may be the therapeutic basis for its clinical application in the treatment of opiate addicts.

Acetylcholine↗

PubMed1999

[Increased release of orphanin FQ (OFQ) in brain of chronic morphine tolerant rats].

The changes in OFQ-immunoreactivity (OFQ-ir) content and release of cerebroventricular perfusate, periaqueductal gray (PAG) and amygadala of chronic morphine tolerant rats were measured with radioimmunoassay (RIA). The results indicate: (1) chronic morphine tolerance was achieved in rats by injecting increasing doses of morphine (10, 20, 40, 50, 60 mg/kg, s.c., tid). The content of OFQ-ir in cerebroventricular perfusate in the rats of normal saline (NS) group remained at a steady level during the injections from d 1 to d 5, while in the morphine-treated group of rats the content of OFQ-ir showed 25% increase (P < 0.05 vs NS) and 52% increase (P < 0.01 vs NS) after 3 and 5 days' morphine injection respectively. (2) The content of OFQ-ir in PAG of rats receiving morphine injection for 1, 3 and 5 days showed respectively increases of 17% (P < 0.05), 48% (P < 0.05) and 80% (P < 0.01) against the NS group. (3) The content of OFQ-ir in rat amygdala receiving 1 day injection of morphine showed a 8% decrease, which was not significantly different from NS group. However, there was a 36% and 55% (P < 0.05) increase respectively after injection for 3 and 5 days. It is suggested that in the later stage of chronic morphine treatment, large amount of OFQ was released from rat brain to antagonize the effect of opioids, which may play an important role in the development of morphine tolerance.

Amygdala↗

PubMed1992

The NMDA receptor antagonist MK-801 prevents long-lasting non-associative morphine tolerance in the rat.

Several studies have demonstrated that the N-methyl-D-aspartate (NMDA) antagonist MK-801 attenuates the development of morphine tolerance and withdrawal. These studies employed repeated morphine injections to induce tolerance, a procedure in which learning has been suggested to play a significant role in tolerance development. MK-801 has been reported to block some types of learning, and it is unclear, therefore, whether the effect of MK-801 on tolerance development is due to its antagonism of associative (learning) or non-associative factors. Moreover, previous studies have tested the effects of MK-801 on morphine tolerance only up to 48 h after its induction; yet morphine tolerance can persist for many months, and it is not known whether MK-801 can block long-lasting tolerance. In the present study, therefore, we adopted a model of morphine tolerance in which the involvement of learning is minimized by using a single injection of morphine in a sustained-release preparation, and we tested tolerance for up to 56 days. In the first experiment, simultaneously administering MK-801 (0.2 mg/kg, s.c.) and morphine (60 mg/kg, s.c.), each in a sustained-release preparation, abolished tolerance that lasted at least 12 days. Analgesia was measured in the hot-plate test following a test dose of morphine (15 mg/kg, i.p.). In the second experiment, delivering MK-801 and morphine as before, the duration of morphine-induced catalepsy and analgesia was prolonged. Nevertheless, 24 h later one symptom of naloxone-precipitated withdrawal was significantly attenuated in these same animals.(ABSTRACT TRUNCATED AT 250 WORDS)

Analgesia↗

PubMed1999

Morphine tolerance and dependence in mice with history of repeated exposures to NMDA receptor channel blockers.

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.

Analgesics, Opioid↗

PubMed1991

Characteristics of mu and delta opioid binding sites in striatal slices of morphine-tolerant and -dependent mice.

Previously, we demonstrated the enhanced affinity of opioid receptors for naloxone in striatal slices from morphine-dependent mice. In our present study, binding characteristics of the mu opioid receptor agonists, [D-Ala2,MePhe4,Gly-ol5]enkephalin (DAMGO) and dihydromorphine, the delta opioid receptor agonist, [D-Ala2, D-Leu5]enkephalin (DADLE), and the opioid antagonist, naloxone, were examined in striatal slices from morphine-tolerant and -dependent mice. Striatal slices from mice that were implanted with a morphine pellet for 3,7 and 21 days displayed significant decreases in Kd values (5.1, 4.6 and 5.5 nM, respectively) of [3H]DAMGO when compared to those in slices from control animals that were not implanted or implanted with placebo pellets (9.6 and 9.3 nM, respectively). Also, a significant increase in the binding affinity of naloxone, but not that of dihydromorphine, was observed in striatal slices of mice that were implanted with a morphine pellet for 3 days. Significant increases in the Bmax of delta binding sites in striatal slices of mice that were implanted with a morphine pellet for 3, 7 and 21 days (20.7, 18.1 and 17.7 pmol/mg tissue, respectively) were observed when compared to that in slices from control mice that were implanted with placebo pellets (11.4 pmol/mg tissue). The enhancement in the binding affinity of DAMGO and naloxone and the increased density of DADLE binding sites paralleled the development of morphine tolerance and dependence and [D-Pen2,D-Pen5]enkephalin cross-tolerance in whole animals. An antinociceptive potentiation between morphine and DAMGO was observed in morphine-tolerant and -dependent mice whereas in naive animals the effects of the two drugs were additive.(ABSTRACT TRUNCATED AT 250 WORDS)

Analgesics↗

PubMed1995

Alterations in L-type calcium channels in the brain and spinal cord of acutely treated and morphine-tolerant mice.

Opiate tolerance has been associated with changes in neuronal intracellular calcium levels. In vivo studies have indicated the involvement of dihydropyridine (DHP)-sensitive ('L-type') voltage-gated calcium channels in the morphine-tolerant state. In this study, we assessed how the morphine-tolerant state would affect the antinociception produced by intrathecal administration of two agents (Bay K 8644 and thapsigargin) that increase intracellular calcium. Morphine-tolerant mice displayed a 7-fold greater ED50 for Bay K 8644 antinociception than placebo-treated animals; no difference was found in the dose-response curve for thapsigargin. To further explore the role of the L-type channel in morphine tolerance development, we performed radiolabeled nitrendipine binding studies in the spinal cord and brain regions associated with pain modulation from acutely treated, tolerant, and control mice. Our treatment protocol produced a 4-fold shift in the ED50 for s.c. morphine antinociception, as determined by the tail-flick procedure. Binding site number and affinity were determined using Scatchard analysis for the following timepoints: 20 min and 60 min after s.c. injection of morphine or vehicle, as well as after 4 days of chronic administration, and after naloxone-precipitated withdrawal. Although some changes were observed in the affinity of nitrendipine for its receptor, a significant change in these measures was found only following naloxone administration, which produced increases in Bmax in both placebo- and morphine-treated mice.

Analgesics, Opioid↗

PubMed2000

Study the mechanisms of U-50,488 to prevent the development of morphine tolerance in guinea pigs.

Previously we have shown that low dose of [trans-3,4-dichloro-N-methyl-N-[2-(1-pyrrolidinyl)cyclohexyl]-benzeneacetamide hydrochloride] (U-50,488) could prevent the development of morphine tolerance in guinea pigs. In the present study we tried to investigate the role of glutamate and nitric oxide in this process. Male Hartley guinea pigs (200-300 g) were chronically treated s.c. with either saline or morphine (15 mg/kg) or morphine + U-50,488 (0.003 mg/kg) twice a day for 7 days. Antinociceptive activity was assessed by hot-plate test on the first, fourth and seventh day. Spinal cord slices (450 microm) were prepared 30 min after drug treatment on eighth day and [3H] glutamate and nitric oxide (NO) released were determined. We found that coadministration of U-50,488 (0.003 mg/kg) suppressed the development of morphine tolerance to antinociceptive effect as we reported before. The percentage of in vitro spinal release of [3H] glutamate by 100 microM morphine was significantly higher in the chronic morphine group than the control group. On the other hand, coadministration of U-50,488 with morphine for 7 days blocked this effect significantly. The basal NO level released from the spinal cord slices was significantly higher in chronic morphine group but not in chronic (morphine + U-50,488) group. In vitro morphine (100 microM) increased the NO level in control group and chronic (morphine + U-50,488) group and also further increased NO in chronic morphine group. From the NMDA-displaced [3H] glutamate binding in guinea pig spinal cord, we found that the Bmax decreased in chronic morphine group but not in the chronic (morphine + U-50,488) group. In conclusion, chronic morphine treatment may activate the NMDA receptors by increasing the release of glutamate which causes the increase of synthesis and release of NO and following uncertain mechanisms to induce the development of morphine tolerance. And the mechanisms of U-50,488 to prevent the development of morphine tolerance may involve the inhibition of glutamate released by chronic morphine and also the decrease of NO induced by chronic morphine.

3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cycloh↗

PubMedDate not supplied

[A comprehensive study of the neurochemical and immune mechanisms of morphine tolerance: the effects of naloxone].

To test the authors' hypothesis about the role of endopeptidase (enkephalinase A, in particular) in mechanisms of morphine tolerance and blocking action of small doses of naloxone, they studied nociception reactions, morphine antibodies titres and enkephalinase A activity after morphine, d-phenylalanine and naloxone injection in brain structures. It is shown that activity of enkephalinase A in structures of endogenous antinociceptive system increased simultaneously with morphine antibodies titres in tolerance condition. Injection of small dose naloxone inhibited enkephalinase activity in brain structures and decreased morphine antibodies titres to these in control morphine-sensitive rats and therefore suppressed morphine tolerance. Prolonged naloxone injection decreased morphine antibodies titres to the levels of intact animals and highly increased titers of antiidiotypic morphine antibodies. Thus, these results confirm the role of enkephalinase as a neuromodulator. A strong relationship exists between enkephalinase and immune mechanisms of development of morphine tolerance which can be blocked by small naloxone doses. It is concluded that naloxone in small doses can be used in patients to suppress morphine tolerance.

Analgesics, Opioid↗

PubMed1995

Blockade of morphine tolerance by ACEA-1328, a novel NMDA receptor/glycine site antagonist.

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-1,4-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.

Analgesics↗