Attenuation of Acute Morphine Withdrawal in (original) (raw)
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Neuropsychopharmacology, 2002
The present study examined the ability of LY235959, a competitive N-methyl-D-aspartate (NMDA) receptor antagonist, to attenuate behaviors and c-fos mRNA expression associated with acute morphine withdrawal in the infant rat. Rat pups were given a single dose of morphine (10.0 mg/kg, s.c.) or saline. Two hours later, pups were removed from the dam and injected with either LY235959 (10.0 mg/kg, s.c.) or saline. Fifteen minutes later acute morphine withdrawal was precipitated with naltrexone (10.0 mg/kg, s.c.) and behaviors were recorded every 15 s for the next 60 min. Immediately after behavioral testing, brain and spinal cord were assayed for c-fos mRNA analysis by solution hybridization. The intensity of the morphine withdrawal syndrome was reduced in pups pretreated with LY235959. Withdrawal behaviors such as head moves, moving paws, rolling, and walking were decreased, and vocalizations were completely eliminated in pups pretreated with LY2359559. Acute morphine withdrawal increased c-fos mRNA expression in the brain and the spinal cord, which was attenuated by pre-treatment of LY235959. Thus, in the 7-day-old rat, as in the adult, NMDA receptors play a role in the behavioral and molecular manifestations of acute morphine withdrawal.
The Journal of pharmacology and experimental therapeutics, 2015
Opioid withdrawal causes a dysphoric state that can lead to complications in pain patients and can propagate use in drug abusers and addicts. Opioid withdrawal changes the activity of neurons in the nucleus accumbens, an area rich in both opioid-binding mu opioid receptors and glutamate-binding NMDA receptors (GluNs). Since the accumbens is an area important for reward and aversion, plastic changes in this area during withdrawal could alter future behaviors in animals. We discovered an increase in phosphorylation of serine 897 in the NR1 subunit of the NMDA receptor (pNR1) during acute morphine withdrawal. This serine can be phosphorylated by protein kinase A (PKA) and dephosphorylated by calcineurin. We next demonstrated that this increased pNR1 change is associated with an increase in NR1 surface expression. NR1 surface expression and pNR1 levels during acute withdrawal were both reduced by the NMDA receptor antagonist MK-801 and the PKA inhibitor H89. We also found that pNR1 leve...
Psychopharmacology, 2000
Rationale: There is increasing evidence that the N-methyl-D-aspartate (NMDA) receptor and the nitric oxide system are involved in opiate dependence in the adult rat, but whether these results in the adult apply to the infant rat is unknown. Objectives: Here we examined the effects of NMDA receptor antagonists and nitric oxide synthase (NOS) inhibitors, which reduce the opiate abstinence syndrome in adult animals, on morphine withdrawal in the infant rat. Methods: Neonatal rats were injected with morphine sulfate (10.0 mg/kg) twice daily for 6.5 days. On the 7th day, pups were injected with NOS inhibitors (L-NAME or 7-NI), NMDA receptor antagonists (MK-801 or AP-5), or vehicle. After 15 min, the pups were injected with naltrexone (1 mg/kg) to precipitate withdrawal. Behavior for each pup was identified and recorded every 15 s for 10 min before naltrexone injection and 15 min after naltrexone injection. Results: Both L-NAME and 7-NI significantly reduced most withdrawal behaviors in the infant rat, a result in line with previous studies in the adult rat. In contrast, AP-5 reduced some withdrawal behaviors but also increased others (e.g., moving paws). MK-801 was likewise ineffective in reducing most withdrawal behaviors and increased certain withdrawal behaviors (walking and wall climbing). Conclusions: In the infant rat, the production of nitric oxide is involved in opiate withdrawal whereas the NMDA receptor may not yet be functionally active or may play only a minor role.
Inhibition of morphine withdrawal by the NMDA receptor antagonist MK-801 in rat is age-dependent
Synapse, 2001
This study investigated the effects of the NMDA receptor antagonist MK-801 on the development of morphine dependence in 7-, 14-, and 21-day-old rat pups. For 6.5 days, starting at 1, 8, or 15 days of age, rats were pretreated with MK-801 (0.03 or 0.1 mg/kg, bid) or saline; 15 min later, morphine sulfate (10 mg/kg) or saline was injected to induce opiate dependence. On the afternoon of the seventh day, pups were injected with MK-801 (0.1 mg/kg) or saline and 15 min later with naltrexone (1 mg/kg) to precipitate withdrawal. Pups were then placed in a warm chamber with the litter and their behavior scan-sampled every 15 sec for a total of 15 min. MK-801 failed to inhibit morphine withdrawal in the 7-day-old rat, but did attenuate the development of morphine dependence in both the 14-and 21-day-old rats. These results suggest that the NMDA receptor is not functionally active in opiate withdrawal until around the second to third week of postnatal life in the rat and that there exists a transition period for the NMDA receptor to play a role in the development of opiate dependence and withdrawal.
Neuroscience Letters, 2008
Studies have shown that N-methyl-D-Aspartate (NMDA) receptors play a critical role in morphine analgesia and motoric processes at different levels of the central nervous system. In this study, we used cortex specific NR1 knockout mice (C57BL/6 strain) to elucidate the role of cortical NMDA receptors in morphine analgesia and motor coordination. On post-natal day 20, mice (CTL and KO) received vehicle (saline) or morphine (10mg/kg) and paw withdrawal latency (PWL) to a noxious thermal stimulus was measured. On post-natal day 21, motor coordination was measured using the rotating pole test. No differences in KO mice were found with respect to PWL following administration of saline or morphine (p > 0.05). However, sex-dependent differences were in motor coordination, with male KO mice showing a greater motor impairment in the rotating pole test than female KO mice (p < 0.05). The present results demonstrate that NMDA receptors are involved in both the analgesic effects of morphine and motor coordination, with the existence of sex-related differences in motor coordination.
Regional Fos expression induced by morphine withdrawal in the 7-day-old rat
Developmental Psychobiology, 2009
Human infants are often exposed to opiates chronically but the mechanisms by which opiates induce dependence in the infant are not well studied. In the adult the brain regions involved in the physical signs of opiate withdrawal include the periaqueductal gray area, the locus coeruleus, amygdala, ventral tegmental area, nucleus accumbens, hypothalamus, and spinal cord. Microinjection studies show that many of these brain regions are involved in opiate withdrawal in the infant rat. Our goal here was to determine if these regions become metabolically active during physical withdrawal from morphine in the infant rat as they do in the adult. Following chronic morphine or saline treatment, withdrawal was precipitated in 7-day-old pups with the opiate antagonist naltrexone. Cells positive for Fos-like immunoreactivity were quantified within select brain regions. Increased Fos-like labeled cells were found in the periaqueductal gray, nucleus accumbens, locus coeruleus, and spinal cord. These are consistent with other studies showing that the neural circuits underlying the physical signs of opiate withdrawal are similar in the infant and adult. ß 2009 Wiley Periodicals, Inc. Dev Psychobiol 51: 544-552, 2009.
Effect of Morphine Treatment on mRNA Expression of GluN3A Subunit of the NMDA Receptor in Rat Brain
Journal of Reward Deficiency Syndrome and Addiction Science, 2016
N-methyl-D-aspartate (NMDA) receptors are mainly involved in opioid addiction and are highly expressed in the brain reward pathway. Presence of GluN3A subunit in the composition of NMDA receptor decreases conductance of receptor channel. Opioid administration may change the expression pattern of NMDA receptor subunits. Here we have investigated the mRNA expression alterations of GluN3A subunit of the NMDA receptor in the rat brain after acute and chronic morphine administration. Male Wistar rats received chronic intraperitoneal injections of escalating doses of morphine twice daily for 6 days. Control animals received saline instead of morphine with the same protocol. Two other groups received acute single dose of morphine (30 mg/kg) or saline, respectively. The mRNA expression of GluN3A subunit of NMDA receptor in prefrontal cortex, hippocampus, striatum, and nucleus accumbens was evaluated using real-time PCR method. The mRNA expression level of GluN3A subunit was significantly increased (1.5 fold) in prefrontal cortex in chronic morphine administered rats compared to control group. No statistically significant difference was observed between control and chronic morphine treated rats in other sites of the brain. In acute morphine administered animals, no significant difference was observed in GluN3A subunit expression in evaluated sites of the brain compared to the control group. It is concluded that chronic morphine administration leads to the up-regulation of GluN3A subunit of NMDA receptor in prefrontal cortex. Involvement of this alteration in features of opioid addiction needs to be further studies in the future.
Physiology and Pharmacology, 2015
Introduction: Morphine withdrawal syndrome is mediated via several central and peripheral neurological pathways. In the present study we investigated the role of N- methyl-D aspartic acid (NMDA) glutamate receptor on naloxone-induced withdrawal syndrome in morphine-conditioned mice. Materials and Methods: We designed two separate experiments. In experiment one, 30 male NMRI mice were divided into 5 groups, pretreated with memantine (0.1, 1 and 5 mg/kg; I.P.) followed by morphine-dependence period for 3 days. In the other experiment, 48 male NMRI mice distributed into 8 groups, pretreated with intra- accumbens (IAc) memantine (1 and 5 µg/animal) within the right, left and both side of nucleus accumbens (RNAcc, LNAcc and BNAcc) followed by I.P. morphine- dependence (3 days). On day 4, in both experiments, morphine was injected into mice, followed by naloxone. Then naloxone-induced total jumping count, jump height and defecation in morphine-conditioned mice were recorded for 30 min. Re...