Mechanism Of Morphine Dependence Research Articles

JWA regulates chronic morphine dependence via the delta opioid receptor

Opioid dependence is correlated with the adaptive changes at the cellular level following chronic opioid use, and believed to be the main cause for the relapse of drug taking behavior of addicts. Despite decades of intensive studies, the underlying mechanisms of morphine dependence are still unclear. Here, we present evidence that JWA was induced by chronic morphine treatment in specific brain regions, and knockdown of JWA expression significantly reduced the withdrawal response to chronic morphine treatment in rats. We further demonstrated that the morphine induced DOR expression, while activation of DARPP-32 and MAP kinase was suppressed by JWA knockdown. Through an in vitro cell model of chronic morphine exposure, we also found that JWA is required for maintaining the stability of DOR via the ubiquitin–proteasome pathway. These observations suggest that JWA is directly involved in the regulation of chronic morphine dependence.

Chronic morphine administration induces over-expression of aldolase C with reduction of CREB phosphorylation in the mouse hippocampus

In recent studies, alterations in the activity and expression of metabolic enzymes, such as those involved in glycolysis, have been detected in morphine-dependent patients and animals. Increasing evidence demonstrates that the hippocampus is an important brain region associated with morphine dependence, but the molecular events occurring in the hippocampus following chronic exposure to morphine are poorly understood. Aldolase C is the brain-specific isoform of fructose-1, 6-bisphosphate aldolase which is a glycolytic enzyme catalyzing reactions in the glycolytic, gluconeogenic, and fructose metabolic pathways. Using Western blot and immunofluorescence assays, we found the expression of aldolase C was markedly increased in the mouse hippocampus following chronic morphine treatment. Naloxone pretreatment before morphine administration suppressed withdrawal jumping, weight loss, and overexpression of aldolase C. CREB is a transcription factor regulated through phosphorylation on Ser133, which is known to play a key role in the mechanism of morphine dependence. When detecting the expression of phosphorylated CREB (p-CREB) in the mouse hippocampus using Western blot and immunohistochemistry, we found CREB phosphorylation was clearly decreased following chronic morphine treatment. Interestingly, laser-confocal microscopy showed that overexpression of aldolase C in mouse hippocampal neurons was concomitant with the decreased immunoreactivity of p-CREB. The results suggest potential links between the morphine-induced alteration of aldolase C and the regulation of CREB phosphorylation, a possible mechanism of morphine dependence.

Morphine-Induced Changes of Adenylate and Guanylate Cyclase in Locus Ceruleus, Periaqueductal Gray, and Substantia Nigra in Rats

Objectives: To observe the changes of adenylate cyclase (AC) and guanylate cyclase (GC) in the cerebral regions including the locus ceruleus, periaqueductal gray, and substantia nigra in rats that were physiologically dependent on morphine. We also investigated the relationship of enzymatic changes in these cerebral regions to the mechanism of morphine dependence. Methods: A morphine-dependent rat model was established and withdrawal symptoms evaluated. Enzyme histochemistry was used to detect the variations of AC and GC in cerebral regions. Results: Compared to controls, AC and GC significantly increased in morphine-dependent groups. Comparisons of four different morphine-dependent groups also showed AC and GC significantly differed at weeks 1, 2, 4, and 8. Conclusions: Results found that the content of AC and GC increased in these cerebral regions in rats that demonstrated morphine dependence and appeared to be closely linked to increases in AC and GC activity.

Lack of cyclic AMP-specific phosphodiesterase 4 activation during naloxone-precipitated morphine withdrawal in rats

Intracellular cyclic AMP regulation systems play an important role in the mechanisms of morphine dependence and withdrawal. In the present study, to clarify the involvement of phosphodiesterase (PDE) 4, degradation enzyme of cyclic AMP in morphine dependence and withdrawal we investigated the activities of PDE4 after naloxone-precipitation in single morphine treatment and repeated morphine treatment (morphine-dependence) rats. Naloxone (5 mg/kg, s.c.) challenge caused a significant withdrawal signs such as jumping in morphine-dependent rats following repeated treatment with morphine (4, 8, 12, and 16 mg/kg, twice a day for 4 days), but not in single morphine-treated rats (16 mg/kg, single). Naloxone challenge caused an increase in PDE4 activities in the brain of rats treated with single morphine in connection with the elevation of brain cyclic AMP. In contrast, increase in the PDE4 activities was not caused by naloxone challenge in all brain regions of morphine-dependent rats, although brain cyclic AMP was significantly increased. These results suggest that the lack of PDE4 activation leading to remarkable elevation of cyclic AMP is involved in naloxone-precipitated morphine withdrawal symptoms.

Acute and Chronic Effects of Nitrendipine on Naloxone Precipitated Morphine Withdrawal in Mice

There is growing evidence indicating that neuronal calcium channels play an important role in the mechanism of morphine dependence. In this study, the effects of acute and chronic administration of nitrendipine on naloxone precipitated morphine withdrawal signs were investigated. Mice were rendered dependent to morphine by subcutaneous injection of morphine over a period of 5 days. In chronic studies, nitrendipine (25 and 50 mg/kg, i.p.), or vehicle injections were given once a day during the morphine treatment, and the last injection of nitrendipine was given 24 h before the morphine withdrawal. For acute studies, nitrendipine (25 and 50 mg/kg, i.p.) was given 1 h after the last dose of morphine (1 h before naloxone). A single injection of nitrendipine at 25 mg/kg was ineffective in blocking most signs of morphine withdrawal, however, at 50 mg/kg nitrendipine blocked signs such as hair raising, sniffing, diarrhea and number of jumping. The concurrent injections of nitrendipine with morphine prevented most signs of morphine withdrawal. In agreement with previous findings, these results suggest that alterations in voltage-sensi tive calcium channels play a role in the adaptations that occur on chronic treatment with morphine.

The mechanisms of morphine dependence and it's withdrawal syndrome: study in mutant mice

To investigate the involvement of catecholamines and/or the cyclic AMP (cAMP) systems in the development of drug dependence, we examined whether morphine dependence was developed in tyrosine hydroxylase (TH) heterozygous (TH+/-) and cAMP response element binding protein (CREB) binding protein (CBP) heterozygous (CBP+/-) mice. Morphine (10 mg/kg) induced place preference in the wild-type mice. In the TH+/- and CBP+/- mice, however, we could not find any morphine-induced place preference. When the wild-type mice pretreated with morphine (10 mg/kg) twice a day for 5 days were challenged with naloxone (5 mg/kg), they showed increased numbers of jumping, rearing and forepaw tremor as a sign of withdrawal symptom and increased level of cAMP in the thalamus/hypothalamus, but not in the striatum. However, increased numbers of jumping and forepaw tremor in the TH+/- and CBP+/- mice and increased level of cAMP in the thalamus/hypothalamus of TH+/- mice were not observed. These results suggest that catecholamines and CBP are involved in the development of morphine dependence, and that some changes in the catecholaminergic and/or cAMP system induced by repeated morphine treatment play an important role in the addiction of morphine.

Alterations of dopaminergic neurotransmission after chronic morphine treatment: Pre- and postjunctional studies in striatal tissue

Repeated morphine administration reversed the acute effects of morphine in rats, e.g. catalepsy and akinesia, and induced symptoms suggesting an activation of dopaminergic mechanisms. In morphine-withdrawn rats, the potency or intrinsic activity of dopamine in stimulating the synthesis of cyclic AMP in striatal homogenates was not significantly altered. However, the K+-induced release of 14C-dopamine from striatal slices of morphine-withdrawn rats was significantly increased, compared with that from striatal slices of saline-treated controls. The results suggest that chronic morphine administration to rats increases the dopaminergic neurotransmission in brain by a pre-synaptic (prejunctional) mechanism, probably reflecting some kind of adaptation to the acute morphine action, which decreases the dopaminergic neurotransmission. The nigro-straital dopaminergic system, therefore, seems to be a good model to study acute morphine actions and mechanisms of morphine dependence at the cellular level.

21) - Studies on the mechanism of morphine dependence -- An attempt to isolate and purify the morphine receptor --

21) - Studies on the mechanism of morphine dependence -- An attempt to isolate and purify the morphine receptor --