Signs Of Morphine Withdrawal Syndrome Research Articles

Antidrug effects of GTS201 dipeptide, an imitation of the second bird BDNF, in morphine-addicted rats

BACKGROUND: The V.V. Zakusov Research Institute of Pharmacology developed hybrid digital sensors for the first, second, and fourth BDNF patches (GSB-214, GTSB-201, and GSB-106, respectively). When tested in vitro, on an oxidative stress model, in the culture of hippocampal neurons NT-22, the compound GTS201 (hexamethylenediamide bis-hexanoyl-seryl-lys), a simulator of the 2nd series of BDNF, activates the TrkB spy receptor and MAPK/Erk kinase pathway but does not affect the PI3K/Akt signature pathway and has neuroprotective activity similar to BDNF.
 AIM: To study the effect of GTS-201 dipeptide on the behavior of laboratory white rats during the formation of their dependency state and morphine withdrawal syndrome.
 MATERIALS AND METHODS: Morphine dependence in rats was developed due to administration of morphine in a doses escalation manner ranging from 10 to 20 mg/kg twice daily at 8-h intervals for 5 days. GTS-201 was given in 1- or 5-mg/kg doses for once in 30 minutes before morphine on the 5th day of the experiment or daily (in one of the groups) for 5 days in the morning 30 minutes before morphine administration. On the 5th day of the experiment, animals were tested for the presence of specific signs of morphine withdrawal syndrome in an open field for 5 minutes. Four experimental groups were formed: group 1 morphine hr. + naloxone (active control group); group 2 morphine hr. + GTS-201 (1) + naloxone; group 3 morphine hr. + GTS-201 (5) + naloxone; and group 4 morphine hr. + GTS-201 (1 5) + naloxone. Designations: hr. morphine administration within 5 days; (1) and (5) doses of substances in mg/kg, (1 5) chronic administration of the peptide for 5 days.
 RESULTS: When studying the effect of GTS-201 dipeptide on behavioral, somatic, and neurological markers of animal behavior after morphine withdrawal, significant changes in the severity of individual signs of withdrawal syndrome were noted. Manifestations of diarrhea were significantly decreased in all groups of animals injected with the peptide. In animals from group 3, morphine hr. + GTS201 (5) + naloxone showed the maximum effect: diarrhea was decreased by 71.0% (p 0.001), convulsions were decreased by 83.3 % (p 0.05), running was decreased by 71.4% (p 0.01), and vocalization was decreased by 62.5% (p 0.05). GTS-201, administered at a dose of 1 mg/kg once, eliminated the appearance of escape attempts in group 2, but the peptide at the same dose completely blocked convulsive reactions in rats in group 4. Despite significant changes in individual indicators, the total index (of morphine withdrawal syndrome for groups chronically injected with morphine) did not change statistically significantly compared with group 1 of active control. In the control group, its value in points was 7.3 0.36 (100%), whereas in groups 24, it ranged from 6.2 (84.9%) to 6.5 (89.0%; p 0.05).
 CONCLUSIONS: It is assumed that the antiaddictive dipeptide activity of GTS-201 is mediated by activation of these receptors and markers/the Erk-kinase signaling pathway, which does not exclude the involvement of opioid receptor mechanisms in the implementation of the observed behavioral phenomena.

Relief of Morphine Withdrawal Symptoms by Japanese Sake Yeast Supplement (Saccharomyces cerevisiae sake) Through Adenosine A1 Receptor Activation in Mice

Background: Morphine withdrawal syndrome is often treated with chemical drugs; however, these drugs can have concerning side effects. Some natural substances might offer safer alternatives for managing withdrawal symptoms. The neuroprotective activity of the adenosine A1 receptor (A1R) in the central nervous system (CNS) has been mentioned before. As a novel natural agent, Japanese sake yeast is enriched with adenosine analogs. Objectives: As the first report, the present study was designed to evaluate the effects of the Japanese sake yeast supplement against the excitatory signs of morphine withdrawal syndrome in mice. Methods: Mice were treated orally (gavage) with sake yeast at doses of 100, 200, and 300 mg kg-1 once daily for a week. Furthermore, during the last 3 days of receiving sake yeast, the animals were made physically dependent on morphine by being given twice-daily subcutaneous injections of increasing doses of morphine (30 - 90 mg/kg) for 3 consecutive days. The withdrawal syndrome was induced in animals through the intraperitoneal (i.p.) administration of naloxone (3 mg kg-1) or was elicited spontaneously. After the examination of withdrawal signs, the animals were decapitated, and their brains were prepared for histopathology. Results: Sake yeast alleviated the intensity of ptosis, piloerection, diarrhea, irritability, and tremor during the two withdrawal syndrome protocols (P

Circadian rhythm influences naloxone induced morphine withdrawal and neuronal activity of lateral paragigantocellularis nucleus

Investigations have shown that the circadian rhythm can affect the mechanisms associated with drug dependence. In this regard, we sought to assess the negative consequence of morphine withdrawal syndrome on conditioned place aversion (CPA) and lateral paragigantocellularis (LPGi) neuronal activity in morphine-dependent rats during light (8:00−12:00) and dark (20:00−24:00) cycles. Male Wistar rats (250−300 g) were received 10 mg/kg morphine or its vehicle (Saline, 2 mL/kg/12 h, s.c.) in 13 consecutive days for behavioral assessment tests. Then, naloxone-induced conditioned place aversion and physical signs of withdrawal syndrome were evaluated during light and dark cycles. In contrast to the behavioral part, we performed in vivo extracellular single-unit recording for investigating the neural response of LPGi to naloxone in morphine-dependent rats on day 10 of morphine/saline exposure. Results showed that naloxone induced conditioned place aversion in both light and dark cycles, but the CPA score during the light cycle was larger. Moreover, the intensity of physical signs of morphine withdrawal syndrome was more severe during the light cycle (rest phase) compare to the dark one. In electrophysiological experiments, results indicated that naloxone evoked both excitatory and inhibitory responses in LPGi neurons and the incremental effect of naloxone on LPGi activity was stronger in the light cycle. Also, the neurons with the excitatory response exhibited higher baseline activity in the dark cycle, but the neurons with the inhibitory response showed higher baseline activity in the light cycle. Interestingly, the baseline firing rate of neurons recorded in the light cycle was significantly different in response (excitatory/inhibitory) -dependent manner. We concluded that naloxone-induced changes in LPGi cellular activity and behaviors of morphine-dependent rats can be affected by circadian rhythm and the internal clock.

Peptide Mimetic of BDNF Loop 4 Blocks Behavioral Signs of Morphine Withdrawal Syndrome and Prevents the Increase in ΔFosB Level in the Striatum of Rats.

Activity of compound GSB-106, a low-molecular mimetic of loop 4 of the brain neurotrophic factor (BDNF), was studied in experimental morphine withdrawal syndrome simulated in outbred rats. Single and subchronic (5 intraperitoneal injections) administration of GSB-106 in a dose of 0.1 mg/kg significantly reduced the total index of morphine withdrawal syndrome by 55.2 and 45.6%, respectively. GSB-106 reduced the severity of some behavioral signs (piloerection, gnashing of teeth, wet-dog shaking, and runaway attempts), but had no effect on mechanical allodynia formed in the rats with dependence. Subchronic treatment with GSB-106 prevented the increase in the content of ΔFosB (product of early response gene) in the striatum induced by morphine withdrawal. The results confirmed the concept on the involvement of neurotrophins, specifically BDNF and its analogs, in the mechanisms associated with the formation of opiate dependence.

An Experimental Study of Ethanolic Extract of Myristica fragrans in Morphine Dependence

Objective: To evaluate the role of ethanolic extract of Myristica fragrans in morphine dependence. Methods: Wistar albino rats were made moderate and severe grade morphine dependence by administering morphine sulphate in dose of 10 mg /kg (i.p.), twice daily for 4 days and by increasing doses of 10-100 mg/kg (i.p.), twice daily for 7 days, respectively. The signs of spontaneous abstinence syndrome were recorded 12 hours in both studies after the last dose of morphine for 30 minutes and quantified by ‘counted’ and ‘checked’ signs. Ethanolic extract of Myristica fragrans (EEMF) was administered p.o. in different regimen: (a) EEMF 200 mg/kg along with morphine twice daily for 4 days and 7 days in moderately and severely induced morphine dependence group, respectively. (b) EEMF 400 mg/kg (p.o.), single dose10 hours after the last dose of morphine in both moderately and severely induced morphine dependence rats.Result: Oral administration of EEMF in both study groups caused significant reduction in the scores of counted and checked signs of morphine abstinence syndrome as compared to active morphine control group. The reduction was significantly more in regimen ‘a’ as compared to regimen ‘b’.Conclusion: Ethanolic extract of Myristica fragrans seed significantly reduced the mean scores of various’counted signs’ and ‘checked signs’ of morphine withdrawal syndrome and might give a solution as a substitute therapy in morphine de-addiction.Bangladesh Journal of Medical Science Vol.15(2) 2016 p.224-229

Dendrosomal Curcumin Nanoformulation Attenuates Naloxone Precipitated Morphine Withdrawal Signs in Rats

Curcuminis known to possess a wide range of therapeutic and pharmacological properties as anti-inflammatory, antitumor, antinociceptive and neuroprotective agents. The recent achievements of nanotechnology illustrate a novel approach in treatment of drug abuse and addiction. Curcumin as a new candidate can be exploited for drug abuse treatment, but its low bioavailability and water solubility is the most important obstacles and limits its application. Here, curcumin was efficiently encapsulated in a nontoxic nanocarrier, labeled dendrosome, to overcome these problems. The present study is designed to investigate the effect of intraperitoneal (i.p.) administration of Dendrosomal curcumin (DNC) on the behavioral signs of morphine withdrawal syndrome. Male Wistar rats weighing 250-300 g were rendered dependent on morphine by subcutaneous (s.c.) administration of morphine sulfate (6, 16, 26, 36, 46, 56 and 66 mg/kg, 2 ml/kg) at set intervals of 24 h for 7 days. The animals received i.p. administration of DNC(12.5 mg/kg) immediately after each morphine injection. On day 8, naloxone (2 mg/ kg, i.p.) was injected and behavioral signs of morphine withdrawal were assessed for 25 min. Our results show that i.p. injection of DNC significantly decreases naloxone precipitated morphine withdrawal signs. The present study indicates that intraperitoneal administration of Dendrosomal curcumin exerts a significant effect on morphine dependency in rats.

The effect of vitamin C on morphine self-administration in rats

Background:Recent studies have shown that addiction may be caused by abnormality of neurotransmission in the brain. Two neurotransmitters that involve into morphine addiction are dopamine and glutamate. The glutamatergic and dopaminergic systems are also involved in morphine tolerance and morphine withdrawal syndrome signs. Ascorbic acid (AA), as the antioxidant releases from the glutamatergic neurons, modulates the action of the dopamine and glutamate systems. In this study, the effect of AA on morphine self-administration and morphine withdrawal symptoms has been investigated.Materials and Methods:Male Wistar rats (250 - 300g) were anesthetized with ketamine (11%) and xailazine (15%). The cannula was inserted into the right jugular vein, and it was fixed subcutaneously on the skull. After surgery the animals were placed in individual home cages, and they were allowed to recover from the operation for five days, before the test. The animals were subjected to self-administration morphine for12 consecutive days, two-hour/sessions. The number of infusions and number of active and passive lever pressings were recorded.Results:An intra peritoneal injection of Ascorbic acid (AA) (400 mg/kg, i.p.), 30 minutes before morphine self-administration, produced a significant decrease in 12 days self-administration of morphine and withdrawal syndrome signs (P < 0.05). The morphine withdrawal signs (MWS) were recorded after naloxone precipitation, which decreased significantly with the injection of AA (400,700mg/kg), (<0.05). The number of self-infusions and the number of active lever pressings had significantly decreased after AA injection (P < 0.05).Conclusion:The chronic administration of AA may prevent the development of tolerance and physical dependence on morphine self-administration via the glutamatergic system.

Orexin type 1 receptor antagonism in Lateral Paragigantocellularis nucleus attenuates naloxone precipitated morphine withdrawal symptoms in rats

Orexin neuropeptides have been reported to be involved in morphine induced physical dependence and withdrawal. The Lateral Paragigantocellularis (LPGi) is a key brain region implicated in the expression of somatic signs of morphine withdrawal syndrome. Orexin A and orexin type 1 receptor have been found in LPGi neurons but the effect of orexin on the expression of opiate dependence and withdrawal phenomena in this brain structure has not been studied yet. In this study, the effect of intra-LPGi administration of SB 334867 (selective orexin type 1 receptor antagonist) on the behavioral signs of morphine withdrawal syndrome was investigated. Male Wistar rats weighing 250–300g were rendered dependent by adding morphine sulfate (Temad, Tehran, Iran) to their drinking water in increasing concentrations of 0.1, 0.2, 0.3mg/ml for every 48h and 0.4mg/ml during the next 15 days. Behavioral signs of morphine withdrawal were assessed in a transparent cylindrical Plexiglas test chamber (30cm diameter, 50cm height) for 25min. One group of animals received intra-LPGi injection of SB 334867 (0.2μl, 100μM) immediately before naloxone. In the control group, SB-334867 vehicle (DMSO 1%, 0.2μl) was microinjected into LPGi. Our results indicate that intra-LPGi administration of SB 334867 significantly decreases naloxone precipitated morphine withdrawal signs. Thus, it seems that orexin might have a pivotal role in the expression of morphine withdrawal signs through affecting orexin type 1 receptor in LPGi nucleus.

Antagonism of orexin type 1 receptors in the locus coeruleus attenuates signs of naloxone-precipitated morphine withdrawal in rats

It has been shown that orexin neuropeptides contribute to morphine-induced physical dependence. The locus coeruleus (LC), which receives a dense extra-hypothalamic orexinergic projection, is a key brain region implicated in the expression of somatic signs of morphine withdrawal syndrome. The aim of the present study is to investigate the role of LC orexin type 1 receptors (OXR1) on naloxone-precipitated morphine withdrawal signs in rats. Adult male Wistar rats were rendered dependent on morphine by subcutaneous (s.c.) injection of morphine sulfate (10 mg/kg) at an interval of 12 h for 9 days. On day 10, naloxone (1 mg/kg i.p.) was injected 2 h after morphine administration. Somatic signs of withdrawal were then evaluated in a clear Plexiglas test chamber (30 cm diameter, 50 cm height) for 25 min. One group of animals received intra-LC SB-334867-A, a selective OXR1 antagonist, (100 μM, 0.2 μl) immediately before naloxone. In the control group, SB-334867-A vehicle was microinjected into the LC in the same manner. The results showed that intra-LC OXR1 receptor blockade significantly decreased the somatic signs of withdrawal including chewing, diarrhea, scratching, teeth chattering, wet-dog shake and ptosis. These results suggest that activation of OXR1 in the LC might be involved in the expression of withdrawal signs in morphine dependent rats.

Comparative pathological study of Matricaria chamomilla and Methadone effects on liver of morphine dependent rats

Addiction to opiates such as morphine is one of the major world health problems. Some reports show that Matricaria chamomilla extract contains flavonoids, which exert Benzodiazepine-like activity and inhibited the expression of abstinence syndrome in morphine-dependent animals. Objective: To determined and comparison the effect of Matricaria chamomilla extract injection on morphine withdrawal syndrome signs (MWS) in rats and pathological study of Mc and Methadone on liver of Morphine dependent Rats. Materials and Methods: 32 male rats (200-300gr) (n=8) were tested in 4 groups: saline group which was received only saline, Morphine group which was received only Morphine (10mg/kg) for 10 days, Mc group were received Mc extract (20mg/kg I.P) 30 min before Morphine administration and Methadone group. In the end of training day all groups received naloxane (5mg/kg I.P) 3hours after last injection of morphine and then the frequencies of withdrawal behavior were assessed for 30min with use of Open field test and liver pathological condition has been studied. Results: Our results show that I.P administration of MC extract dose dependently attenuates most of morphine withdrawal syndrome and no finding any liver lesion in Mc group, but Methadone has many serious pathological effects on liver, some of them potentially fatal. Conclusion: These result suggested that injection of MC extract in to the I.P is helpful for morphine withdrawal syndrome treatment and is safer than Methadone therapy.

Prevention effect of Matricaria chamomilla on withdrawal syndrome in morphine dependent rats

Addiction to opiates such as morphine is one of the major public health problems. Some reports show that Matricaria chamomilla extract contains flavonoids, which exert Benzodiazepine-like activity and inhibited the expression of abstinence syndrome in morphine-dependent animals. Objective: To determined and comparison the effect of Matricaria chamomilla extract injection on morphine withdrawal syndrome signs (MWS) in rats. Methods: 30 male rats (200-300gr) (n=6) were tested in 2 groups: control and morphine groups ( twice daily for 7 days) and divided in 4 sub groups: saline group which was received only saline and Mc group were received Mc extract (10, 20, 50mg/kg I.P) in day 7, 30 min before naloxan administration. In the end of training day all groups were received naloxane (5mg/kg I.P) 3hour after last injection of morphine and then the frequencies of withdrawal behavior were assessed for 30min.Finding: Our results show that I.P administration of MC extract dose dependently attenuates most of morphine withdrawal syndrome. Conclusion: These result suggested that injection of MC extract in to the I.P is helpful for morphine withdrawal syndrome treatment.

Electrical stimulation of nucleus raphe dorsalis changes morphine self-administration and withdrawal symptoms in rats

The involvement of antero-dorsal part of the nucleus raphe dorsalis (NRD) in motivational aspects of drug-taking behaviour during initiation of drug self-administration was investigated using a recently developed behavioural paradigm. In separate experiments animals were allowed to self-administer morphine (1 mg/kg per inf) ten consecutive daily 3-h sessions. During all morphine self-administration sessions lever-press behaviour was measured in absence of electrical stimulation of NRD, as an index of the motivational aspects involved in drug-taking behaviour. The electrical stimulation (pulse 0.5 ms, 150 μA, 20 Hz) of NRD 30 min before morphine self-administration produced a significant decrease in the initiation of morphine self-administration during all sessions (reduced number of lever-press behaviour). After the last test session, morphine withdrawal syndrome signs (wet dog shakes, jumping, writhing and diarrhoea) in the naloxone-induced behaviour were measured. Our results showed that these withdrawal syndrome signs decreased by application of electrical stimulation in NRD, in comparison with morphine groups. It is concluded that serotonergic system in the NRD might be involved in the motivational processes underlying morphine self-administration.

Evidence for a role of nitric oxide of the central nervous system in morphine abstinence syndrome.

Two potent inhibitors of nitric oxide synthase (NOS), namely, NG-nitro-L-arginine (NNA) and NG-monomethyl-L-arginine (NMMA) were administered intracerebroventricularly (i.c.v.) in morphine-dependent mice to investigate their effects on abrupt withdrawal and naltrexone-precipitated abstinence signs. Male Swiss-Webster mice were rendered dependent on morphine by subcutaneous implantation of a morphine pellet containing 75 mg of morphine base. Mice implanted with placebo pellets served as controls. NMMA or NNA administered i.c.v. had minimal effects on body weight loss and hypothermia that occur during abrupt withdrawal of morphine. When administered i.c.v., both NNA or NMMA (0.1, 1 and 10 micrograms/mouse) dose-dependently inhibited naltrexone-induced stereotyped jumping behavior in mice. I.c.v. administration of NMMA also attenuated withdrawal induced fecal pellet formation. This effect, however, was not dose-dependent. In conclusion, these results suggest that brain NO plays an important role in the expression of behavioral signs of morphine withdrawal syndrome. In addition, these results support the idea that NOS inhibitors may be potentially useful in the treatment of opioid withdrawal syndrome.

Comparative study in mice of flunitrazepam vs. diazepam on morphine withdrawal syndrome

1. 1. There is some evidence that benzodiazepine may modify the opioid withdrawal syndrome. We have investigated the effect of two different benzodiazepines, diazepam and flunitrazepam, on the morphine withdrawal syndrome experimentaly induced in mice. 2. 2. Opiate dependence has been induced by administration of morphine s.c. over a period of five days. Two hours after last morphine administration withdrawal syndrome was induced by s.c. injection of naloxone (5mg/kg). The number of jumps, wet-dog-shakes and paw tremor, and the presence or absence of ptosis, diarrhea, teeth chatering and body tremor were evaluated after naloxone injection. 3. 3. All the signs of morphine withdrawal syndrome was antagonized by flunitrazepam and diazepam, only wet-dog-shake was strongly increased by flunitrazepam.

Morphine withdrawal syndrome: Differential participation of structures located within the amygdaloid complex and striatum of the rat

The participation of amygdaloid and striatal structures in the various signs of morphine withdrawal syndrome (MWS) has been investigated using two complementary approaches: intracerebral application of naloxone in various nuclei of dependent rats and effects of various lesions and transections on systemically induced MWS. In morphine dependent rats local application of naloxone (10 μg in 0.1 μl solution) in the vicinity of either the central nucleus of the amygdala or the lateral anterior nucleus but not in adjacent amygdaloid or striatal nuclei elicited the jump sign. Diarrhea was more frequently elicited by application of naloxone in the striatum or centromedial amygdala than the basolateral parts of the complex. In contrast, there was no specific anatomical correlates to the remaining signs including wet shakes, paw tremor, teeth chattering and chewing. Bilateral electrolytic lesion of the central amygdala or combined transection of the stria terminalis and so-called ventral amygdalofugal pathway eliminated the jump without affecting the remaining signs. In contrast a large bilateral destruction of the entire striatum did not significantly affect the various signs. Bilateral transection of the stria terminalis reduced only the occurrence of the wet shakes. Also, a transection of the medial forebrain bundle considerably reduced the 3 main signs, i.e. jump, wet shakes and diarrhea. These results suggest that, in analogy to the acute actions of morphine, MWS should not be considered as a unitary phenomenon but as an ensemble of signs which probably reflect the intense activation induced by naloxone in a number of brain sites consequent to the abrupt interruption of opioid actions in a dependent animal. The significance of these results is discussed with reference to previous anatomical, biochemical and behavioural studies performed on the amygdala.