Morphine Withdrawal Symptoms Research Articles

Drepadom - a Homecare Protocol for Vaso-Occlusive Crisis for Sickle Cell Disease Patients

INTRODUCTION Vaso-occlusive crisis (VOC) is first cause of emergency room (ER) admissions and hospitalizations for sickle-cell disease (SCD) patients. Acute chest syndrome (ACS) is a complication that can occur during VOC and prolong hospitalization, and is the main cause of death in SCD patients. The PRESEV score (Bartolucci - eBioMed 2016), established by our team, allows physicians to evaluate the risk of developing ACS and is calculated upon arrival to the ER and has been validated by an international multicenter study in five different countries (PRESEV 2 - ASH 2020). During the Covid-19 pandemic, we set up a temporary system to monitor VOC patients at home using a telephone hotline and homecare services. The success of this system led to the establishment of DREPADOM, a home-care protocol for VOC management for patients with low risk of developing ACS, or who can be discharged early from the hospital, as standard care (DREPADOM - ASH 2021). Since 2021, Drepadom has been successfully running in seven hospitals in the Parisian region. DESCRIPTION OF SETTING Drepadom has two inclusion modes: 1/ Patients arriving at the ER for VOC with a PRESEV score ≤ 6 and not presenting any exclusion criteria; 2/ patients that are discharged early following hospitalization for VOC and/or ACS (after at least 3 days of hospitalization for patients with PRESEV > 6 upon ER arrival). The Drepadom homecare protocol is activated by a coordinator, who coordinates delivery of PO opioids and parenteral treatments, and a home oxygen concentrator, to the patients' home within four hours. Drepadom uses an online platform and mobile app (Link4Life), where the patient's medical record is shared to the homecare nurse who will perform house calls twice a day. During each visit, the nurse enters the patient's vitals into the app, which are monitored by an on-call SCD expert physician. The online platform also hosts a secure messaging service where nurses, doctors and coordinators can communicate in real-time regarding patient status and care, as well as an automatic alert system that is triggered when vitals fall outside of a predetermined range set by SCD experts. Patient safety is further ensured with a daily calls to the patient using a decision-making algorithm supervised by SCD experts, who arbitrate according to the evolution of the situation (stopping/continuing outpatient follow-up vs. rehospitalization). RESULTS Over a 30-month period we had 209 inclusions for 170 patients into DREPADOM. Of these, 105 were inclusions from the ER and 104 were early discharges (ED). SCD genotype distribution was 83.2% SS, 10.5% SC, and 5.8% S-bThalassemia and female to male ratio was 128:81. In both ER and ED groups, median age was 31 [27-40], 74% of patients were under hydroxyurea treatment and median homecare follow-up duration was 3 [2-4] days. No significant differences in population characteristics were found between the ER and ED groups. In the ER group, 96/105 patients (91.4%) were included with PRESEV ≤ 6. 9/105 (8.6%) patients were included with a PRESEV score >6 only in 2021 during the Covid-19 pandemic, when the ER was saturated. In the PRESEV ≤ 6 group, 9/96 (9.4%) patients were rehospitalized: 1 for ACS (PRESEV = 4), 4 for uncontrolled VOC pain, 2 for chest pain, 2 for fever/infection unrelated to VOC. In the PRESEV >6 group, 3/9 (33%) were hospitalized, one for ACS (PRESEV = 8), one for uncontrolled VOC pain and one for issues with veinous access. In the ED group, patients were hospitalized for a median of 4.5 [3-7] days before being discharged. 27 patients (26%) were included in a post-ACS context. 48/104 (46.2%) had a PRESEV ≤6, of which only 2/48 (4.2%) were rehospitalized for uncontrolled VOC pain. Of the 56/104 (53.8%) patients included with a PRESEV > 6, 8/56 (14.3%) were rehospitalized: 1 for ACS, 3 for uncontrolled VOC pain, 1 for chest pain, 1 for fever/infection unrelated to VOC, 1 for issues with veinous access, and 1 for morphine withdrawal symptoms. For both ER and ED groups, a total of 22/209 patients (11%) required rehospitalization (Figure 1), and no deaths or ICU were reported in either group. PERSPECTIVES Our results confirm that Drepadom is a successful and safe tool to reduce hospital stay for SCD patients.

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

The gut microbiome contributes to somatic morphine withdrawal behavior and implicates a TLR2 mediated mechanism

ABSTRACT The ongoing opioid epidemic has left millions of people suffering from opioid use disorder due to the over-prescription of highly addictive substances. Chronic opioid exposure leads to dependence, where the absence of the drug results in negative symptoms of withdrawal, often driving patients to continue drug use; however, few therapeutic strategies are currently available to combat the cycle of addiction and the severity of morphine withdrawal. This study investigates the microbiome as a potential therapeutic target for morphine withdrawal, as gut dysbiosis caused by morphine use has been proven to contribute to other aspects of opioid use disorders, such as tolerance. Results show that although the microbiome during morphine withdrawal trends toward recovery from morphine-induced dysbiosis, there continues to be a disruption in the alpha and beta diversity as well as the abundance of gram-positive bacteria that may still contribute to the severity of morphine withdrawal symptoms. Germ-free mice lacking the microbiome did not develop somatic withdrawal symptoms, indicating that the microbiome is necessary for the development of somatic withdrawal behavior. Notably, only TLR2 but not TLR4 whole-body knockout models display less withdrawal severity, implicating that the microbiome, through a gram-positive, TLR2 mediated mechanism, drives opioid-induced somatic withdrawal behavior.

The (–)-Borneol Effect on Addiction/Abstinence by Morphine in Mice

Opioids such as morphine are the first choice in acute and chronic pain treatment. However, they lead to addiction. Several studies have searched (i) to find a molecule that can replace morphine use or (ii) to reduce its adverse effects. This work aimed to evaluate whether (–)-Borneol [(–)-BOR], a bicyclic monoterpene, in doses of 25, 50, and 100 mg/kg (i.p.), has an antiaddictive effect on morphine (5 mg/kg, i.p.) and reduces its withdrawal symptoms precipitated by naloxone (8 mg/kg, i.p.) in Swiss mice. Furthermore, the (–)-BOR genotoxic potential was also investigated by the comet assay. The antiaddictive effect of (–)-BOR was evaluated by the conditioned preference place (CPP). The CPP was induced by morphine administration during the conditioning phase. The effects of (–)-BOR on the rewarding characteristics of morphine were tested in mice with the administration of (–)-BOR, naloxone, or vehicle (NaCl 0.9%), 30 min before morphine. This work also investigated the (–)-BOR effect on morphine withdrawal symptoms precipitated by naloxone. Morphine withdrawal symptoms were induced by administering morphine twice daily for 5 days, precipitated by naloxone administration on the sixth day. The effect of (–)-BOR on reducing morphine withdrawal symptoms was evaluated in mice that received (–)-BOR before daily morphine administration. Finally, the comet assay was performed to assess the DNA damage degree caused by the (–)-BOR (100 mg/kg, i.p.) administration. The comet assay was performed on peripheral blood taken from the tail of each animal. Cyclophosphamide (50 mg/kg, i.p.) was used to induce DNA damage. After starting the protocol, analyses were performed for 4 h (acute effect) and 24 h (repair effect). The (–)-BOR (100 mg/kg, i.p.) significantly attenuated (*** p < 0.001) the acquisition of morphine-induced CPP and reduced only the jumping behavior in the morphine withdrawal model. The best-studied dose was 100 mg/kg, being evaluated, then, in the comet assay. (–)-BOR at 100 mg/kg did not show the genotoxic effect when compared with the cyclophosphamide group (CYCLO, 50 mg/kg, i.p.) after 4 h or 24 h, a period that corresponded to the repair time of DNA fragmentation. The study showed that (–)-BOR attenuated the acquisition of CPP by morphine and made opioid withdrawal milder. In the comet assay, although (–)-BOR caused DNA damage, this damage was significantly less than the damage by CYCLO, at either 4 h or 24 h after the treatments.

The effect of 5-HT2A receptor stimulation on morphine withdrawal symptoms in mice

The effect of 5-HT2A receptor stimulation on morphine withdrawal symptoms in mice

Intranasal Leptin Prevents Opioid-Induced Respiratory Depression in Obese, Opioid Tolerant Mice

Opioid-induced respiratory depression (OIRD) is the primary cause of death associated with opioids and individuals with obesity are particularly susceptible due to comorbid obstructive sleep apnea (OSA). Repeated exposure to opioids, as in the case of pain management, results in diminished therapeutic effect and/or the need for higher doses to maintain the same effect. With limited means to address the negative impact of repeated exposure it is critical to develop drugs that prevent deaths induced by opioids without reducing beneficial analgesia or causing withdrawal symptoms. We have previously shown that intranasal (IN) leptin can reverse apneas, hypoventilation, and upper airway obstruction while enhancing analgesia following acute morphine administration. Here we hypothesize that OIRD as a result of chronic opioid use can be attenuated by administration of IN leptin without acute withdrawal while also maintaining analgesia in both lean mice and mice with diet-induced obesity (DIO). To test this hypothesis, an opioid tolerance protocol was developed and a model of OIRD in mice chronically receiving morphine and tolerant to morphine analgesia was established. Subsequently, sleep and breathing were recorded by barometric plethysmography following acute or chronic administration of IN leptin. Operant behavioral assays and Pavlovian conditioning procedures were used to determine the impact of IN leptin on the analgesic efficacy of morphine and opioid withdrawal symptoms. Acute administration of IN leptin significantly attenuated OIRD in DIO male mice decreasing the apnea index by 58.9% and apnea time by 60.1%. In lean mice leptin was ineffective. Chronic IN leptin induced > 50% reduction in the OIRD in morphine tolerant DIO male mice suggesting the protective effect of leptin remained after the two-week treatment. Morphine caused a complete loss of temperature aversion which was not reduced by intranasal leptin indicating IN leptin does not decrease morphine analgesia. IN leptin did not modify naloxone conditional place aversion or naloxone withdrawal symptoms, suggesting that IN treatment does not induce opioid withdrawal. We conclude that IN leptin is ineffective in lean mice but prevents OIRD in obesity by increasing hypercapnic sensitivity when leptin resistance at the BBB is present without reducing analgesia or inducing withdrawal. NIH R61HL156240; NIH R01HL128970; NIH R41DA056239 This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

The effect of acute topiramate administration on morphine withdrawal syndrome and brain-derived neurotrophic factor in central nervous system

ABSTRACT Objectives Nucleus accumbens plays an important role in opioid addiction. Topiramate, increases postsynaptic gamma-aminobutyric acid receptor activity and antagonizes glutamatergic activity. Brain-derived neurotrophic factor (BDNF), which plays a key role in synaptic plasticity, is produced from proBDNF. The aim of this study is to investigate the effects of 100 µM topiramate applied into the lateral ventricle or nucleus accumbens on naloxone-induced morphine withdrawal and the BDNF/proBDNF ratio in the frontal cortex. Methods In the study, 36 adult male Wistar rats weighing 250–350 g were used. Morphine dependence was created with morphine pellets following guide cannula implantations. Withdrawal findings were evaluated in naloxone-induced morphine withdrawal syndrome following topiramate administration, and locomotor activity measurements were performed simultaneously. The brains of sacrificed animals were removed for determination of BDNF/proBDNF ratio. Results Topiramate administered by either route significantly suppressed the number of jumps in morphine withdrawal. Topiramate applied into the nucleus accumbens significantly reduced stereotypical behavior in morphine withdrawal, but did not cause any changes in other locomotor activity behaviors. Topiramate applied into the lateral ventricle significantly decreased the BDNF/proBDNF ratio, whereas administered into the nucleus accumbens significantly increased this ratio. Conclusion The findings of this study indicate that topiramate administered into the lateral ventricle and nucleus accumbens reduces naloxone-induced morphine withdrawal symptoms, stereotypical locomotor activity, and changes the BDNF/proBDNF ratio.

Nicorandil reduces morphine withdrawal symptoms, potentiates morphine antinociception, and ameliorates liver fibrosis in rats

AimsChronic liver disease (CLD) is a serious medical condition affecting patients globally and pain management poses a unique challenge. ATP-sensitive potassium channels (KATP) are expressed in nociceptive neurons and hepatic cells. We tested the hypothesis whether morphine and nicorandil, KATP channel opener, alone and in combination possess hepatoprotective, antinociceptive effect and alter morphine physical dependence. Main methodsIntraperitoneal injection (i.p.) of carbon tetrachloride (CCl4) induced liver fibrosis in male Wistar rats. Nicorandil (15 mg/kg/day) was administered per os for two weeks. Morphine (3.8, 5, 10 mg/kg, i.p.) was administered prior to antinociception testing in tail flick and formalin tests. Morphine physical dependence following naloxone injection, fibrotic, oxidative stress markers, and liver histopathology were assessed. Key findingsMorphine alone, produced insignificant changes of serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), hyaluronic acid (HA), hepatic hydroxyproline (Hyp), malondialdehyde (MDA), and superoxide dismutase (SOD) levels and exerted significant antinociception in the pain models. Nicorandil alone protected against liver damage (decreased serum ALT, AST, HA, hepatic Hyp, MDA, increased SOD levels, improved fibrosis scores). Nicorandil/morphine combination produced remarkable hepatoprotection and persistent analgesia compared to morphine alone as evidenced by reduced (EC50) of morphine. Nicorandil augmented morphine analgesia and markedly decreased withdrawal signs in morphine-dependent rats. SignificanceThe data showed for the first time, the hepatoprotection and augmented antinociception mediated by nicorandil/morphine combination in liver fibrosis via antioxidant and antifibrotic mechanisms. Nicorandil ameliorated withdrawal signs in morphine dependence in CLD. Thus, combining nicorandil/morphine provides a novel treatment strategy to ameliorate hepatic injury, potentiate antinociception and overcome morphine-induced physical dependence in liver fibrosis.

The Effects of Bupropion and Varenicline on Morphine Withdrawal Syndrome in Rats

Objective: Opioid dependence is a chronic and complex disorder characterized by relapse and remission. Chronic administration of morphine causes symptoms of physical and psychological dependence. The purpose of the present study was to investigate the effect of anti-addictive drugs such as bupropion and varenicline on morphine dependence and naloxone precipitated withdrawal syndrome in a rat model. Materials and Methods: To assess the physical dependence of morphine, Wistar albino rats were intraperitoneal (i.p.) administered increasing doses of morphine twice daily for 5 days, 4 hours after a single dose of morphine on day 6, and 15 minutes before subcutaneous (s.c.) naloxone (2 mg/kg, s.c.) administration to elicit withdrawal symptoms. Physical dependence was evaluated by giving intraperitoneal bupropion (5, 10 and 20 mg/kg, i.p.) and varenicline (0.5. 1 and 2 mg/kg, s.c) for 15 minutes. Results: The morphine-dependent rats had significantly more withdrawal symptoms than naive control rats. The results demonstrated administration of bupropion and varenicline during induction of morphine dependence attenuated the most of the severity of withdrawal symptoms. Co-administration of bupropion reduced withdrawal symptoms such as jumping, wet dog shaking, weight loss and total withdrawal symptoms. Co-administration of varenicline was found to be effective on withdrawal symptoms such as bupropion, but had no effect on weight loss. Conclusion: These outcomes provide preliminary data that bupropion and varenicline could be used as a candidate drugs to attenuate morphine withdrawal symptoms.

Effects of linagliptin on morphine dependence in larval zebrafish (Danio rerio)

Abstract Drug addiction is a chronic, recurrent disease of the central nervous system that leads to the development of comorbidities and premature death. Despite extensive scientific research concerning addiction, no effective method of addiction pharmacotherapy has been known so far. Glucagon-like peptide 1 has been suggested to play a role in the rewarding effect of addictive drugs. Linagliptin is a selective dipeptidyl peptidase-4 inhibitor that suppresses the rapid degradation of endogenous glucagon-like peptide-1. In clinical practice, it is used as an antidiabetic drug, but recent studies have confirmed its role in the activity of the central nervous system. This pilot study was conducted to ascertain whether linagliptin might influence morphine dependence – a locomotor activity test was carried out to assess the intensity of morphine withdrawal symptom. The obtained results clearly confirmed that linagliptin (0.01 and 0.1 mM) reduced the locomotor activity in morphine-dependent larval zebrafish. The undertaken experiments clearly indicates that linagliptin is involved in the addictive effects of morphine, thus, further studies on higher organisms should be carried out.

Thymol Nanopolymer Synthesis and Its Effects on Morphine Withdrawal Syndrome in Comparison With Clonidine in Rats.

The drug delivery system is valuable in the treatment of the disease. A nanopolymer as a thymol and Thymbra spicata release system was synthesized and its effects on morphine withdrawal syndrome in comparison with clonidine in rats were studied. The nanopolymer was characterized by different methods, namely, IR, HNMR, CNMR, GPC, DLS, and AFM. Thymol in T. spicata extract was assessed. The loading and release rate of thymol and T. spicata extract on the nanopolymer were evaluated by HPLC. The median lethal dose (LD50) of the T. spicata extract, thymol, extract nanopolymer, and thymol nanopolymer was studied. The frequency of jumping, rearing, and teeth chattering in naloxone-induced morphine withdrawal syndrome was studied. Synthesized nanopolymer was desirable as a carrier for the drug. The loaded amount of extract and thymol on nanopolymer was estimated 55 ± 3.2% and 48 ± 2.6% and the drug released was 71 and 68%, respectively. LD50 of the T. spicata extract, thymol, extract nanopolymer, and thymol nanopolymer was 975, 580, 1,250, and 650 mg/kg, respectively. This study showed that thymol nanopolymer was more effective than clonidine to reduce the frequency of morphine withdrawal symptoms. Our results suggest that T. spicata extract, thymol, extract nanopolymer, and thymol nanopolymer are mighty in reducing the narcotic withdrawal signs. The mechanism of action and therapeutic potential is maybe similar to clonidine.

Influence of Selective Dopamine Agonist Ropinirole on Conditioned Place Preference and Somatic Signs of Morphine Withdrawal in Rats.

The underlying mechanism of dependence and rewarding effects of morphine is imperative to understand. The primary aim of this study was to investigate whether ropinirole D2/3 agonist affects the rewarding and reinforcing properties of morphine-induced conditioned place preference (CPP) and withdrawal syndromes in rats. On day one, the animals were randomly divided to conduct the pre-test. The morphine (10 mg/kg, i.p.) and/or saline was administered on alternate days in an 8-day CPP session. On day 10, 15 min prior to the post-conditioning test (expression), a single dose of ropinirole (1, 2, and 5 mg/kg, i.p.) was given to rats. In extinction session, ropinirole was injected daily, and CPP was extinguished by repeated testing, with intervals of 3 days. Finally, reinstatement was assessed by administering ropinirole (1, 2, and 5 mg/kg) 15 min before the morphine injection. Morphine dependence was developed by administering increasing doses of morphine (10–50 mg/kg, i.p.). To assess withdrawal symptoms, ropinirole (1, 2, and 5 mg/kg) was injected 15 min before naloxone (2 mg/kg, s.c.) administration. The present study confirms that ropinirole attenuates expression and reinstatement of CPP, while it precipitates the extinction of morphine-induced CPP. Naloxone-precipitated morphine withdrawal symptoms, including wet dog shakes and weight loss, were attenuated although jumping was increased by a single ropinirole injection. Thus, ropinirole was influential in attenuating expression, reducing drug seeking and weakening reinstatement via the dopaminergic system. These findings show that ropinirole might affect neuro-adaptive changes related to dependence.

Administration of Orexin-A into the Rat Thalamic Paraventricular Nucleus Enhances the Naloxone Induced Morphine Withdrawal.

Orexin neuropeptides are implicated in physical dependence on opioids and expression of withdrawal symptoms in drug abuse. The paraventricular nucleus of the midline thalamus (PVT) has a high expression of orexin receptors. The current research studied the effect of orexin-A in the PVT area on the development of behavioral indices produced by morphine withdrawal in rats. Male Wistar rats weighing 250-300 gr were utilised. To produce drug dependence, morphine (6, 16, 26, 36, 46, 56, and 66 mg/kg, 2 ml/kg) was injected at an interval of 24 hrs for 7 days. To assess the involvement of the orexin in withdrawal syndrome, we injected orexin-A (100 μM, 200 nl) into the PVT for 7 days before each morphine injection. On the day after the last injection of morphine, naloxone (2.5 mg/kg, i.p.) was injected to elicit the morphine withdrawal symptoms which were observed and checked for 25 min. The results of the current research showed that the orexin-A in PVT enhances the severity of behavioral symptoms prompted by the injection of naloxone in drug-dependent rats. These observations imply that targeting the orexin receptors in PVT might exhibit a new therapeutic strategy for the future treatment of dependence.

Comparison of an Addictive Potential of μ-Opioid Receptor Agonists with G Protein Bias: Behavioral and Molecular Modeling Studies.

Among different approaches to the search for novel—safer and less addictive—opioid analgesics, biased agonism has received the most attention in recent years. Some μ-opioid receptor agonists with G protein bias, including SR compounds, were proposed to induce diminished side effects. However, in many aspects, behavioral effects of those compounds, as well as the mechanisms underlying differences in their action, remain unexplored. Here, we aimed to evaluate the effects of SR-14968 and SR-17018, highly G protein-biased opioid agonists, on antinociception, motor activity and addiction-like behaviors in C57BL/6J mice. The obtained results showed that the compounds induce strong and dose-dependent antinociception. SR-14968 causes high, and SR-17018 much lower, locomotor activity. Both agonists develop reward-associated behavior and physical dependence. The compounds also cause antinociceptive tolerance, however, developing more slowly when compared to morphine. Interestingly, SR compounds, in particular SR-17018, slow down the development of antinociceptive tolerance to morphine and inhibit some symptoms of morphine withdrawal. Therefore, our results indicate that SR agonists possess rewarding and addictive properties, but can positively modulate some symptoms of morphine dependence. Next, we have compared behavioral effects of SR-compounds and PZM21 and searched for a relationship to the substantial differences in molecular interactions that these compounds form with the µ-opioid receptor.

Chemical composition of Zhumeria majdae essential oil and its effects on the expression of morphine withdrawal syndrome and tolerance to the anticonvulsant effect of morphine on pentylenetetrazole-induced seizures in mice

Regarding the proven anticonvulsant effect of Zhumeria majdae essential oil (ZMEO) in previous studies we were prompted to investigate the ZMEO effects on the tolerance to the anticonvulsant effects of morphine and the morphine withdrawal syndrome. Tolerance to the morphine anticonvulsant effect was induced in mice by subcutaneous injection of 2.5 mg/kg of morphine for 4 days. Subsequent doses of ZMEO (20 mg/kg) were used to study the expression and development of morphine tolerance. Clonidine was used as the standard drug to inhibit the morphine withdrawal syndrome symptoms. To study the ZMEO effect on withdrawal syndrome, mice received appropriate morphine values for 4 days and on the fifth day, 60 min before administration of naloxone. The effective dose of ZMEO was determined and the number of jumps, stands and changes in the dry stool weight, as symptoms of withdrawal syndrome were evaluated. The dose of 20 mg/kg of ZMEO decreased the tolerance in development and expression groups significantly. Counting the number of jumping, standing and defecation were assessed 30 min after morphine and 1 h after the vehicle and clonidine. The dose of 40 mg/kg ZMEO decreased all the signs of withdrawal syndrome significantly. ZMEO was analyzed by GC/MS and linalool (53.1%) and camphor (23.8%) were characterized as the main components. The results suggest that ZMEO possesses constituent(s) that have activity against tolerance to the anticonvulsant effects of morphine and the morphine withdrawal symptoms.

Ascorbic Acid Effect on Morphine Withdrawal Symptoms in Rats

Introduction: Today, drug addiction is an important healthcare issue. Any helps to drug withdrawal may decrease its prevalence in the society. Ascorbic acid is a component, which can affect neurotransmitter systems as a regulator along with its cofactor role. Noradrenergic and dopaminergic systems are two important neurotransmitter systems in the opiate withdrawal syndrome. It seems that ascorbic acid can decrease the symptoms of opiate withdrawal through regulating the related systems. In this regard, the current study aimed to evaluate the effect of ascorbic acid on the symptoms of morphine withdrawal in Syrian mice. Materials and Methods: Male Syrian mice in eight experimental groups received incremental doses of morphine as 10, 20, 30 and 40 mg/kg within the first, second, third, and fourth days of the experiment, respectively, through intraperitoneal injection, twice a day, and the control group received and equal amount of saline. On the fifth day, six groups of morphine addicts received ascorbic acid with six doses of 10, 50, 100, 200,400 and 800 mg/kg through intraperitoneal injection. Then, naloxone 2 mg/kg was injected to all groups including morphine alone and morphine with acute does of ascorbic acid. Then, withdrawal symptoms were evaluated for 30 minutes. Results: Administration of an acute dose of ascorbic acid reduced dose dependent withdrawal symptoms in such a way that 10, 50, and 100 mg/kg doses of ascorbic acid reduced “writhing” symptom, 200 mg/kg reduced “jumping” symptom, and 400 and 800 mg/kg reduced “climbing, jumping, and standing” symptoms. Conclusion: It seems that ascorbic acid administration can improve the symptoms of opiate withdrawal syndrome. More studies on human population can also indicate the therapeutic effect of ascorbic acid on drug withdrawal.

Oleanolic Acid Attenuates Morphine Withdrawal Symptoms in Rodents: Association with Regulation of Dopamine Function.

IntroductionOleanolic acid (OA) has been shown to be useful for the treatment of mental disorders.MethodsIn this study, we investigated the effects of OA in animal models of spontaneous withdrawal and naloxone-precipitated withdrawal and evaluated the effects of OA on the acquisition, extinction, and reinstatement of morphine-induced conditioned place preference (CPP).ResultsOA significantly improved symptoms of withdrawal, and significantly reduced the acquisition and reinstatement of morphine-induced conditioned place preference. Moreover, OA significantly reduced the serum content of 5-hydroxy tryptamine (5-HT) and dopamine (DA) in a dose-dependent manner, and reduced norepinephrine (NE) and 5-HT content in the frontal cortex (PFC), while significantly increasing endorphin content in rats. OA also significantly reduced serum DA content in mice.ConclusionThese results indicate that OA can improve the withdrawal symptoms of rats and mice by regulating the DA system and suggest that OA may be useful in treatment of morphine addiction.

Minocycline alleviates the symptoms of morphine withdrawal via the CaMKII-Ras-ERK signaling pathway

ObjectiveTo investigate the effect of minocycline on morphine withdrawal symptoms. MethodsWe established a rat model of morphine dependence, then injected the animals with naloxone to induce withdrawal symptoms. Minocycline was injected into the midbrain periaqueductal gray and its effect on withdrawal symptoms and Ca2+-dependent protein kinase (CaMKII), Ras, and phospho-extracellular signal-regulated kinase (p-ERK) expression was observed. ResultsMinocycline inhibited withdrawal symptoms such as “wet dog” shakes, teeth chatter, and ptosis, perhaps by inhibiting the activation of microglia and the expression of CaMKII, Ras, and p-ERK. Minocycline had no effect on the behavior of control rats or on CaMKII, Ras, or p-ERK expression. ConclusionMinocycline alleviates morphine withdrawal symptoms by inhibiting the activation of microglia and downregulating the expression of CaMKII, Ras, and p-ERK.

Functional observation after morphine withdrawal: effects of SJP-005

Rationale and objectiveSJP-005 (ketotifen and ibuprofen) is being developed as a potential new treatment for opioid withdrawal. Three studies were conducted to evaluate the early phase (acute, day 1) and late phase (days 2–12) effects of SJP-005 on discontinuation-induced morphine withdrawal.MethodsSprague-Dawley rats received subcutaneous morphine twice daily for 18 days and ceased on day 19. Twice daily, oral dosages of placebo or SJP-005 (1 mg/kg ketotifen and 15 mg/kg ibuprofen) were administered starting 4 days before (study 1), 2 days before (study 2), or immediately after (study 3) morphine cessation. Functional observations were made up to 12 h after treatment cessation on day 19 (early phase), and immediately after treatment on days 20–30 (late phase). Treatment effects (mean overall score, and individual symptoms) were compared with placebo using ANOVA, and Tukey’s tests in case of multiple comparisons.ResultsAcross the studies, the number of withdrawal signs on day 19 (early phase) and days 20–30 (late phase) was lower with SJP-005 compared with placebo. The effects of SJP-005 when treatment was initiated 2 days before morphine cessation by discontinuation were most pronounced and statistically significant in the late phase (F(1,18) = 14.10, p = 0.001). In particular, a significant reduction was observed in hypersensitivity to touch (F(1,18) = 13.65, p = 0.002). A 50% reduction in withdrawal symptoms was observed 9.0 days after placebo versus 4.5 days after SJP-005. After 9.0 days, all withdrawal symptoms were absent in the SJP-005 group, while symptoms in the placebo group were still evident on day 18.ConclusionCompared to placebo, SJP-005 significantly reduced the incidence and duration of discontinuation-induced morphine withdrawal symptoms when treatment was initiated 2 days before morphine cessation.

Simvastatin prevents morphine antinociceptive tolerance and withdrawal symptoms through antioxidative effect and nitric oxide pathway in mice

Oxidative stress and the nitric oxide (NO) pathway are involved in the development of opioid analgesic tolerance and dependence. Simvastatin modulates NO and oxidative stress, so the present study aimed to investigate its effect on the development and expression of morphine analgesic tolerance and withdrawal signs in mice. Morphine tolerance and dependence were induced by twice daily morphine injection (10 mg/kg, s.c.) for 5 consecutive days. Tolerance was assessed by the hot-plate test and dependence by naloxone challenge, on the sixth day. To determine if the NO is involved in the effects of simvastatin, mice were pre-treated with l-arginine (200 mg/kg) or the NO synthesis inhibitors (L-NAME; 30 mg/kg) along with simvastatin (300 mg/kg). The results showed that acute and chronic administration of simvastatin reversed the antinociceptive tolerance of morphine and attenuated withdrawal signs in morphine-dependent mice, and this effect is reversed by l-arginine and augmented by l-NAME. Also, the concentration of NO and oxidative stress factors such as malondialdehyde content, total thiol, and glutathione peroxidase (GPx) activity in brain tissues was evaluated. Chronic administration of simvastatin reduced NO and malondialdehyde, and increased total thiol and GPx levels in the cerebral cortex and hippocampus of morphine-dependent mice which were antagonized by l-arginine, and augmented by l-NAME. In summary, simvastatin attenuates morphine-induced antinociceptive tolerance and withdrawal symptoms, at least partly, through antioxidative properties and nitric oxide pathway.