Assessing effects of tamoxifen on tolerance, dependence, and glutamate and glutamine levels in frontal cortex and hippocampus in chronic morphine treatment.

Tamoxifen has been shown to reduce glutamate release from presynaptic glutamatergic nerves and reverse tolerance to morphine-induced respiratory depression. Changes in glutamatergic neurotransmission in the central nervous system contribute to morphine tolerance, dependence, and withdrawal. This study, therefore, evaluated effects of tamoxifen on development of analgesic tolerance and dependence, and brain glutamate and glutamine levels in chronic morphine administration. Mice implanted with placebo or morphine pellets were injected with tamoxifen (0.6-2 mg/kg) or vehicle twice daily for 3 days. Nociceptive response was evaluated in the hot plate and tail immersion tests, 4, 48 and 72 h post-implant, and following a challenge dose of morphine (10 mg/kg). Withdrawal signs were determined after naloxone (1 mg/kg) administration. Morphine increased nociceptive threshold which declined over time. At 72 h, acute morphine elicited tolerance to the analgesic effect in the hot plate test in vehicle or tamoxifen administered animals. In the tail immersion test, however, tolerance to morphine analgesia was observed in tamoxifen, but not vehicle, co-administration. Tamoxifen did not reduce withdrawal signs. In contrast to previous reports, glutamate and glutamine levels in the hippocampus and frontal cortex did not change in the morphine-vehicle group. Confirming previous findings, tamoxifen (2 mg/kg) decreased glutamate and glutamine concentrations in the hippocampus in animals with placebo pellets. Both doses of tamoxifen significantly changed glutamate and/or glutamine concentrations in both regions in morphine pellet implanted animals. These results suggest that tamoxifen has no effect on dependence but may facilitate tolerance development to the antinociception, possibly mediated at the spinal level, in chronic morphine administration.

Molecular Mechanism of Neuroprotective Effect of Melatonin on Morphine Addiction and Analgesic Tolerance: an Update.

Drug addiction is a global health problem and continues to place an enormous financial burden on society. This addiction is characterized by drug dependence sensitization and craving. Morphine has been widely used for pain relief, but chronic administration of morphine causes analgesic tolerance, hyperalgesia, and addiction, all of which limit its clinical usage. Alterations of multiple molecular pathways have been reported to be involved in the development of drug addiction, including mitochondrial dysfunction, excessive oxidative stress and nitric oxide stress, and increased levels of apoptosis, autophagy, and neuroinflammation. Preclinical and clinical studies have shown that the co-administration of melatonin with morphine leads to a reversal of these affected pathways. In addition, murine models have shown that melatonin improves morphine-induced analgesic tolerance and addictive behaviors, such as behavioral sensitization, reward effect, and physical dependence. In this review, we attempt to summarize the recent findings about the beneficial effect and molecular mechanism of melatonin on mitochondrial dysfunction, uncontrolled autophagy, and neuroinflammation in morphine addiction and morphine analgesic tolerance. We propose that melatonin might be a useful supplement in the treatment opiate abuse.

Sintocalmy, a Passiflora incarnata Based Herbal, Attenuates Morphine Withdrawal in Mice.

Chronic opioid use changes brain chemistry in areas related to reward processes, memory, decision-making, and addiction. Both neurons and astrocytes are affected, ultimately leading to dependence. Passiflora incarnata L. (Passifloraceae) is the basis of frequently used herbals to manage anxiety and insomnia, with proven central nervous system depressant effects. Anti-addiction properties of P. incarnata have been reported. The aim of this study was to investigate the effect of a commercial extract of Passiflora incarnata (Sintocalmy®, Aché Laboratory) in the naloxone-induced jumping mice model of morphine withdrawal. In addition, glial fibrillary acidic protein (GFAP) and S100 calcium-binding protein B (S100B) levels were assessed in the frontal cortex and hippocampus, and DNA damage was verified on blood cells. In order to improve solubilization a Sintocalmy methanol extract (SME) was used. SME is mainly composed by flavonoids isovitexin and vitexin. The effects of SME 50, 100 and 200 mg/kg (i.p.) were evaluated in the naloxone-induced withdrawal syndrome in mice. SME 50 and SME 100 mg/kg decreased naloxone-induced jumping in morphine-dependent mice without reducing locomotor activity. No alterations were found in GFAP levels, however SME 50 mg/kg prevented the S100B increase in the frontal cortex and DNA damage. This study shows anti-addiction effects for a commercial standardized extract of P. incarnata and suggests the relevance of proper clinical assessment.

Kratom Alkaloids, Natural and Semi-Synthetic, Show Less Physical Dependence and Ameliorate Opioid Withdrawal.

Chronic administration of opioids produces physical dependence and opioid-induced hyperalgesia. Users claim the Thai traditional tea "kratom" and component alkaloid mitragynine ameliorate opioid withdrawal without increased sensitivity to pain. Testing these claims, we assessed the combined kratom alkaloid extract (KAE) and two individual alkaloids, mitragynine (MG) and the analog mitragynine pseudoindoxyl (MP), evaluating their ability to produce physical dependence and induce hyperalgesia after chronic administration, and as treatments for withdrawal in morphine-dependent subjects. C57BL/6J mice (n = 10/drug) were administered repeated saline, or graded, escalating doses of morphine (intraperitoneal; i.p.), kratom alkaloid extract (orally, p.o.), mitragynine (p.o.), or MP (subcutaneously, s.c.) for 5 days. Mice treated chronically with morphine, KAE, or mitragynine demonstrated significant drug-induced hyperalgesia by day 5 in a 48 °C warm-water tail-withdrawal test. Mice were then administered naloxone (10 mg/kg, s.c.) and tested for opioid withdrawal signs. Kratom alkaloid extract and the two individual alkaloids demonstrated significantly fewer naloxone-precipitated withdrawal signs than morphine-treated mice. Additional C57BL/6J mice made physically dependent on morphine were then used to test the therapeutic potential of combined KAE, mitragynine, or MP given twice daily over the next 3 days at either a fixed dose or in graded, tapering descending doses. When administered naloxone, mice treated with KAE, mitragynine, or MP under either regimen demonstrated significantly fewer signs of precipitated withdrawal than control mice that continued to receive morphine. In conclusion, while retaining some liabilities, kratom, mitragynine, and mitragynine pseudoindoxyl produced significantly less physical dependence and ameliorated precipitated withdrawal in morphine-dependent animals, suggesting some clinical value.

Saffron (Crocus sativus L.) stigma reduces symptoms of morphine-induced dependence and spontaneous withdrawal in rats.

Background: Chronic morphine induces physical and psychological dependence signs. Saffron (Crocus sativus L.) stigma has been shown to have anxiolytic, antidepressant, and antinociceptive properties and to alleviate naloxone-precipitated withdrawal signs.Objectives: Therefore, this study was designed to examine the effects of saffron aqueous extract on the severity of physical-psychological dependence, voluntary morphine consumption, and the cerebrospinal fluid (CSF) serotonin levels following locomotor sensitization in morphine-dependent rats and in rats undergoing morphine withdrawal.Materials: Adult male rats were treated with morphine (10 mg/kg, sc twice daily) for 10 days. Rats received saffron extract (60 mg/kg, ip) daily, during the induction of morphine dependence and/or withdrawal. Then, rats were tested for spontaneous withdrawal signs, anxiety using the elevated plus-maze, depression using sucrose preference test, and voluntary morphine consumption using a two-bottle choice paradigm, and then challenged with morphine (1 mg/kg, ip) to evaluate of locomotor sensitization and CSF serotonin levels.Results: The results showed saffron extract during induction of morphine dependence decreased the severity of withdrawal signs (P = .05), while it had no effect on anxiety and depression-like behaviors. Saffron extract during morphine withdrawal exhibited an increase in the percentage (or ratio) of open/total arm entries (P = .017), higher levels of sucrose preference (P = .0001), a lower morphine preference ratio (P = .02) and also, a decrease in locomotor activity (P = .004) and an increase in the CSF serotonin levels (P = .041) in rats challenged to morphine.Conclusions: Saffron extract may exert a protective effect against morphine-induced behavioral sensitization in rats, probably through increasing serotonin levels.

Effects of processed Aconiti tuber on the extinction and reinstatement of morphine-induced conditioned place preference in rats.

AIM OF THE STUDY: To investigate the effect of processed Aconiti tuber (PAT) administered during or after the time of conditioned place preference (CPP) training on the extinction and reinstatement of morphine-priming CPP in rats. The dynorphin level in rats' nucleus accumbens (NAc) is detected as a target of the Dynorphin/Kappa Opioid Receptor (KOR) system for the possible mechanism. MATERIALS AND METHODS: Eight groups of rats were subcutaneously (s.c.) injected with morphine (10mg/kg) (on days 2,4,6,8) or saline (1ml/kg) (on days 3,5,7,9) alternately for 8 days. Five groups, including groups (Mor + Water, Mor + PAT (1.0/3.0g/kg) (S) and Sal + PAT(1.0/3.0g/kg)), were orally given distilled water or PAT 1.0 or 3.0 g/kg daily on days 1-8 during CPP training while other three groups, including groups (Sal + Water and Mor + PAT (1.0/3.0g/kg)(P), were given distilled water or PAT daily from day 10 until CPP was extinct. Morphine 1mg/kg (s.c.) was used to reinstate the extinct CPP and the CPP scores were recorded. The dynorphin concentration in nucleus accumbens (NAc) was assayed by radioimmunoassay after the last CPP measurement. RESULTS: 1) The CPP extinction shortened in Mor + PAT (1.0/3.0 g/kg) (S) groups but extended in Mor + PAT (1.0/3.0 g/kg)(P) groups. 2) Morphine-priming CPP did not change either in Mor + PAT (1.0/3.0 g/kg) (S) or Mor + PAT (1.0/3.0 g/kg)(P) groups. 3) The dynorphin concentration in NAc increased either in Mor + PAT (1.0/3.0 g/kg)(S) or Mor + PAT (1.0/3.0 g/kg)(P) groups. CONCLUSIONS: 1) PAT shortened the extinction from morphine induced CPP when administrated before CPP acquisition, whereas it extended the extinction when administrated after CPP formation. 2) PAT administrated during or after CPP training did not affect morphine-priming reinstatement of morphine induced CPP. 3) Dynorphin/KOR system might be a target to regulate morphine-induced CPP extinction but not reinstatement.

Lyophilized Kratom Tea as a Therapeutic Option for Opioid Dependence.

BACKGROUND: Made as a tea, the Thai traditional drug "kratom" reportedly possesses pharmacological actions that include both a coca-like stimulant effect and opium-like depressant effect. Kratom has been used as a substitute for opium in physically-dependent subjects. The objective of this study was to evaluate the antinociception, somatic and physical dependence produced by kratom tea, and then assess if the tea ameliorated withdrawal in opioid physically-dependent subjects. METHODS: Lyophilized kratom tea (LKT) was evaluated in C57BL/6J and opioid receptor knockout mice after oral administration. Antinociceptive activity was measured in the 55 °C warm-water tail-withdrawal assay. Potential locomotor impairment, respiratory depression and locomotor hyperlocomotion, and place preference induced by oral LKT were assessed in the rotarod, Comprehensive Lab Animal Monitoring System, and conditioned place preference assays, respectively. Naloxone-precipitated withdrawal was used to determine potential physical dependence in mice repeatedly treated with saline or escalating doses of morphine or LKT, and LKT amelioration of morphine withdrawal. Data were analyzed using one- and two-way ANOVA. RESULTS: Oral administration of LKT resulted in dose-dependent antinociception (≥1 g/kg, p.o.) absent in mice lacking the mu-opioid receptor (MOR) and reduced in mice lacking the kappa-opioid receptor. These doses of LKT did not alter coordinated locomotion or induce conditioned place preference, and only briefly reduced respiration. Repeated administration of LKT did not produce physical dependence, but significantly decreased naloxone-precipitated withdrawal in morphine dependent mice. CONCLUSIONS: The present study confirms the MOR agonist activity and therapeutic effect of LKT for the treatment of pain and opioid physical dependence.

Effect of Essential Oil of Zhumeria majdae on Morphine Tolerance and Dependence in Mice.

OBJECTIVE: To evaluate the effects of Zhumeria majdae essential oil (ZMEO) on morphine dependence and tolerance in mice. METHODS: ZMEO (10, 20, and 40 mg/kg) and clonidine (0.1 mg/kg) as the positive control were injected intraperitoneally (i.p.). The effect of ZMEO and clonidine on the dependence were evaluated by counting the number of jumps induced by naloxone (5 mg/kg) while the tolerance was evaluated by the tail-flick test. RESULTS: ZMEO at the dose of 10 mg/kg during the development period led to a significant inhibition of morphine tolerance (P<0.01), while it led to reduced morphine dependence with the doses of 20 and 40 mg/kg. ZMEO at two dose levels of 20 and 40 mg/kg indicated significant antinociceptive activity (P>0.01), and significantly reduced the withdrawal signs (number of jumps) of mice (P>0.01). CONCLUSIONS: ZMEO had significant effects on morphine tolerance and dependence. The linalool rich essential oil of Z. majdae plays a major role in the reduction of tolerance and dependence induced by morphine.

[Argentinian women and the uses of drugs: A sociohistorical analysis of female drug use in Argentina (1860-1930)]. / Mujeres argentinas y usos de drogas: análisis sociohistórico del uso femenino de sustancias psicoactivas en Argentina (1860-1930).

This article describes cases presented by experts from the legislative and medical-legal fields regarding the use of psychoactive substances among Argentinian women from 1878 to 1930. Background information is presented regarding the relationship between women and the use different drugs, medical interventions on the female body where psychoactive substances were used are analyzed, and experts' descriptions of cases of female drug users are detailed. Experts' discourses during this period did not attempt to comprehend the specificities of female consumption, but were rather used to position the issue of drug use as a social problem. This was done using three prototypes: the victim of a sick husband; the prostitute who encourages drug use among the weak in spirit (natural-born criminals); and the virtuous young woman who succumbs to drug addiction in spite of her father's rule. Each figure reinforces the need for state intervention and increased social control.

Este trabajo describe casos expuestos por expertos de los ámbitos legislativo y médico-legal periodístico, en los que se reporta el consumo de sustancias psicoactivas por parte de mujeres de Argentina, entre 1878 y 1930. Se presentan antecedentes sobre mujeres y usos de distintos fármacos, se analizan las intervenciones médicas que utilizan sustancias psicoactivas sobre el cuerpo femenino, y se detallan los casos de mujeres consumidoras desde las miradas expertas. En este periodo, los discursos expertos no buscaron comprender la especificidad femenina del consumo, sino promover el tema drogas como un problema. Esto se produce utilizando tres prototipos: la víctima de un marido enfermo, la prostituta que envicia a los débiles de espíritu (criminal nata), y la joven virtuosa que contraviene la ley del padre y sucumbe en la toxicomanía. Cada figura refuerza la necesidad de intervención estatal y control social.

Circular RNA expression profiling in the nucleus accumbens: Effects of electroacupuncture treatment on morphine-induced conditioned place preference.

Electroacupuncture (EA) has been developed on the basis of traditional Chinese acupuncture. EA can suppress craving in opioid addicts and opioid-seeking responses in rodents. However, the molecular mechanism of EA on the rewarding properties of morphine and craving responses is not known. Here, we have applied a conditioned place preference paradigm in mice to measure morphine-induced rewarding effects along with EA treatment. Circular RNAs (circRNAs) can function as micro RNA (miRNA) sponges to effectively regulate gene expression levels. CircRNA profiling within the nucleus accumbens (NAc) was performed in EA-treated and sham-treated mice. Following RNAseq, data were analyzed by gene ontology (GO) and Kyoto Encyclopedia Genes and Genomes (KEGG) tools. We identified 112 significantly differentially expressed circRNAs, including 51 that were up-regulated and 61 that were down-regulated. Our bioinformatics analyses show that these differentially expressed circRNAs map into pathways that are mainly involved with renin secretion and the cGMP-PKG signaling. We further constructed a circRNA-miRNA network that predicts the potential roles of the differentially expressed circRNAs and the interaction of circRNAs with miRNAs. Our secondary sequencing and bioinformatics analysis in the NAc after EA treatment on morphine-induced CPP provides putative novel targets on molecular mechanisms involved in morphine reinforcement and possibly craving.

Acute naloxone-precipitated morphine withdrawal elicits nausea-like somatic behaviors in rats in a manner suppressed by N-oleoylglycine.

RATIONALE: Acute naloxone-precipitated morphine withdrawal (MWD) produces a conditioned place aversion (CPA) in rats even after one or two exposures to high-dose (20 mg/kg, sc) morphine followed 24-h later by naloxone (1 mg/kg, sc). However, the somatic withdrawal reactions produced by acute naloxone-precipitated MWD in rats have not been investigated. A recently discovered fatty acid amide, N-oleoylglycine (OlGly), which has been suggested to act as a fatty acid amide hydrolase (FAAH) inhibitor and as a peroxisome proliferator-activated receptor alpha (PPARα) agonist, was previously shown to interfere with a naloxone-precipitated MWD-induced CPA in rats. OBJECTIVES: The aims of these studies were to examine the somatic withdrawal responses produced by acute naloxone-precipitated MWD and determine whether OlGly can also interfere with these responses. RESULTS: Here, we report that following two exposures to morphine (20 mg/kg, sc) each followed by naloxone (1 mg/kg, sc) 24 h later, rats display nausea-like somatic reactions of lying flattened on belly, abdominal contractions and diarrhea, and display increased mouthing movements and loss of body weight. OlGly (5 mg/kg, ip) interfered with naloxone-precipitated MWD-induced abdominal contractions, lying on belly, diarrhea and mouthing movements in male Sprague-Dawley rats, by both a cannabinoid 1 (CB1) and a PPARα mechanism of action. Since these withdrawal reactions are symptomatic of nausea, we evaluated the potential of OlGly to interfere with lithium chloride (LiCl)-induced and MWD-induced conditioned gaping in rats, a selective measure of nausea; the suppression of MWD-induced gaping reactions by OlGly was both CB1 and PPARα mediated. CONCLUSION: These results suggest that the aversive effects of acute naloxone-precipitated MWD reflect nausea, which is suppressed by OlGly.

Influence of Silybum Marianum on Morphine Addicted Rats, Biochemical Parameters and Molecular Simulation Studies on µ-Opioid Receptor.

The present study aimed to investigate effects of medicinal plant (Silybum marianum) on the animals with treatment of morphine addiction compared to chemical drug (Naloxane). Also, this study was conducted to evaluate the role of Silybum marianum on factors of serum ALT, AST activities and activity of the antioxidant enzyme:superoxide dismutase (SOD) as well as the extent of lipid peroxidation of Morphine addicted rats.High performance liquid chromatography (HPLC) has been used to measure Morphine in the serum, enzymes functions well as lipid peroxidation of Morphine addicted animals. Results demonstrate treatment with S. Marianum for opium rats at dose 400 mg/kg led to a major reduction in serum morphine compared to Naloxane (400 mg/kg>200 mg/kg>100 mg/kg>Naloxane. The positive effect of dose-dependence on liver enzymes function (ALT and AST) in order of 400 mg/kg>Naloxane>200 mg/kg>100 mg/kg. Furthermore, the findings show that the malondialdehyde levels are increased in opium-treated animals. However, the extracts also demonstrate a significant reduction in the MDA levels compared to the control, 400 mg/kg>200 mg/kg>Naloxane>100 mg/kg. Increase of Silybum marianum extract in rats pretreated significantly elevated the activities of superoxide dismutase (SOD).At last, our data suggest that Silibinin as the main component found in Milk thistle is more selective toward µ-Opioid Receptor than Morphine and Naloxane as a narcotic receptor antagonist.

Chromium picolinate reduces morphine-dependence in rats, while increasing brain serotonin levels.

Chromium is an essential trace element with anti-diabetic and anti-depressant effect; the latter is considered related to chromium properties of increasing brain serotonin. Cr3+ salts were shown to improve some forced swimming-parameters and to induce rewarding effects, which are additive to those of morphine, but Cr effect on addictive processes has not been tested. AIM: The present study aimed to assess chromium picolinate (CrPi) influence on morphine-dependence in rats. MATHERIAL AND METHODS: We used five groups of 10 rats. Groups 1 and 2 (controls) received saline, respectively CrPi, 0.01 mg/kg/day, for 10 days. In groups 3, 4 and 5 dependence was induced with progressively-increased morphine doses (from 5 - day 1-90 mg/kg/day - day 10, s.c.). Group 3 received only morphine, while groups 4 and 5 received CrPi, i.p., 10 and respectively 5 µg/kg/day, during the 10 days of dependence induction. On day 11, groups 3, 4, and 5 were administered 90 mg/kg morphine, and, 2 h later, all rats received naloxone, 2 mg/kg s.c., to precipitate withdrawal. We compared withdrawal intensity in group 3 vs. groups 4 and 5, assessing both individual symptoms and Gellert-Holtzman global withdrawal score. Upon rats sacrifice at the end of the experiments, brain serotonin (5HT) in certain areas and serum Cr were assessed. RESULTS: Some withdrawal signs were unequally influenced by CrPi: compulsive mastication was reduced by both CrPi doses (p < 0.05), while teeth chattering and grooming were significantly reduced only by the higher dose (p < 0.05). Withdrawal score was reduced by both CrPi doses: from 132.4 ±â€¯9.87 - group 3 to 122.2 ±â€¯6.47 - group 4 (p < 0.01 vs. group 3) and 124.1 ±â€¯8.41 - group 5 (p < 0.05 vs. group 3). CrPi reduction of withdrawal is accompanied by increased brain 5 H T, mainly in the prefrontal cortex (646.3 ±â€¯8.51 - group 3 vs. 661.5 ±â€¯14.63 - group 4, p < 0.01 and 660.7 ±â€¯14.01 pg/mg tissue - group 5, p < 0.05 vs. group 3). CrPi also increases brain 5 H T in non-dependent rats (prefrontal cortex: 541.6 ±â€¯31.80, group 1 and 565.5 ±â€¯16. 46 pg/mg tissue, group 2, p < 0.05). Administration of CrPi determined a dose-dependent increase of serum Cr. CONCLUSIONS: Our study evidenced a slight, but significant reduction of morphine dependence in rats induced by chromium picolinate, accompanied by increased brain serotonin. This might be considered a supplementary evidence for chromium anti-depressant effect and its serotonin-mediated mechanisms.

Effect of Yulangsan Polysaccharide on the Reinstatement of Morphine-Induced Conditioned Place Preference in Sprague-Dawley Rats.

We previously reported that Yulangsan polysaccharide (YLSP), which was isolated from the root of Millettia pulchra Kurz, attenuates withdrawal symptoms of morphine dependence by regulating the nitric oxide pathway and modulating monoaminergic neurotransmitters. In this study, we investigated the effects and mechanism of YLSP on the reinstatement of morphine-induced conditioned place preference (CPP) in rats. A CPP procedure was employed to assess the behavior of rats, and indicators of serum and four brain regions (nucleus accumbens, ventral tegmental area, hippocampus and prefrontal cortex) were determined to explore its underlying mechanism. YLSP inhibited priming morphine-induced reinstatement of CPP in a dose-dependent manner. YLSP markedly reduced nitric oxide and nitric oxide synthase levels in the brain. Moreover, YLSP significantly decreased the dopamine and norepinephrine levels in the serum and brain. Furthermore, YLSP significantly decreased cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP) concentrations, inhibited the expression of dopamine D1 receptors and cAMP response element binding protein mRNA, and improved the expression of dopamine D2 receptor mRNA in the four brain regions. Our findings indicated that YLSP could inhibit the reinstatement of morphine-induced CPP possibly by modulating the NO-cGMP and D1R-cAMP signaling pathways.

Hyperbaric Oxygen Attenuates Withdrawal Symptoms by Regulating Monoaminergic Neurotransmitters and NO Signaling Pathway at Nucleus Accumbens in Morphine-Dependent Rats.

In this study, we examined whether hyperbaric oxygen (HBO2) plays a detoxification role in withdrawal symptoms in a morphine-dependent rat model. The model was established through injections of morphine at increasing doses for 7 days. Withdrawal symptoms were induced by naloxone injection on the 8th day. The detoxification effect of HBO2 was evaluated using the withdrawal symptom scores, biochemical indices and neurotransmitters. Compared with the model group, HBO2 therapy significantly attenuated the withdrawal symptom scores, body weight loss and the level of norepinephrine level, whereas it increased the dopamine level and tyrosine hydroxylase expression in the nucleus accumbens. Moreover, HBO2 therapy substantially alleviated the NO, NOS, cAMP, and cGMP levels. Our findings indicate that HBO2 can effectively alleviate withdrawal symptoms induced by morphine dependence, and these effects may be attributed to the modulation of monoaminergic neurotransmitters and the suppression of the NO-cGMP signaling pathway.

Effects of acupuncture on the anxiety-like behavior induced by withdrawal from chronic morphine use.

OBJECTIVES: In the previous studies, it has been demonstrated that acupuncture treatment was effective on the suppression of withdrawal signs as well as self-administration behavior induced by morphine. Based on, the present study has investigated whether acupuncture could attenuate the anxiety-like behavior induced by withdrawal from chronic morphine treatment. MATERIALS & METHODS: Male Sprague-Dawley rats weighing 270-300g were treated saline or morphine hydrochloride (10mg/kg, s.c.) for 2 weeks. Following abstinence of 5days in home cage, rats were subjected to the measurement of anxiety-like behavior in the elevated plus maze. Bicuculline (1mg/kg, i.p.) and SCH 50911 (2mg/kg, i.p.) were used to investigate the possible mechanism of acupuncture effects focusing on the GABA receptors system. RESULTS: Acupuncture at HT7 increased the time spent in open arms significantly. Also, these effects of acupuncture at HT7 were blocked by GABAA receptor antagonist. CONCLUSION: Results of the present study suggest that acupuncture at HT7 can attenuate anxiety-like behavior induced by withdrawal from chronic morphine treatment through the mediation of GABAA receptor system.

Prevention of morphine dependence and tolerance by Nepeta menthoides was accompanied by attenuation of Nitric oxide overproduction in male mice.

ETHNOPHARMACOLOGICAL RELEVANCE: Repeated administration of morphine for chronic pain leads to dependence and tolerance that limits clinical usage. Nepeta menthoides is commonly known as Iranian Ustukhuddoos and are administered in traditional medicine for gastrodynia, bone pain, blood depurative and restlessness. AIMS OF STUDY: To investigate the effects of Nepeta menthoides on expression and acquisition of morphine dependence and tolerance in mice with regard to oxidative stress. MATERIALS AND METHODS: Morphine dependence in mice was developed by administration of gradually increasing doses of morphine twice daily for 7 consecutive days. In experimental groups, administration of Nepeta menthoides (200 and 400mg/kg), methadone and their combination were performed 60min prior to each morphine injection (for acquisition) or the last injection of morphine on test day (for expression). Morphine tolerance was measured by the tail-immersion test before and after the administration of a single dose of morphine (100mg/kg; i.p.) on the test day (8th day). Morphine dependence was also evaluated by counting the number of jumps after the injection of naloxone (5mg/kg; i.p.). RESULTS: Nepeta menthoides, similar to methadone, significantly prevented the development (but not the expression) of morphine dependence, tolerance, and potentiated morphine antinociception and also reduced (23.23±1.15) Nitric oxide (NO) overproduction (35.23±3.36) (in compared with naloxone group (6.3±0.52)). However, single and repeated application of the extract could not change high single-dose morphine analgesia. CONCLUSION: It appears that Nepeta menthoides and methadone prevented morphine dependence and tolerance, partly through inhibition of the NO overproduction.

Protective effects of atorvastatin against morphine-induced tolerance and dependence in mice.

BACKGROUND: In this study, we evaluated the effects of atorvastatin, a lipid-lowering medication on morphine-induced tolerance and dependence in mice. METHODS: Tolerance was induced by subcutaneous administration of morphine (20mg/kg) to animals, twice a day for 9days. Atorvastatin was given at the doses of 5, 10 and 20mg/kg, 30min before each morphine administration, once daily for 9days. Hot plate test was employed to assess antinociceptive effect of morphine on days 1, 3, 5, 7 and 9. Dependence was evaluated by naloxone-precipitated withdrawal syndrome. We attempted to verify withdrawal regulation of induced nitric oxide synthase (iNOS), astroglia marker, glial fibrillary acidic protein (GFAP), ionized calcium-binding protein (Iba1), a microglia activation marker, a pro-inflammatory mediator, tumor necrosis alpha (TNF-α) and immune receptor, toll like receptor 4 (TLR-4) genes by real-time polymerase chain reaction (RT-PCR). Lipid peroxidation was estimated by assessing malondialdehyde (MDA) content in the spinal cord of animals. RESULTS: Tolerance to antinociceptive effects of morphine was observed on days 7 and 9. Decrease in morphine-induced antinociception was reversed by concomitant intraperitoneal administration of atorvastatin (10 and 20mg/kg). Atorvastatin (10 and 20mg/kg) mitigated naloxone-induced withdrawal parameters. Brain expression levels of TNF-α, GFAP, Iba1 and iNOS increased in morphine withdrawn animals which were attenuated by nine days treatment with atorvastatin. Increased MDA was also normalized in withdrawn animals received atorvastatin. CONCLUSION: Atorvastatin exhibits meaningful protective effects against both tolerance to antinociceptive effects of morphine and withdrawal-induced behavioral profile. Neuroprotective effects of atorvastatin is further supported via inhibition of glia activity and antioxidant effects.

Salvia officinalis L. attenuates morphine analgesic tolerance and dependence in rats: possible analgesic and sedative mechanisms.

BACKGROUND: Salvia officinalis L. (SO) has effects on the central nervous system, including anti-addiction properties that may involve an opioid mechanism. OBJECTIVE: Effects of a hydroalcoholic extract of SO on nociception and on morphine-induced tolerance and dependence were evaluated in rats. METHODS: Tolerance and dependence were induced by injection of morphine (10 mg/kg, s.c.) or escalating doses of morphine (2.5, 2.5, 5, 10, 20, 40 and 50 mg/kg, s.c.) twice daily for 7 days. SO (400, 600 and 800 mg/kg, i.g.) was administered before morphine. The tail-flick and naloxone precipitation withdrawal tests were used to evaluate tolerance and dependence. Sedative effects as well as total polyphenolic and flavonoid were also measured. RESULTS: The morphine-treated group showed significant decrements in the percentage maximum possible effect (%MPE) on days 5 and 7 compared to the first day, illustrating morphine tolerance. Higher doses decreased morphine tolerance. Furthermore, SO (600 and 800 mg/kg) attenuated almost all of the withdrawal signs including weight loss, jumping, penis licking, teeth chattering, wet dog shakes, rearing, standing, sniffing, face grooming and paw tremor and increased sleep duration (64.5 ± 9.7, 100.3 ± 4.7, respectively). Total polyphenolic and flavonoid content of SO was 138 and 69 mg per g of dried extract, respectively. CONCLUSION: SO has antinociceptive effects and may decrease tolerance and dependence induced by repeated morphine administration. However, to determine whether treatment with SO blocks tolerance by interfering with neurobiological mechanisms that mediate the development of morphine tolerance will require further studies.

Acupuncture Suppresses Morphine Craving in Progressive Ratio Through the GABA System.

Previous studies revealed that acupuncture suppressed both morphine self-administration and morphine-seeking behavior after abstinence. Based on these results, this study examined whether acupuncture attenuated morphine-craving under a progressive ratio (PR) schedule and investigated the possible neuronal mechanism. Male Sprague-Dawley rats were trained to self-administer morphine (0.5 mg/kg) at a fixed ratio for 9 days, and rats who achieved stable infusion were switched to a PR schedule. When animals had taken no more morphine for 1 hour, the number of infusions was defined as the break point (BP). After PR training, animals that had established a stable BP received acupuncture the next day. Acupuncture was applied for 1 minute immediately before the test session. Bicuculline (1.0 mg/kg) and SCH 50911 (2.0 mg/kg) were given 30 minutes prior to acupuncture. The c-Fos levels in the ventral tegmental area (VTA) and the nucleus accumbens (NAc) were examined. Acupuncture at SI5 reduced the BP significantly. Moreover, the effects of acupuncture were blocked by either bicuculline or SCH 50911. Immunofluorescence revealed that acupuncture at SI5 decreased c-Fos expressions in the VTA and the NAc. This study demonstrates that acupuncture at SI5 is effective for the treatment of morphine-craving and that this effect is mediated via the GABA pathway.