Opioids and the developing brain: time to rethink perinatal care for infants of opioid-dependent mothers.

Illicit use of opioids is a global health crisis with major implications for women and children. Strategies for managing opioid use disorder (OUD) in pregnancy have been tested over the past 40 years, but studies have focused on maternal and pregnancy outcomes, with less attention given to long-term follow-up of exposed children. Here, we provide a narrative review of recent advances in the assessment and management of neonatal opioid withdrawal syndrome (NOWS), and we summarise evidence from multiple domains-neuroimaging, electrophysiology, visual development and function, neurodevelopment, behaviour, cognition and education-which suggests that prenatal opioid exposure modifies child development. Further studies are required to determine the optimal management of pregnant women with OUD and babies with NOWS. We identify knowledge gaps and suggest that future study designs should evaluate childhood outcomes, including infant brain development and long-term neurocognitive and visual function.

Clinical and Imaging Study of Repetitive Transcranial Magnetic Stimulation in the Treatment of Morphine Dependence Through mGluR5/TDP43/NR2B Pathway.

Morphine is tolerable after long-term use. After long-term use, it will have a great impact on the human body, and the treatment effect is not good. In recent years, the continuous development of repetitive transcranial magnetic stimulation (rTMS) treatment technology has made a treatment. Drug-resistant morphine dependence has a breakthrough. In this article, to study the effect of repeated transcranial magnetic stimulation in the treatment of morphine dependence through mGluR5/TDP43/NR2B pathway, experiments were carried out on rats to compare the changes in the images of rats after different periods of morphine use and their effects on morphine withdrawal. During the period, the performance of rats provides a reference for repeated transcranial stimulation to treat morphine dependence. According to the experimental results, after stopping morphine, withdrawal from the rats, irritable acts, and patience diminished. This is a decrease of more than 50% in comparison with the one of the normal group. There was a different degree of variability in the treatment images of mGluR5/TDP43 and so on after rTMS treatment, and the changes were large. These reductions in detoxification responses in rodents suggest that rTMS serves an instrumental role in the prevention and treatment of phosphorylation related to morphine dependence.

Fecal microbiota transplantation and antibiotic treatment attenuate naloxone-precipitated opioid withdrawal in morphine-dependent mice.

Opioid addiction can produce severe side effects including physical dependence and withdrawal. Perturbations of the gut microbiome have recently been shown to alter opioid-induced side-effects such as addiction, tolerance and dependence. In the present study, we investigated the influence of the gut microbiome on opioid withdrawal by evaluating the effects of fecal microbiota transplantation (FMT), antibiotic and probiotic treatments, and pharmacological inhibition of gut permeability in a mouse model of opioid dependence. Repeated intraperitoneal (i.p.) morphine treatment produced physical dependence that was quantified by measuring somatic signs of withdrawal (i.e. number of jumps) precipitated using the opioid antagonist naloxone. Morphine-dependent mice that received FMT from morphine-treated donor mice exhibited fewer naloxone-precipitated jumps compared to morphine-dependent counterparts receiving FMT from saline-treated donor mice. Microbial contents in the mouse cecum were altered by morphine treatment but were not differentially impacted by FMT. A broad-spectrum antibiotic cocktail (ABX) regimen reduced the bacterial load and attenuated naloxone-precipitated morphine withdrawal in morphine-dependent mice, whereas commercially available probiotic strains did not reliably alter somatic signs of opioid withdrawal. ML-7, a pharmacological inhibitor of gut permeability, reduced the morphine-induced increase in gut permeability in vivo but did not reliably alter somatic signs of naloxone-precipitated opioid withdrawal. Our results suggest that the gut microbiome impacts the development of physical dependence induced by chronic morphine administration, and that therapeutic manipulations of the gut microbiome may reduce opioid withdrawal.

Effectiveness and safety of repetitive transcranial magnetic stimulation for the treatment of morphine dependence: A retrospective study.

ABSTRACT: Morphine dependence (MD) is a very common complication because of the chronic morphine consumption. Studies suggest that repetitive transcranial magnetic stimulation (rTMS) can be used for the treatment of MD. However, there is still lacking evidence to support rTMS for MD. Thus, this retrospective study aimed to investigate the effectiveness and safety of rTMS for patients with MD.In this retrosepctive study, a total of 100 patients with MD were included, and they were divided into a rTMS group (n = 50), and a control group (n = 50). All patients in both groups received occupational therapy. In addition, patients in the rTMS group received rTMS. All patients in both groups received a total of 8 weeks treatment. The outcomes comprised of morphine craving intensity, depression, anxiety, and sleep quality, which were appraised by Visual Analogue Scale (VAS), Self-Rating Depression Scale (SDS), Self-Rating Anxiety Scale (SAS), and Pittsburgh Sleep Quality Index (PSQI), respectively. In addition, treatment-related adverse events were also considered for assessment.After 8 weeks treatment, patients in the rTMS group exerted better benefits in improving VAS (P < .01), SDS (P < .01), SAS (P < .01), and PSQI (P < .01), than patients in the control group. In addition, this study did not identify treatment-related adverse events in both groups.The findings of this study showed that rTMS treatment showed promising effectiveness on patients with MD. However, future studies should focus on warranting the present findings.

Engineered endomorphin-2 gene: A novel therapy for improving morphine reinstatement in CPP model of rats by using deficient adenovirus as the vector.

Optimal therapeutics to deal with high relapse rates when discontinued is urgent for opioid dependence treatments. Endogenous endomorphin-2 (EM2) level in the central nervous system (CNS) down-regulates obviously after sustained morphine exposure, which suggested that to up-regulate the EM2 level could be a novel method for reinstatement. But the clinical applications of EM2 through conventional administration are limited owing to its short half-life. In our study, we engineered an EM2 gene to achieve the sustained release of EM-2 in CNS by utilizing a signal peptide of mouse growth factor for out-secreting EM2 and a deficient adenovirus as the vector. By intrathecally injecting engineering EM2 gene, a sustained increase of EM2 concentration in the cerebral spinal fluid (CSF) was observed along with a reduction of CPP scores. Also, the activation of astrocytes was suppressed in the hippocampus. In summary, this study provides evidence and reference for using intraspinal gene therapy with a combination of mouse growth factor and EM2 to treat morphine reinstatement.

Treadmill exercise attenuates the severity of physical dependence, anxiety, depressive-like behavior and voluntary morphine consumption in morphine withdrawn rats receiving methadone maintenance treatment.

This study was designed to examine whether treadmill exercise would attenuate the severity of physical dependence, methadone-induced anxiety, depression and voluntary morphine consumption in morphine withdrawn rats receiving methadone maintenance treatment (MMT). The rats were chronically treated with bi-daily doses (10 mg/kg, at 12 h intervals) of morphine for 14 days. The exercising rats receiving MMT were forced to run on a motorized treadmill for 30 days during morphine withdrawal. Then, rats were tested for the severity of morphine dependence, the elevated plus-maze (EPM), sucrose preference test (SPT) and voluntary morphine consumption using a two-bottle choice (TBC) paradigm. The results showed that naloxone- precipitated opioid withdrawal signs were decreased in exercising morphine-dependent rats receiving MMT than sedentary rats. Also, the exercising morphine-dependent rats receiving MMT exhibited an increased time on open arms, preference for sucrose and a lower morphine preference ratio than sedentary rats. We conclude that treadmill exercise decreased the severity of physical dependence, anxiety/depressive-like behaviors and also the voluntary morphine consumption in morphine withdrawn rats receiving MMT. Thus, exercise may benefit in the treatment of addicts during MMT.

Effects of treadmill exercise on methadone withdrawal-induced locomotor sensitization and the ventral pallidum and ventral tegmental area BDNF levels in morphine withdrawn rats receiving methadone maintenance treatment.

This study examined the effects of treadmill exercise on the methadone withdrawal -induced locomotor sensitization, the ventral tegmental area (VTA) and ventral pallidum (VP) BDNF levels in morphine withdrawn rats receiving methadone maintenance treatment (MMT). The rats were chronically treated with bi-daily doses (10 mg/kg, at 12 h intervals) of morphine for 14 days. The exercising rats receiving MMT were forced to run on a motorized treadmill for 30 days during morphine withdrawal. Then, rats were exposed to a 14-day methadone withdrawal period, without any exercise and then challenged with morphine (1 mg/kg, ip) and evaluated for locomotor activity. Also, the VTA-VP BDNF levels were assessed before and after receiving MMT. The sedentary morphine-dependent rats receiving MMT and morphine-dependent rats receiving saline challenged to morphine exhibited a higher level of locomotor activity compared to Sal/Sal/Sed group after withdrawal of drug. While, the level of locomotor activity was lower in the D/Meth/Sed than in D/Sal/Sed rats. The VP BDNF level and the locomotors response were higher and lower, respectively in the D/Meth/Sed and D/Sal/Exc than the D/Sal/Sed rats. Exercise had no effect on the locomotors response and the VP BDNF levels in morphine-dependent rats receiving MMT. Our results showed that the sedentary morphine-dependent rats challenged to morphine enhanced the morphine-induced hyperlocomotion, whereas decreased the VP BDNF levels. MMT resulted in a persistent of locomotor sensitization caused by morphine withdrawal, though milder. Exercise had no effect on the locomotors response and the VTA-VP BDNF levels in the D/Meth/Exc.

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.

Maternal swimming exercise during pregnancy attenuates anxiety/depressive-like behaviors and voluntary morphine consumption in the pubertal male and female rat offspring born from morphine dependent mothers.

This study was designed to examine whether maternal swimming exercise during pregnancy would attenuate prenatally morphine-induced anxiety, depression and voluntary consumption of morphine in the pubertal male and female rat offspring. Pregnant rats during the development of morphine dependence were allowed to swim (30-45min/d, 3days per a week) on gestational days 11-18. Then, the pubertal male and female rat offspring were tested for the elevated plus-maze (EPM), sucrose preference test (SPT) and voluntary morphine consumption using a two-bottle choice (TBC) paradigm. The results showed that male and female rat offspring born of the swimmer morphine-dependent mothers exhibited an increase in EPM open arm time and entries, higher levels of sucrose preference than their sedentary control mothers. Voluntary consumption of morphine was less in the male and female rat offspring born of the swimmer morphine-dependent mothers as compared with their sedentary control mothers during three periods of the intake of drug. Thus, swimming exercise in pregnant morphine dependent mothers decreased anxiety, depressive-like behavior and also the voluntary morphine consumption in the pubertal male and female offspring, which may prevent prenatally morphine-induced behavioral sensitization in offspring.

RETRACTED: Exploring the mechanism by which accumbal deep brain stimulation attenuates morphine-induced reinstatement through manganese-enhanced MRI and pharmacological intervention.

This article has been retracted: please see Elsevier Policy on Article Withdrawal (https://www.elsevier.com/about/our-business/policies/article-withdrawal). This article has been retracted at the request of the authors. The authors have requested to retract this paper as the corresponding author had not sought the prior agreement of his co-authors to submit the paper for publication.

Best Practices and Innovations for Managing Codeine Misuse and Dependence.

PURPOSE: Promoting and ensuring safe use of codeine containing medicines remains a public health issue given the rise in reporting of misuse and dependence particularly in countries where available over-the-counter (OTC). The aim of this unique study was to identify best practices in management of opioid abuse and dependence, particularly codeine, and innovations to meet challenges surrounding safe and compliant use, patient awareness-raising, reducing health harms and enhancing successful treatment of dependence. METHODS: A mixed methods approach using three data points was used that included : (1) analysis of data from existing scoping reviews to identify potential areas for innovation (2) interviews with key national stakeholders from public health, pharmaceutical, regulatory, primary care and addiction practice in three distinct regulatory regimes (Ireland, United Kingdom and South Africa); and (3) a circular email request for information on potential innovations to members of the European Medicine's Agency European Network of Centres for Pharmacoepidemiology and Pharmacovigilance (ENCEPP). Data from these three sources were analysed to identify best practices and opportunities for innovation. RESULTS: Best practices and potential innovations were identified under the nine headings: (1) manufacture; (2) product information and public education; (3) responsible prescribing; (4) monitoring and surveillance; (5) dispensing, screening and brief interventions in community pharmacies; (6) safety in the workplace and on the road; (7) internet supply of codeine and online support; (8) treatment of codeine dependence; and (9) learning resources and training for health professionals. CONCLUSIONS: Challenges ensuring availability of codeine containing medicines for legitimate therapeutic use, while minimising misuse, dependence and related health harms warrant consideration of new innovations. Most promising innovative potential lies across the products' retail lifecycle from manufacture to prescriber and community pharmacy practitioner.This article is open to POST-PUBLICATION REVIEW. Registered readers (see "For Readers") may comment by clicking on ABSTRACT on the issue's contents page.

Oxycodone physical dependence and its oral self-administration in C57BL/6J mice.

Abuse of prescription opioids, such as oxycodone, has markedly increased in recent decades. While oxycodone's antinociceptive effects have been detailed in several preclinical reports, surprisingly few preclinical reports have elaborated its abuse-related effects. This is particularly surprising given that oxycodone has been in clinical use since 1917. In a novel oral operant self-administration procedure, C57BL/6J mice were trained to self-administer water before introducing increasing concentrations of oxycodone (0.056-1.0mg/ml) under post-prandial conditions during daily, 3-h test sessions. As the concentration of oxycodone increased, the numbers of deliveries first increased, then decreased in an inverted U-shape fashion characteristic of the patterns of other drugs self-administered during limited access conditions. After post-prandial conditions were removed, self-administration at the highest concentration was maintained suggesting oral oxycodone served as a positive reinforcer. In other mice, using a novel regimen of physical dependence, mice were administered increasing doses of oxycodone (9.0-33.0mg/kg, s.c.) over 9 days, challenged with naloxone (0.1-10.0mg/kg, s.c.), and then observed for 30min. Naloxone dose-dependently increased the observed number of somatic signs of withdrawal, suggesting physical dependence of oxycodone was induced under this regimen. This is the first report demonstrating induction of oral operant self-administration of oxycodone and dose-dependent precipitations of oxycodone withdrawal in C57BL/6J mice. The use of oral operant self-administration as well as the novel physical dependence regimen provides useful approaches to further examine the abuse- and dependence-related effects of this highly abused prescription opioid.

The Influence of Polyethylene Glycol Solution on the Dissolution Rate of Sustained Release Morphine.

INTRODUCTION: Whole bowel irrigation (WBI) is a management option for overdose of medications poorly adsorbed to activated charcoal, with modified release properties, or for body packers. Polyethylene glycol (PEG) is a mixture of ethylene oxide polymers of varying molecular weight. PEG with an average molecular weight of 3350 g/mol is used for WBI. PEG electrolyte lavage solution has been shown in vitro to hasten the dissolution of acetaminophen. The impact of PEG on the pharmacokinetics of extended release pharmaceuticals is unknown. Lower average molecular weight PEG mixtures are used as solvents and excipients. We sought to investigate the impact of PEG on the release of morphine from several extended release morphine formulations. METHODS: An in vitro gastric model was developed. To test the validity of our model, we first investigated the previously described interaction of ethanol and Avinza®. Once demonstrated, we then investigated the effect of PEG with several extended release morphine formulations. RESULTS: In the validation portion of our study, we confirmed an ethanol Avinza® interaction. Subsequently, we did not observe accelerated release of morphine from Avinza® or generic extended release morphine in the presence of PEG. CONCLUSION: The use of PEG for gastric decontamination following ingestion of these extended release morphine formulations is unlikely to accelerate morphine release and aggravate intoxication.

Effect of environmental enrichment on physical and psychological dependence signs and voluntary morphine consumption in morphine-dependent and morphine-withdrawn rats.

This study was designed to examine the effect of environmental enrichment during morphine dependency and withdrawal on the severity of naloxone-precipitated withdrawal signs, anxiety, and depressive-like behaviors and voluntary morphine consumption in morphine-dependent rats. The rats were injected with bi-daily doses (10 mg/kg, 12 h intervals) of morphine for 14 days following rearing in a standard environment (SE) or enriched environment (EE) during the development of morphine dependence and withdrawal. Then, rats were tested for withdrawal signs after naloxone injection, anxiety (the elevated plus maze) and depression-related behavior (sucrose preference test), and voluntary consumption of morphine using a two-bottle choice paradigm, in morphine-dependent and morphine-withdrawn rats. The results showed that EE decreased naloxone-precipitated withdrawal signs, but not anxiety or sucrose preference during dependence on morphine. The EE-withdrawn rats showed an increase in the elevated plus maze open arm time and entries and higher levels of sucrose preference than SE rats. Voluntary consumption of morphine was lower in the EE-withdrawn rats than in the SE groups in the second period of drug intake. Thus, exposure to EE reduced the severity of morphine dependence and voluntary consumption of morphine, alongside reductions in anxiety and depression-related behavior in morphine-withdrawn rats.

Targeted exosome-mediated delivery of opioid receptor Mu siRNA for the treatment of morphine relapse.

Cell-derived exosomes have been demonstrated to be efficient carriers of small RNAs to neighbouring or distant cells, highlighting the preponderance of exosomes as carriers for gene therapy over other artificial delivery tools. In the present study, we employed modified exosomes expressing the neuron-specific rabies viral glycoprotein (RVG) peptide on the membrane surface to deliver opioid receptor mu (MOR) siRNA into the brain to treat morphine addiction. We found that MOR siRNA could be efficiently packaged into RVG exosomes and was associated with argonaute 2 (AGO2) in exosomes. These exosomes efficiently and specifically delivered MOR siRNA into Neuro2A cells and the mouse brain. Functionally, siRNA-loaded RVG exosomes significantly reduced MOR mRNA and protein levels. Surprisingly, MOR siRNA delivered by the RVG exosomes strongly inhibited morphine relapse via the down-regulation of MOR expression levels. In conclusion, our results demonstrate that targeted RVG exosomes can efficiently transfer siRNA to the central nervous system and mediate the treatment of morphine relapse by down-regulating MOR expression levels. Our study provides a brand new strategy to treat drug relapse and diseases of the central nervous system.

Formation of aversive memories associated with conditioned drug withdrawal requires BDNF expression in the amygdala in acute morphine-dependent rats.

AIM: Brain-derived neurotrophic factor (BDNF) plays an important role in learning and memory in multiple brain areas. In the present study, we investigated the roles of BDNF in aversive memories associated with conditioned drug withdrawal in acute morphine-dependent rats. METHODS: Conditioned place aversion (CPA) was induced in male SD rats exposed to a single dose of morphine (10 mg/kg, sc) followed by naloxone (0.3 mg/kg, sc). In some rats, BDNF receptor antagonist K252a (8.5 ng per side) or BDNF scavenger TrkB-FC (0.65 µg per side) was bilaterally microinjected into amygdala before naloxone injection. BDNF mRNA and protein expression levels in amygdala were detected after the behavior testing. RESULTS: CPA behavior was induced in rats by the naloxone-precipitated morphine withdrawal, which was accompanied by significantly increased levels of BDNF mRNA and protein in the amygdala. Bilateral microinjection of TrkB-FC or K252a into the amygdala completely blocked CPA behavior in the rats. CONCLUSION: Formation of aversive memories associated with conditioned drug withdrawal in acute morphine-dependent rats requires BDNF expression in the amygdala.

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.

Nanotherapeutic approach for opiate addiction using DARPP-32 gene silencing in an animal model of opiate addiction.

Opiates act on the dopaminergic system of the brain and perturb 32 kDa dopamine and adenosine 3', 5'-monophosphate-regulated phosphoprotein (DARPP-32) function. The DARPP-32 mediated inhibition of protein phosphatase-1 (PP-1) and modulation of transcriptional factor CREB is critical to the changes in neuronal plasticity that result in behavioral responses during drug abuse. To investigate the role of DARPP-32 mediated signaling on withdrawal behavior in a rat model of opiate addiction, we used intracerebral administration of gold nanorods (GNR) complexed to DARPP-32 siRNA to silence DARPP-32 gene expression and measure its effects on the opiate withdrawal syndrome. We hypothesized that DARPP-32 siRNA will suppress the neurochemical changes underlying the withdrawal syndrome and therefore prevent conditioned place aversion by suppressing or removing the constellation of negative effects associated with withdrawal, during the conditioning procedure. Our results showed that opiate addicted animals treated with GNR-DARPP-32 siRNA nanoplex showed lack of condition place aversive behavior consequent to the downregulation of secondary effectors such as PP-1 and CREB which modify transcriptional gene regulation and consequently neuronal plasticity. Thus, nanotechnology based delivery systems could allow sustained knockdown of DARPP-32 gene expression which could be developed into a therapeutic intervention for treating drug addiction by altering reward and motivational systems and interfere with conditioned responses.

Swimming reduces the severity of physical and psychological dependence and voluntary morphine consumption in morphine dependent rats.

Previous studies have indicated that voluntary exercise decreases the severity of the anxiogenic-like behaviors in both morphine-dependent and withdrawn rats. This study examined the effects of regular swimming exercise during the development of dependency and spontaneous morphine withdrawal on the anxiety-depression profile and voluntary morphine consumption in morphine dependent rats. The rats were chronically treated with bi-daily doses (10 mg/kg, at 12h intervals) of morphine over a period of 14 days. The exercising rats were allowed to swim (45 min/d, five days per a week, for 14 or 21 days) during the development of morphine dependence and withdrawal. Then, rats were tested for the severity of morphine dependence, the elevated plus-maze (EPM), sucrose preference test (SPT) and voluntary morphine consumption using a two-bottle choice paradigm in animal models of craving. The results showed that withdrawal signs were decreased in swimmer morphine dependent rats than sedentary rats (P<0.05). Also, the swimmer morphine-dependent and withdrawn rats exhibited an increase in EPM open arm time and entries (P<0.05), higher levels of sucrose preference (P<0.001) than sedentary rats. Voluntary consumption of oral morphine was less in the swimmer morphine-withdrawn rats than the sedentary groups during four periods of the intake of drug (P<0.01). We conclude that regular swimming exercise reduces the severity of morphine dependence and voluntary morphine consumption with reducing anxiety and depression in morphine-dependent and withdrawn rats. Thus, swimming exercise may be a potential method to ameliorate some of the deleterious behavioral consequences of morphine dependence.

Effects of phosphodieastrase type 5 inhibitions on morphine withdrawal symptoms in mice / Efectos comportamentales por inhibición de la fosfodiesterasa tipo 5 sobre los síntomas de abstinencia de morfina en ratones

BACKGROUND: Chronic morphine exposure creates dependence and, upon cessation, withdrawal symptoms. Studies indicate the phosphodiesterase type 5 (PDE5) inhibitor sildenafil may provide centrally mediated benefits against withdrawal, and therefore, this study evaluated morphine withdrawal signs in dependent mice with and without sildenafil treatment. METHOD: Dependence was induced by repeated treatments with morphine over 5 consecutive days. The morphine-dependent mice received sildenafil (1, 5, 10, or 20 mg/kg, i.p.) 15 min prior to the precipitation of morphine withdrawal. On the last day, naloxone was injected 2 hours after the last morphine injection, and withdrawal signs were evaluated for 30 min after naloxone injection. RESULTS: The administration of sildenafil reduced all of the morphine withdrawal symptoms. CONCLUSIONS: The administration of sildenafil diminished morphine withdrawal signs in morphine-dependent mice. We hypothesize that the mechanism involves enhanced cyclic guanosine monophosphate (cGMP) activity, but further studies are recommended for a better understanding

ANTECEDENTES: se sabe que la exposición crónica a la morfina conduce a la dependencia. El cese en el consumo de morfina conlleva al desarrollo del síndrome de abstinencia. Numerosos estudios indican los efectos beneficiosos del sildenafil en el sistema nervioso central. Es por ello que el presente estudio evaluó el efecto del sildenafil sobre el síndrome de abstinencia a la morfina. MÉTODO: los ratones dependientes de morfina recibieron dosis diferentes de sildenafil (1, 5, 10 o 20 mg/kg i.p.) 15 minutos antes de producir el síndrome de abstinencia a la morfina. En el último día, la naloxona se inyectó dos horas después de la última inyección de morfina. Los signos de abstinencia fueron evaluados durante 30 minutos después de la inyección de naloxona. RESULTADOS: la administración de sildenafil redujo todos los síntomas de abstinencia relacionados con la morfina. CONCLUSIONES: se puede concluir que la administración de sildenafil disminuyó los signos de abstinencia a la morfina. Estos resultados muestran cómo los incrementos en el nivel del GMP cíclico mediante la vía PDE5 reduce los síntomas de abstinencia a la morfina