At present, the problem of drug addiction treatment mainly lies in the high relapse rate of drug addicts. Addictive drugs will bring users a strong sense of euphoria and promote drug seeking. Once the drug is withdrawn, there will be withdrawal symptoms such as strong negative emotions and uncomfortable physical reactions. The recurrence of context-induced withdrawal memory is an important reason for drug relapse. Our previous study has shown increased c-Fos expression in prelimbic cortex (PrL) neurons projecting to paraventricular nucleus of the thalamus (PVT) (PrL^-PVT) during conditioned context-induced retrieval of morphine withdrawal memory. However, whether PrL^-PVT neurons are involved in withdrawal memory retrieval and the underlying molecular mechanisms remain unknown. In this study, we used conditioned place aversion (CPA) model combined with in vivo calcium signal recording, chemogenetics and nucleus drug injection methods to investigate the role and molecular mechanism of PrL^-PVT neurons in retrieval of morphine withdrawal memory. The results showed that the calcium signals of PrL^-PVT neurons were significantly enhanced by withdrawal-related context; Inhibition of PrL^-PVT neurons blocked the conditioned context-induced morphine withdrawal memory retrieval; Activation of PrL^-PVT neurons caused animals to escape from the context; After the inhibition of NMDA receptors in the PrL, withdrawal-related context failed to increase c-Fos and Arc expressions in PrL^-PVT neurons. The above results suggest that NMDA receptors in PrL^-PVT neurons are associated with retrieval of morphine withdrawal memory. This study is of great significance for further understanding the neural circuit mechanism of withdrawal memory retrieval as well as the intervention and prevention of drug relapse.
Animals ; Substance Withdrawal Syndrome/physiopathology* ; Morphine/adverse effects* ; Neurons/physiology* ; Receptors, N-Methyl-D-Aspartate/metabolism* ; Male ; Rats ; Paraventricular Hypothalamic Nucleus/metabolism* ; Memory ; Rats, Sprague-Dawley ; Morphine Dependence/physiopathology* ; Midline Thalamic Nuclei/physiology* ; Neural Pathways/metabolism*

Fentanyl is a fully synthetic opioid with analgesic and anesthetic properties. It has become a primary driver of the deadliest opioid crisis in the United States and elsewhere, consequently imposing devastating social, economic, and health burdens worldwide. However, the neural mechanisms that underlie the behavioral effects of fentanyl and its analogs are largely unknown, and approaches to prevent fentanyl abuse and fentanyl-related overdose deaths are scarce. This review presents the abuse potential and unique pharmacology of fentanyl and elucidates its potential mechanisms of action, including neural circuit dysfunction and neuroinflammation. We discuss recent progress in the development of pharmacological interventions, anti-fentanyl vaccines, anti-fentanyl/heroin conjugate vaccines, and monoclonal antibodies to attenuate fentanyl-seeking and prevent fentanyl-induced respiratory depression. However, translational studies and clinical trials are still lacking. Considering the present opioid crisis, the development of effective pharmacological and immunological strategies to prevent fentanyl abuse and overdose are urgently needed.
Humans ; Fentanyl/therapeutic use* ; Opioid-Related Disorders/drug therapy* ; Drug Overdose/prevention & control* ; Analgesics, Opioid/adverse effects* ; Vaccines/therapeutic use* ; Brain

Abuse of pharmaceutical drugs is a major public health and social problem worldwide. Mostly abused drugs mainly include opioids such as morphine, tramadol, methadone and fentanyl, sedative-hypnotics such as benzodiazepines and non-benzodiazepines, and central stimulants such as Ritalin (methylphenidate), Adderall (amphetamine and dextroamphetamine) and modafinil. Abuse of pharmaceutical drugs not only causes direct damage to multiple systems of the body, but also significantly increases risks of mental and physical diseases, imposing a heavy burden on individuals, families and society. Therefore, the prevention and control of pharmaceutical drug abuse are of vital importance. The Chinese government has taken strict administration measures for pharmaceutical drugs with abuse risk. However, confronting endless new drugs and changing abuse trends, it is necessary to further strengthen management and prevention of pharmaceutical drugs, monitor the trend of abuse, establish rapid response mechanisms, popularize relevant knowledge, and develop specific therapeutic drugs and intervention means, in order to promote prevention and treatment of pharmaceutical drug abuse.
Analgesics, Opioid/adverse effects* ; Central Nervous System Stimulants/adverse effects* ; Humans ; Illicit Drugs/adverse effects* ; Substance-Related Disorders/prevention & control*

Preclinical studies suggest that the GABA receptor is a potential target for treatment of substance use disorders. Baclofen (BLF), a prototypical GABA receptor agonist, is the only specific GABA receptor agonist available for application in clinical addiction treatment. The nucleus accumbens shell (AcbSh) is a key node in the circuit that controls reward-directed behavior. However, the relationship between GABA receptors in the AcbSh and memory reconsolidation was unclear. The aim of this study was to investigate the effect of intra-AcbSh injection of BLF on the reconsolidation of morphine reward memory. Male C57BL/6J mice were used to establish morphine conditioned place preference (CPP) model and carry out morphine reward memory retrieval and activation experiment. The effects of intra-AcbSh injection of BLF on morphine-induced CPP, reinstatement of CPP and locomotor activity were observed after environmental cues activating morphine reward memory. The results showed that intra-AcbSh injection of BLF (0.06 nmol/0.2 μL/side or 0.12 nmol/0.2 μL/side), rather than vehicle or BLF (0.01 nmol/0.2 μL/side), following morphine reward memory retrieval abolished morphine-induced CPP by disrupting its reconsolidation in mice. Moreover, this effect persisted for more than 14 days, which was not reversed by a morphine priming injection. Furthermore, intra-AcbSh injection of BLF without morphine reward memory retrieval had no effect on morphine-associated reward memory. Interestingly, administration of BLF into the AcbSh had no effect on the locomotor activity of mice during testing phase. Based on these results, we concluded that intra-AcbSh injection of BLF following morphine reward memory could erase morphine-induced CPP by disrupting its reconsolidation. Activating GABA receptor in AcbSh during drug memory reconsolidation may be a potential approach to prevent drug relapse.
Animals ; Baclofen ; administration & dosage ; Conditioning, Classical ; GABA-B Receptor Agonists ; administration & dosage ; Locomotion ; Male ; Memory ; Mice ; Mice, Inbred C57BL ; Morphine ; Nucleus Accumbens ; drug effects ; Opioid-Related Disorders ; Reward

OBJECTIVE: To explore the epidemic situation of cannabis use among drug users with compulsory detained detoxification treatment in China. METHODS: Using the data from the Drug Abuse Population Estimation in the Key Cities of the Ministry of Public Security, we analyzed the sociodemographic characteristics and substance use of cannabis abusers with compulsory detained detoxification treatment in 55 provincial capital cities and key cities of China. Chi-square test, Fisher exact test and Kruskal-Wallis rank sum test were used to compare the prevalence of cannabis, heroin, synthetic and mixed drug use among patients with detoxification treatment, as well as the differences in polydrug use and areas among cannabis users. RESULTS: In the study, 25 366 drug users with compulsory detained detoxification treatment were recruited, of whom 2.2% (546/25 366) used cannabis in the previous year before the treatment. The proportion of males was 83.5%, and the proportion of ethnic minorities was 41.0%. Those who received junior high school education or above accounted for 30.8%, and the unemployed accounted for 44.1%. The average age was (33.3±8.2) years, the average age of beginning drug use was (24.8±7.7) years, and the average duration between the first drug abuse and first detoxification treatment was (5.4±4.6) years. The prevalence of cannabis use was higher among those drug users who were 35-year-old and younger, ethnic minorities, employees and residents in Xinjiang. Of the cannabis users, 91.4% used polydrug, 13.6% combined with heroin alone, 42.1% combined with synthetic drugs alone and 35.7% combined with both of heroin and synthetic drugs. Of the cannabis users, 49.6% came from 3 regions: Xinjiang Uygur Autonomous Region, Jiangsu Province and Shanghai City. The cannabis users in Xinjiang had a high proportion of ethnic minorities who received junior high school education and below. Moreover, 79.6% of them combined cannabis use with heroin. The cannabis users in Jiangsu, Zhejiang and Shanghai areas had a higher proportion of ethnic Han who received better education (high school and above). Moreover, 92.7% of them combined cannabis use with methamphe-tamine. CONCLUSION The prevalence of cannabis use among the population with compulsory detained detoxification treatment is higher than that among drug users under surveillance, but there are obvious regional cluster effect and high possibility of polydrug abuse. Thus, it's important to strengthen the monitoring of cannabis use, to increase the control of cannabis and to formulate China's anti-cannabis policy among different population.
Adolescent ; Adult ; Cannabis ; China ; Drug Users ; Female ; Heroin Dependence ; Humans ; Male ; Opiate Substitution Treatment ; Young Adult

OBJECTIVE: Reaction time is defined as the time from the start of a stimulus to the start of the voluntary movement. Time plays an important role in undertaking daily living activities. Reaction time is an important factor in respect of both quality of life and of capabilities demonstrated in the work environment. Alcohol and some addictive substances have effect on RT. The aim of this study was to compare the visual and auditory reaction times of patients with opioid use disorder with healthy control subjects. METHODS: The study was applied to two groups as the opioid use disorder group and the control group. A Sociodemographic and Clinical Data Form was prepared for each patient including age, gender, marital status and education level. Using a computer program the response to visual screen color change (red/blue) and to an auditory ‘beep’ sound of the computer system were recorded. The Student’s t-test was applied as a statistical method. RESULTS: The results showed longer reaction times in the patients with opioid use disorder. CONCLUSION: To add improving reaction time approaches in opioid use disorder treatment may contribute to treatment by increasing quality of life and work performance.
Activities of Daily Living ; Computer Systems ; Drug Users ; Education ; Heroin Dependence ; Humans ; Marital Status ; Methods ; Mortuary Practice ; Opioid-Related Disorders ; Quality of Life ; Reaction Time ; Work Performance

MicroRNA-132 (miR-132), a small RNA that regulates gene expression, is known to promote neurogenesis in the embryonic nervous system and adult brain. Although exposure to psychoactive substances can increase miR-132 expression in cultured neural stem cells (NSCs) and the adult brain of rodents, little is known about its role in opioid addiction. So, we set out to determine the effect of miR-132 on differentiation of the NSCs and whether this effect is involved in opioid addiction using the rat morphine self-administration (MSA) model. We found that miR-132 overexpression enhanced the differentiation of NSCs in vivo and in vitro. Similarly, specific overexpression of miR-132 in NSCs of the adult hippocampal dentate gyrus (DG) during the acquisition stage of MSA potentiated morphine-seeking behavior. These findings indicate that miR-132 is involved in opioid addiction, probably by promoting the differentiation of NSCs in the adult DG.
Animals ; Cell Differentiation ; Cell Line, Tumor ; Dentate Gyrus ; metabolism ; Gene Expression Regulation ; Male ; MicroRNAs ; metabolism ; Neural Stem Cells ; metabolism ; Opioid-Related Disorders ; metabolism ; Rats, Sprague-Dawley

Objective: To investigate the association between three single nucleotide polymorphism (SNP) genes DRD2 (rs1800497, rs6275, and rs1799978) and the dosage used on methadone maintenance treatment (MMT). Methods: From the methadone maintenance treatment centers, 257 MMT patients were recruited to participate in a case-control study and divided into two groups-control groups under low dosage (n=89) and case (n=168) group with high dosage. Quanto software was used to estimate the sample size as 180. Information related to social-demographic status, history on drug use and medication were collected. And DRD2 SNPs were genotyped to explore the relationship between polymorphism of DRD2 gene and the dosage of methadone maintenance treatment. Results: Distributions of DRD2 rs6275 between different groups were significantly different. Patients carrying TC genotype needed lower dose of methadone when compared to the patients that carrying CC genotype counterparts (OR=0.338, 95% CI: 0.115-0.986). Patients that carrying C allele at rs6275 needed lower methadone dose than those that carrying genotype TT (OR=0.352, 95% CI: 0.127-0.975). Distributions of genotypes, alles in the other two SNPs (rs1800497, rs1799978) were not significantly different between groups under different dosages. Conclusion: DRD2 rs6275 was associated with dosage of methadone used for the MMT patients. However, no significant associations were found between rs1800497, rs1799978 and the dosage of methadone.
Alleles ; Case-Control Studies ; Drug Dosage Calculations ; Genotype ; Humans ; Methadone/therapeutic use* ; Opiate Substitution Treatment ; Opioid-Related Disorders/rehabilitation* ; Polymorphism, Single Nucleotide/genetics* ; Receptors, Dopamine D2/genetics*

Objective: To investigate the prevalence of diphenoxylate abuse and related factors of forced drug abstainer in Gansu province. Methods: By using a self-designed questionnaire, an epidemiologic investigation was carried out among 2 108 forced drug abstainer selected from the compulsory isolation detoxification center of Gansu province. A case-control study was conducted to analyze the factors related with diphenoxylate abuse. Results: The diphenoxylate abuse rate among forced drug abstainer in Gansu was 19.8% (406/2 046), ranking first in medical drug abuse. Multiple logistic regression analysis showed that factors as relieving withdrawal symptoms (OR=2.08, 95%CI: 1.01- 4.32), ways to obtain diphenoxylate (other ways: OR=1.00; regular clinic: OR=27.67, 95%CI: 2.64-289.82; friend: OR=0.01, 95%CI: 0.01-0.03), degree of euphoria (high: OR=1.00; medium: OR =3.36, 95%CI: 1.18-9.55; low: OR=26.16, 95%CI: 10.30-66.42), years of drug abuse (<5 years: OR=1.00; 10-15 years: OR=2.48, 95%CI: 1.02-6.04), abuse at home or in friend's house (OR=3.04, 95%CI: 1.08-8.68), abuse in car (OR=0.05, 95%CI: 0.00-0.68) and detoxification for the first time (OR=0.61, 95%CI: 0.43-0.86) were the possible influencing factors for diphenoxylate abuse. Conclusions: The prevalence of diphenoxylate abuse in forced drug abstainer in Gansu was relatively high. Reasons of abusing, the way to obtain diphenoxylate, whether using drug together with friends, degree of euphoria, years of abuse, abuse place and times for detoxification were related factors influencing the abuse of diphenoxylate.
Analgesics, Opioid/supply & distribution* ; Case-Control Studies ; China ; Diphenoxylate/supply & distribution* ; Humans ; Substance Withdrawal Syndrome ; Substance-Related Disorders/psychology* ; Surveys and Questionnaires

When facing the worldwide abuse of opioid substance, one of the effective responses is opioid substitution therapy (OST). However, different OST service patterns may affect the therapeutic outcome. Using the System Engineering Initiative for Patient Safety (SEIPS) model, we can analyze the factors that affecting the outcomes of patients from the perspective work system. In this paper, SEIPS model is used to describe the existing OST service model. According to the operation mechanism of the methadone maintenance treatment in China and the existing OST service model, some suggestions are put forward to carry out effective OST service in the country.
Analgesics, Opioid/adverse effects* ; China ; Delivery of Health Care ; Humans ; Methadone/therapeutic use* ; Opiate Substitution Treatment ; Opioid-Related Disorders/therapy* ; Treatment Outcome