Caenorhabditis Elegans Exhibits Morphine Addiction-like Behavior via the Opioid-like Receptor NPR-17

Addiction has become a profound societal problem worldwide, and few effective treatments are available. The nematode Caenorhabditis elegans (C. elegans) is an excellent invertebrate model to study neurobiological disease states. C. elegans reportedly developed a preference for cues that had previously been paired with addictive drugs, similar to place conditioning findings in rodents. Moreover, several recent studies discovered and reported the existence of an opioid-like system in C. elegans. Still unclear, however, is whether C. elegans exhibits addictive-like behaviors for opioids, such as morphine. In the present study, we found that C. elegans exhibited dose-dependent preference for morphine using the conditioned chemosensory-cue preference (CCP) test. This preference was blocked by co-treatment with the opioid receptor antagonist naloxone. C. elegans also exhibited aversion to naloxone-precipitated withdrawal from chronic morphine exposure. The expression of morphine-induced CCP and morphine withdrawal were abolished in worms that lacked the opioid-like receptor NPR-17. Dopamine-deficient mutant (cat-2 (e1112)) worms also did not exhibit morphine-induced CCP. These results indicate that the addictive function of the opioid system exists in C. elegans, which may serve as a useful model of opioid addiction.

α-Conotoxin TxIB Inhibits Development of Morphine-Induced Conditioned Place Preference in Mice via Blocking α6β2* Nicotinic Acetylcholine Receptors

Morphine, the main component of opium, is a commonly used analgesic in clinical practice, but its abuse potential limits its clinical application. Nicotinic acetylcholine receptors (nAChRs) in the mesolimbic circuitry play an important role in the rewarding effects of abused drugs. Previous studies have showed that α6β2* (* designated other subunits) nAChRs are mainly distributed in dopaminergic neurons in the midbrain area, which regulates the release of dopamine. So α6β2* nAChRs are regarded as a new target to treat drug abuse. α-Conotoxin TxIB was discovered in our lab, which is the most selective ligand to inhibit α6β2* nAChRs only. Antagonists of α6β2* nAChRs decreased nicotine, cocaine, and ethanol rewarding effects previously. However, their role in morphine addiction has not been reported so far. Thus, it is worth evaluating the effect of α-conotoxin TxIB on the morphine-induced conditioned place preference (CPP) and its behavioral changes in mice. Our results showed that TxIB inhibited expression and acquisition of morphine-induced CPP and did not produce a rewarding effect by itself. Moreover, repeated injections of TxIB have no effect on learning, memory, locomotor activity, and anxiety-like behavior. Therefore, blocking α6/α3β2β3 nAChRs inhibits the development of morphine-induced CPP. α-Conotoxin TxIB may be a potentially useful compound to mitigate the acquisition and/or retention of drug-context associations.

The Ameliorative Effects of Isorhynchophylline on Morphine Dependence Are Mediated Through the Microbiota-Gut-Brain Axis

Morphine abuse is a global public health problem. Increasing evidence has shown that gut microbiota dysbiosis plays an important role in several central nervous system diseases. However, whether there is an association between gut microbiota and morphine dependence remains unclear. In this study, the effects of isorhynchophylline on morphine dependence were evaluated based on the microbiota-gut-brain axis (MGBA). The results showed that isorhynchophylline could reverse the changes in alpha and beta diversity, composition, and richness of the intestinal flora occurring in morphine-dependent zebrafish, as well as the morphine-induced changes in the expression of MGBA-related genes in BV2 cells and the brain and intestine of zebrafish. Based on the results, we then used antibiotics to evaluate whether disrupting the gut microbiota would affect morphine addiction in zebrafish. The results showed that the antibiotic-induced intestinal floral imbalance changed the behavior of morphine-dependent zebrafish, the characteristics of the zebrafish intestinal flora, and the expression of MGBA-related genes in the zebrafish brain and intestine. Importantly, we also show that, following antibiotic administration, the ameliorative effects of isorhynchophylline on morphine addiction were lost. Together, our results indicate that the gut microbiota interacts with the brain, and dysbiosis of the intestinal flora may affect the efficacy of isorhynchophylline in the body. Our findings provide a novel framework for understanding the mechanisms of morphine addiction through the MGBA and may provide new therapeutic strategies for the use of Chinese medicines in the prevention of drug addiction.

A Comprehensive Review on the Role of Non-Coding RNAs in the Pathophysiology of Bipolar Disorder

Aim: Bipolar disorder is a multifactorial disorder being linked with dysregulation of several genes. Among the recently acknowledged factors in the pathophysiology of bipolar disorder are non-coding RNAs (ncRNAs). Methods: We searched PubMed and Google Scholar databases to find studies that assessed the expression profile of miRNAs, lncRNAs and circRNAs in bipolar disorder. Results: Dysregulated ncRNAs in bipolar patients have been enriched in several neuron-related pathways such as GABAergic and glutamatergic synapses, morphine addiction pathway and redox modulation. Conclusion: Altered expression of these transcripts in bipolar disorder provides clues for identification of the pathogenesis of this disorder and design of targeted therapies for the treatment of patients.

Mechanism of Dopaminergic Nerve Transmission in Different Doses of Morphine Addiction and Stress-Induced Depression

Depression not only threatens the health and quality of life of patients but also brings a huge mental and economic burden to the patients’ families. This paper mainly studies the mechanism of dopaminergic neurotransmission in different doses of morphine addiction and stress-induced depression. In the experiment, 40 male SD rats were selected. The experiment established a rat model of chronic stress depression. The rats used in this model are all raised in a single cage, and there will be various stimuli every day for 21 days, but high-intensity continuous stimuli must be avoided, and the same stimuli will not appear continuously. The experiment established a depression animal model through chronic unpredictable mild stress (CUMS), combined with the conditioned position preference (CPP) model of morphine addiction to detect the establishment of CPP in such animals, so as to explore certain stress stimuli or depression, the influence on morphine addiction, and the relationship between them. The second or third branches of pyramidal neurons were selected to analyze the PL and CA3 regions. When analyzing the density of dendrites, each animal selected at least 8 dendrites in order to count the number of dendrites and selected a length of 20 μm on each branch to record the number of dendrites. All measured values are expressed as average ± standard deviation and analyzed by SPSS17.0 statistical software, and Levene test is used in the scattered consistency test. The average NIV of PEN before injection was 11.92 ± 2.90 Hz, and the average latency was 0.16 ± 0.03 s. The results indicate that CUMS may reduce the conditioned learning and memory ability by damaging the learning loop, rather than affecting the reward loop to weaken the establishment of morphine-dependent CPP.

Effects of Ganoderma Lucidum Extract on Morphine-Induced Addiction and Memory Impairment in Mice

Ganoderma lucidum extract (Lingzhi) has been used so far with various pharmacological effects. However, the reports on its effects on drug addiction, especially morphine, and morphine-induced memory impairment in vivo, remain limited. In the present study, the effect of G. lucidum extracts on preventing morphine addiction was evaluated by the conditioned place preference model. The extract's learning and memory improvement activities on morphine-induced memory loss were examined using Y maze, novel recognition, and Morris water maze tests. The results found that G. lucidum extracts at doses of 200-400 mg/kg decreased conditioned place preference score and increased the percentage of alteration, novel object exploration, and prolongation of locating hidden platform. With these doses, G. lucidum extracts prevented morphine addiction and improved short-term memory, visual memory, and long-term memory impairment caused by morphine. Our results first demonstrated that G. lucidum extracts promised as an effective natural source in treating drug addiction and morphine-induced memory loss.

Prefrontal cortex eQTLs/mQTLs enriched in genetic variants associated with alcohol use disorder and other diseases

Aim: This study aimed to investigate the function of genome-wide association study (GWAS)-identified variants associated with alcohol use disorder (AUD)/comorbid psychiatric disorders. Materials & methods: Genome-wide genotype, transcriptome and DNA methylome data were obtained from postmortem prefrontal cortex (PFC) of 48 Caucasians (24 AUD cases/24 controls). Expression/methylation quantitative trait loci (eQTL/mQTL) were identified and their enrichment in GWAS signals for the above disorders were analyzed. Results: PFC cis-eQTLs (923 from cases+controls, 27 from cases and 98 from controls) and cis-mQTLs (9,932 from cases+controls, 264 from cases and 695 from controls) were enriched in GWAS-identified genetic variants for the above disorders. Cis-eQTLs from AUD cases were mapped to morphine addiction-related genes. Conclusion: PFC cis-eQTLs/ cis-mQTLs influence gene expression/DNA methylation patterns, thus increasing the disease risk.