Fentanyl-Type Antagonist of the μ-Opioid Receptor: Important Role of Axial Chirality in the Active Conformation.

In recent years, synthetic opioids have emerged as a predominant cause of drug-overdose-related fatalities, causing the "opioid crisis." To design safer therapeutic agents, we accidentally discovered μ-opioid receptor (MOR) antagonists based on fentanyl with a relatively uncomplicated chemical composition that potentiates structural modifications. Here, we showed the development of novel atropisomeric fentanyl analogues that exhibit more potent antagonistic activity against MOR than naloxone, a morphinan MOR antagonist.

Synthetic cannabinoid CP-55,940 induces apoptosis in a human skeletal muscle model via regulation of CB receptors and L-type Ca channels.

Rhabdomyolysis has been reported in patients who abuse synthetic cannabinoids. However, no studies have yet assessed whether these cases reflect the direct cytotoxicity of synthetic cannabinoids on skeletal muscle, a possibility that the present study sought to address. Specifically, this study investigated the cytotoxicity of the synthetic cannabinoid CP-55,940, a compound that acts equally on both types of cannabinoid receptors (CB and CB), in a human embryonic rhabdomyosarcoma (RD) cell line.

Synthetic cannabinoids enhanced ethanol-induced motor impairments through reduction of central glutamate neurotransmission.

Marijuana or synthetic cannabinoids and alcohol are often used together, with these combinations causing motor impairments that can subsequently lead to motor vehicle accidents. This study investigated the combined use of both synthetic cannabinoids and ethanol and their effect on motor coordination in mice in addition to examining the neurochemical changes in the cerebellum. Ethanol (2 g/kg, i.

[Dependence and Cytotoxicity of Components of Cannabis].

Cannabis use among the younger population in Japan has been steadily increasing. The aim of the present review is to highlight recent knowledge regarding the molecular mechanisms of action and health risks associated with cannabis and synthetic cannabinoid consumption. We investigated the effects of Δ-tetrahydrocannabinol (THC) and synthetic cannabinoids on place conditioning in ICR mice.

[Present Conditions of Marijuana Regulation in USA: Medical and Recreational Use].

In most countries marijuana is regulated by the Single Convention on Narcotic Drugs. In Japan marijuana use is illegal under the Marijuana Control Law. In USA, marijuana is also classified as a schedule I drug, which is the most stringent regulation category under federal law.

Δ-Tetrahydrocannabinol elicited 22-kHz ultrasonic vocalization changes after air puff stimulus through CB receptor in adult rats.

Δ-Tetrahydrocannabinol (THC) is known to have various pharmacological effects mediated through activation of cannabinoid CB and CB receptors in rodents. In adult rats, 22- and 50-kHz ultrasonic vocalizations (USVs) serve as an effective communication system and as indicators of negative and positive states, respectively. The present study was performed to determine whether THC affects USVs in adult rats, and to determine the roles of cannabinoid receptors in these effects.

Synthetic cannabinoid AM2201 induces seizures: Involvement of cannabinoid CB receptors and glutamatergic transmission.

Abuse of synthetic cannabinoids is a serious social problem worldwide. Intentional ingestion of synthetic cannabinoids can cause severe toxicity, including seizures. Here we investigated the effects of acute administration of synthetic cannabinoids on the induction of epileptic seizures by monitoring electroencephalographic activity in freely moving mice.

Pyrolysis of UR-144, a synthetic cannabinoid, augments an affinity to human CB receptor and cannabimimetic effects in mice.

Drug abusers most often smoke 'herbal incense' as a cigarette or inhale it using a smoking tool. Smoking may cause pyrolysis of the drug and produce decomposed products of which biological effect has never been investigated. The synthetic cannabinoid UR-144 is known to undergo thermal degradation, giving a ring-opened isomer, so-called UR-144 degradant.

[Drug Dependence and Toxicity of Law-Evading Drugs: Their Mechanisms Explored from Basic Research].

The number of law-evading chemical substances that pose serious health risks to humans is increasing worldwide, including Japan and the Western world, and their abuse is becoming a serious social problem. Analysis of the chemical substances in these herbal products revealed the presence of synthetic cannabinoids. This review summarizes the pharmacological actions and dangers of chemical substances contained in law-evading herbal products by focusing on synthetic cannabinoids as a group of chemical substances contained in these products.

[Drug Dependence and Cytotoxicity of Law-evading Drugs: Their Identities Explored from Basic Research].

  Cases of people experiencing disturbed consciousness or dyspnea, causing traffic accidents, or requiring ambulance transport to hospital due to abuse of law-evading chemical substances have become a serious social problem in Japan. Most law-evading herbal products are marketed as incense or herbs and consist of finely chopped, dry vegetative matter mixed with chemical substances (drugs). Analysis of the chemical substances in these herbal products has demonstrated that they contain synthetic cannabinoids.

[Pharmacological properties of law-evading chemical substances].

In recent years, frequent cases of people suffering disturbed consciousness, dyspnea, etc. due to abuse of synthetic cannabis and being transported by ambulance or causing traffic accidents are occurring and are becoming a serious social problem in Japan. Most law-evading herbal products have colorful illustrations and logos and are sold as incense or herbs.

Current status of substance abuse and HIV infection in Japan.

Japan has experienced an epidemic of methamphetamine (MAP) abuse three times: The first epidemic was from 1951 to 1957, the second epidemic was from 1970 to 1994, and the third epidemic started in 1995 and continues today. Fortunately, HIV infection is not as serious a problem in Japan as it is in other countries. The major route of HIV infection in Japan has been through male homosexual transmission.

Splenectomy modifies hyperactive states of the dopaminergic system induced by morphine in C57BL/6J-bg(J)/bg(J) (beige-J) mice.

Genetic factors affect the locomotor activity induced by morphine, which mainly depends on the activation of dopaminergic systems, and morphine has distinct pharmacological activities in C57BL/6J-bg(J)bg(J) (beige-J) mice, which have genetic deficiencies in immunological function. We previously showed that beige-J mice exhibited greater locomotor activity and dopamine turnover, whereas splenectomy reduced this hyperlocomotion and dopamine turnover, which suggests that beige-J mice could be an experimental animal model for investigating hyperactivation of the dopaminergic system, and that the spleen may contribute to the susceptibility to activation of the dopaminergic system. Furthermore, morphine can induce hyperlocomotion mediated by activation of the dopaminergic system.

Dopaminergic hyperactivity accompanied by hyperlocomotion in C57BL/6J-bg(J)/bg(J) (beige-J) mice.

Genetic factors affect locomotor activity, which mainly depends on the activation of dopaminergic systems. C57BL/6J-bg(J)bg(J) (beige-J) mice, which exhibit deficiencies in immunological function, show behavioral hyperactivity. The present study was designed to investigate the locomotor activity of beige-J mice accompanied by a change in the dopaminergic system.

Cytotoxicity of synthetic cannabinoids on primary neuronal cells of the forebrain: the involvement of cannabinoid CB1 receptors and apoptotic cell death.

The abuse of herbal products containing synthetic cannabinoids has become an issue of public concern. The purpose of this paper was to evaluate the acute cytotoxicity of synthetic cannabinoids on mouse brain neuronal cells. Cytotoxicity induced by synthetic cannabinoid (CP-55,940, CP-47,497, CP-47,497-C8, HU-210, JWH-018, JWH-210, AM-2201, and MAM-2201) was examined using forebrain neuronal cultures.

Ecstasy (3, 4-methylenedioxymethamphetamine) use among Japanese rave population.

Aims: The aim of this study was to examine the prevalence of 3, 4-methylenedioxymethamphetamine (MDMA) use and to identify characteristics of MDMA users among rave attendees in Japan. This is the first rave-population study focusing on MDMA use in Japan.

Methods: The anonymous self-administrative questionnaire was conducted using laptop computers at four rave parties at three different venues in Tokyo, Japan.

[Drug discrimination properties and cytotoxicity of the cannabinoid receptor ligands].

The worldwide distribution of smokable herbal mixtures called "Spice" that contain synthetic cannabinoids with a pharmacological activity similar to delta 9-tetrahydrocannabinol (delta 9-THC) has been reported. The synthetic cannabinoids induce behavior and have biochemical properties similar to naturally occurring cannabinoids such as delta 9-THC. In drug discrimination procedures, animal behavior is differentially reinforced depending on the presence or absence of specific drug stimuli.

Cytotoxicity of synthetic cannabinoids found in "Spice" products: the role of cannabinoid receptors and the caspase cascade in the NG 108-15 cell line.

The worldwide distribution of "Spice" that contains synthetic cannabinoids with a pharmacological activity similar to Δ⁹-tetrahydrocannabinol has been reported. In the current study, we evaluated the cytotoxicity of the synthetic cannabinoids, CP-55,940, CP-47,497 and CP-47,497-C8 towards NG 108-15 cells and investigated their mechanism of cytotoxicity. CP-55,940, CP-47,497 and CP-47,497-C8 were all cytotoxic for NG 108-15 cells in a concentration-dependent manner.

[Animal models for evaluating of drug dependence liability].

Assessment of psychological dependence liability of drug is essential for regulatory compliance and the drug development process. The most reliable method for evaluating the psychic dependence liability of drug is the self-administration paradigm. The conditioned place preference paradigm is also useful method for evaluating the rewarding effect of drugs and is widely used.

[Pharmacological properties and dependence liabilities of synthetic cannabinoids].

Since 2000, types of abused drugs have increased in Japan and abused drugs are diversifying. Chemicals with structures similar to the drugs and stimulants restricted by law are sold as medicines that are not so restricted. Furthermore, drugs that have evaded attention of the law and abuse of these drugs are increasing rapidly.

[Evaluation of the rewarding effects of drugs by conditioned place preference (CPP) paradigm: properties of volatile organic solvents and uncontrolled newly-abused drugs].

The conditioned place preference paradigm has been used to evaluate the motivational effects of drugs. The primary motivational effects of a drug are conditioned to prominent environmental stimuli of a conditioned place preference box, and after several conditionings, animals acquire secondary motivational effects of drugs. If the drug experience produces a positive effect, it is expected that animals will spend more time in the drug-paired place.