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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 (CB1 and CB2), in a human embryonic rhabdomyosarcoma (RD) cell line. Exposure of these cells to CP-55,940 resulted in concentration-dependent decreases in cell viability. These effects were attenuated by pre-incubation with AM251 (30 µM), a selective CB1 receptor antagonist, but not by pre-incubation with AM630 (30 µM), a selective CB2 receptor antagonist. Following treatment with CP-55,940, RD cells exhibited apoptosis, as indicated by the accumulation of annexin-V, activation of caspase-3, and a loss of the mitochondrial membrane potential. Additionally, CP-55,940 treatment of RD cells led to increases in intracellular Ca2+ levels. CP-55,940-induced cell death was significantly attenuated in the absence of extracellular Ca2+, and was partially decreased by pre-incubation with verapamil (5 µM) or diltiazem (5 µM), compounds that block the l-type Ca2+ channel. Our results indicate that the cytotoxicity of CP-55,940 towards RD cells (skeletal muscle cells) is mediated by the CB1 receptor, but not by the CB2 receptor. Our results further suggest that calcium influx through the l-type channel may play an important role in the apoptosis induced by these compounds.

Purpose The aim of this study was to evaluate the neurotoxicity of psychoactive abused 2,5-dimethoxy-substituted phenethylamines “2C series” in monoaminergic neurons. Methods After the exposure to “2C series”, 2,5-dimethoxy-4-propylthiophenethylamine (2C-T-7), 2,5-dimethoxy-4-isopropylthiophenethylamine (2C-T-4), 2,5-dimethoxy-4-ethylthiophenthylamine (2C-T-2), 2,5-dimethoxy-4-iodophenethylamine (2C-I) or 2,5-dimethoxy-4-chlorophenethylamine (2C-C), we examined their neurotoxicity, morphological changes, and effects of concomitant exposure to 3,4-methylenedioxymethamphetamine (MDMA) or methamphetamine (METH), using cultured neuronal dopaminergic CATH.a cells and serotonin-containing B65 cells. Results Single dose exposure to “2C series” for 24 h showed significant cytotoxicity as increase in lactate dehydrogenase (LDH) release from both monoaminergic neurons: 2C-T-7, 2C-C (EC 50 ; 100 µM) > 2C-T-2 (150 µM), 2C-T-4 (200 µM) > 2C-I (250 µM) in CATH.a cells and 2C-T-7, 2C-I (150 µM) > 2C-T-2 (250 µM) > 2C-C, 2C-T-4 (300 µM) in B65 cells. The “2C series”-induced neurotoxicity in both cells was higher than that of MDMA or METH (EC 50 : ≥ 1–2 mM). In addition, apoptotic morphological changes were observed at relatively lower concentrations of “2C series”. The concomitant exposure to non-toxic dose of MDMA or METH synergistically enhanced 2C series drugs-induced LDH release and apoptotic changes in B65 cells, but to a lesser extent in CATH.a cells. In addition, the lower dose of 2C-T-7, 2C-T-2 or 2C-I promoted reactive oxygen species production in the mitochondria of B65 cells, even at the early stages (3 h) without apparent morphological changes. Conclusion The 2,5-dimethoxy-substitution of “2C series” induced severe neurotoxicity in both dopaminergic and serotonin-containing neurons. The non-toxic dose of MDMA or METH synergistically enhanced its neurotoxicity in serotonergic neurons.

Aim The regulation of new psychoactive and dangerous abused substances is very important for the prevention of drug abuse. A simple and effective evaluation method using laboratory animals is needed to regulate designated drugs with high accuracy and speed. Methods In the present study, we used the typical κ‐opioid receptor agonist U50,488H and the typical 5‐HT2A/2C receptor agonist 1‐(2,5‐dimethoxy‐4‐iodophenyl)‐2‐aminopropane hydrochloride (DOI), which have a similar mechanism of action to hallucinogenic drugs, in a conditioned place aversion (CPA) test in mice. In addition, because hallucinogenic drugs can cause emotional abnormalities during hallucinations, we performed a marble‐burying test in mice. Results In the CPA test, both κ‐opioid receptor and 5‐HT2A/2C receptor agonists produced significant aversive effects and abnormal behavior. These aversive effects and abnormal behavior were probably due in part to the hallucinogenic effects of these drugs. Conclusion Therefore, these tests using mice may be useful for evaluating hallucinogenic effects. We hope that these simple and rapid evaluation methods will be used to identify designated drugs. This study developed a simple way to test new psychoactive substances (NPS) in mice. Two drugs, U50,488H and DOI caused aversive and abnormal behaviors in mice, likely linked to their hallucinogenic properties. These results suggest such behavioral tests could help quickly identify and regulate harmful psychoactive drugs.

Purpose Some of the synthetic cannabinoids, often found in recreational drugs of the herbal form, reportedly induce a generalized seizure in drug abusers immediately after smoking. However, it is still unclear what elicits the sensorimotor responses, particularly in the case of hyperreflexia or excitatory behavior during the synthetic cannabinoid exposure. The purpose of this study was to explore the mechanism underlying the hyperreflexia induced by smoke intoxication of XLR-11 [(1-(5-fluoropentyl)-1 H -indol-3-yl)(2,2,3,3-tetramethylcyclopropyl)methanone]. Methods Locomotor activity and body temperature of mice were measured using an implanted Nano-Tag device. The intensity of catalepsy was determined by the bar test. The extracellular dopamine levels in the nucleus accumbens and glutamate levels in the hippocampus were measured by in vivo microdialysis using electrochemical detector-coupled high-performance liquid chromatography and by in vivo enzyme-based biosensor method, respectively. Results Mice exposed to the smoke of XLR-11 exhibited hyperreflexia at the very early phase, followed by hypothermia and catalepsy. The XLR-11 smoke contained XLR-11 and XLR-11 degradant at a ratio of approximately 1:25. Mice treated intraperitoneally with XLR-11 degradant at a dose comparable to the smoke inhalation experiment showed a hyperreflexic effect immediately after the treatment, but XLR-11 showed no such effect. The effects of XLR-11 degradant were significantly suppressed by pretreatment with AM-251, a CB 1 receptor antagonist. Extracellular dopamine and glutamate levels showed no evidence of involvement in the XLR-11 degradant-induced hyperreflexia; on the other hand gabapentin, a GABAergic antiepileptic, significantly suppressed the enhanced locomotor activity. Conclusions The hyperreflexic effect of XLR-11 degradant is mediated by the CB 1 receptor and possibly by GABAergic function.

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. In cumulative numbers, homosexual transmission accounted for 63% of the 11,146 HIV-positive patients and 40% of 5158 AIDS patients as of December 30, 2011. Intravenous drug use accounted for 0.3% and 0.4% of these cases, respectively. Drug abuse has changed during the past 20 years in Japan. The changes are summarized as follows: there has been: (1) a remarkable decrease in solvent abuse; (2) a stabilization of MAP abuse; (3) a penetration of cannabis abuse; (4) an emergence of evasive drug abuse; and (5) a silent increase in medical drug dependence. This implies that: (1) there has been a change from a “solvent dominant type” of use to a “cannabis dominant type,” that is, from a “Japanese type” to a “Western type”; (2) a shift to drugs which do not have a high potential to cause drug-induced psychosis; and (3) a shift from conduct that leads to arrest to conduct that does not lead to arrest. Regardless of whether the drug use is illicit or not, drug dependence is a mental disorder. Japan is urged to deal with drug abuse and dependence using not only the criminal model, but also the medical model.

Morphine produces analgesia at opiate receptors expressed in nociceptive circuits. μ , δ , and κ opiate receptor subtypes are expressed in circuits that can modulate nociception and receive inputs from endogenous opioid neuropeptide ligands. The roles played by each receptor subtype in nociceptive processing in drug-free and morphine-treated states have not been clear, however. We produced homologous, recombinant μ , opiate receptor, heterozygous and homozygous knockout animals that displayed ≈ 54% and 0% of wild-type levels of μ receptor expression, respectively. These mice expressed κ receptors and δ receptors at near wild-type levels. Untreated knockout mice displayed shorter latencies on tail flick and hot plate tests for spinal and supraspinal nociceptive responses than wild-type mice. These findings support a significant role for endogenous opioid-peptide interactions with μ opiate receptors in normal nociceptive processing. Morphine failed to significantly reduce nociceptive responses in hot plate or tail flick tests of homozygous μ receptor knockout mice, and heterozygote mice displayed right and downward shifts in morphine analgesia dose-effect relationships. These results implicate endogenous opioid-peptide actions at μ opiate receptors in several tests of nociceptive responsiveness and support μ receptor mediation of morphine-induced analgesia in tests of spinal and supraspinal analgesia.

The regulation of new psychoactive and dangerous abused substances is very important for the prevention of drug abuse. A simple and effective evaluation method using laboratory animals is needed to regulate designated drugs with high accuracy and speed. In the present study, we used the typical κ-opioid receptor agonist U50,488H and the typical 5-HT receptor agonist 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane hydrochloride (DOI), which have a similar mechanism of action to hallucinogenic drugs, in a conditioned place aversion (CPA) test in mice. In addition, because hallucinogenic drugs can cause emotional abnormalities during hallucinations, we performed a marble-burying test in mice. In the CPA test, both κ-opioid receptor and 5-HT receptor agonists produced significant aversive effects and abnormal behavior. These aversive effects and abnormal behavior were probably due in part to the hallucinogenic effects of these drugs. Therefore, these tests using mice may be useful for evaluating hallucinogenic effects. We hope that these simple and rapid evaluation methods will be used to identify designated drugs.

Homozygous transgenic knockout mice without μ-opioid receptors lack morphine-induced antinociception, locomotion, tolerance, physical dependence, and reward. μ receptors thus appear to play central roles in these morphine actions. Different levels of μ receptor expression are found in different humans and in different animal strains. In vitro studies indicate that some morphine responses persist after inactivation of as many as 90% of the initial μ receptor complement, while others are attenuated after inactivating many fewer receptors. Varying levels of μ receptor reserve could thus exist in different μ-expressing neuronal populations in vivo. Heterozygous μ receptor knockout mice express half of wild-type μ receptor levels. Tests of morphine actions in these mice reveal evidence for differing μ receptor reserves in brain circuits that mediate distinct opiate effects. Heterozygotes display attenuated locomotion, reduced morphine self-administration, intact tolerance, rightward shifts in morphine lethality dose/effect relationships, and variable effects on place preference compared to wild-type mice. They demonstrate full physical dependence, as measured by naloxone-precipitated abstinence following five days of morphine administration. Neuroadaptive changes in sites other than μ receptors could be involved in some of these results. Nevertheless, these data document substantial influences that individual differences in levels of μ receptor expression could exert on distinct opiate drug effects. They support the idea that functional μ receptor reserve differs among the diverse neuronal populations that mediate distinct properties of opiate drugs.

An unbiased place preference conditioning procedure was used to examine the influence of the non-opioid peptide, dynorphin A 2-17 (DYN 2-17), upon the conditioned and unconditioned effects of opiate withdrawal in the rat. Rats were implanted SC with two pellets containing 75 mg morphine or placebo. Single-trial place conditioning sessions with saline and the opioid receptor antagonist naloxone (0.1-1.0 mg/kg; SC) commenced 4 days later. Ten minutes before SC injections, animals received an IV infusion of saline or DYN 2-17 (0.1-5.0 mg/kg). Additional groups of placebo- and morphine-pelleted animals were conditioned with saline and DYN 2-17. During each 30-min conditioning session, somatic signs of withdrawal were quantified. Tests of place conditioning were conducted in pelleted animals 24 h later. Naloxone produced wet-dog shakes, body weight loss, ptosis and diarrhea in morphine-pelleted animals. Morphine-pelleted animals also exhibited significant aversions for an environment previously associated with the administration of naloxone. These effects were not observed in placebo-pelleted animals. DYN 2-17 pretreatment resulted in a dose-related attenuation of somatic withdrawal signs. However, conditioned place aversions were still observed in morphine-pelleted animals that had received DYN 2-17 in combination with naloxone. Furthermore, the magnitude of this effect did not differ from control animals. These data demonstrate that the administration of DYN 2-17 attenuates the somatic, but not the conditioned aversive effects of antagonist-precipitated withdrawal from morphine in the rat. Differential effects of this peptide in modulating the conditioned and unconditioned effects of opiate withdrawal are suggested.

Homozygous transgenic knockout mice without mu-opioid receptors lack morphine-induced antinociception, locomotion, tolerance, physical dependence, and reward. mu receptors thus appear to play central roles in these morphine actions. Different levels of mu receptor expression are found in different humans and in different animal strains. In vitro studies indicate that some morphine responses persist after inactivation of as many as 90% of the initial mu receptor complement, while others are attenuated after inactivating many fewer receptors. Varying levels of mu receptor reserve could thus exist in different mu-expressing neuronal populations in vivo. Heterozygous mu receptor knockout mice express half of wild-type mu receptor levels. Tests of morphine actions in these mice reveal evidence for differing mu receptor reserves in brain circuits that mediate distinct opiate effects. Heterozygotes display attenuated locomotion, reduced morphine self-administration, intact tolerance, rightward shifts in morphine lethality dose/effect relationships, and variable effects on place preference compared to wild-type mice. They demonstrate full physical dependence, as measured by naloxone-precipitated abstinence following five days of morphine administration. Neuroadaptive changes in sites other than mu receptors could be involved in some of these results. Nevertheless, these data document substantial influences that individual differences in levels of mu receptor expression could exert on distinct opiate drug effects. They support the idea that functional mu receptor reserve differs among the diverse neuronal populations that mediate distinct properties of opiate drugs.