Opioid use disorder is classified as a chronic recurrent disease of the central nervous system (CNS) which leads to personality disorders, co-morbidities and premature death. It develops as a result of long-term administration of various abused substances, along with morphine. The pharmacological action of morphine is associated with its stimulation of opioid receptors. Opioid receptors are a group of G protein-coupled receptors and activation of these receptors by ligands induces significant molecular changes inside the cell, such as an inhibition of adenylate cyclase activity, activation of potassium channels and reductions of calcium conductance. Recent data indicate that other signalling pathways also may be involved in morphine activity. Among these are phospholipase C, mitogen-activated kinases (MAP kinases) or β-arrestin. The present review focuses on major mechanisms which currently are considered as essential in morphine activity and dependence and may be important for further studies.

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Schizophrenia and depression are heterogeneous disorders. The complex pathomechanism of the diseases imply that medication responses vary across patients. Many psychotropic drugs are available but achieving optimal therapeutic effect can be challenging. The evidence correlates well with clinical observations, suggesting that new atypical antipsychotic drugs are effective against negative and cognitive symptoms of schizophrenia, as well as against affective symptoms observed in depression. The purpose of this review presents the background and evidence for the use of the new second/third-generation antipsychotics (aripiprazole, cariprazine, lurasidone, asenapine, brexpiprazole, lumateperone, pimavanserin) in treatment of schizophrenia and depression. We have first provided a brief overview of the major neurobiological underpinnings of schizophrenia and depression. We then shortly discuss efficacy, safety and limitations of ongoing pharmacotherapy used in depression and schizophrenia. Mainly, we have focused this review on the therapeutic potential of new atypical antipsychotic drugs—currently existing—to be effective in psychotic, as well as in affective disorders.

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In Vivo Characterization of the Ultrapotent Monoacylglycerol Lipase Inhibitor {4- [bis-(benzo[d] [1,3]dioxol-5-yl)methyl]-piperidin-1-yl}(1H-1,2,4-triazol-1-yl)methanone Niina Aaltonen, Ewa Kedzierska, Jolanta Orzelska-Górka, Marko Lehtonen, Dina Navia-Paldanius, Hermina Jakupovic, Juha R. Savinainen, Tapio Nevalainen, Jarmo T. Laitinen, Teija Parkkari, and Mikko Gynther ABSTRACT Monoacylglycerol lipase (MAGL) is a serine hydrolase that acts as a principal degradative enzyme for the endocannabinoid 2-arachidonoylglycerol (2-AG). In addition to terminating the signaling function of 2-AG, MAGL liberates arachidonic acid to be used as a primary source for neuroinflammatory prostaglandin synthesis in the brain. MAGL activity also contributes to cancer pathogenicity by producing precursors for tumor-promoting bioactive lipids. Pharmacological inhibitors of MAGL provide valuable tools for characterization of MAGL and 2-AG signaling pathways. They also hold great therapeutic potential to treat several pathophysiological conditions, such as pain, neurodegenerative disorders, and cancer. We have previously reported piperidine triazole urea, {4-[bis- , to be an ultrapotent and highly selective inhibitor of MAGL in vitro. Here, we characterize in vivo effects of JJKK-048. Acute in vivo administration of JJKK-048 induced a massive increase in mouse brain 2-AG levels without affecting brain anandamide levels. JJKK-048 appeared to be extremely potent in vivo. Activity-based protein profiling revealed that JJKK-048 maintains good selectivity toward MAGL over other serine hydrolases. Our results are also the first to show that JJKK-048 promoted significant analgesia in a writhing test with a low dose that did not cause cannabimimetic side effects. At a high dose, JJKK-048 induced analgesia both in the writhing test and in the tail-immersion test, as well as hypomotility and hyperthermia, but not catalepsy. IntroductionEndocannabinoids are lipid-structured signaling molecules that act as natural ligands for cannabinoid CB 1 and CB 2 receptors, which are also the targets of the psychoactive component of Cannabis sativa. The two most intensively studied endocannabinoids are 2-arachidonoylglycerol (2-AG) and anandamide (AEA) (Devane et al., 1992;Mechoulam et al., 1995;Sugiura et al., 1995). Generally, endocannabinoids are synthesized on demand from plasma membrane phospholipid precursors, and after exerting their effect by activating specific receptors, they are rapidly degraded by enzymatic activity. The principal brain endocannabinoid is 2-AG, which regulates central nervous system development and synaptic plasticity (Bisogno et al., 1999;Berghuis et al., 2007;Hashimotodani et al., 2007). Endocannabinoids also regulate cognition, emotional functions, and food intake, and are involved in several pathophysiological processes, including pain and neurodegenerative diseases (Pacher et al., 2006;Di Marzo and Petrosino, 2007;Sugiura, 2009). However, for therapeutic purposes, direct activation of cannabinoid receptors has proved to be c...