Chemical Composition, Antitumor Properties, and Mechanism of the Essential Oil from Plagiomnium acutum T. Kop.

Plagiomnium acutum T. Kop. (P. acutum) has been used as a traditional Chinese medicine for thousands of years to treat cancer but lacks evidence. The objective of this work was to reveal the chemical composition of P. acutum essential oil (PEO) and explore its potential antitumor activity and molecular mechanism. PEO was prepared by the simultaneous distillation-extraction method and characterized by gas chromatography/mass spectroscopy. CCK8 assay, flow cytometry, western blot, and immunofluorescence techniques were used to analyze the effects and mechanism of PEO against cancer cells. A total of 74 constituents of PEO were identified, with diterpenes (26.5%), sesquiterpenes (23.89%), and alcohols (21.81%) being the major constituents. Two terpenoids, selina-6-en-4-ol and dolabella-3,7-dien-18-ol, were detected in PEO for the first time. PEO showed significant cell growth inhibitory activity on HepG2 and A549 cells by blocking the G1 phase and inducing apoptosis, which may be attributed to its upregulation of p21Cip1 and p27Kip1 proteins and interference with mitochondrial membrane potential effect. Dolabella-3,7-dien-18-ol accounts for 25.5% of PEO and is one of the main active components of PEO, with IC50 values in HepG2 and A549 cells of (25.820 ± 0.216) µg/mL and (23.597 ± 1.207) µg/mL, respectively. These results confirmed the antitumor medicinal value of P. acutum and showed great application potential in the pharmaceutical industry.

Psychometric properties of the French version of the Kogan's Attitudes toward Older People scale: A cross-sectional study conducted on Cameroonian nursing students.

To determine the psychometric properties of a French version of the KOP scale on Cameroonian French-speaking nursing students.A cross-sectional study was conducted where a self-administered questionnaire in French was given to a convenience sample of 296 nursing students registered for three different nursing programs.The French version of the KOP scale demonstrated moderate psychometric properties. The internal consistency, indicated by the Cronbach's alpha, was moderate, while the explanatory factor analysis showed two factor loadings, which explained 58.44% of the total variance. CONCLUSION: The French version of the KOP scale can be a useful tool for studies in French-speaking African countries to assess the degree of ageism toward older adults. It is suggested that the original KOP scale be retranslated by African translators and administered to larger French-speaking populations in other countries.

Dysregulation of Nociceptin/Orphanin FQ and Dynorphin Systems in the Extended Amygdala of Alcohol Preferring Marchigian Sardinian (msP) Rats.

Previous studies have shown that genetically selected Marchigian Sardinian alcohol-preferring (msP) rats consume excessive amounts of ethanol to self-medicate from negative moods and to relieve innate hypersensitivity to stress. This phenotype resembling a subset of alcohol use disorder (AUD) patients, appears to be linked to a dysregulation of the equilibrium between stress and antistress mechanisms in the extended amygdala. Here, comparing water and alcohol exposed msP and Wistar rats we evaluate the transcript expression of the anti-stress opioid-like peptide nociceptin/orphanin FQ (N/OFQ) and its receptor NOP as well as of dynorphin (DYN) and its cognate κ-opioid receptor (KOP). In addition, we measured the transcript levels of corticotropin-releasing factor (CRF), CRF receptor 1 (CRF1R), brain-derived neurotrophic factor (BDNF) and of the tropomyosin receptor kinase B receptor (Trk-B). Results showed an innately up-regulation of the CRFergic system, mediating negative mood and stress responses, as well as an inherent up-regulation of the anti-stress N/OFQ system, both in the amygdala (AMY) and bed nucleus of the stria terminalis (BNST) of msP rats. The up-regulation of this latter system may reflect an attempt to buffer the negative condition elicited by the hyperactivity of pro-stress mechanisms since results showed that voluntary alcohol consumption dampened N/OFQ. Alcohol exposure also reduced the expression of dynorphin and CRF transmissions in the AMY of msP rats. In the BNST, alcohol intake led to a more complex reorganization of these systems increasing receptor transcripts in msP rats, along with an increase of CRF and a decrease of N/OFQ transcripts, respectively. Moreover, mimicking the effects of alcohol in the AMY we observed that the activation of NOP receptor by intracerebroventricular administration of N/OFQ in msP rats caused an increase of BDNF and a decrease of CRF transcripts. Our study indicates that both stress and anti-stress mechanisms are dysregulated in the extended AMY of msP rats. The voluntary alcohol drinking, as well as NOP agonism, have a significant impact on neuropeptidergic systems arrangement, bringing the systems back to normalization.

Hospital nurses' knowledge regarding older patients: a multicenter study.

BACKGROUND: Nursing care in hospitals increasingly involves older adults. A nursing workforce able to care for the ageing population is therefore critical for ensuring quality older adult care. Gaining insight in the knowledge and attitudes of nurses regarding older patients in the Netherlands is needed to develop and increase the impact of education- and quality improvement programs which can positively influence nurses' knowledge and attitudes regarding older patients. METHODS: A cross-sectional multicenter study was performed. Data was collected in ten tertiary medical teaching hospitals well spread across the Netherlands (89 wards, 2902 nurses). Knowledge levels were measured using the Knowledge about Older Patient-Quiz (KOP-Q), consisting of 30 true-false questions. Knowledge levels of registered nurses are compared with knowledge levels known from literature of first year nursing students; last year nursing students; nurses; and nurse specialist. Potential associated factors considered were: age; sex; education; experience; opinions and preferences. Opinion and preferences regarding working with older patients were measured by three questions: 1) which patient group nurses preferred to work with; 2) how nurses feel about the increase of older patients in the hospital; and 3) whether nurses find it difficult to care for older patients. RESULTS: From all wards, a representative sample of 1743 registered hospital nurses working on all 89 wards participated. On all wards, a large range in knowledge levels is observed between nurses, with 37% of nurses presenting knowledge levels comparable with nursing student and 31% of nurses presenting knowledge levels comparable with nurse specialists. Knowledge is related to age (p < .001), work experiences (p < .001), preparatory secondary education (p < .001) and nurses education level (p = .012). A minority (12.5%) prefers working with older patients and most nurses do not find it difficult. CONCLUSIONS: This study shows that there is a large diversity in knowledge levels of Dutch hospital nurses in every hospital, on every ward. A majority of nurses demonstrate negative opinions and preferences. This implies that older patients admitted can receive different levels of quality of care on the same day as nurses with different knowledge levels provide care during the various shifts. Findings demonstrate an urgent need for education programs with themes regarding essential care for older patients in the Netherlands.

Measurement of nurses' attitudes and knowledge regarding acute care older patients: Psychometrics of the OPACS-US combined with the KOP-Q.

In clinical practice, identifying positive and negative attitudes toward older patients is very important to improve quality of care provided to them. The Older People in Acute Care Survey - United States (OPACS-US) is an instrument measuring hospital nurses attitudes regarding older patients. However, psychometrics have never been assessed. Furthermore, knowledge being related to attitude and behavior should also be measured complementing the OPACS-US. The purpose of this study was to assess structural validity and reliability of the OPACS-US and assess whether the OPACS-US can be complemented with the Knowledge about Older Patients-Quiz (KOP-Q). A multicenter cross sectional design was conducted. Registered nurses (n = 130, mean age 39,9 years; working experience 14,6 years) working in four general hospitals were included in the study. Nurses completed the OPACS-US section A: practice experiences, B: general opinion and the KOP-Q online. Findings demonstrated that the OPACS-US is a valid and reliable survey instrument that measures practice experiences and general opinion. Furthermore, the OPACS-US can be combined with the KOP-Q adding a knowledge construct, and is ready for use within education and/or quality improvement programs in the USA.

Serendipity or prepared mind? Recollections of the KOP translocation (1967) and of one form of Perrault syndrome.

The human X/autosome translocation, designated KOP, was discovered by Dr. Philip D. Pallister in Montana in 1967 in a young man with apparent Klinefelter syndrome. Collaboratively it was possible to elucidate the genetic nature of his unprecedented chromosome rearrangement and its developmental effects in mother and son. In retrospect, these clinical and genetic studies at the height of the somatic cell genetics era (Ruddle, Siniscalco, etc.) presented human genetics with a highly productive opportunity to begin gene mapping of autosomes and the X chromosome. The late Victor McKusick considered the discovery of the KOP translocation, as he determined personally in Montana, one of the major transforming events in human genetics. The Perrault syndrome evaluated in two families in Montana and one in Sicily for familial deafness, primary amenorrhea and neurologic impairment (progressive in some), turned out to be heterogeneous. In the "hands" of Dr. M.-C. King of Seattle four forms of Perrault syndrome have been identified. The autosomal recessive mutation present in the P family studied with Dr. Pallister in Helena, turned out to affect the mitochondrial histidyl tRNA synthetase gene present in prokaryotes, annelids, fungi and mammals, hence, must already have been present in LUCA some 3.8 billion years ago.

Contribution of the opioid system to depression and to the therapeutic effects of classical antidepressants and ketamine.

Major depressive disorder (MDD) afflicts approximately 5 % of the world population, and about 30-50 % of patients who receive classical antidepressant medications do not achieve complete remission (treatment resistant depressive patients). Emerging evidence suggests that targeting opioid receptors mu (MOP), kappa (KOP), delta (DOP), and the nociceptin/orphanin FQ receptor (NOP) may yield effective therapeutics for stress-related psychiatric disorders. As depression and pain exhibit significant overlap in their clinical manifestations and molecular mechanisms involved, it is not a surprise that opioids, historically used to alleviate pain, emerged as promising and effective therapeutic options in the treatment of depression. The opioid signaling is dysregulated in depression and numerous preclinical studies and clinical trials strongly suggest that opioid modulation can serve as either an adjuvant or even an alternative to classical monoaminergic antidepressants. Importantly, some classical antidepressants require the opioid receptor modulation to exert their antidepressant effects. Finally, ketamine, a well-known anesthetic whose extremely efficient antidepressant effects were recently discovered, was shown to mediate its antidepressant effects via the endogenous opioid system. Thus, although opioid system modulation is a promising therapeutical venue in the treatment of depression further research is warranted to fully understand the benefits and weaknesses of such approach.

Deciphering the molecular basis of the kappa opioid receptor selectivity: A Molecular Dynamics study.

Selective antagonists for the kappa opioid receptor (KOP) have the potential to treat opiate and alcohol addiction, as well as depression and other CNS disorders. Over the years, the development of KOP-selective antagonists yielded very few successful compounds. Recently, N-substituted trans-3,4-dimethyl-4-(3-hydroxyphenyl)piperidines have emerged as a novel class of pure opioid receptor antagonists, including the marketed Mu opioid receptor (MOP) peripheral antagonist Alvimopan and the potent KOP antagonist JDTic. However, the selectivity determinants of this class of compounds towards the opioid receptor subtypes are still vague and understudied. In this work, we have performed Molecular Dynamics (MD) simulation to gain insights into the differential binding of this class of compounds into KOP, as exemplified by Alvimopan and JDTic. Our study indicated that the selectivity largely depends on ligands interaction with the selectivity pocket formed by Val108, Thr111, and Val118, supported by two additional polar and hydrophobic contacts with Asp138 and Trp287, respectively. Our results also demonstrate, for the first time, that non-morphinan ligands can still adopt the "message-address model" for KOP efficacy and selectivity by binding to Glu297.

Involvement of GRK2 in modulating nalfurafine-induced reduction of excessive alcohol drinking in mice.

Though it is well known that G protein-coupled receptor kinase 2 [GRK2] is involved in regulation of mu opioid receptor [MOR] desensitization and morphine-related behaviors, the potential role of GRK2 in regulation of kappa opioid receptor [KOR] functions in vivo has not been established yet. A couple of recent studies have found that GRK2 activity desensitizes KOR functions via decreasing G protein-coupled signaling with sensitizing arrestin-coupled signaling. Nalfurafine, a G protein-biased KOR full agonist, produces an inhibitory effect on alcohol intake in mice, with fewer side effects (sedation, aversion, or anxiety/depression-like behaviors). Using RNA sequencing (RNA-seq) analysis, we first identified that nuclear transcript level of grk2 [adrbk1] (but not other grks) was significantly up-regulated in mouse nucleus accumbens shell (NAcs) after chronic excessive alcohol drinking, suggesting alcohol specifically increased NAcs grk2 expression. We then tested whether selective GRK2/3 inhibitor CMPD101 could alter alcohol intake and found that CMPD101 alone had no effect on alcohol drinking. Therefore, we hypothesized that the grk2 increase in the NAcs could modulate the nalfurafine effect on alcohol intake via interacting with the G protein-mediated KOR signaling. Nalfurafine decreased alcohol drinking in a dose-related manner, and pretreatment with CMPD101 enhanced the reduction in alcohol intake induced by nalfurafine, indicating an involvement of GRK2/3 blockade in modulating G protein-biased KOR agonism of nalfurafine. Together, our study provides initial evidence relevant to the transcriptional change of grk2 gene in the NAc shell after excessive alcohol drinking. Pharmacological GRK2/3 blockade enhanced nalfurafine's efficacy, suggesting a GRK2/3-mediated mechanism, probably through the G protein-mediated KOR signaling.

Nociceptive behavior and central neuropeptidergic dysregulations in male and female mice of a Fabry disease animal model.

Fabry disease (FD) is an X-linked inherited disorder characterized by glycosphingolipid accumulation due to deficiency of α-galactosidase A (α-Gal A) enzyme. Chronic pain and mood disorders frequently coexist in FD clinical setting, however underlying pathophysiologic mechanisms are still unclear. Here we investigated the mechanical and thermal sensitivity in α-Gal A (-/0) hemizygous male and the α-Gal A (-/-) homozygous female mice. We also characterized the gene expression of dynorphinergic, nociceptinergic and CRFergic systems, known to be involved in pain control and mood disorders, in the prefrontal cortex, amygdala and thalamus of α-Gal A (-/0) hemizygous male and the α-Gal A (-/-) homozygous female mice. Moreover, KOP receptor protein levels were evaluated in the same areas. Fabry knock-out male, but not female, mice displayed a decreased pain threshold in both mechanical and thermal tests compared to their wild type littermates. In the amygdala and prefrontal cortex, we observed a decrease of pDYN mRNA levels in males, whereas an increase was assessed in females, thus suggesting sex-related dysregulation of stress coping and pain mechanisms. Elevated mRNA levels for pDYN/KOP and CRF/CRFR1 systems were observed in male and female thalamus, a critical crossroad for both painful signals and cognitive/emotional processes. KOP receptor protein level changes assessed in the investigated areas, appeared mostly in agreement with KOP gene expression alterations. Our data suggest that α-Gal A enzyme deficiency in male and female mice is associated with distinct neuropeptide gene and protein expression dysregulations of investigated systems, possibly related to the neuroplasticity underlying the neurological features of FD.

In vitro profiling of opioid ligands using the cAMP formation inhibition assay and the ß-arrestin2 recruitment assay: No two ligands have the same profile.

Previously, we showed that no two of seven opioids administered by the intracerebroventricular route had the same potency rank order for evoking antinociception, constipation and respiratory depression in rats. To gain insight at the cellular level, this study was designed to systematically investigate the activity profiles of six commonly used opioid ligands using the forskolin-stimulated cAMP assay and a ß-arrestin2 recruitment assay in cultured HEK-293 cells transfected with MOP(µ), DOP(δ) or KOP(κ) receptors(-r). Morphine was a potent agonist at the MOP-r in the cAMP assay whereas it was a weak agonist at the KOP-r and DOP-r. Oxycodone had moderate efficacy and low potency at the MOP-r. Buprenorphine was a potent MOP-r and DOP-r agonist; its efficacy rank order was DOP > MOP > KOP. Fentanyl was a potent agonist at the MOP-r; its efficacy rank order was MOP > DOP > KOP. For DPDPE, its agonist efficacy was confined to the DOP-r, whereas for U69593, its efficacy rank order was KOP>> MOP. For the ß-arrestin2 assay, fentanyl had full efficacy at the MOP-r whereas morphine and oxycodone were weak with insignificant efficacy at DOP and KOP receptors. Buprenorphine did not recruit ß-arrestin2 at all three opioid-receptors. DPDPE and U69593 had full efficacy for ß-arrestin2 recruitment to the DOP-r and KOP-r respectively. Despite the low efficacy and potency of morphine, oxycodone and buprenorphine in recruiting ß-arrestin2 to the MOP-r herein, these opioids all evoked respiratory depression and constipation in rats. Together, our findings discount a key role for ß-arrestin2 recruitment at the MOP-r in evoking opioid-related side-effects.

Discussion and Comments on KOP and ∆Keff.

This article addresses online discussions with comments related to Kop and ∆Keff used in fatigue crack growth (FCG) analyses and modeling. The author of this article assembled an online discussion pertaining to the critical issues and challenges on Kop and ∆Keff, which took place during the summer of 2020. The meetings were titled, Recent Advances on FCG Investigations and Modeling.

Molecular Basis of Opioid Action: From Structures to New Leads.

Since the isolation of morphine from the opium poppy over 200 years ago, the molecular basis of opioid action has remained the subject of intense inquiry. The identification of specific receptors responsible for opioid function and the discovery of many chemically diverse molecules with unique opioid-like efficacies have provided glimpses into the molecular logic of opioid action. Recent revolutions in the structural biology of transmembrane proteins have, for the first time, yielded high-resolution views into the 3-dimensional shapes of all 4 opioid receptors. These studies have begun to decode the chemical logic that enables opioids to specifically bind and activate their receptor targets. A combination of spectroscopic experiments and computational simulations has provided a view into the molecular movements of the opioid receptors, which itself gives rise to the complex opioid pharmacology observed at the cellular and behavioral levels. Further diversity in opioid receptor structure is driven by both genetic variation and receptor oligomerization. These insights have enabled computational drug discovery efforts, with some evidence of success in the design of completely novel opioids with unique efficacies. The combined progress over the past few years provides hope for new, efficacious opioids devoid of the side effects that have made them the scourge of humanity for millennia.

mTORC1 pathway is involved in the kappa opioid receptor activation-induced increase in excessive alcohol drinking in mice.

KOP-r agonist U50,488H produces strong aversion and anxiety/depression-like behaviors that enhance alcohol intake and promote alcohol seeking and relapse-like drinking in rodents. Mammalian target of rapamycin complex 1 (mTORC1) pathway in mouse striatum is highly involved in excessive alcohol intake and seeking, and in the U50,488H-induced conditioned place aversion. Therefore, we hypothesized that KOP-r activation increases alcohol consumption through the mTORC1 activation. This study focuses on: (1) how chronic excessive alcohol drinking (4-day drinking-in-the-dark paradigm followed by 3-week chronic intermittent access drinking paradigm [two-bottle choice, 24-h access every other day]) affected nuclear transcript levels of the mTORC1 pathway genes in mouse nucleus accumbens shell (NAcs), using transcriptome-wide RNA sequencing analysis; and (2) whether selective mTORC1 inhibitor rapamycin could alter excessive alcohol drinking and prevent U50,488H-promoted alcohol intake. Thirteen nuclear transcripts of mTORC1 pathway genes showed significant up-regulation in the NAcs, with two genes down-regulated, after excessive alcohol drinking, suggesting the mTORC1 pathway was profoundly disrupted. Single administration of rapamycin decreased alcohol drinking in a dose-dependent manner. U50,488H increased alcohol drinking, and pretreatment with rapamycin, at a dose lower than effective doses, blocked the U50,488H-promoted alcohol intake in a dose-dependent manner, indicating a mTORC1-mediated mechanism. Our results provide supportive and direct evidence relevant to the transcriptional profiling of the critical mTORC1 genes in mouse NAc shell: with functional and pharmacological effects of rapamycin, altered nuclear transcripts in the mTORC1 signaling pathway after excessive alcohol drinking may contribute to increased alcohol intake triggered by KOP-r activation.

Video-based tools to enhance nurses' geriatric knowledge: A development and pilot study.

BACKGROUND: The need for health care professionals with geriatric knowledge is expected to increase due to aging of society. Educational tools that fit the specific learning styles of nurses and nursing students might be useful for this. Serioussoap.nl (available in Dutch and English) is an educational tool that integrates video-based gaming and storytelling, and it might be an effective way to improve the geriatric knowledge of nurses or nursing students. OBJECTIVES: To investigate the effect of Serioussoap.nl on the geriatric knowledge of nurses and nursing students, and to evaluate its usability. DESIGN: We conducted a development and an explorative pilot study, using a pretest posttest quantitative design to investigate the effect of Serioussoap.nl on geriatric knowledge. A qualitative approach was used to evaluate its usability. PARTICIPANTS AND SETTING: Three vocational nursing schools (n = 119 second/third year students), one baccalaureate nursing university (n = 77 first year vocational nurses) and one home-care organization (n = 44 vocational nurses) in the Netherlands participated in the quantitative study, and 94 vocational students participated in the qualitative study. METHODS: We measured the effect on geriatric knowledge with the Knowledge of Older People Questionnaire (KOP-Q, score 0-30). The qualitative study included observations of 94 participants while they played Serioussoap.nl, four semi-structured focus groups and eleven individual interviews. RESULTS: The study demonstrated a significant increase of geriatric knowledge of 7.8% (+2.3 score on the KOP-Q, 95% Confidence Interval (1.4-3.2, p < 0.001). The qualitative data showed that Serioussoap.nl contributed to the reflective learning-style and enhanced meaningful learning. CONCLUSION: Serioussoap.nl increased the students' geriatric knowledge and was perceived as a suitable and effective educational tool for vocational nursing students and nurses.

Effects of Kappa opioid receptor blockade by LY2444296 HCl, a selective short-acting antagonist, during chronic extended access cocaine self-administration and re-exposure in rat.

RATIONALE: Cocaine addiction is a chronic brain disease characterized by compulsive drug intake and dysregulation of brain reward systems. Few preclinical studies have modeled the natural longitudinal course of cocaine addiction. Extended access self-administration protocols are powerful tools for modeling the advanced stages of addiction; however, few studies have duration of drug access longer than 12 h/session, potentially limiting their construct validity. Identification of changes in cocaine intake patterns during the development of addictive-like states may allow better treatments for vulnerable subjects. The kappa opioid receptor (KOPr) system has been implicated in the neurobiological regulation of addictive states as well as mood and stress disorders, with selective KOPr antagonists proposed as possible pharmacotherapeutic agents. Chronic cocaine exposure increases the expression of KOPr and its endogenous agonists, the dynorphins, in several brain areas in rodents. OBJECTIVES: To examine the behavioral pattern of intake during chronic (14 days) 18 h intravenous cocaine self-administration (0.5 mg/kg/infusion) and the effect of a novel short-acting KOPr antagonist LY2444296 HCl (3 mg/kg) administered during sessions 8 to 14 of chronic 18 h/day cocaine self-administration and prior to a single re-exposure session after 2 cocaine-free withdrawal days. RESULTS: Both daily and hourly cocaine intake patterns changed over 14 days of 18 h self-administration. LY pretreatment affected the pattern of self-administration across the second week of extended access cocaine self-administration and prevented the increase in cocaine intake during re-exposure. CONCLUSIONS: Overall, the KOPr antagonist attenuated escalated cocaine consumption in a rat model of extended access cocaine self-administration.

Clinically utilized kappa-opioid receptor agonist nalfurafine combined with low-dose naltrexone prevents alcohol relapse-like drinking in male and female mice.

Alcohol relapse is a treatment goal for alcohol dependence and the target for medications' development. Clinically utilized nalfurafine (NFF) is a potent and selective kappa- opioid receptor (KOP-r) agonist, with fewer side effects (e.g., sedation or anhedonia) than classic KOP-r full agonists. We have recently found that NFF reduces excessive alcohol drinking in mice via a KOP-r-mediated mechanism. Here, we further investigated whether NFF alone (1-10 µg/kg) or in combination with naltrexone (NTX, mu-opioid receptor [MOP-r] antagonist) altered alcohol relapse-like drinking using a mouse alcohol deprivation effect (ADE) paradigm to mimic the relapse episodes in human alcoholics. Nalmefene (NMF, clinically utilized KOP-r partial agonist with MOP-r antagonism) was used as a reference compound for the effects on mouse ADE of new NFF + NTX combination. After exposed to 3-week intermittent- access alcohol drinking (two-bottle choice, 24-h access every other day), both male and female mice displayed excessive alcohol intake and then pronounced ADE after 1-week abstinence. NFF prevented the ADE in a dose-dependent manner in both male and female mice. A combination of NFF with NTX reduced the ADE without sex differences at doses lower than those individual effective ones, suggesting synergistic effects between the two compounds. NMF prevented the ADE in both sexes, while selective KOP-r antagonist nor-BNI had no effect. Our new study suggests that a combination of clinically-utilized, potent KOP-r agonist NFF with low-dose NTX has therapeutic potential in alcohol "relapse" treatment.

Effects of mesyl salvinorin B alone and in combination with naltrexone on alcohol deprivation effect in male and female mice.

Alcohol relapse plays a major role in alcohol dependence and is an important focus for the treatment of alcoholism. The alcohol deprivation effect (ADE) is a widely used paradigm in rodents to model the relapse episodes that occur in human alcoholics. Mesyl Salvinorin B (MSB) is a potent and selective kappa opioid receptor (KOP-r) full agonist, with fewer side effects (e.g., sedation or anhedonia) than classic KOP-r full agonists and a longer duration of action in mice than the structurally similar salvinorin A. We have recently found that MSB prevents cocaine seeking in a rat self-administration model and reduces excessive alcohol drinking in a mouse escalation model via a KOP-r-mediated mechanism. Here, we further investigated whether MSB alone (0.3-3 mg/kg) or in combination with naltrexone (mu-opioid receptor antagonist at 1 mg/kg) altered alcohol "relapse" drinking using a mouse ADE paradigm. Both male and female mice, exposed to 3-week intermittent access alcohol drinking in a two-bottle choice paradigm with 24-h access every other day, developed excessive alcohol intake and then displayed pronounced ADE after 1-week abstinence. Acute administration of MSB prevented the ADE at 3 mg/kg in both male and female mice. Upon investigation of potential synergistic effects between naltrexone and MSB, we found that acute administration of a combination of MSB (0.3 mg/kg) and naltrexone (1 mg/kg) reduced the ADE at doses lower than those individual effective doses, with no sex difference. Our study suggests that the KOP-r full agonist MSB both alone and in combination with naltrexone shows potential in alcohol "relapse" treatment models.

Mu-opioid peptide (MOP) and nociceptin/orphanin FQ peptide (NOP) receptor activation both contribute to the discriminative stimulus properties of cebranopadol in the rat.

The novel potent analgesic cebranopadol is an agonist at nociceptin/orphanin FQ peptide (NOP) and classical opioid receptors, with the highest in-vitro activity at NOP and mu-opioid peptide (MOP) receptors, and somewhat lower activity at kappa-opioid peptide (KOP) and delta-opioid peptide (DOP) receptors. We addressed the question of which of these pharmacological activities contribute to the stimulus properties of cebranopadol using a rat drug discrimination procedure. First, cebranopadol was tested in generalization tests against a morphine cue, including receptor-specific antagonism. Second, cebranopadol was established as a cue, and MOP, NOP, KOP and DOP receptor-selective agonists were tested in generalization tests. Third, cebranopadol in combination with receptor-selective antagonists was tested against the cebranopadol cue. Cebranopadol generalized to the morphine cue. Full generalization was only seen at clearly supra-analgesic doses. The effect of cebranopadol was reduced by naloxone, but was enhanced by the NOP receptor antagonist J-113397. In cebranopadol-trained rats, cebranopadol as well as morphine produced generalization. A NOP receptor agonist did not, while a DOP receptor agonist and a KOP receptor agonist weakly generalized to the cebranopadol cue. Conversely, generalization of cebranopadol was reduced by naloxone and J-113397, but not by a DOP or a KOP receptor antagonist. These results suggest a contribution of MOP receptor activity and a relative lack of contribution of DOP and KOP receptor activity to cebranopadol's stimulus properties. The findings regarding the contribution of NOP receptor activity were equivocal, but interestingly, the morphine-like stimulus property of cebranopadol appears to be reduced by its intrinsic NOP receptor activity.

The Knowledge-about-Older-Patients - Quiz (KOP-Q) for nurses: Cross-cultural validation between the Netherlands and United States of America.

BACKGROUND: The Knowledge about Older Patients-Quiz (KOP-Q) is designed as a unidimensional scale measuring knowledge of hospital nurses about older patients. Furthermore, the KOP-Q measures a second unidimensional construct, certainty of hospital nurses about their knowledge. The KOP-Q is developed and validated in the Netherlands. Whether the KOP-Q can be used in other countries is unknown given the cultural and language differences. OBJECTIVES: Investigate the level of measurement invariance of the KOP-Q between the Netherlands and United States of America (USA). DESIGN: A multicenter international cross-sectional design. SETTINGS: Four general hospitals in the Netherlands and four general hospitals in the USA. PARTICIPANTS: Nurses from the Netherlands (n=201) and the USA (n=130) were invited to participate by email from the ward manager, distributing flyers and present messages on the online hospital communication boards. Questions of the KOP-Q were completed online. METHOD: The level of measurement invariance (configural, metric or scalar invariance) across countries was tested by running increasingly constrained structural equation models, and testing whether these models fitted the data. RESULTS: Both the knowledge and certainty construct of the KOP-Q proved unidimensional in the Netherlands and USA sample. Test results of the measurement invariance across the Netherlands and USA indicated a stable, partial scalar invariance (15 items full scalar invariance) for the knowledge items and full scalar invariance for the certainty items. CONCLUSIONS: The KOP-Q shows to function uniformly across both language groups and can therefore be used to assess nurses' knowledge and their certainty about this knowledge which can be important for educational and/or quality improvement programs in the USA. Furthermore, the KOP-Q is suitable to make comparisons between the Netherlands and the USA using latent variable models. Before the KOP-Q can be used in other countries, cross-cultural tests should again be performed.