Abnormal nociception and opiate sensitivity of STOP null mice exhibiting elevated levels of the endogenous alkaloid morphine

<p>Abstract</p> <p>Background-</p> <p>Mice deficient for the stable tubule only peptide (STOP) display altered dopaminergic neurotransmission associated with severe behavioural defects including disorganized locomotor activity. Endogenous morphine, which is present in nervous tissues and synthesized from dopamine, may contribute to these behavioral alterations since it is thought to play a role in normal and pathological neurotransmission.</p> <p>Results-</p> <p>In this study, we showed that STOP null brain structures, including cortex, hippocampus, cerebellum and spinal cord, contain high endogenous morphine amounts. The presence of elevated levels of morphine was associated with the presence of a higher density of mu opioid receptor with a higher affinity for morphine in STOP null brains. Interestingly, STOP null mice exhibited significantly lower nociceptive thresholds to thermal and mechanical stimulations. They also had abnormal behavioural responses to the administration of exogenous morphine and naloxone. Low dose of morphine (1 mg/kg, i.p.) produced a significant mechanical antinociception in STOP null mice whereas it has no effect on wild-type mice. High concentration of naloxone (1 mg/kg) was pronociceptive for both mice strain, a lower concentration (0.1 mg/kg) was found to increase the mean mechanical nociceptive threshold only in the case of STOP null mice.</p> <p>Conclusions-</p> <p>Together, our data show that STOP null mice displayed elevated levels of endogenous morphine, as well as an increase of morphine receptor affinity and density in brain. This was correlated with hypernociception and impaired pharmacological sensitivity to mu opioid receptor ligands.</p

Real-world nudging, pricing, and mobile physical activity coaching was insufficient to improve lifestyle behaviours and cardiometabolic health: the Supreme Nudge parallel cluster-randomised controlled supermarket trial

Background: Context-specific interventions may contribute to sustained behaviour change and improved health outcomes. We evaluated the real-world effects of supermarket nudging and pricing strategies and mobile physical activity coaching on diet quality, food-purchasing behaviour, walking behaviour, and cardiometabolic risk markers. Methods: This parallel cluster-randomised controlled trial included supermarkets in socially disadvantaged neighbourhoods across the Netherlands with regular shoppers aged 30–80 years. Supermarkets were randomised to receive co-created nudging and pricing strategies promoting healthier purchasing (N = 6) or not (N = 6). Nudges targeted 9% of supermarket products and pricing strategies 3%. Subsequently, participants were individually randomised to a control (step counter app) or intervention arm (step counter and mobile coaching app) to promote walking. The primary outcome was the average change in diet quality (low (0) to high (150)) over all follow-up time points measured with a validated 40-item food frequency questionnaire at baseline and 3, 6, and 12 months. Secondary outcomes included healthier food purchasing (loyalty card-derived), daily step count (step counter app), cardiometabolic risk markers (lipid profile and HbA1c via finger prick, and waist circumference via measuring tape), and supermarket customer satisfaction (questionnaire-based: very unsatisfied (1) to very satisfied (7)), evaluated using linear mixed-models. Healthy supermarket sales (an exploratory outcome) were analysed via controlled interrupted time series analyses. Results: Of 361 participants (162 intervention, 199 control), 73% were female, the average age was 58 (SD 11) years, and 42% were highly educated. Compared to the control arm, the intervention arm showed no statistically significant average changes over time in diet quality (β − 1.1 (95% CI − 3.8 to 1.7)), percentage healthy purchasing (β 0.7 (− 2.7 to 4.0)), step count (β − 124.0 (− 723.1 to 475.1), or any of the cardiometabolic risk markers. Participants in the intervention arm scored 0.3 points (0.1 to 0.5) higher on customer satisfaction on average over time. Supermarket-level sales were unaffected (β − 0.0 (− 0.0 to 0.0)). Conclusions: Co-created nudging and pricing strategies that predominantly targeted healthy products via nudges were unable to increase healthier food purchases and intake nor improve cardiometabolic health. The mobile coaching intervention did not affect step count. Governmental policy measures are needed to ensure more impactful supermarket modifications that promote healthier purchases. Trial registration: Dutch Trial Register ID NL7064, 30 May 2018, https://www.onderzoekmetmensen.nl/en/trial/2099

Real-world nudging, pricing, and mobile physical activity coaching was insufficient to improve lifestyle behaviours and cardiometabolic health: the Supreme Nudge parallel cluster-randomised controlled supermarket trial

Background: Context-specific interventions may contribute to sustained behaviour change and improved health outcomes. We evaluated the real-world effects of supermarket nudging and pricing strategies and mobile physical activity coaching on diet quality, food-purchasing behaviour, walking behaviour, and cardiometabolic risk markers. Methods: This parallel cluster-randomised controlled trial included supermarkets in socially disadvantaged neighbourhoods across the Netherlands with regular shoppers aged 30–80 years. Supermarkets were randomised to receive co-created nudging and pricing strategies promoting healthier purchasing (N = 6) or not (N = 6). Nudges targeted 9% of supermarket products and pricing strategies 3%. Subsequently, participants were individually randomised to a control (step counter app) or intervention arm (step counter and mobile coaching app) to promote walking. The primary outcome was the average change in diet quality (low (0) to high (150)) over all follow-up time points measured with a validated 40-item food frequency questionnaire at baseline and 3, 6, and 12 months. Secondary outcomes included healthier food purchasing (loyalty card-derived), daily step count (step counter app), cardiometabolic risk markers (lipid profile and HbA1c via finger prick, and waist circumference via measuring tape), and supermarket customer satisfaction (questionnaire-based: very unsatisfied (1) to very satisfied (7)), evaluated using linear mixed-models. Healthy supermarket sales (an exploratory outcome) were analysed via controlled interrupted time series analyses. Results: Of 361 participants (162 intervention, 199 control), 73% were female, the average age was 58 (SD 11) years, and 42% were highly educated. Compared to the control arm, the intervention arm showed no statistically significant average changes over time in diet quality (β − 1.1 (95% CI − 3.8 to 1.7)), percentage healthy purchasing (β 0.7 (− 2.7 to 4.0)), step count (β − 124.0 (− 723.1 to 475.1), or any of the cardiometabolic risk markers. Participants in the intervention arm scored 0.3 points (0.1 to 0.5) higher on customer satisfaction on average over time. Supermarket-level sales were unaffected (β − 0.0 (− 0.0 to 0.0)). Conclusions: Co-created nudging and pricing strategies that predominantly targeted healthy products via nudges were unable to increase healthier food purchases and intake nor improve cardiometabolic health. The mobile coaching intervention did not affect step count. Governmental policy measures are needed to ensure more impactful supermarket modifications that promote healthier purchases. Trial registration: Dutch Trial Register ID NL7064, 30 May 2018, https://www.onderzoekmetmensen.nl/en/trial/2099

Localization of endogenous morphine-like compounds in the mouse spinal cord

International audienceMorphine, codeine, morphine-6-glucuronide, and morphine-3-glucuronide are synthesized de novo in mammalian cells and in the central nervous system. Knowledge on endogenous morphine-like compound distribution in the adult mouse brain has been recently improved, and new hypotheses have been suggested about the potential implications in brain physiology. Endogenous morphine-like compounds have been shown to be synthesized in the spinal cord, but their localization is unknown. Here we describe the distribution of endogenous morphine-like compounds (morphine and/or its glucuronides and/or codeine) in the adult mouse spinal cord using a well-validated antibody. By using different microscopy approaches, we found the presence of morphine, codeine, or morphine glucuronides in γ-aminobutyric acid (GABA)-ergic neurons and astrocytes of the spinal cord. Whereas GABAergic neurons containing endogenous morphine-like compounds were located primarily in the ventral horn, astrocytes that were labeled for morphine-like compounds were found throughout the gray matter and the white matter. Our study demonstrates the possibility that endogenous morphine-like compounds in the central nervous system have other functions beyond their analgesic functions

Comparison of serum and lithium-heparinate plasma for the accurate measurements of endogenous and exogenous morphine concentrations

International audienceNo abstract availabl

Mapping of endogenous morphine-like compounds in the adult mouse brain: Evidence of their localization in astrocytes and GABAergic cells.

International audienceEndogenous morphine, morphine-6-glucuronide, and codeine, which are structurally identical to vegetal alkaloids, can be synthesized by mammalian cells from dopamine. However, the role of brain endogenous morphine and its derivative compounds is a matter of debate, and knowledge about its distribution is lacking. In this study, by using a validated antibody, we describe a precise mapping of endogenous morphine-like compounds (morphine and/or its glucuronides and/or codeine) in the mouse brain. First, a mass spectrometry approach confirmed the presence of morphine and codeine in mouse brain, but also, of morphine-6-glucuronide and morphine-3-glucuronide representing two metabolites of morphine. Second, light microscopy allowed us to observe immunopositive cell somas and cytoplasmic processes throughout the mouse brain. Morphine-like immunoreactivity was present in various structures including the hippocampus, olfactory bulb, band of Broca, basal ganglia, and cerebellum. Third, by using confocal microscopy and immunofluroscence co-localization, we characterized cell types containing endogenous opiates. Interestingly, we observed that morphine-like immunoreactivity throughout the encephalon is mainly present in γ-aminobutyric acid (GABA)ergic neurons. Astrocytes were also labeled throughout the entire brain, in the cell body, in the cytoplasmic processes, and in astrocytic feet surrounding blood vessels. Finally, ultrastructural localization of morphine-like immunoreactivity was determined by electron microscopy and showed the presence of morphine-like label in presynaptic terminals in the cerebellum and postsynaptic terminals in the rest of the mouse brain. In conclusion, the presence of endogenous morphine-like compounds in brain regions not usually involved in pain modulation opens the exciting opportunity to extend the role and function of endogenous alkaloids far beyond their analgesic functions

Real-world nudging, pricing, and mobile physical activity coaching was insufficient to improve lifestyle behaviours and cardiometabolic health: the Supreme Nudge parallel cluster-randomised controlled supermarket trial.

BACKGROUND: Context-specific interventions may contribute to sustained behaviour change and improved health outcomes. We evaluated the real-world effects of supermarket nudging and pricing strategies and mobile physical activity coaching on diet quality, food-purchasing behaviour, walking behaviour, and cardiometabolic risk markers. METHODS: This parallel cluster-randomised controlled trial included supermarkets in socially disadvantaged neighbourhoods across the Netherlands with regular shoppers aged 30-80 years. Supermarkets were randomised to receive co-created nudging and pricing strategies promoting healthier purchasing (N = 6) or not (N = 6). Nudges targeted 9% of supermarket products and pricing strategies 3%. Subsequently, participants were individually randomised to a control (step counter app) or intervention arm (step counter and mobile coaching app) to promote walking. The primary outcome was the average change in diet quality (low (0) to high (150)) over all follow-up time points measured with a validated 40-item food frequency questionnaire at baseline and 3, 6, and 12 months. Secondary outcomes included healthier food purchasing (loyalty card-derived), daily step count (step counter app), cardiometabolic risk markers (lipid profile and HbA1c via finger prick, and waist circumference via measuring tape), and supermarket customer satisfaction (questionnaire-based: very unsatisfied (1) to very satisfied (7)), evaluated using linear mixed-models. Healthy supermarket sales (an exploratory outcome) were analysed via controlled interrupted time series analyses. RESULTS: Of 361 participants (162 intervention, 199 control), 73% were female, the average age was 58 (SD 11) years, and 42% were highly educated. Compared to the control arm, the intervention arm showed no statistically significant average changes over time in diet quality (β - 1.1 (95% CI - 3.8 to 1.7)), percentage healthy purchasing (β 0.7 ( - 2.7 to 4.0)), step count (β - 124.0 (- 723.1 to 475.1), or any of the cardiometabolic risk markers. Participants in the intervention arm scored 0.3 points (0.1 to 0.5) higher on customer satisfaction on average over time. Supermarket-level sales were unaffected (β - 0.0 (- 0.0 to 0.0)). CONCLUSIONS: Co-created nudging and pricing strategies that predominantly targeted healthy products via nudges were unable to increase healthier food purchases and intake nor improve cardiometabolic health. The mobile coaching intervention did not affect step count. Governmental policy measures are needed to ensure more impactful supermarket modifications that promote healthier purchases. TRIAL REGISTRATION: Dutch Trial Register ID NL7064, 30 May 2018, https://www.onderzoekmetmensen.nl/en/trial/20990

Real-world nudging, pricing, and mobile physical activity coaching was insufficient to improve lifestyle behaviours and cardiometabolic health: the Supreme Nudge parallel cluster-randomised controlled supermarket trial

Background: Context-specific interventions may contribute to sustained behaviour change and improved health outcomes. We evaluated the real-world effects of supermarket nudging and pricing strategies and mobile physical activity coaching on diet quality, food-purchasing behaviour, walking behaviour, and cardiometabolic risk markers. Methods: This parallel cluster-randomised controlled trial included supermarkets in socially disadvantaged neighbourhoods across the Netherlands with regular shoppers aged 30–80 years. Supermarkets were randomised to receive co-created nudging and pricing strategies promoting healthier purchasing (N = 6) or not (N = 6). Nudges targeted 9% of supermarket products and pricing strategies 3%. Subsequently, participants were individually randomised to a control (step counter app) or intervention arm (step counter and mobile coaching app) to promote walking. The primary outcome was the average change in diet quality (low (0) to high (150)) over all follow-up time points measured with a validated 40-item food frequency questionnaire at baseline and 3, 6, and 12 months. Secondary outcomes included healthier food purchasing (loyalty card-derived), daily step count (step counter app), cardiometabolic risk markers (lipid profile and HbA1c via finger prick, and waist circumference via measuring tape), and supermarket customer satisfaction (questionnaire-based: very unsatisfied (1) to very satisfied (7)), evaluated using linear mixed-models. Healthy supermarket sales (an exploratory outcome) were analysed via controlled interrupted time series analyses. Results: Of 361 participants (162 intervention, 199 control), 73% were female, the average age was 58 (SD 11) years, and 42% were highly educated. Compared to the control arm, the intervention arm showed no statistically significant average changes over time in diet quality (β − 1.1 (95% CI − 3.8 to 1.7)), percentage healthy purchasing (β 0.7 ( − 2.7 to 4.0)), step count (β − 124.0 (− 723.1 to 475.1), or any of the cardiometabolic risk markers. Participants in the intervention arm scored 0.3 points (0.1 to 0.5) higher on customer satisfaction on average over time. Supermarket-level sales were unaffected (β − 0.0 (− 0.0 to 0.0)). Conclusions: Co-created nudging and pricing strategies that predominantly targeted healthy products via nudges were unable to increase healthier food purchases and intake nor improve cardiometabolic health. The mobile coaching intervention did not affect step count. Governmental policy measures are needed to ensure more impactful supermarket modifications that promote healthier purchases. Trial registration: Dutch Trial Register ID NL7064, 30 May 2018, https://www.onderzoekmetmensen.nl/en/trial/2099

Real-world nudging, pricing, and mobile physical activity coaching was insufficient to improve lifestyle behaviours and cardiometabolic health: the Supreme Nudge parallel cluster-randomised controlled supermarket trial

Abstract Background Context-specific interventions may contribute to sustained behaviour change and improved health outcomes. We evaluated the real-world effects of supermarket nudging and pricing strategies and mobile physical activity coaching on diet quality, food-purchasing behaviour, walking behaviour, and cardiometabolic risk markers. Methods This parallel cluster-randomised controlled trial included supermarkets in socially disadvantaged neighbourhoods across the Netherlands with regular shoppers aged 30–80 years. Supermarkets were randomised to receive co-created nudging and pricing strategies promoting healthier purchasing (N = 6) or not (N = 6). Nudges targeted 9% of supermarket products and pricing strategies 3%. Subsequently, participants were individually randomised to a control (step counter app) or intervention arm (step counter and mobile coaching app) to promote walking. The primary outcome was the average change in diet quality (low (0) to high (150)) over all follow-up time points measured with a validated 40-item food frequency questionnaire at baseline and 3, 6, and 12 months. Secondary outcomes included healthier food purchasing (loyalty card-derived), daily step count (step counter app), cardiometabolic risk markers (lipid profile and HbA1c via finger prick, and waist circumference via measuring tape), and supermarket customer satisfaction (questionnaire-based: very unsatisfied (1) to very satisfied (7)), evaluated using linear mixed-models. Healthy supermarket sales (an exploratory outcome) were analysed via controlled interrupted time series analyses. Results Of 361 participants (162 intervention, 199 control), 73% were female, the average age was 58 (SD 11) years, and 42% were highly educated. Compared to the control arm, the intervention arm showed no statistically significant average changes over time in diet quality (β − 1.1 (95% CI − 3.8 to 1.7)), percentage healthy purchasing (β 0.7 ( − 2.7 to 4.0)), step count (β − 124.0 (− 723.1 to 475.1), or any of the cardiometabolic risk markers. Participants in the intervention arm scored 0.3 points (0.1 to 0.5) higher on customer satisfaction on average over time. Supermarket-level sales were unaffected (β − 0.0 (− 0.0 to 0.0)). Conclusions Co-created nudging and pricing strategies that predominantly targeted healthy products via nudges were unable to increase healthier food purchases and intake nor improve cardiometabolic health. The mobile coaching intervention did not affect step count. Governmental policy measures are needed to ensure more impactful supermarket modifications that promote healthier purchases. Trial registration Dutch Trial Register ID NL7064, 30 May 2018, https://www.onderzoekmetmensen.nl/en/trial/2099