Banning psychoactive substances is not enough, we need education too.

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The streptozocin model of diabetes induces neuropathic pain, anhedonia and impaired burrowing in rats

Proceedings of the British Pharmacological Society at http://www.pA2online.org/abstracts/Vol13Issue3abst252P.pdfMany diabetic patients experience chronic neuropathic pain leading to a reduced quality of life which poses a huge economic burden to the health system and society. There is a dire need to develop more efficacious analgesics as the majority of patients respond poorly to available treatments. The predictive validity of animal models for analgesia may be improved by reinstating specific innate rodent emotional wellbeing behaviours suppressed by pain (e.g. burrowing, sucrose preference). Streptozocin (STZ) given systemically to rats induces rapid and sustained changes that are seen in diabetic patients i.e. hyperglycaemia, polydypsia and frequently neuropathic pain. In this study we investigated whether the development of STZ induced diabetes in rats over 18 days reduces burrowing and sucrose preference (a measure of anhedonia) in line with neuropathic pain (static allodynia) and if these wellbeing behaviours can be improved by the analgesic, pregabalin and/or social paired housing.Non peer reviewedFinal Published versio

Editorial: Exploring neuroinflammatory pathways that contribute to chronic pain

© 2022 Lione and Fisher. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). https://creativecommons.org/licenses/by/4.0/Peer reviewe

Editorial: Exploring neuroinflammatory pathways that contribute to chronic pain, volume II

© 2024 The Author(s). This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY), https://creativecommons.org/licenses/by/4.0/Peer reviewe

Methylglyoxal, A Metabolite Increased in Diabetes is Associated with Insulin Resistance, Vascular Dysfunction and Neuropathies

The published manuscript is available at EurekaSelect via http://www.eurekaselect.com/openurl/content.php?genre=article&doi=10.2174/1389200217666151222155216 © 2018 Bentham Science PublishersBackground: Diabetes mellitus (DM) is a pandemic metabolic disease characterized by a chronically elevated blood glucose concentration (hyperglycemia) due to insulin dysfunction. Approximately 50% of diabetics show diabetes complications by the time they are diagnosed. Vascular dysfunction, nephropathy and neuropathic pain are common diabetes complications. Chronic hyperglycemia contributes to reactive oxygen species (ROS) generation such as methylglyoxal (MGO). Methods: Peer reviewed research papers were studied through bibliographic databases searching focused on review questions and inclusion/exclusion criteria. The reviewed papers were appraised according to the searching focus. The characteristics of screened papers were described, and a deductive qualitative content analysis methodology was applied to the included studies using a conceptual framework to yield this comprehensive systematic review. Results: Sixty-six papers were included in this review. Eleven papers related methylglyoxal generation to carbohydrates metabolism, ten papers related lipid metabolism to methylglyoxal and 5 papers showed the proteolytic pathways that contribute to methylglyoxal generation. Methylglyoxal metabolism was derived from 7 papers. Descriptive figure 1 was drawn to explain methylglyoxal sources and how diabetes increases methylglyoxal generation. Furthermore, twenty-six papers related methylglyoxal to diabetes complications from which 9 papers showed methylglyoxal ability to induce insulin dysfunction, an effect which was described in schematic figure 2. Additionally, fifteen papers revealed methylglyoxal contribution to vascular dysfunction and 3 papers showed methylglyoxal to cause neuropathic pain. Methylglyoxal-induced vascular dysfunction was drawn in a comprehensive figure 3. This review correlated methylglyoxal with diabetes and diabetes complications which were summarised in table 1. Conclusion: The findings of this review suggesting methylglyoxal as an essential therapeutic target for managing diabetes in the future.Peer reviewedFinal Accepted Versio

Co-Incubation with PPARβ/δ Agonists and Antagonists Modeled Using Computational Chemistry: Effect on LPS Induced Inflammatory Markers in Pulmonary Artery

© 2021 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/)Peroxisome proliferator activated receptor beta/delta (PPARβ/δ) is a nuclear receptor ubiquitously expressed in cells, whose signaling controls inflammation. There are large discrepan-cies in understanding the complex role of PPARβ/δ in disease, having both anti‐ and pro‐effects on inflammation. After ligand activation, PPARβ/δ regulates genes by two different mechanisms; induction and transrepression, the effects of which are difficult to differentiate directly. We studied the PPARβ/δ‐regulation of lipopolysaccharide (LPS) induced inflammation (indicated by release of nitrite and IL‐6) of rat pulmonary artery, using different combinations of agonists (GW0742 or L−165402) and antagonists (GSK3787 or GSK0660). LPS induced release of NO and IL‐6 is not significantly reduced by incubation with PPARβ/δ ligands (either agonist or antagonist), however, co-incubation with an agonist and antagonist significantly reduces LPS‐induced nitrite production and Nos2 mRNA expression. In contrast, incubation with LPS and PPARβ/δ agonists leads to a significant increase in Pdk−4 and Angptl−4 mRNA expression, which is significantly decreased in the presence of PPARβ/δ antagonists. Docking using computational chemistry methods indicates that PPARβ/δ agonists form polar bonds with His287, His413 and Tyr437, while antagonists are more promiscuous about which amino acids they bind to, although they are very prone to bind Thr252 and Asn307. Dual binding in the PPARβ/δ binding pocket indicates the ligands retain similar binding energies, which suggests that co‐incubation with both agonist and antagonist does not prevent the specific binding of each other to the large PPARβ/δ binding pocket. To our knowledge, this is the first time that the possibility of binding two ligands simultaneously into the PPARβ/δ binding pocket has been explored. Agonist binding followed by antagonist simultaneously switches the PPARβ/δ mode of action from induction to transrepression, which is linked with an increase in Nos2 mRNA expression and nitrite production.Peer reviewedFinal Published versio

USE OF NOVEL PSYCHOACTIVE SUBSTANCES (NPS) OF NATURAL ORIGIN: AN INTERNATIONAL SURVEY

Aim NPS recreational use are mostly derived and modified from constituents of natural origin. Here we investigated the motivation of natural NPS use, perception of potential associated health risks and demographic factors associated with natural NPS use. Methodology The Bristol Online Survey was in English and advertised on the drug forum Bluelight and social media Facebook pages and via University email between 1 July and 17 November 2018 (812 responses; 458 NPS users). This pharmacoepidemiologic study was evaluated using SPSS software (IBM SPSS Statistics version 24;MacOS Sierra 10.12.3). Results The main motivation (67%) for natural NPS use was curiosity to ‘’experience something new and different’’ with a low perception of health risk (85%). The preferred natural NPS was magic mushrooms (psilocybin, 95%) often in combination with cannabis (63%). Gender, living area, educational background, smoking frequency and employment significantly affected (P<0.001) natural NPS use. Male respondents, residents of suburban and rural areas, smokers and respondents with low educational level represented the majority of natural NPS users as well as the employed, the unable to work and retired groups. Similarly, sexual orientation significantly affected (p<0.05) natural NPS use. Conclusion Users’ low perception of natural NPS safety profile and the fact that natural NPS use correlates with a lower level of education, indicates a need for enhanced statutory targeted prevention interventions in schools. Many users (67%) reported natural NPS make them happier and more optimistic about life emphasizing the need to study the potential application of these substances in appropriate clinical settings for therapeutic purposes in mental health.Peer reviewe

The non-genomic effects of the PPARβγ agonist GW0742 on streptozotocin treated rat aorta

Copyright© Bentham Science Publishers; For any queries, please email at [email protected]: The ubiquitous nuclear receptor PPARβ/δ is increasingly being studied in regards to numerous diseases including diabetes following on the finding that PPARβ/δ agonist GW0742 controls Type 1 Diabetes in rats. Studies have shown that GW0742 has off target, non- PPARβ/δ effects in the cell although there are some key questions that remain to be addressed in respect to the significance of this control on vascular tone. Methods: Using isometric organ baths, rat aorta rings were exposed to ROCK inhibitors and the changes in contraction and dilation measured. Results: Our data shows that the PPARβ/δ agonist GW0742 (10 -7M) inhibits contractile responses to U46619 and phenylephrine, and that these responses are similar in normal and Streptozotocin (STZ) diabetic rat aorta. ROCK inhibitors Fasudil and Y27632 significantly reduced GW0742 mediated dilation of naïve rat aorta, but Fasudil had no effect on GW0742 dilation in STZ diabetic rat aorta. In contrast, STZ diabetic rat aorta pre-contracted with high [K +] Krebs lacked a dilatory response to GW0742, which taken together indicates that the mechanism of action of GW0742 mediated dilation changes in the diabetic state compared to non-diabetic state. Conclusion: This is the first direct evidence demonstrating the non- PPARβ/δ effect of GW0742 on contraction is irrespective to the diabetic state, and that GW0742 has the potential to induce vasodilation via multiple off-target mechanisms.Peer reviewedFinal Accepted Versio