Anti-nociceptive and desensitizing effects of olvanil on capsaicin-induced thermal hyperalgesia in the rat

Background: Olvanil (NE 19550) is a non-pungent synthetic analogue of capsaicin, the natural pungent ingredient of capsicum which activates the transient receptor potential vanilloid type-1 (TRPV1) channel and was developed as a potential analgesic compound. Olvanil has potent anti-hyperalgesic effects in several experimental models of chronic pain. Here we report the inhibitory effects of olvanil on nociceptive processing using cultured dorsal root ganglion (DRG) neurons and compare the effects of capsaicin and olvanil on thermal nociceptive processing in vivo; potential contributions of the cannabinoid CB1 receptor to olvanil’s anti-hyperalgesic effects were also investigated. Methods: A hot plate analgesia meter was used to evaluate the anti-nociceptive effects of olvanil on capsaicin-induced thermal hyperalgesia and the role played by CB1 receptors in mediating these effects. Single cell calcium imaging studies of DRG neurons were employed to determine the desensitizing effects of olvanil on capsaicin-evoked calcium responses. Statistical analysis used Student’s t test or one way ANOVA followed by Dunnett’s post-hoctest as appropriate. Results: Both olvanil (100 nM) and capsaicin (100 nM) produced significant increases in intracellular calcium concentrations [Ca2+]I in cultured DRG neurons. Olvanil was able to des ensitise TRPV1 responses to further capsaicin exposure more effectively than capsaicin. Intra plantar injection of capsaicin (0.1, 0.3 and 1μg) produced a robust TRPV1-dependant thermal hyperalgesia in rats, whilst olvanil (0.1, 0.3 and 1μg) produced no hyperalgesia, emphasizing its lack of pungency. The highest dose of olvanil significantly reduced the hyperalgesic effects of capsaicin in vivo. Intraplantar injection of the selective cannabinoid CB1 receptor antagonist rimonabant (1μg) altered neither capsaicin-induced thermal hyperalgesia nor the desensitizing properties of olvanil, indicating a lack of involvement of CB1receptors. Conclusions: Olvanil is effective in reducing capsaicin-induced thermal hyperalgesia, probably via directly desensitizingTRPV1 channels in a CB 1 receptor-independent fashion. The results presented clearly support the potential for olvanil in the development of new topical analgesic preparations for treating chronic pain conditions while avoiding the unwanted side effects of capsaicin treatments

Australian Aboriginal Birth Cohort study: follow-up processes at 20 years

Background: In 1987, a prospective study of an Australian Aboriginal Birth Cohort was established focusing on the relationships of fetal and childhood growth with the risk of chronic adult disease. However as the study is being conducted in a highly marginalized population it is also an important resource for cross-sectional descriptive and analytical studies. The aim of this paper is to describe the processes of the third follow up which was conducted 20 years after recruitment at birth. Methods: Progressive steps in a multiphase protocol were used for tracing, with modifications for the expected rural or urban location of the participants. Results: Of the original 686 cohort participants recruited 68 were untraced and 27 were known to have died. Of the 591 available for examination 122 were not examined; 11 of these were refusals and the remainder were not seen for logistical reasons relating to inclement weather, mobility of participants and single participants living in very remote locations. Conclusion: The high retention rate of this follow-up 20 years after birth recruitment is a testament to the development of successful multiphase protocols aimed at overcoming the challenges of tracing a cohort over a widespread remote area and also to the perseverance of the study personnel. We also interpret the high retention rate as a reflection of the good will of the wider Aboriginal community towards this study and that researchers interactions with the community were positive. The continued follow-up of this life course study now seems feasible and there are plans to trace and reexamine the cohort at age 25 years.Susan Sayers, Gurmeet Singh, Dorothy Mackerras, Megan Lawrance,Wendy Gunthorpe, Lisa Jamieson, Belinda Davison, Kobi Schutz and Joseph Fit

Development and preliminary validation of the 'Caring for Country' questionnaire: measurement of an Indigenous Australian health determinant

<p>Abstract</p> <p>Background</p> <p>'Caring for Country' is defined as Indigenous participation in interrelated activities with the objective of promoting ecological and human health. Ecological services on Indigenous-owned lands are belatedly attracting some institutional investment. However, the health outcomes associated with Indigenous participation in 'caring for country' activities have never been investigated. The aims of this study were to pilot and validate a questionnaire measuring caring for country as an Indigenous health determinant and to relate it to an external reference, obesity.</p> <p>Methods</p> <p>Purposively sampled participants were 301 Indigenous adults aged 15 to 54 years, recruited during a cross-sectional program of preventive health checks in a remote Australian community. Questionnaire validation was undertaken with psychometric tests of internal consistency, reliability, exploratory factor analysis and confirmatory one-factor congeneric modelling. Accurate item weightings were derived from the model and used to create a single weighted composite score for caring for country. Multiple linear regression modelling was used to test associations between the caring for country score and body mass index adjusting for socio-demographic factors and health behaviours.</p> <p>Results</p> <p>The questionnaire demonstrated adequate internal consistency, test-retest validity and proxy-respondent validity. Exploratory factor analysis of the 'caring for country' items produced a single factor solution that was confirmed via one-factor congeneric modelling. A significant and substantial association between greater participation in caring for country activities and lower body mass index was demonstrated. Adjusting for socio-demographic factors and health behaviours, an inter-quartile range rise in caring for country scores was associated with 6.1 Kg and 5.3 Kg less body weight for non-pregnant women and men respectively.</p> <p>Conclusion</p> <p>This study indicates preliminary support for the validity of the caring for country concept and a questionnaire designed to measure it. This study also highlights the importance of investigating Indigenous-asserted health promotion activities. Further studies in similar populations are merited to test the generalisability of this questionnaire and to explore associations with other important Indigenous health outcomes.</p

The Efficacy of Sodium Channel Blockers to Prevent Phencyclidine-Induced Cognitive Dysfunction in the Rat: Potential for Novel Treatments for Schizophrenia □ S

ABSTRACT Sodium channel inhibition is a well precedented mechanism used to treat epilepsy and other hyperexcitability disorders. The established sodium channel blocker and broad-spectrum anticonvulsant lamotrigine is also effective in the treatment of bipolar disorder and has been evaluated in patients with schizophrenia. Double-blind placebo-controlled clinical trials found that the drug has potential to reduce cognitive symptoms of the disorder. However, because of compound-related side-effects and the need for dose titration, a conclusive evaluation of the drug&apos;s efficacy in patients with schizophrenia has not been possible. In this series of studies in the rat, we compared the efficacy of the two new molecules to prevent a cognitive deficit induced by the N-methyl-D-aspartic acid receptor antagonist phencyclidine (PCP) in the reversal-learning paradigm in the rat. We also explored the effects of the drugs to prevent brain activation and neurochemical effects of PCP. We found that, like lamotrigine, both GSK2 and GSK3 were able to prevent the deficit in reversal learning produced by PCP, thus confirming their potential in the treatment of cognitive symptoms of schizophrenia. However, higher doses than those required for anticonvulsant efficacy of the drugs were needed for activity in the reversal-learning model, suggesting a lower therapeutic window relative to mechanism-dependent central side effects for this indication

Measuring emotional and social wellbeing in Aboriginal and Torres Strait Islander populations: an analysis of a Negative Life Events Scale

Aboriginal and Torres Strait Islander Australians experience widespread socioeconomic disadvantage and health inequality. In an attempt to make Indigenous health research more culturally-appropriate, Aboriginal and Torres Strait Islander Australians have called for more attention to the concept of emotional and social wellbeing (ESWB). Although it has been widely recognised that ESWB is of crucial importance to the health of Aboriginal and Torres Strait Islander peoples, there is little consensus on how to measure in Indigenous populations, hampering efforts to better understand and improve the psychosocial determinants of health. This paper explores the policy and political context to this situation, and suggests ways to move forward. The second part of the paper explores how scales can be evaluated in a health research setting, including assessments of endorsement, discrimination, internal and external reliability

A Proton Leak Current through the Cardiac Sodium Channel Is Linked to Mixed Arrhythmia and the Dilated Cardiomyopathy Phenotype

Cardiac Na+ channels encoded by the SCN5A gene are essential for initiating heart beats and maintaining a regular heart rhythm. Mutations in these channels have recently been associated with atrial fibrillation, ventricular arrhythmias, conduction disorders, and dilated cardiomyopathy (DCM)

Drug-induced mild therapeutic hypothermia obtained by administration of a transient receptor potential vanilloid type 1 agonist

<p>Abstract</p> <p>Background</p> <p>The use of mechanical/physical devices for applying mild therapeutic hypothermia is the only proven neuroprotective treatment for survivors of out of hospital cardiac arrest. However, this type of therapy is cumbersome and associated with several side-effects. We investigated the feasibility of using a transient receptor potential vanilloid type 1 (TRPV1) agonist for obtaining drug-induced sustainable mild hypothermia.</p> <p>Methods</p> <p>First, we screened a heterogeneous group of TRPV1 agonists and secondly we tested the hypothermic properties of a selected candidate by dose-response studies. Finally we tested the hypothermic properties in a large animal. The screening was in conscious rats, the dose-response experiments in conscious rats and in cynomologus monkeys, and the finally we tested the hypothermic properties in conscious young cattle (calves with a body weight as an adult human). The investigated TRPV1 agonists were administered by continuous intravenous infusion.</p> <p>Results</p> <p>Screening: Dihydrocapsaicin (DHC), a component of chili pepper, displayed a desirable hypothermic profile with regards to the duration, depth and control in conscious rats. Dose-response experiments: In both rats and cynomologus monkeys DHC caused a dose-dependent and immediate decrease in body temperature. Thus in rats, infusion of DHC at doses of 0.125, 0.25, 0.50, and 0.75 mg/kg/h caused a maximal ΔT (°C) as compared to vehicle control of -0.9, -1.5, -2.0, and -4.2 within approximately 1 hour until the 6 hour infusion was stopped. Finally, in calves the intravenous infusion of DHC was able to maintain mild hypothermia with ΔT > -3°C for more than 12 hours.</p> <p>Conclusions</p> <p>Our data support the hypothesis that infusion of dihydrocapsaicin is a candidate for testing as a primary or adjunct method of inducing and maintaining therapeutic hypothermia.</p

Oral health and social and emotional well-being in a birth cohort of Aboriginal Australian young adults

Background: Social and emotional well-being is an important component of overall health. In the Indigenous Australian context, risk indicators of poor social and emotional well-being include social determinants such as poor education, employment, income and housing as well as substance use, racial discrimination and cultural knowledge. This study sought to investigate associations between oral health-related factors and social and emotional well-being in a birth cohort of young Aboriginal adults residing in the northern region of Australia's Northern Territory. Methods: Data were collected on five validated domains of social and emotional well-being: anxiety, resilience, depression, suicide and overall mental health. Independent variables included socio-demographics, dental health behaviour, dental disease experience, oral health-related quality of life, substance use, racial discrimination and cultural knowledge. Results: After adjusting for other covariates, poor oral health-related items were associated with each of the social and emotional well-being domains. Specifically, anxiety was associated with being female, having one or more decayed teeth and racial discrimination. Resilience was associated with being male, having a job, owning a toothbrush, having one or more filled teeth and knowing a lot about Indigenous culture; while being female, having experienced dental pain in the past year, use of alcohol, use of marijuana and racial discrimination were associated with depression. Suicide was associated with being female, having experience of untreated dental decay and racial discrimination; while being female, having experience of dental disease in one or more teeth, being dissatisfied about dental appearance and racial discrimination were associated with poor mental health. Conclusion: The results suggest there may be value in including oral health-related initiatives when exploring the role of physical conditions on Indigenous social and emotional well-being.Lisa M Jamieson, Yin C Paradies, Wendy Gunthorpe, Sheree J Cairney and Susan M Sayer

Low omega-6 vs. low omega-6 plus high omega-3 dietary intervention for Chronic Daily Headache: Protocol for a randomized clinical trial

<p>Abstract</p> <p>Background</p> <p>Targeted analgesic dietary interventions are a promising strategy for alleviating pain and improving quality of life in patients with persistent pain syndromes, such as chronic daily headache (CDH). High intakes of the omega-6 (n-6) polyunsaturated fatty acids (PUFAs), linoleic acid (LA) and arachidonic acid (AA) may promote physical pain by increasing the abundance, and subsequent metabolism, of LA and AA in immune and nervous system tissues. Here we describe methodology for an ongoing randomized clinical trial comparing the metabolic and clinical effects of a low n-6, average n-3 PUFA diet, to the effects of a low n-6 plus high n-3 PUFA diet, in patients with CDH. Our primary aim is to determine if: A) both diets reduce n-6 PUFAs in plasma and erythrocyte lipid pools, compared to baseline; and B) the low n-6 plus high n-3 diet produces a greater decline in n-6 PUFAs, compared to the low n-6 diet alone. Secondary clinical outcomes include headache-specific quality-of-life, and headache frequency and intensity.</p> <p>Methods</p> <p>Adults meeting the International Classification of Headache Disorders criteria for CDH are included. After a 6-week baseline phase, participants are randomized to a low n-6 diet, or a low n-6 plus high n-3 diet, for 12 weeks. Foods meeting nutrient intake targets are provided for 2 meals and 2 snacks per day. A research dietitian provides intensive dietary counseling at 2-week intervals. Web-based intervention materials complement dietitian advice. Blood and clinical outcome data are collected every 4 weeks.</p> <p>Results</p> <p>Subject recruitment and retention has been excellent; 35 of 40 randomized participants completed the 12-week intervention. Preliminary blinded analysis of composite data from the first 20 participants found significant reductions in erythrocyte n-6 LA, AA and %n-6 in HUFA, and increases in n-3 EPA, DHA and the omega-3 index, indicating adherence.</p> <p>Trial Registration</p> <p>ClinicalTrials.gov <a href="http://www.clinicaltrials.gov/ct2/show/(NCT01157208)">(NCT01157208)</a></p