Persistent changes in nociceptor translatomes govern hyperalgesic priming in mouse models.

Hyperalgesic priming is a model system that has been widely used to understand plasticity in painful stimulus-detecting sensory neurons, called nociceptors. A key feature of this model system is that following priming, stimuli that do not normally cause hyperalgesia now readily provoke this state. We hypothesized that hyperalgesic priming occurs due to reorganization of translation of mRNA in nociceptors.

A novel reuptake inhibitor, IP2015, induces erection by increasing central dopamine and peripheral nitric oxide release.

Background And Purpose: An estimated 40% of patients with erectile dysfunction have a poor prognosis for improvement with currently available treatments. The present study investigated whether a newly developed monoamine transport inhibitor, IP2015, improves erectile function.

Experimental Approach: We investigated the effects of IP2015 on monoamine uptake and binding, erectile function in rats and diabetic mice and the effect on corpus cavernosum contractility.

Finding new analgesics: Computational pharmacology faces drug discovery challenges.

Despite the worldwide prevalence and huge burden of pain, pain is an undertreated phenomenon. Currently used analgesics have several limitations regarding their efficacy and safety. The discovery of analgesics possessing a novel mechanism of action has faced multiple challenges, including a limited understanding of biological processes underpinning pain and analgesia and poor animal-to-human translation.

"Of mice and men": the relevance of Cometin and Erythropoietin origin for its effects on murine spiral ganglion neuron survival and neurite outgrowth .

Neurotrophic factors (NTF) play key roles in the survival of neurons, making them promising candidates for therapy of neurodegenerative diseases. In the case of the inner ear, sensorineural hearing loss (SNHL) is characterized over time by a degeneration of the primary auditory neurons, the spiral ganglion neurons (SGN). It is well known that selected NTF can protect SGN from degeneration, which positively influences the outcome of cochlear implants, the treatment of choice for patients with profound to severe SNHL.

Preclinical target validation for non-addictive therapeutics development for pain.

Introduction: The Helping to End Addiction Long-term Initiative supports a wide range of programs to develop new or improved prevention and opioid addiction treatment strategies. An essential component of this effort is to accelerate development of non-opioid pain therapeutics. In all fields of medicine, therapeutics development is an arduous process and late-stage translational efforts such as clinical trials to validate targets are particularly complex and costly.

Meteorin Alleviates Paclitaxel-Induced Peripheral Neuropathic Pain in Mice.

Chemotherapy-induced peripheral neuropathy is a challenging condition to treat, and arises due to severe, dose-limiting toxicity of chemotherapeutic drugs such as paclitaxel. This often results in debilitating sensory and motor deficits that are not effectively prevented or alleviated by existing therapeutic interventions. Recent studies have demonstrated the therapeutic effects of Meteorin, a neurotrophic factor, in reversing neuropathic pain in rodent models of peripheral nerve injury induced by physical trauma.

Inhibition of P2X7 receptors by Lu AF27139 diminishes colonic hypersensitivity and CNS prostanoid levels in a rat model of visceral pain.

Visceral pain is a prominent feature of various gastrointestinal diseases. The P2X7 receptor is expressed by multiple cell types including dorsal root ganglion satellite glial cells, macrophages, and spinal microglia, all of which have been implicated in nociceptive sensitization. We have used the selective and CNS penetrant P2X7 receptor antagonist Lu AF27139 to explore this receptor's role in distinct rat models of inflammatory and visceral hypersensitivity.

Preliminary evidence that caffeine improves attention in multiple sclerosis.

There are no licensed drugs to boost cognitive performance in multiple sclerosis (MS). Here, we provide preliminary evidence that caffeine can improve attention in people with MS. Participants were tested on three different metrics of attentional functioning [choice reaction times, Stroop performance and a Rapid Serial Visual Presentation (RSVP) task] repeated across four sessions (baseline, one week after caffeine abstention and two sessions on days 8 and 9 where participants were pseudorandomized to receive counterbalanced caffeine or decaffeinated products).

P2X7 receptor-mediated release of microglial prostanoids and miRNAs correlates with reversal of neuropathic hypersensitivity in rats.

Background: P2X7 receptor antagonists have potential for treating various central nervous system (CNS) diseases, including neuropathic pain, although none have been approved for clinical use. Reasons may include insufficient understanding of P2X7 receptor signalling in pain, and the lack of a corresponding preclinical mechanistic biomarker.

Methods: Lu AF27139 is a highly selective and potent small molecule antagonist at rat, mouse and human forms of the P2X7 receptor, with excellent pharmacokinetic and CNS permeability properties.

Caffeine and attentional control: improved and impaired performance in healthy older adults and Parkinson's disease according to task demands.

Introduction: Caffeine is frequently consumed to boost goal-directed attention. These procognitive effects may occur due to the adenosine-mediated enhancement of monoamines, such as dopamine, after caffeine administration. As such, caffeine's beneficial effects may be altered in conditions such as Parkinson's disease (PD).

Reporting errors in plain radiographs for lower limb trauma-a systematic review and meta-analysis.

Introduction: Plain radiographs are a globally ubiquitous means of investigation for injuries to the musculoskeletal system. Despite this, initial interpretation remains a challenge and inaccuracies give rise to adverse sequelae for patients and healthcare providers alike. This study sought to address the limited, existing meta-analytic research on the initial reporting of radiographs for skeletal trauma, with specific regard to diagnostic accuracy of the most commonly injured region of the appendicular skeleton, the lower limb.

The influence of rat strain on the development of neuropathic pain and comorbid anxio-depressive behaviour after nerve injury.

Back-translating the clinical manifestations of human disease burden into animal models is increasingly recognized as an important facet of preclinical drug discovery. We hypothesized that inbred rat strains possessing stress hyper-reactive-, depressive- or anxiety-like phenotypes may possess more translational value than common outbred strains for modeling neuropathic pain. Rats (inbred: LEW, WKY, F344/ICO and F344/DU, outbred: Crl:SD) were exposed to Spared Nerve Injury (SNI) and evaluated routinely for 6 months on behaviours related to pain (von Frey stimulation and CatWalk-gait analysis), anxiety (elevated plus maze, EPM) and depression (sucrose preference test, SPT).

ATP sensitive potassium (K) channel inhibition: A promising new drug target for migraine.

Background: Recently, the adenosine triphosphate (ATP) sensitive potassium channel opener levcromakalim was shown to induce migraine attacks with a far higher incidence than any previous provoking agent such as calcitonin gene-related peptide. Here, we show efficacy of ATP sensitive potassium channel inhibitors in two validated rodent models of migraine.

Methods: In female spontaneous trigeminal allodynic rats, the sensitivity of the frontal region of the head was tested by an electronic von Frey filament device.

Conceptualizations of help-seeking for mental health concerns in First Nations communities in Canada: A comparison of fit with the Andersen Behavioral Model.

This qualitative study explored the fit between on-reserve First Nations community members' conceptualizations of help-seeking for mental health concerns and the Andersen Behavioral Model of Health Services Use. Youth, adults and elders (N = 115) living and or working in eight distinct First Nations communities within a tribal council area in Canada participated in focus groups or individual interviews that were transcribed, coded and then analyzed using a thematic analysis approach informed by grounded theory methodology. Resulting themes were then mapped onto the Andersen Behavioral Model of Health Services Use.

Cancer incidence, stage at diagnosis and outcomes among Manitoba First Nations people living on and off reserve: a retrospective population-based analysis.

Background: Substantial cancer-related disparities exist between First Nations and non-Indigenous Canadians. The objectives of this study were to compare cancer incidence, stage at diagnosis and mortality outcomes between Status First Nations people living on reserve and off reserve in Manitoba.

Methods: We conducted a retrospective analysis of population-level administrative health databases in Manitoba.

Comparing cancer incidence, stage at diagnosis and outcomes of First Nations and all other Manitobans: a retrospective analysis.

Background: Globally, epidemiological evidence suggests cancer incidence and outcomes among Indigenous peoples are a growing concern. Although historically cancer among First Nations (FN) peoples in Canada was relatively unknown, recent epidemiological evidence reveals a widening of cancer related disparities. However evidence at the population level is limited.

Qualitative case study investigating PAX-good behaviour game in first nations communities: insight into school personnel's perspectives in implementing a whole school approach to promote youth mental health.

Objectives: PAX-Good Behaviour Game (PAX-GBG) is associated with improved mental health among youth. First Nations community members decided on a whole school approach to facilitate PAX-GBG implementation, by offering intervention training to all staff members in their schools. Our objective is to gain a greater understanding of how this approach was viewed by school personnel, in order to improve implementation in remote and northern First Nations communities.

Stress sensitivity and cutaneous sensory thresholds before and after neuropathic injury in various inbred and outbred rat strains.

Chronic pain is associated with altered affective state, stress, anxiety and depression. Conversely, stress, anxiety and depression can all modulate pain perception. The relative link between these behavioural constructs in different inbred and outbred rat strains, known to be variously hypo/hyperresponsive to stress has not been determined.

Antihyperalgesic effects of Meteorin in the rat chronic constriction injury model: a replication study.

Data from preclinical research have been suggested to suffer from a lack of inherent reproducibility across laboratories. The goal of our study was to replicate findings from a previous report that demonstrated positive effects of Meteorin, a novel neurotrophic factor, in a rat model of neuropathic pain induced by chronic constriction injury (CCI). Notably, 5 to 6 intermittent subcutaneous (s.

Targeting CGRP via receptor antagonism and antibody neutralisation in two distinct rodent models of migraine-like pain.

Introduction: Rodent disease models can play an indispensable role in drug development. Confirming that translationally-relevant disease mechanisms are engaged in such models is a crucial facet of this process. Accordingly, we have validated the role of calcitonin gene-related peptide signaling in a mouse model of glyceryl trinitrate-provoked migraine-like pain and a spontaneous rat model of migraine-like pain by assessing their pharmacological responsiveness to the small molecule calcitonin gene-related peptide receptor antagonist olcegepant, and the humanised monoclonal calcitonin gene-related peptide antibody ALD405.