Browse by Audience
MaR1 is a specialized pro-resolving lipid mediator with anti-inflammatory and analgesic activities. In this study, we addressed the modulation of peripheral and spinal cord cells by MaR1 in inflammatory pain context.
Learn More >Trigeminal spinal subnucleus caudalis (Vc) neurons that project to the ventral posteromedial thalamic nucleus (VPM) and parabrachial nucleus (PBN) are critical for orofacial pain processing. We hypothesized that persistent trigeminal nerve injury differentially alters the proportion of Vc neurons that project to VPM and PBN in a modality-specific manner. Neuroanatomical approaches were used to quantify the number of Vc neurons projecting to VPM or PBN following chronic constriction injury of the infraorbital nerve (ION-CCI) and subsequent upper lip stimulation.Male rats received injections of retrograde tracer fluorogold into the contralateral VPM or PBN on day 7 after ION-CCI, and at 3 days after that either capsaicin-injection or noxious mechanical stimulation was applied to the upper lip ipsilateral to nerve injury. ION-CCI rats displayed greater forelimb wiping to capsaicin-injection and mechanical allodynia of the lip than sham rats. Total cell counts for phosphorylated extracellular signal-regulated kinase-immunoreactive (pERK-IR) neurons after capsaicin or mechanical lip stimuli were higher in ION-CCI than sham rats as was the percentage of pERK-IR PBN projection neurons. However, the percentage of pERK-IR VPM projection neurons was also greater in ION-CCI than sham rats after capsaicin but not mechanical lip stimuli.The present findings suggest that persistent trigeminal nerve injury increases the number of Vc neurons activated by capsaicin or mechanical lip stimuli. By contrast, trigeminal nerve injury modifies the proportion of Vc nociceptive neurons projecting to VPM and PBN in a stimulus modality-specific manner and may reflect differential involvement of ascending pain pathways receiving C-fiber and mechanosensitive afferents.
Learn More >The presence of pain in elderly persons with cognitive decline is often neglected, under-reported, underestimated, misdiagnosed and not adequately treated, with consequences that have a strong impact on health, independence in activities of daily living and quality of life. There is no empirical evidence that people with dementia experience less pain; therefore, in patients with severe cognitive impairment the progression of cognitive decline dramatically affects the ability to verbalize the presence of pain. Self-assessment scales are considered the "gold standard" for pain assessment, but the presence of cognitive impairment is likely to reduce the reliability of these measures. Treatment of pain in elderly with cognitive decline or dementia is based on non-pharmacological and pharmacological strategies. Pharmacological treatment should consider physiological changes, high comorbidity and drug interactions that occur frequently in the elderly. This narrative review aims to describe current knowledge, methods of detection and treatment approaches for chronic pain in elderly persons with cognitive deficits.
Learn More >Chronic pain is highly prevalent worldwide and represents a significant socioeconomic and public health burden. Several aspects of chronic pain, for example back pain and a severity-related phenotype 'chronic pain grade', have been shown previously to be complex heritable traits with a polygenic component. Additional pain-related phenotypes capturing aspects of an individual's overall sensitivity to experiencing and reporting chronic pain have also been suggested as a focus for investigation. We made use of a measure of the number of sites of chronic pain in individuals within the UK general population. This measure, termed Multisite Chronic Pain (MCP), is a complex trait and its genetic architecture has not previously been investigated. To address this, we carried out a large-scale genome-wide association study (GWAS) of MCP in ~380,000 UK Biobank participants. Our findings were consistent with MCP having a significant polygenic component, with a Single Nucleotide Polymorphism (SNP) heritability of 10.2%. In total 76 independent lead SNPs at 39 risk loci were associated with MCP. Additional gene-level association analyses identified neurogenesis, synaptic plasticity, nervous system development, cell-cycle progression and apoptosis genes as enriched for genetic association with MCP. Genetic correlations were observed between MCP and a range of psychiatric, autoimmune and anthropometric traits, including major depressive disorder (MDD), asthma and Body Mass Index (BMI). Furthermore, in Mendelian randomisation (MR) analyses a causal effect of MCP on MDD was observed. Additionally, a polygenic risk score (PRS) for MCP was found to significantly predict chronic widespread pain (pain all over the body), indicating the existence of genetic variants contributing to both of these pain phenotypes. Overall, our findings support the proposition that chronic pain involves a strong nervous system component with implications for our understanding of the physiology of chronic pain. These discoveries may also inform the future development of novel treatment approaches.
Learn More >Current guidelines recommend opioid therapy to chronic non-malignant pain (CNP) patients when the benefits for pain and function outweigh risks. This systematic review examined the effects of opioid therapy on sleep – a valued functional outcome- in CNP. Electronic and hand searches of relevant studies up through July 2017 identified 18 eligible studies providing data from 3,746 CNP patients for analysis. Twelve of these studies were randomised controlled trials of up to 12-month in duration. Morphine sulfate, oxycodone and transdermal fentanyl were the most tested therapies (n = 4 each). Only two studies used objective sleep measures in addition to self-report ratings, questionnaires or sleep diaries. Whilst calmer sleep with less body/leg movements and fewer awakenings could be achieved following opioid therapy, these might occur with increased sleep-disordered breathing and a much-shortened rapid eye movement (REM) sleep latency. Both the narrative synthesis and exploratory meta-analysis suggest that opioid therapy in CNP is associated with improved self-reported sleep quality. However, the effect is inconsistent, small (Standardised Mean Difference = 0.36), and may be accompanied by excessive daytime sleepiness. As a Cochrane-recommended assessment revealed "unclear" or "high" overall risk of bias for all studies, future opioid trials of stronger methodology and better reporting are needed to confirm and elucidate the effect.
Learn More >Analgesic design and evaluation have been driven by the desire to create high-affinity high-selectivity mu (μ)-opioid peptide (MOP) receptor agonists. Such ligands are the mainstay of current clinical practice, and include morphine and fentanyl. Advances in this sphere have come from designing pharmacokinetic advantage, as in rapid metabolism for remifentanil. These produce analgesia, but also the adverse-effect profile that currently defines this drug class: ventilatory depression, tolerance, and abuse liability. The MOP receptor is part of a family, and there are significant functional interactions between other members of the family (delta [δ]-opioid peptide [DOP], kappa [κ]-opioid peptide [KOP], and nociceptin/orphanin FQ receptor [NOP]). Experimentally, MOP agonism and DOP antagonism produce anti-nociception (animals) with no tolerance, and low doses of MOP and NOP ligands synergise to antinociceptive advantage. In this latter context, the lack of effect of NOP agonists on ventilation is an additional advantage. Recent development has been to move towards low-selectivity multifunctional 'mixed ligands', such as cebranopadol, or ligand mixtures, such as Targinact®. Moreover, the observation that β-arrestin coupling underlies the side-effect profile for MOP ligands (from knockout animal studies) led to the discovery of biased (to G-protein and away from β-arrestin intracellular signalling) MOP ligands, such as oliceridine. There is sufficient excitement in the opioid field to suggest that opioid analgesics without significant side-effects may be on the horizon, and the 'opioid Holy Grail' might be in reach.
Learn More >Cloxyquin has been reported as a specific activator of TRESK (K2P18.1, TWIK-related spinal cord K+ channel) background potassium channel. In this study, we have synthetized chemically modified analogues of cloxyquin and tested their effects on TRESK and other K2P channels. The currents of murine K2P channels, expressed heterologously in Xenopus oocytes, were measured by two-electrode voltage clamp, whereas the native background K+ conductance of mouse dorsal root ganglion (DRG) neurons was examined by the whole-cell patch clamp method. Some of the analogues retained the activator character of the parent compound, but more interestingly, other derivatives inhibited mouse TRESK current. The inhibitor analogues (A2764 and A2793) exerted state-dependent effect. The degree of inhibition by 100 µM A2764 (77.8±1.5%, n=6) was larger in the activated state of TRESK (i.e. after calcineurin-dependent stimulation) than in the resting state of the channel (42.8±4.3% inhibition, n=7). The selectivity of the inhibitor compounds was tested on several K2P channels. A2793 inhibited TASK-1 (100 µM, 53.4±6%, n=5), while A2764 was more selective for TRESK, it only moderately influenced TREK-1 and TALK-1. The effect of A2764 was also examined on the background K+ currents of DRG neurons. A subpopulation of DRG neurons, prepared from wild-type animals, expressed background K+ currents sensitive to A2764, while the inhibitor did not affect the currents in the DRG neurons of TRESK-deficient mice. Accordingly, A2764 may prove to be useful for the identification of TRESK current in native cells, and for the investigation of the role of the channel in nociception and migraine.
Learn More >Migraine is a disabling, chronic neurological disease leading to severe headache episodes affecting 13.2% of the Swedish population. Migraine leads to an extensive socio-economic burden in terms of healthcare costs, reduced workforce and quality of life (QoL) but studies of the health-economic consequences in a Swedish context are lacking. The objective of this study is to map the health-economic consequences of migraine in a defined patient population in terms of healthcare consumption, production loss and QoL in Sweden.
Learn More >