Browse by Audience
Carbonic anhydrase-8 (CA8) is an intracellular protein that functions as an allosteric inhibitor of inositol trisphosphate receptor-1 (ITPR1) critical to intracellular Ca++ release, synaptic functions and neuronal excitability. We showed previously that murine nociception and analgesic responses are regulated by the expression of this gene in dorsal root ganglion (DRG) associated with a cis-eQTL. In this report, we identify an exon-level cis-eQTL (rs6471859) that regulates human DRG CA8 alternative splicing, producing a truncated 1,697bp transcript (e.g., CA8-204). Our functional genomic studies show the "G" allele at rs6471859 produces a cryptic 3'UTR splice site regulating expression of CA8-204. We developed constructs to study the expression and function of the naturally occurring CA8-204G transcript (G allele at rs6471859), CA8-204C (C allele at rs6471859 reversion mutation) and CA8-201 (full length transcript). CA8-204G transcript expression occurred predominantly in non-neuronal cells (HEK293), while CA8-204C expression was restricted to neuronal derived cells (NBL) in vitro. CA8-204G produced a stable truncated transcript in HEK293 cells that was barely detectable in NBL cells. We also show CA8-204 produces a stable peptide that inhibits pITPR1 and Ca++ release in HEK293 cells. These results imply homozygous G/G individuals at rs6471859, which are common in the general population, produce exclusively CA8-204G that is barely detectable in neuronal cells. CA8 null mutations that greatly impact neuronal functions are associated with severe forms of spinal cerebellar ataxia, and our data suggest G/G homozygotes should display a similar phenotype. To address this question, we show in vivo using AAV8-FLAG-CA8-204G and AAV8-V5-CA8-201 gene transfer delivered via intra-neural sciatic nerve injection (SN), that these viral constructs are able to transduce DRG cells and produce similar analgesic and anti-hyperalgesic responses to inflammatory pain. Immunohistochemistry (IHC) examinations of DRG tissues further show CA8-204G peptide is expressed in advillin expressing neuronal cells, but to a lesser extent compared to glial cells. These findings explain why G/G homozygotes that exclusively produce this truncated functional peptide in DRG evade a severe phenotype. These genomic studies significantly advance the literature regarding structure-function studies on CA8-ITPR1 critical to calcium signaling pathways, synaptic functioning, neuronal excitability and analgesic responses.
Learn More >The purpose of this review is to explore the effects of the opioid crisis on pediatric patients in the postoperative setting and provide recommendations for well-tolerated opioid prescribing practices.
Learn More >Vulvodynia is a debilitating, chronic vulvar pain condition. Community-based case-control studies have consistently shown associations between early-life chronic stressors and vulvodynia onset.
Learn More >The goal of this project was to use computational models to investigate which types of primary sensory neurons are modulated by dorsal root ganglion stimulation (DRGS) to provide pain relief.
Learn More >Current definitions of pain do not necessitate tissue damage. This is important because it does justice to the pain patient in whom a nociceptive source is not detectable. However, in conjunction with exciting findings regarding supraspinal pain modulation and a (perceived) failure of identifying nociceptive sources in individual patients, this might have led to a devaluation of the role of nociception for chronic pain. In this review, the relative importance of nociception versus psychological factors for chronic pain is examined by scrutinizing the example of pain present several months following surgical joint replacement for severe osteoarthritis.
Learn More >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 >