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Pain-related sensory input is processed in the spinal dorsal horn (SDH) before being relayed to the brain. That processing profoundly influences whether stimuli are correctly or incorrectly perceived as painful. Significant advances have been made in identifying the types of excitatory and inhibitory neurons that comprise the SDH, and there is some information about how neuron types are connected, but it remains unclear how the overall circuit processes sensory input or how that processing is disrupted under chronic pain conditions. To explore SDH function, we developed a computational model of the circuit that is tightly constrained by experimental data. Our model comprises conductance-based neuron models that reproduce the characteristic firing patterns of spinal neurons. Excitatory and inhibitory neuron populations, defined by their expression of genetic markers, spiking pattern, or morphology, were synaptically connected according to available qualitative data. Using a genetic algorithm, synaptic weights were tuned to reproduce projection neuron firing rates (model output) based on primary afferent firing rates (model input) across a range of mechanical stimulus intensities. Disparate synaptic weight combinations could produce equivalent circuit function, revealing degeneracy that may underlie heterogeneous responses of different circuits to perturbations or pathological insults. To validate our model, we verified that it responded to reduction of inhibition (i.e. disinhibition) and ablation of specific neuron types in a manner consistent with experiments. Thus validated, our model offers a valuable resource for interpreting experimental results and testing hypotheses to plan experiments for examining normal and pathological SDH circuit function.We developed a multiscale computer model of the posterior part of spinal cord gray matter (spinal dorsal horn), involved in perception of touch and pain. The model reproduces several experimental observations and makes predictions about how specific types of spinal neurons and synapses influence projection neurons that send information to the brain. Misfiring of these projection neurons can produce anomalous sensations associated with chronic pain. Our computer model will not only assist in planning future experiments, but will also be useful for developing new pharmacotherapy for chronic pain disorders, connecting the effect of drugs acting at the molecular scale with emergent properties of neurons and circuits that shape the pain experience.
Learn More >As a predominately positive emotion, nostalgia serves various adaptive functions, including a recently revealed analgesic effect. The current fMRI study aimed to explore the neural mechanisms underlying the nostalgia-induced analgesic effect on noxious thermal stimuli of different intensities. Human participants' (males and females) behavior results showed that the nostalgia paradigm significantly reduced participants' perception of pain, particularly at low pain intensities. fMRI analysis revealed that analgesia was related to decreased brain activity in pain-related brain regions, including the lingual and parahippocampal gyrus. Notably, anterior thalamic activation during the nostalgia stage predicted posterior parietal thalamus activation during the pain stage, suggesting that the thalamus might play a key role as a central functional linkage in the analgesic effect. Moreover, while thalamus-PAG functional connectivity was found to be related to nostalgic strength, PAG-dlPFC functional connectivity was found to be associated with pain perception, suggesting possible analgesic modulatory pathways. These findings demonstrate the analgesic effect of nostalgia and, more importantly, shed light on its neural mechanism.Nostalgia is known to reduce individuals' perception of physical pain. The underlying brain mechanisms, however, are unclear. Our study found that the thalamus plays a key role as a functional linkage between nostalgia and pain, suggesting a possible analgesic modulatory mechanism of nostalgia. These findings have implications for the underlying brain mechanisms of psychological analgesia.
Learn More >To summarize the characteristics of home practice adherence in patients with chronic pain randomized to a 10-week group mind-body activity program with () and without () a digital monitoring device, and test the association between home practice adherence and improvement in physical and emotional treatment outcomes. Data were collected in a pilot randomized controlled trial (RCT) of the ( = 41) and ( = 41) programs. Participants submitted weekly home practice logs depicting their daily physical activity and practice of relaxation and gratitude skills. Participants completed assessments of physical (patient-reported, performance-based, and accelerometer-measured) and emotional function outcomes both before and after the programs. Participants in both programs were combined due to the identical session and home practice content. Participants reported engaging in physical activity on average 30.62 days (SD = 20.28, 48.6% of intervention days), relaxation skill practice on average 29.87 days (SD = 21.16, 47.4% of intervention days), and gratitude practice on average 32.10 days (SD = 22.12, 51.0% of intervention days). The average duration of physical activity and relaxation skill practice were 44.40 min a day (SD = 59.44) and 11.15 min a day (SD = 12.00), respectively. The duration of physical activity was significantly associated with decrease depression symptoms ( = 0.049, η = 0.056). No other association was found between home practice and change in outcomes. Patients with chronic pain are generally able and willing to engage in home practice during a mind-body activity intervention. Emphasizing longer duration of physical activity practice may contribute to an improvement in depression. Future fully powered RCTs with rigorous assessment of home practice adherence and dose-response designs may further elucidate the role of home practice in improvements in treatment outcomes. NCT03412916.
Learn More >Preclinical and clinical research has suggested the existence of pregnancy-associated analgesia, wherein responses to painful stimulation or pain from disease decrease during pregnancy. We combined data from multiple years (2012-2015) of the National Health Interview Survey to examine high-impact pain by Hispanic ethnicity and race in women with no prior pregnancy, during pregnancy, and previously pregnant. High-impact pain was less common for women during pregnancy (10.3%; 95% confidence interval [CI]: 7.0%-13.7%) than it was for women who had never been pregnant (13.7%; 95% CI: 12.8%-14.5%) and for women who had previously been pregnant (19.8%; 95% CI: 16.0%-23.7%). However, when we examined the data by Hispanic ethnicity and race, we found that non-Hispanic White (NHW) women were less likely to report high-impact pain during pregnancy, but non-Hispanic Black (NHB) women and Hispanic White women were not. In women who reported no prior pregnancy, NHW women were most likely to report high-impact pain, followed by NHB women and Hispanic women. In analyses, we found that while menstrual problems were associated with increased odds of having high-impact pain, an interaction was not observed between menstrual problems and race/ethnicity ( = 0.48). This cross-sectional study presents a nationally representative examination of the prevalence of high-impact pain across pregnancy status. Using a nationally representative sample of women, we have demonstrated that the prevalence of high-impact pain varies across pregnancy status and that race/ethnicity and the presence of menstrual problems independently affect this prevalence.
Learn More >To examine predictors and consequences of prescription opioid use among a cohort of women living with HIV (WLWH) and women without HIV from 2000 to 2019. The Women's Interagency HIV Study is a multisite, prospective cohort study. Cumulative proportion of visits with prescription opioid use was categorized as follows: minimal (0%-9%), intermediate (10%-39%), and chronic (>40%). Logistic regression examined independent predictors, and proportional hazards regression estimated unadjusted and adjusted hazards of all-cause mortality, comparing intermediate and chronic prescription opioid use with minimal use. Annual prevalence of prescription opioid use significantly increased from 12.6% to 19.3% from 2000 to 2019 ( < 0.0001). Prescription opioid use was minimal in 75%, intermediate in 16%, and chronic in 9% of women. WLWH had 56% higher odds of chronic prescription opioid use compared with women without HIV. Even after adjusting for quality-of-life scores including ratings of pain, women with intermediate and chronic prescription opioid use had greater odds of being sexual minorities (lesbian or bisexual), unemployed, and were more likely to report benzodiazepine and nonprescription substance use compared with those with minimal use. Intermediate and chronic prescription opioid use were each associated with an almost 1.5-fold increased risk of all-cause mortality. Despite federally mandated opioid prescribing guidelines, prescription opioid use and related mortality significantly increased in women experiencing physical and psychosocial vulnerabilities. The higher mortality rate found among prescription opioid users may reflect the many underlying chronic medical and psychosocial conditions for which these opioids were prescribed, as well as complications of opioids themselves. Findings underscore the need for non-opioid and nonpharmacological interventions for chronic pain, particularly in sexual minorities and WLWH. Avoiding concurrent use of opioids with benzodiazepines and nonprescription drugs might reduce mortality. Clinical Trial Registration Number: NCT00000797.
Learn More >Inhibiting receptor tyrosine kinases is commonly achieved by two main strategies targeting either the intracellular kinase domain by low molecular weight compounds or the extracellular ligand-binding domain by monoclonal antibodies. Identifying small molecules able to inhibit RTKs at the extracellular level would be highly desirable to gain exquisite selectivity but is believed to be challenging owing to the size of RTK endogenous ligands (cytokines, growth factors) and the topology of RTK extracellular domains. We here report the high-throughput screening of the French Chemical Library (48K compounds) for extracellular inhibitors of the Fms-like tyrosine kinase 3 (FLT3) receptor tyrosine kinase, by a homogeneous time-resolved fluorescence competition assay. A total of 679 small molecular weight ligands (1.4%) were confirmed to strongly inhibit (>75%) the binding of the fluorescent labeled FLT3 ligand (FL cytokine) to FLT3 overexpressed in HEK-293 cells, at two different concentrations (5 and 20 μM). Concentration-response curves, obtained for 111 lead-like molecules, confirmed the unexpected tolerance of the FLT3 extracellular domain for low molecular weight druggable inhibitors exhibiting submicromolar potencies, chemical diversity, and promising pharmacokinetic properties. Further investigation of one hit confirmed inhibitory properties in dorsal root ganglia neurons and in a mouse model of neuropathic pain.
Learn More >Neuromodulation Interventions for the Treatment of Painful Diabetic Neuropathy: a Systematic Review.
Painful diabetic neuropathy (PDN) is a prevalent and debilitating condition, characterized by severe burning, tingling, and lancinating pain usually located in the distal lower extremities. In addition to manifesting with severe pain, PDN may also be associated with poor quality of life and sleep, mood disorders, burns, falls, and social withdrawal. The authors appraised the current body of literature for evidence on neuromodulation interventions for PDN.
Learn More >Molecular mechanisms underlying trigeminal neuralgia (TN) have been poorly understood. Recently, different biomarkers have been studied in several chronic neuropathic diseases or in neuronal damage, but their role in TN has not yet been investigated. Here, we firstly analyzed the serum levels of the neuron-specific enolase (NSE) (as an index of neuronal tissue damage) in TN patients submitted to surgical treatment. Different cytokines and interleukins related to inflammation were also studied.
Learn More >Chronic low back pain (CLBP) is among the most common types of pain in adults. Currently, injections and analgesic and nonsteroidal anti-inflammatory drugs are often provided for patients with CLBP. However, their effectiveness remains questionable, and the safest approach to CLBP remains debated. Meditation-based therapies constitute an alternative treatment with high potential for widespread availability. We evaluated the applicability of meditation-based therapies for CLBP management.
Learn More >Successful treatment of opioid misuse among people with chronic pain has proven elusive. Guidelines recommend nonopioid therapies, but the efficacy of mindfulness-based interventions for opioid misuse is uncertain.
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