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Human Labor Pain Is Influenced by the Voltage-Gated Potassium Channel K6.4 Subunit.

By studying healthy women who do not request analgesia during their first delivery, we investigate genetic effects on labor pain. Such women have normal sensory and psychometric test results, except for significantly higher cuff pressure pain. We find an excess of heterozygotes carrying the rare allele of SNP rs140124801 in KCNG4. The rare variant K6.4-Met419 has a dominant-negative effect and cannot modulate the voltage dependence of K2.1 inactivation because it fails to traffic to the plasma membrane. In vivo, Kcng4 (K6.4) expression occurs in 40% of retrograde-labeled mouse uterine sensory neurons, all of which express K2.1, and over 90% express the nociceptor genes Trpv1 and Scn10a. In neurons overexpressing K6.4-Met419, the voltage dependence of inactivation for K2.1 is more depolarized compared with neurons overexpressing K6.4. Finally, K6.4-Met419-overexpressing neurons have a higher action potential threshold. We conclude that K6.4 can influence human labor pain by modulating the excitability of uterine nociceptors.

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Eleven things not to say to healthcare professionals during the COVID-19 pandemic.

On March 11, 2020, the infection caused by the COVID-19 virus was declared a pandemic. Throughout this pandemic, healthcare professionals have experienced difficulties stemming from poor communications, resource scarcity, lack of transparency, disbelief, and threats to the safety of their loved ones, their patients, and themselves. As part of these hardships, negative statements have been heard repeatedly. This paper describes 11 scenarios of unhelpful and dysfunctional messages heard by the authors and their colleagues during the COVID-19 pandemic, reported to us by a combination of peers, administrative leadership, and the public. We explain why not to use such messaging, and we suggest more helpful and compassionate expressions based upon recommendations published by scientific organizations and well-established psychological principles. The first 10 scenarios discussed include 1) lack of understanding regarding the extent of the pandemic, 2) shaming over not seeing patients in person, 3) lack of clear and consistent communication from leadership on pandemic-related practice changes, 4) opinions that personal protective equipment use by healthcare professionals causes fear or is unnecessary, 5) forcing in-person care without appropriate personal protective equipment, 6) the risk of exposure to asymptomatic individuals as it relates to opening clinics, 7) media gag orders, 8) pay and benefit reductions, 9) spreading of misinformation about the COVID-19 pandemic, and 10) workload expectations. The 11th scenario addresses healthcare professionals' psychological and physical reactions to this challenging and prolonged stressful situation. We close by discussing the need for support and compassion at this difficult and unpredictable time and by offering suggestions to foster resilience and feelings of self-efficacy among healthcare professionals.

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Gene coexpression patterns predict opiate-induced brain-state transitions.

Opioid addiction is a chronic, relapsing disorder associated with persistent changes in brain plasticity. Reconfiguration of neuronal connectivity may explain heightened abuse liability in individuals with a history of chronic drug exposure. To characterize network-level changes in neuronal activity induced by chronic opiate exposure, we compared FOS expression in mice that are morphine-naïve, morphine-dependent, or have undergone 4 wk of withdrawal from chronic morphine exposure, relative to saline-exposed controls. Pairwise interregional correlations in FOS expression data were used to construct network models that reveal a persistent reduction in connectivity strength following opiate dependence. Further, we demonstrate that basal gene expression patterns are predictive of changes in FOS correlation networks in the morphine-dependent state. Finally, we determine that regions of the hippocampus, striatum, and midbrain are most influential in driving transitions between opiate-naïve and opiate-dependent brain states using a control theoretic approach. This study provides a framework for predicting the influence of specific therapeutic interventions on the state of the opiate-dependent brain.

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En pointe: dancers report their pain less variably than do controls.

The subjective nature of pain and the lack of a gold standard for objective measurement hinders effective assessment, diagnosis, and treatment. Some individuals, such as professional dancers, are better in assessing and reporting bodily sensations. This observational study aimed to assess whether dancers report their pain less variably, than other people do. After consenting, subjects completed the Focused Analgesia Selection Task (FAST), which assesses subjects' variability of pain reports. FAST outcomes, ICC and R reflect the magnitude of variability of pain reports observed. In addition, subjects underwent a taste task, which similarly assesses variability of tastes (salty and sweet) intensity reports and completed the Multidimensional Assessment of Interoceptive Awareness (MAIA) questionnaire. Thirty-three professional dancers and thirty-three healthy aged-matched controls were recruited. The dancers exhibited less variability of pain reports then controls (P=0.013), but not in case of tastes-reports. Years of practice was positively correlated with pain reporting variability (r=0.447, P=0.009, and r=0.380, P=0.029; for FAST ICC and R, respectively). MAIA sub-scores correlated with pain reporting variability: R and ICC with emotional awareness (r=0.260, P=0.040, and r=0.274, P=0.030, respectively), and R with trusting [r=0.254, P=0.044]). Perspective The difference between dancers and controls in the magnitude of variability of pain reports is probably due to the dancers' extensive training, which focuses on attention to body signals. Our results suggest that training can improve subjective pain reports, which are essential for quality clinical care.

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Nonsteroidal Anti-inflammatory Drugs vs Cognitive Behavioral Therapy for Arthritis Pain: A Randomized Withdrawal Trial.

Nonsteroidal anti-inflammatory drugs (NSAIDs) are commonly prescribed for knee osteoarthritis. However, they are associated with uncertain long-term clinical benefit and significant toxic effects.

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Discovery of a Highly Selective Sigma-2 Receptor Ligand, 1-(4-(6,7-Dimethoxy-3,4-dihydroisoquinolin-2(1H)-yl)butyl)-3-methyl-1H-benzo[d]imidazol-2(3H)-one (CM398), with Drug-Like Properties and Antinociceptive Effects In Vivo.

The sigma-2 receptor has been cloned and identified as Tmem97, which is a transmembrane protein involved in intracellular Ca regulation and cholesterol homeostasis. Since its discovery, the sigma-2 receptor has been an extremely controversial target, and many efforts have been made to elucidate the functional role of this receptor during physiological and pathological conditions. Recently, this receptor has been proposed as a potential target to treat neuropathic pain due to the ability of sigma-2 receptor agonists to relieve mechanical hyperalgesia in mice model of chronic pain. In the present work, we developed a highly selective sigma-2 receptor ligand (sigma-1/sigma-2 selectivity ratio > 1000), 1-(4-(6,7-dimethoxy-3,4-dihydroisoquinolin-2(1H)-yl)butyl)-3-methyl-1H- benzo[d]imidazol-2(3H)-one (CM398), with an encouraging in vitro and in vivo pharmacological profile in rodents. In particular, radioligand binding studies demonstrated that CM398 had preferential affinity for sigma-2 receptor compared with sigma-1 receptor and at least four other neurotransmitter receptors sites, including the norepinephrine transporter. Following oral administration, CM398 showed rapid absorption and peak plasma concentration (Cmax) occurred within 10 min of dosing. Moreover, the compound showed adequate, absolute oral bioavailability of 29.0%. Finally, CM398 showed promising anti-inflammatory analgesic effects in the formalin model of inflammatory pain in mice. The results collected in this study provide more evidence that selective sigma-2 receptor ligands can be useful tools in the development of novel pain therapeutics and altogether, these data suggest that CM398 is a suitable lead candidate for further evaluation.

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Low-dose methadone for refractory chronic migraine accompanied by medication-overuse headache: a prospective cohort study.

A refractory chronic migraine (RCM) accompanied by medication-overuse headache (MOH) is an extremely disabling disease. Evidence suggests that in selected patients, chronic opioids may be a valuable therapeutic option for RCM. The aim of the present study was to evaluate the effectiveness and safety of prophylaxis with low-dose methadone (LDM) in patients affected by RCM with continuous headache and MOH.

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Depolarization-dependent C-Raf signaling promotes hyperexcitability and reduces opioid sensitivity of isolated nociceptors after spinal cord injury.

Chronic pain caused by spinal cord injury (SCI) is notoriously resistant to treatment, particularly by opioids. After SCI, dorsal root ganglion neurons show hyperactivity and chronic depolarization of resting membrane potential (RMP) that is maintained by cAMP signaling through PKA and EPAC. Importantly, SCI also reduces the negative regulation by Gαi of adenylyl cyclase and its production of cAMP, independent of alterations in G protein-coupled receptors and/or G proteins. Opioid reduction of pain depends upon coupling of opioid receptors to Gαi/o family members. Combining high-content imaging and cluster analysis, we show that in male rats SCI decreases opioid responsiveness in vitro within a specific subset of small-diameter nociceptors that bind isolectin B4. This SCI effect is mimicked in nociceptors from naïve animals by a modest 5 min depolarization of RMP (15 mM K; -45 mV), reducing inhibition of cAMP signaling by mu-opioid receptor agonists DAMGO and morphine. Disinhibition and activation of C-Raf by depolarization-dependent phosphorylation are central to these effects. Expression of an activated C-Raf reduces sensitivity of adenylyl cyclase to opioids in non-excitable HEK293 cells, while inhibition of C-Raf or treatment with the hyperpolarizing drug retigabine restores opioid responsiveness and blocks spontaneous activity of nociceptors after SCI. Inhibition of ERK downstream of C-Raf also blocks SCI-induced hyperexcitability and depolarization, without direct effects on opioid responsiveness. Thus, depolarization-dependent C-Raf and downstream ERK activity maintain a depolarized resting membrane potential and nociceptor hyperactivity after SCI, providing a self-reinforcing mechanism to persistently promote nociceptor hyperexcitability and limit the therapeutic effectiveness of opioids.Chronic pain induced by spinal cord injury (SCI) is often permanent and debilitating, and usually refractory to treatment with analgesics, including opioids. SCI-induced pain in a rat model has been shown to depend upon persistent hyperactivity in primary nociceptors (injury-detecting sensory neurons), associated with a decrease in the sensitivity of adenylyl cyclase production of cAMP to inhibitory Gαi proteins in dorsal root ganglia. This study shows that SCI and one consequence of SCI — chronic depolarization of resting membrane potential — decrease sensitivity to opioid-mediated inhibition of cAMP and promote hyperactivity of nociceptors by enhancing C-Raf activity. ERK activation downstream of C-Raf is necessary for maintaining ongoing depolarization and hyperactivity, demonstrating an unexpected positive feedback loop to persistently promote pain.

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Low plasma levels of calcitonin gene-related peptide in persistent post-traumatic headache attributed to mild traumatic brain injury.

To investigate the role of calcitonin gene-related peptide (CGRP) in persistent post-traumatic headache (PTH) attributed to mild traumatic brain injury (TBI).

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Signs and symptoms, quality of life and psychosocial data in 1331 post-traumatic trigeminal neuropathy patients seen in two tertiary referral centres in two countries.

Post-traumatic trigeminal neuropathy (PTN) is a disturbance of function or pathological change of the trigeminal nerve branches following trauma and has an important impact on patient's quality of life (QoL).

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