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Bradykinin (BK) is an endogenous peptide involved in vascular permeability and inflammation. It has opposite effects (inducing hyperalgesia or antinociception) when administered directly in the central nervous system. The aim of this study was to evaluate whether BK may also present this dual effect when injected peripherally in a PGE-induced nociceptive pain model, as well as to investigate the possible mechanisms of action involved in this event in mice.
Learn More >This cross-sectional study aimed to compare the waveform morphology through noninvasive intracranial pressure (ICP-NI) measurement between patients with migraine and controls, and to analyze the association with clinical variables. Twenty-nine women with migraine, age 32.4 (11.2) years and headache frequency of 12.6 (7.5) days per month and twenty-nine women without headache, age 32.1 (9.0) years, were evaluated. Pain intensity, migraine disability, allodynia, pain catastrophizing, central sensitization and depression were evaluated. The ICP-NI monitoring was performed by a valid method consisting of an extracranial deformation sensor positioned in the patients' scalp, which allowed registration of intracranial pressure waveforms. Heart rate and blood pressure measurements were simultaneously recorded during 20 min in the supine position. The analyzed parameter was the P2/P1 ratio based on mean pulse per minute which P1 represents the percussion wave related to the arterial blood pression maximum and P2 the tidal wave, middle point between the P1 maximum and the dicrotic notch. There was no between-groups difference in the P2/P1 ratio (mean difference: 0.04, IC95%: -0.07 to 0.16, p = 0.352, F (1,1) = 0.881) adjusted by body mass index covariable. The Multiple Linear Regression showed non-statistical significance [F (5,44) = 1.104; p = 0.372; R = 0.11)] between the P2/P1 ratio and body mass index, presence of migraine, central sensitization, pain catastrophizing and depression. We found no correlation (p > 0.05) between P2/P1 ratio and migraine frequency, migraine onset, pain intensity, pain intensity at day of examination, disability, allodynia. Migraine patients did not present alterations in the waveform morphology through ICP-NI compared to women without headache and no association with clinical variables was found.
Learn More >Chronic musculoskeletal pain and insomnia frequently co-occur and are known independent risk factors for anxiety and depression. However, the interplay between these two conditions on the risk of anxiety and depression has not been explored.
Learn More >Postpartum depression (PPD) is a common complication of cesarean section. S-ketamine given intravenously during surgery can help prevent PPD. However, whether S-ketamine in patient-controlled intravenous analgesia (PCIA) can reduce the incidence of PPD is unknown. This study assessed the effect of S-ketamine as an adjuvant in PCIA for preventing PPD in women undergoing cesarean delivery.
Learn More >Substantial empirical evidence has shown that intolerance of uncertainty is a central transdiagnostic feature in psychopathology and it has been suggested to be a pain-related psychological factor contributing to the experience of chronic pain. However, research in this area is virtually nonexistent. The objective of this study was to investigate associations between pain severity, catastrophizing, and anxiety in people with chronic nononcological pain, while assuming that intolerance of uncertainty moderates these relationships.
Learn More >Spatial transcriptomics of dorsal root ganglia identifies molecular signatures of human nociceptors.
Nociceptors are specialized sensory neurons that detect damaging or potentially damaging stimuli and are found in the dorsal root ganglia (DRG) and trigeminal ganglia. These neurons are critical for the generation of neuronal signals that ultimately create the perception of pain. Nociceptors are also primary targets for treating acute and chronic pain. Single-cell transcriptomics on mouse nociceptors has transformed our understanding of pain mechanisms. We sought to generate equivalent information for human nociceptors with the goal of identifying transcriptomic signatures of nociceptors, identifying species differences and potential drug targets. We used spatial transcriptomics to molecularly characterize transcriptomes of single DRG neurons from eight organ donors. We identified 12 clusters of human sensory neurons, 5 of which are C nociceptors, as well as 1 C low-threshold mechanoreceptors (LTMRs), 1 Aβ nociceptor, 2 Aδ, 2 Aβ, and 1 proprioceptor subtypes. By focusing on expression profiles for ion channels, G protein-coupled receptors (GPCRs), and other pharmacological targets, we provided a rich map of potential drug targets in the human DRG with direct comparison to mouse sensory neuron transcriptomes. We also compared human DRG neuronal subtypes to nonhuman primates showing conserved patterns of gene expression among many cell types but divergence among specific nociceptor subsets. Last, we identified sex differences in human DRG subpopulation transcriptomes, including a marked increase in calcitonin-related polypeptide alpha () expression in female pruritogen receptor-enriched nociceptors. This comprehensive spatial characterization of human nociceptors might open the door to development of better treatments for acute and chronic pain disorders.
Learn More >Adaptor protein 2-associated kinase 1 (AAK1) is a serine/threonine kinase that was identified as a therapeutic target for the potential treatment of neuropathic pain. Inhibition of AAK1 in the central nervous system, particularly within the spinal cord, was found to be the relevant site for achieving an antinociceptive effect. We previously reported that compound is a brain-penetrant, AAK1 inhibitor that showed efficacy in animal models for neuropathic pain. One approach we took to improve upon the potency of involved tying the amide back into the neighboring phenyl ring to form a bicyclic heterocycle. Investigation of the structure-activity relationships (SARs) of substituents on the resultant quinazoline and quinoline ring systems led to the identification of , a brain-penetrant, AAK1-selective inhibitor with improved enzyme and cellular potency compared to . The synthesis, SAR, and in vivo evaluation of a series of quinazoline and quinoline-based AAK1 inhibitors are described herein.
Learn More >Youth living with chronic sickle cell disease (SCD) pain are at risk for psychosocial distress and high levels of pain catastrophizing that contribute to functional impairment. This study aimed to identify the unique long-term impact of pain catastrophizing on pain impairment among youth with SCD. Youth with chronic SCD pain (N = 63, 10-18 years old, 58.3% female, 95.1% Black or African American) were recruited within comprehensive SCD clinics and completed a battery of measures at baseline and 4-months follow-up. A linear hierarchical regression examined baseline demographic and clinical characteristics (child SCD genotype, age, and average pain intensity), psychosocial functioning (anxiety, depression), and pain catastrophizing as predictors of pain interference at 4-months follow-up. Pain catastrophizing was the only unique predictor of pain interference at 4-months follow-up. Among youth with chronic SCD pain, pain catastrophizing warrants greater consideration as an important predictor that influences pain management and overall functioning.
Learn More >Rural disparities exist in access to multidisciplinary pain care with higher rates of opioid prescribing in rural regions. Among Veterans, who have prevalent rates of chronic pain, women often evidence complex presentations, multiple comorbidities, and dissatisfaction with care. This study investigates the impact of rurality on pain care for women specifically, and whether this varies from the impact of rurality for men.
Learn More >The current paradigm is that inflammatory pain passively resolves following the cessation of inflammation. Yet, in a substantial proportion of patients with inflammatory diseases, resolution of inflammation is not sufficient to resolve pain, resulting in chronic pain. Mechanistic insight into how inflammatory pain is resolved is lacking. Here, we show that macrophages actively control resolution of inflammatory pain remotely from the site of inflammation by transferring mitochondria to sensory neurons. During resolution of inflammatory pain in mice, M2-like macrophages infiltrate the dorsal root ganglia that contain the somata of sensory neurons, concurrent with the recovery of oxidative phosphorylation in sensory neurons. The resolution of pain and the transfer of mitochondria requires expression of CD200 receptor (CD200R) on macrophages and the non-canonical CD200R-ligand iSec1 on sensory neurons. Our data reveal a novel mechanism for active resolution of inflammatory pain.
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