Browse by Audience
σ-1 receptors (σR) modulate nociceptive signaling, driving the search for selective antagonists to take advantage of this promising target to treat pain. In this study, a new series of benzylpiperazinyl derivatives has been designed, synthesized, and characterized for their affinities toward σR and selectivity over the σ-2 receptor (σR). Notably, 3-cyclohexyl-1-{4-[(4-methoxyphenyl)methyl]piperazin-1-yl}propan-1-one () showed the highest σR receptor affinity ( σ = 1.6 nM) among the series with a significant improvement of the σR selectivity ( σ/ σ 886) compared to the lead compound ( σ/ σ 432). Compound was further tested in a mouse formalin assay of inflammatory pain and chronic nerve constriction injury (CCI) of neuropathic pain, where it produced dose-dependent (3-60 mg/kg, i.p.) antinociception and anti-allodynic effects. Moreover, compound demonstrated no significant effects in a rotarod assay, suggesting that this σR antagonist did not produce sedation or impair locomotor responses. Overall, these results encourage the further development of our benzylpiperazine-based σR antagonists as potential therapeutics for chronic pain.
Learn More >Diabetic polyneuropathy (DPN) is the most common complication in diabetes and can be painful in up to 26% of all diabetic patients. Peripheral nerves are shielded by the blood-nerve barrier (BNB) consisting of the perineurium and endoneurial vessels. So far, there are conflicting results regarding the role and function of the BNB in the pathophysiology of DPN. In this study, we analyzed the spatiotemporal tight junction protein profile, barrier permeability, and vessel-associated macrophages in Wistar rats with streptozotocin-induced DPN. In these rats, mechanical hypersensitivity developed after 2 weeks and loss of motor function after 8 weeks, while the BNB and the blood-DRG barrier were leakier for small, but not for large molecules after 8 weeks only. The blood-spinal cord barrier remained sealed throughout the observation period. No gross changes in tight junction protein or cytokine expression were observed in all barriers to blood. However, expression of Cldn1 mRNA in perineurium was specifically downregulated in conjunction with weaker vessel-associated macrophage shielding of the BNB. Our results underline the role of specific tight junction proteins and BNB breakdown in DPN maintenance and differentiate DPN from traumatic nerve injury. Targeting claudins and sealing the BNB could stabilize pain and prevent further nerve damage. KEY MESSAGES: • In diabetic painful neuropathy in rats: • Blood nerve barrier and blood DRG barrier are leaky for micromolecules. • Perineurial Cldn1 sealing the blood nerve barrier is specifically downregulated. • Endoneurial vessel-associated macrophages are also decreased. • These changes occur after onset of hyperalgesia thereby maintaining rather than inducing pain.
Learn More >The purpose of this study was to determine predictors of pain severity among older United States (US) adults with pain.This cross-sectional, retrospective study utilized 2017 Medical Expenditure Panel Survey data. Eligible participants were alive for the calendar year, aged ≥50 years, and reported pain in the past 4 weeks. Hierarchical logistic regression models, adjusting for the survey design, were used to identify significant predictors of pain severity (i.e., extreme/quite a bit or moderate/little pain).An estimated 14,250,534 adults aged ≥50 with pain reported extreme/quite a bit of pain. Many variables were associated with extreme/quite a bit of pain, including: age 50 to 64 vs ≥65 years (adjusted odds ratio [AOR] = 1.49, 95% confidence interval [95% CI] = 1.22-1.82); males vs females (AOR = 0.80, 95% CI = 0.67-0.95); white race vs others (AOR = 0.75, 95% CI = 0.61-0.92); married vs other marital status (AOR = 1.31, 95% CI = 1.08-1.57); income <200% vs ≥200% federal poverty level (AOR = 1.30, 95% CI = 1.06-1.60); employed vs unemployed (AOR = 0.47, 95% CI = 0.37-0.60); limitation vs no limitation (AOR = 2.64, 95% CI = 2.09-3.33); 0, 1, 3, or 4 vs ≥5 chronic conditions (AOR ranged from 0.39 for 0 conditions to 0.77 for 4 conditions); excellent/very good or good vs fair/poor perceived physical health status (AOR ranged from 0.28 for excellent/very good to 0.40 for good); smokers vs non-smokers (AOR = 1.56, 95% CI = 1.27-1.93); exercise versus no exercise (AOR = 0.74, 95% CI = 0.62-0.88); and South vs West census region (AOR = 1.34, 95% CI = 1.04-1.74).This study found several characteristics could predict pain severity among older US adults who reported extreme/quite a bit of pain. These characteristics may guide specific areas of focus to improve patients' pain management.
Learn More >The Global burden of disease study ranked migraine as the sixth most common disorder worldwide in 2016, with significant social and economic sequelae. In this study, we assessed the efficacy of different Calcitonin gene-related peptide (CGRP) receptor blockers as potential pharmacological approaches and compare them to placebo using the systematic review (SR) and network meta-analysis (NMA) approach. We performed a computerized search of SCOPUS, PubMed, Cochrane central, and Embase databases through January 2019 and included randomized controlled trials (RCTs), which were performed on episodic and chronic migraine patients who used Erenumab, Eptinezumab, Fremanezumab, or Galcanezumab. The combined analysis revealed that after six, eight, and twelve weeks of intervention, the medications with the most potent effects in comparison to placebo were Fremanezumab 900 mg, (SMD = -0.55, 95% CI [-0.97, -0.12]); Erenumab 140 mg, (SMD = -0.51, 95% CI [-0.61, 0.41]); and Erenumab 140 mg, (SMD = -0.48, 95% CI [-0.571, 0.39]), respectively. For chronic migraine patients, Fremanezumab 900 mg, Erenumab 140 mg, in addition to Erenumab 70 mg, were associated with the highest efficacy after 6, 8, and 12 weeks, correspondingly. The analysis of combined groups data (Chronic and Episodic) showed that Fremanezumab was the most effective drug after six weeks, where Erenumab was the most effective after 8 and 12 weeks. The current evidence retrieved from this NMA suggests that Fremanezumab was the most effective anti-migraine medication in decreasing MHDs per month after six weeks in both chronic and episodic patients.
Learn More >Increased symptoms related to central sensitization have previously been reported in inflammatory bowel disease (IBD) patients, identified by the original central sensitization inventory (CSI-25). However, the recently developed CSI short form (CSI-9) may be more clinically useful. The aim of the present study was to evaluate the performance of CSI-9 compared to the original CSI-25 in individuals with IBD. Study objectives were to investigate the criterion validity of the CSI-9 to the CSI-25, assess individual association of the CSI measures with clinical features of IBD and pain presentations, and to establish disease-specific CSI-9 and CSI-25 cut-off scores for discriminating the presence of self-reported pain in individuals with IBD.
Learn More >Provoked vestibulodynia (PVD) is a chronic pain disorder characterized by local hypersensitivity and severe pain with pressure localized to the vulvar vestibule. Despite decades of study, the lack of identified biomarkers has slowed the development of effective therapies. The primary aim of this study was to use metabolomics to identify novel biochemical mechanisms in vagina and blood underlying brain biomarkers and symptoms in PVD, thereby closing this knowledge gap. Using a cross-sectional case-control observational study design, untargeted and unbiased metabolomic profiling of vaginal fluid and plasma was performed in women with PVD compared to healthy controls. In women with PVD, we also obtained assessments of vulvar pain, vestibular and vaginal muscle tenderness, and 24-hour symptom intensity alongside resting-state brain functional connectivity of brain regions involved in pain processing and modulation. Compared to healthy controls, women with PVD demonstrated differences primarily in vaginal (but not plasma) concentrations of metabolites of the sphingolipid signaling pathways, suggesting localized effects in vagina and vulvar vestibule rather than systemic effects. Our findings reveal that dysregulation of sphingolipid metabolism in PVD is associated with increased vulvar pain and muscle tenderness, sexual dysfunction, and decreased functional connectivity strength in pain processing/modulatory brain regions. This data collectively suggests that alterations in sphingolipid signaling pathways are likely an important molecular biomarker in PVD that could lead to new targets for therapeutic intervention.
Learn More >Most studies investigating the course of recent-onset low back pain (LBP) included patients from primary care. We aimed to describe the prognosis in people with recent-onset LBP presenting to emergency departments (EDs) and to identify prognostic factors for non-recovery. This inception cohort study with a one-year follow-up recruited 600 consecutive acute LBP patients presenting to four EDs. The outcomes measured the days to recover from pain, recover from disability, return to previous work hours and duties, and complete recovery. Within 12 months, 73% of participants (95% CI=69 to 77) recovered from pain, 86% (95% CI=82 to 90) recovered from disability, 75% (95% CI=67 to 82) returned to previous work hours and duties, and 68% (95% CI=64 to 72) completely recovered. The median recovery times were 67 days (95% CI=54 to 80) to recover from pain, 37 days (95% CI=31 to 43) to recover from disability, 37 days (95% CI=25 to 49) to return to previous work hours and duties, and 71 days (95% CI=56 to 85) to recover completely. Higher pain levels, a higher perceived risk of persistent LBP, more days of reduced activity due to LBP, more pain sites, and higher duration of LBP were associated with complete non-recovery within six months. Perspective: This information relates to prognosis and to likely recovery times for patients with recent-onset LBP in EDs. The findings also confirm previous factors associated with poor outcomes in patients with recent-onset LBP.
Learn More >The present experiments determined the effects of the narrow-spectrum antibiotic vancomycin on inflammatory pain-stimulated and pain-depressed behaviors in rats. Persistent inflammatory pain was modeled using dilute formalin (0.5%). Two weeks of oral vancomycin administered in drinking water attenuated Phase II formalin pain-stimulated behavior, and prevented formalin pain-depressed wheel running. Fecal microbiota transplantation (FMT) produced a non-significant trend toward reversal of the vancomycin effect on pain-stimulated behavior. Vancomycin depleted Firmicutes and Bacteroidetes populations in the gut while having a partial sparing effect on Lactobacillus species and Clostridiales. The vancomycin treatment effect was associated with an altered profile in amino acid concentrations in the gut with increases in arginine, glycine, alanine, proline, valine, leucine, and decreases in tyrosine and methionine. These results indicate that vancomycin may have therapeutic effects against persistent inflammatory pain conditions that are distal to the gut. Perspective: The narrow-spectrum antibiotic vancomycin reduces pain-related behaviors in the formalin model of inflammatory pain. These data suggest that manipulation of the gut microbiome may be one method to attenuate inflammatory pain amplitude.
Learn More >Chronic pain and post-traumatic stress disorder (PTSD) frequently co-occur, and research suggests that these two conditions exacerbate one another producing greater impact on normal functioning in combination than separately. The influence of traumatic experiences on both pain and PTSD have been shown, but the nature of this interplay remains unclear. Although Criterion A trauma is required for the diagnosis of PTSD, whether the association between PTSD and chronic pain is dependent on Criterion A is underexplored. In this observational cohort study, we examined the association between pain and PTSD-like symptoms in the context of Criterion A trauma in 5791 men from the Vietnam Era Twin Registry. Correlations and mixed-effects regression models were used to evaluate the relationship between PTSD Checklist-Civilian Version symptoms and multiple indicators of pain from the Short Form McGill Pain Questionnaire across trauma history and chronic pain conditions. 53.21% of the participants experienced trauma consistent with DSM-IV Criterion A for PTSD. The associations between pain indicators and PTSD-like symptoms was stronger for individuals with a history of trauma but remained robust for individuals without trauma history. Small but significant interactions between past trauma and pain indicators and PTSD-like symptoms were observed. Findings were similar in a subsample of participants with history of chronic pain conditions. The relationship between PTSD-like symptoms and indicators of pain were largely independent of trauma consistent with Criterion A, highlighting the need to better understand and address stressful life events in chronic pain patients and pain concerns in individuals reporting trauma. Perspective: This article demonstrates that the relationship between PTSD-like symptoms and indicators of pain is largely independent of trauma consistent with Criterion A. This finding highlights the need to better understand and address stressful life events in chronic pain patients and pain concerns in individuals reporting trauma.
Learn More >Pediatric chronic pain is a challenging problem for children and their families, although it is still under-recognized and under-treated. The aim of this study was to investigate whether a pain neuroscience education program for children (PNE4Kids) delivered to healthy children aged 8 to 12 years old and attended by their parents would result in improved parental knowledge about pain neurophysiology, decreased parental pain catastrophizing about their own pain and their children's, decreased parental pain vigilance and awareness, and decreased fear of pain in children. Twenty-seven healthy child-parent dyads received a 45 min PNE4Kids session. Demographic data were collected, and the Neurophysiology of Pain Questionnaire (NPQ), Fear of Pain Questionnaire-Parent Proxy Report (FOPQ-P), Pain Catastrophizing Scale (PCS), Pain Catastrophizing Scale for Parents (PCS-P), and the Pain Vigilance and Awareness Questionnaire (PVAQ) were completed by the parents before and after the PNE4Kids session. Twenty-six dyads completed study participation. In response to the PNE4Kids session, significant short-term (1 week) improvements were shown in the NPQ ( < 0.001) and the FOPQ-P ( = 0.002). Parents' level of pain knowledge and children's fear of pain, reported by their parents, improved after a 45 min PNE4Kids session. Thus, PNE4Kids should likewise be further investigated in healthy child-parent dyads as it might be useful to target parental and children's pain cognitions at a young age.
Learn More >