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Innocuous touch sensation is mediated by cutaneous low-threshold mechanoreceptors (LTMRs). Aβ slowly adapting type 1 (SA1) neurons constitute one LTMR subtype that forms synapse-like complexes with associated Merkel cells in the basal skin epidermis. Under healthy conditions, these complexes transduce indentation and pressure stimuli into Aβ SA1 LTMR action potentials that are transmitted to the central nervous system, thereby contributing to tactile sensation. However, it remains unknown whether this complex plays a role in the mechanical hypersensitivity caused by peripheral nerve injury. In this study, we characterized the distribution of Merkel cells and associated afferent neurons across four diverse domains of mouse hind paw skin, including a recently described patch of plantar hairy skin. We also showed that in the spared nerve injury (SNI) model of neuropathic pain, Merkel cells are lost from the denervated tibial nerve territory, but are relatively preserved in nearby hairy skin innervated by the spared sural nerve. Utilizing a genetic Merkel cell knockout mouse model, we subsequently examined the importance of intact Merkel cell-Aβ complexes to SNI-associated mechanical hypersensitivity in skin innervated by the spared neurons. We found that in the absence of Merkel cells, mechanical allodynia was partially reduced in male mice, but not female mice, under sural-sparing SNI conditions. Our results suggest that Merkel cell-Aβ afferent complexes partially contribute to mechanical allodynia produced by peripheral nerve injury, and that they do so in a sex dependent manner.Merkel discs or Merkel cell-Aβ afferent complexes are mechanosensory end organs in mammalian skin. Yet, it remains unknown whether Merkel cells or their associated sensory neurons play a role in the mechanical hypersensitivity caused by peripheral nerve injury. We found that male mice genetically lacking Merkel cell-Aβ afferent complexes exhibited a reduction in mechanical allodynia after nerve injury. Interestingly, this behavioral phenotype was not observed in mutant female mice. Our study will facilitate understanding of mechanisms underlying neuropathic pain.
Learn More >Post-traumatic trigeminal neuropathy (PTN) can have a substantial effect on patient well-being. However, the relation between the neuropathic symptoms and their effect on psychosocial functioning remains a matter of debate. The purpose of this study was to evaluate the association between objective and subjective assessments of neurosensory function in PTN and predict neurosensory outcome using baseline measurements.
Learn More >A key clinical problem is identifying the endometriosis patient whose pain is complicated by central nervous system sensitization, where conventional gynecologic treatment (e.g. hormonal therapy or surgery) may not completely alleviate the pain. The Central Sensitization Inventory (CSI) is a questionnaire previously validated in the chronic pain population. The objective of this study was an exploratory proof-of-concept to identify a CSI cut-off in the endometriosis population to discriminate between individuals with significant central contributors (identified by central sensitivity syndromes (CSS)) to their pain compared to those without. We analyzed a prospective data registry at a tertiary referral center for endometriosis, and included subjects aged 18-50 years with endometriosis who were newly or re-referred to the center in 2018. The study sample consisted of 335 subjects with a mean age of 36.0±7.0 years. An increasing number of CSS was significantly correlated with dysmenorrhea, deep dyspareunia, dyschezia, and chronic pelvic pain scores (p's<.001) and with the CSI score (0-100) (r=.731, p<.001). ROC analysis indicated that a CSI cut-off of 40 had sensitivity 78% (95% CI: 72.7% – 84.6%) and specificity 80% (95% CI: 70.3% – 84.5%) for identifying an endometriosis patient with ≥ 3 CSS. In the group with CSI≥40, 18% retrospectively self-reported pain non-responsive to hormonal therapy and 40% self-reported daily pain, compared to 6% and 20% in the CSI<40 group (p=.003 and .002, respectively). In conclusion, a CSI ≥ 40 may be a practical tool to help identify endometriosis patients with pain contributors related to central nervous system sensitization.
Learn More >Mesenchymal stem/stromal cells (MSCs) are multipotent progenitor cells of mesodermal origin. Due to their capacity for self-renewal and differentiation into several cell types, MSCs have been extensively studied in experimental biology and regenerative medicine in recent years. Moreover, MSCs release extracellular vesicles (EVs), which might be partially responsible for their regenerative properties. MSCs regulate several processes in target cells via paracrine signalling, such as immunomodulation, antiapoptotic signalling, tissue remodelling, angiogenesis, and antifibrotic signalling. The aim of this review is to provide a detailed description of the functional properties of MSCs and EVs and their potential clinical applications, with a special focus on pain treatment. The analgesic, anti-inflammatory and regenerative properties of MSCs and EVs will be discussed for several diseases, such as neuropathic pain, osteoarthritis and spinal cord injury.
Learn More >Explore predictors of improvement in headache days and migraine-related disability through a secondary analysis of the cognitive-behavioral therapy plus amitriptyline trial in children and adolescents (Clinical Trials Registration Number: NCT00389038). Participants were 135 youth aged 10-17 years old diagnosed with chronic migraine. Predictor variables included group assignment (treatment or control), baseline scores from depression and quality of life measures, and demographic variables. Criterion variables included headache days and migraine-related disability. Higher baseline depression scores were indicative of more days with headache post-treatment regardless of group assignment. Family income at the higher-end of the low-income range was significantly associated with less migraine-related disability regardless of group assignment (Household Income: HINC-01 in The United States Census Bureau. Bureau, U, 2020). Results from this secondary analysis identify depression symptoms and family income as predictors that can impact headache frequency and migraine-related disability. Self-reported symptoms of depression and family income are important factors to consider as part of the biopsychosocial model of care.
Learn More >Kinesins are the motor proteins that transport excitatory receptors to the synaptic membrane by forming a complex with receptor cargo leading to central sensitization causing neuropathic pain. Many regulatory proteins govern the transit of receptors by activating kinesin, and Aurora kinases are one of them. In this study, we have performed in silico molecular dynamics simulation to delineate the dynamic interaction of Aurora kinase A with its pharmacological inhibitor, tozasertib. The results from the molecular dynamics study shows that tozasertib-Aurora kinase A complex is stabilized through hydrogen bonding, polar interactions, and water bridges. Findings from the studies suggest that tozasertib treatment significantly attenuates lipopolysaccharide (LPS)-induced increase in oxidonitrosative stress and kif11 overexpression in C6 glial cell lines. Further, we investigated the regulation of kif11 and its modulation by tozasertib in an animal model of neuropathic pain. Two weeks post-CCI surgery we observed a significant increase in pain hypersensitivity and kif11 overexpression in DRG and spinal cord of nerve-injured rats. Tozasertib treatment significantly attenuates enhanced pain hypersensitivity along with the restoration of kif11 expression in DRG and spinal cord and oxidonitrosative stress in the sciatic nerve of injured rats. Our findings demonstrate the potential role of tozasertib for the management of neuropathic pain.
Learn More >The molecular mechanism behind pain in degenerative disc disease (DDD) and chronic low back pain (LBP) patients is largely unknown. This present study examines the association of LBP and disability to mediators of the inflammatory cascade, as indexed by mRNA gene expression of pro-inflammatory cytokine markers in the intervertebral disc (IVD).
Learn More >Rimegepant is an orally administered small-molecule calcitonin gene-related peptide (CGRP) receptor antagonist, with demonstrated efficacy in the acute treatment of migraine. Recent estimates from a single-arm trial (BHV3000-201) have also shown evidence of long-term preventive effects in monthly migraine days (MMDs) and health-related quality of life (HRQoL). This study aimed to compare MMDs and HRQoL data for oral rimegepant to those obtained in placebo-controlled trials for injectable anti-CGRP monoclonal antibodies (mAbs) galcanezumab and erenumab.
Learn More >Individuals suffering from chronic low-back pain and obesity face severe physical and functional limitations. According to the fear-avoidance model, kinesiophobia might play a crucial role in the relationship between pain intensity and disability. Thus, the purpose of this study was to verify the role of kinesiophobia as a mediator in the association between pain intensity and disability in individuals with both chronic low-back pain and obesity. A total of 213 individuals with chronic low-back pain and obesity were included in the study. The level of kinesiophobia, pain intensity and disability were all assessed using self-reported questionnaires. We verified through a simple mediation analysis that kinesiophobia partially mediated the association between pain intensity and disability in our sample. According to our findings, we emphasize the crucial role of kinesiophobia as a psychological factor that should be addressed in chronic low-back pain rehabilitative protocols to reduce disability in individuals with obesity.
Learn More >Native Americans (NAs) experience higher rates of chronic pain than the general U.S. population, but the risk factors for this pain disparity are unknown. NAs also experience high rates of stressors and cardiovascular and metabolic health disparities (eg, diabetes, cardiovascular disease) consistent with allostatic load (stress-related wear-and-tear on homeostatic systems). Given that allostatic load is associated with chronic pain, then allostatic load may contribute to their pain disparity. Data from 302 healthy, pain-free men and women (153 NAs, 149 non-Hispanic Whites [NHW]) were analyzed using structural equation modeling to determine whether cardiometabolic allostatic load (body mass index, blood pressure, heart rate variability) mediated the relationship between NA ethnicity and experimental measures of pronociceptive processes: temporal summation of pain (TS-pain) and the nociceptive flexion reflex (TS-NFR), conditioned pain modulation of pain (CPM-pain) and NFR (CPM-NFR), and pain tolerance. Results indicated that NAs experienced greater cardiometabolic allostatic load that was related to enhanced TS-NFR and impaired CPM-NFR. Cardiometabolic allostatic load was unrelated to measures of pain perception (CPM-pain, TS-pain, pain sensitivity). This suggests cardiometabolic allostatic load may promote spinal sensitization in healthy NAs, that is not concomitant with pain sensitization, perhaps representing a unique pain risk phenotype in NAs. Perspective: Healthy, pain-free Native Americans experienced greater cardiometabolic allostatic load that was associated with a pronociceptive pain phenotype indicative of latent spinal sensitization (ie, spinal sensitization not associated with hyperalgesia). This latent spinal sensitization could represent a pain risk phenotype for this population.
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