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Pruritus is an unexpected symptom observed in cholestasis and its mechanism is still unclear. Here, we show that bovine adrenal medulla (BAM) 8-22, an endogenous itch-inducing peptide, could be involved in cholestatic pruritus. It was found that bile duct ligation (BDL) mice, an obstructive cholestasis model, showed increased spontaneous scratching behaviour. Importantly, the mRNA level of proenkephalin, a precursor polypeptide of BAM8-22, was significantly increased in the skin of BDL mice. Furthermore, the mRNA level of Mrgprx1, which encodes a receptor for BAM8-22, was significantly increased in the dorsal root ganglia (DRG) of BDL mice. This was further confirmed by elevation of intracellular calcium levels upon BAM8-22 treatment in primarily-cultured DRG neurons. In addition, BDL mice showed augmented scratching behaviour by BAM8-22, indicating enhanced activity of MRGPRX1. Moreover, the skin homogenate of BDL mice induced elevation of intracellular calcium levels through MRGPRX1. Finally, among the various bile acids, chenodeoxycholic acid significantly increased proenkephalin transcription in a human keratinocyte cell line (HaCaT). In conclusion, cholestatic pruritus could be attributed in part to enhanced action of both BAM8-22 in the skin and its receptor MRGPRX1 in sensory neurons.
Learn More >To describe the demographic, clinical, and treatment characteristics of youth diagnosed with juvenile primary fibromyalgia syndrome (JPFS) who are seen in pediatric rheumatology clinics.
Learn More >Background and aims There is a growing body of evidence, that pain is common at school age. Less is known about the repeatability of pain questionnaires for children. This study aimed to assess the test-retest repeatability of the Finnish version of the electronic pain questionnaire for school-aged children. Methods Primary (n = 79) and lower secondary (n = 127) schoolchildren aged 10-15 years from two schools from the Jyväskylä region of Finland, filled in an electronic questionnaire twice in an interval of 2 weeks. It captured the frequency of pain symptoms with a five-point Likert-scale questionnaire covering nine areas of the body for the last 3 months. The intraclass correlation coefficient (ICC) values 0.40-0.59 reflected fair and 0.60-0.74 good repeatability. Results The highest prevalences of pain were in the head (29%) and neck and shoulder (NS) (23%) areas. ICC values showed good repeatability for questions about pain frequency in the head, NS and lower extremities. In primary school, these values were good in the lower extremities and fair in NS, lower back and the head. In lower secondary school, the ICC values were good in NS and the head, fair in the stomach and lower extremities. Conclusions This electronic questionnaire was an acceptably repeatable indicator to measure the frequency of pain in the most prevalent pain areas: the head and NS. Implications It is important to be aware of the impact of health-related outcomes on children's ability to be successful in their lives. With the help of a simple electronic questionnaire, it is possible to cost-effectively capture, for example, the prevalence and frequency of pain during the school hours. The identification of children's pain symptoms accurately provides more possibilities to prevent and to minimize the chronic pain among schoolchildren.
Learn More >Background and aims The painDETECT questionnaire (PD-Q) has been widely used as a screening tool for the identification of neuropathic pain (NeP) as well as a tool for the characterization of patients' pain profile. In contrast to other NeP screening tools, the PD-Q is the only screening tool with weighted sensory descriptors. It is possible that responses to the PD-Q sensory descriptors are influenced by psychological factors, such as catastrophizing or anxiety, which potentially might contribute to an overall higher score of PD-Q and a false positive identification of NeP. This study aimed to explore (i) the relationship between psychological factors (catastrophizing, anxiety, depression and stress) and the total PD-Q score and (ii) if psychological factors are associated with false positive identifications of NeP on the PD-Q compared to clinically diagnosed NeP. Methods The study was a retrospective review of 1,101 patients attending an outpatient pain centre. Patients were asked to complete the PD-Q, the Pain Catastrophizing Scale (PCS), the Depression, Anxiety and Stress Scale (DASS) and the Brief Pain Inventory (BPI). For patients who were identified by PD-Q as having NeP, their medical records were reviewed to establish if they had a clinical diagnosis of NeP. Results Accounting for missing data, complete datasets of 652 patients (mean age 51 (SD14) years, range 18-88; 57% females) were available for analysis. Based on PD-Q scoring, NeP was likely present in 285 (44%) patients. Depression, anxiety, stress, catastrophizing, BPI pain and BPI interference were all significantly related to each other (p < 0.0001) and patients displaying these traits were significantly more likely to have a positive PD-Q score (p < 0.0001). For patients classified by PD-Q as having NeP, only 50% of patients had a clinical diagnosis of NeP. Anxiety was significantly associated with a false positive classification of NeP on PD-Q (p = 0.0036). Conclusions Our retrospective study showed that psychological factors including catastrophizing, depression, anxiety, and stress were all influential in producing a higher score on the PD-Q. We observed a high rate of false positive NeP classification which was associated with the presence of anxiety. Implications Clinicians and researchers should be aware that a patient's psychological state may influence the responses to PD-Q and consequently the final PD-Q score and its NeP classification.
Learn More >Background and aims In 2008, the International Association for the Study of Pain Special Interest Group on Neuropathic Pain (NeuPSIG) proposed a clinical grading system to help identify patients with neuropathic pain (NeP). We previously applied this classification system, along with two NeP screening tools, the painDETECT (PD-Q) and Leeds Assessment of Neuropathic Symptoms and Signs pain scale (LANSS), to identify NeP in patients with neck/upper limb pain. Both screening tools failed to identify a large proportion of patients with clinically classified NeP, however a limitation of our study was the use of a single clinician performing the NeP classification. In 2016, the NeuPSIG grading system was updated with the aim of improving its clinical utility. We were interested in field testing of the revised grading system, in particular in the application of the grading system and the agreement of interpretation of clinical findings. The primary aim of the current study was to explore the application of the NeuPSIG revised grading system based on patient records and to establish the inter-rater agreement of detecting NeP. A secondary aim was to investigate the level of agreement in detecting NeP between the revised NeuPSIG grading system and the LANSS and PD-Q. Methods In this retrospective study, two expert clinicians (Specialist Pain Medicine Physician and Advanced Scope Physiotherapist) independently reviewed 152 patient case notes and classified them according to the revised grading system. The consensus of the expert clinicians' clinical classification was used as "gold standard" to determine the diagnostic accuracy of the two NeP screening tools. Results The two clinicians agreed in classifying 117 out of 152 patients (ICC 0.794, 95% CI 0.716-850; κ 0.62, 95% CI 0.50-0.73), yielding a 77% agreement. Compared to the clinicians' consensus, both LANSS and PD-Q demonstrated limited diagnostic accuracy in detecting NeP (LANSS sensitivity 24%, specificity 97%; PD-Q sensitivity 53%, specificity 67%). Conclusions The application of the revised NeP grading system was feasible in our retrospective analysis of patients with neck/upper limb pain. High inter-rater percentage agreement was demonstrated. The hierarchical order of classification may lead to false negative classification. We propose that in the absence of sensory changes or diagnostic tests in patients with neck/upper limb pain, classification of NeP may be further improved using a cluster of clinical findings that confirm a relevant nerve lesion/disease, such as reflex and motor changes. The diagnostic accuracy of LANSS and PD-Q in identifying NeP in patients with neck/upper limb pain remains limited. Clinical judgment remains crucial to diagnosing NeP in the clinical practice. Implications Our observations suggest that in view of the heterogeneity in patients with neck/upper limb pain, a considerable amount of expertise is required to interpret the revised grading system. While the application was feasible in our clinical setting, it is unclear if this will be feasible to apply in primary health care settings where early recognition and timely intervention is often most needed. The use of LANSS and PD-Q in the identification of NeP in patients with neck/upper limb pain remains questionable.
Learn More >Background and aims Endometriosis is a gynecologic recurring persistent condition affecting from 8% to 15% of premenopausal women worldwide. About 80% of women with endometriosis have at least one form of chronic pain – a multidimensional experience influenced by a number of psychosocial factors, including pain-related beliefs. The Survey of Pain Attitudes is the most commonly used measure of pain-related beliefs. This study aims to evaluate the psychometric properties of a Portuguese version of a brief version of the SOPA (the SOPA-35) in a sample of Portuguese women with Endometriosis. Methods A sample of 199 Portuguese women with Endometriosis provided demographic and pain history information, and completed a Portuguese version of the SOPA-35 and measures of pain intensity, disability, and psychological function. Analyses were performed to evaluate the factor structure of the Portuguese SOPA-35 items as well as the internal consistency, composite reliability, convergent validity, and concurrent validity of the scale scores. Results Confirmatory factor analysis supported a six-factor solution for a 19-item version of the Portuguese version of the Survey of Pain Attitudes (SOPA-19-P). The six scales evidenced marginal to good reliability (Cronbach's alphas: between 0.60 and 0.84; composite reliability: between 0.61 and 0.84). Four scales evidenced acceptable to good convergent validity (AVE: between 0.51 and 0.63). The findings also supported the concurrent validity of the SOPA-19-P. Conclusions The results support the use of the Portuguese SOPA-19-P for research and clinical purposes with Portuguese women in chronic pain due to endometriosis. Future research is warranted to further develop a European Portuguese version of SOPA. Implications The findings provide psychometric information about the SOPA-19-P. The results are helpful to researchers wishing to study the role of pain-related beliefs and their association with adjustment and treatment outcomes in women with chronic pain due to endometriosis.
Learn More >Multiple sclerosis (MS) is an autoimmune disorder of the central nervous system that can lead to severe physical, cognitive, and neurological deficits that often manifest in young adults. Central neuropathic pain is a common presenting symptom, often prompting patients to seek treatment with opioids, NSAIDS, antiepileptics, and antidepressants despite minimal effectiveness and alarming side-effect profiles. Additionally, spasticity occurs in more than 80% of MS patients and is an important consideration for further study in treatment.
Learn More >Mechanical sensitization is one of the most difficult clinical pain problems to treat. However, the molecular and genetic bases of mechanical nociception are unclear. Here we develop a model of mechanical nociception to investigate the ion channels and signaling pathways that regulate mechanical nociception. We fabricated Von Frey filaments that span the sub-threshold to high noxious range for larvae. Utilizing these, we discovered that pressure (force/area) rather than force per se is the main determinant of aversive rolling responses to noxious mechanical stimuli. We demonstrated that the RTK PDGF/VEGF receptor (Pvr) and its ligands (Pvfs 2 and 3) are required for mechanical nociception and normal dendritic branching. Pvr is expressed and functions in class IV sensory neurons, while Pvf2 and Pvf3 are produced by multiple tissues. Constitutive overexpression of Pvr and its ligands or inducible overexpression of Pvr led to mechanical hypersensitivity that could be partially separated from morphological effects. Genetic analyses revealed that the Piezo and Pain ion channels are required for mechanical hypersensitivity observed upon ectopic activation of Pvr signaling. Platelet-derived growth factor (PDGF), but not vascular endothelial growth factor (VEGF) peptides caused mechanical hypersensitivity in rats. Pharmacological inhibition of vascular endothelial growth factor receptor type 2 (VEGFR-2) signaling attenuated mechanical nociception in rats, suggesting a conserved role for PDGF and VEGFR-2 signaling in regulating mechanical nociception. VEGFR2 inhibition also attenuated morphine analgesic tolerance in rats. Our results reveal that a conserved RTK signaling pathway regulates baseline mechanical nociception in flies and rats.Hypersensitivity to touch is poorly understood and extremely difficult to treat. Using a refined model of mechanical nociception, we discovered a conserved VEGF-related receptor tyrosine kinase signaling pathway that regulates mechanical nociception in flies. Importantly, pharmacological inhibition of VEGFR-2 signaling in rats causes analgesia and blocks opioid tolerance. We have thus established a robust, genetically tractable system for the rapid identification and functional analysis of conserved genes underlying mechanical pain sensitivity.
Learn More >Cortical spreading depression (CSD) is a wave of neuronal depolarization thought to underly migraine aura. Calcitonin gene-related peptide (CGRP) is a potent vasodilator involved in migraine pathophysiology. Evidence for functional connectivity between CSD and CGRP has triggered scientific interest in the possibility that CGRP antagonism may disrupt vascular responses to CSD, and the ensuing plasma protein extravasation (PPE). Using imaging tools that allow us to generate continuous, live, high-resolution views of spatial and temporal changes that affect arteries and veins in the dura and pia, we determined the extent to which CGRP contributes to the induction of arterial dilatation or PPE by CSD in female rats, and how these events are affected by the anti-CGRP monoclonal antibody (anti-CGRP-mAb) fremanezumab. We found that the CSD-induced brief dilatation and prolonged constriction of pial arteries, prolonged dilatation of dural arteries and PPE are all unaffected by fremanezumab, whereas the brief constriction and prolonged dilatation of pial veins are. In comparison, whereas CGRP infusion gave rise to the expected dilatation of dural arteries, which was effectively blocked by fremanezumab, it did not induce dilatation in pial arteries, pial veins, or dural veins. It also failed to induce PPE. Regardless of whether the nociceptors become active before or after the induction of arterial dilatation or PPE by CSD, fremanezumab's inability to prevent them suggests that these events are not mediated by CGRP; a conclusion with important implications for our understanding of anti-CGRP-mAbs' mechanism of action in migraine prevention.The current study identifies fundamental differences between two commonly used models of migraine, CSD induction and systemic CGRP infusion. It raises the possibility that conclusions drawn from one model may not be true or relevant to the other. It sharpens the need to accept the view that to migraine pathophysiology and that it is unlikely that one theory will explain all types of migraine headache or the mechanisms of action of drugs that prevent it. Regarding the latter, it is concluded that not all vascular responses in the meninges are born alike and consequently, that drugs that prevent vascular dilatation through different molecular pathways may have different therapeutic outcomes in different types of migraine.
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