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Peripheral neuropathies result in adaptation in primary sensory and other regions of cortex, and provide a framework for understanding the localized and widespread adaptations that arise from altered sensation. Mesoscale cortical imaging achieves high temporal resolution of activity using optical sensors of neuronal activity to simultaneously image across a wide expanse of cortex and capture this adaptation using sensory-evoked and spontaneous cortical activity. Saphenous nerve ligation in mouse is an animal model of peripheral neuropathy that produces hyperalgesia circumscribed to the hindlimb. We performed saphenous nerve ligation or sham, followed by mesoscale cortical imaging using voltage sensitive dye (VSD) after ten days. We utilized subcutaneous electrical stimulation at multiple stimulus intensities to characterize sensory responses after ligation or sham, and acquired spontaneous activity to characterize functional connectivity and large scale cortical network reorganization. Relative to sham animals, the primary sensory-evoked response to hindlimb stimulation in ligated animals was unaffected in magnitude at all stimulus intensities. However, we observed a diminished propagating wave of cortical activity at lower stimulus intensities in ligated animals after hindlimb, but not forelimb, sensory stimulation. We simultaneously observed a widespread decrease in cortical functional connectivity, where midline association regions appeared most affected. These results are consistent with localized and broad alterations in intracortical connections in response to a peripheral insult, with implications for novel circuit level understanding and intervention for peripheral neuropathies and other conditions affecting sensation.
Learn More >Prostatodynia is the main symptom of chronic prostatitis and the main reason that patients go to the hospital for treatment. Although a variety of factors, including inflammatory immune response, nervous system sensitization, and psychological factors, have been shown to play important roles in the induction and development of chronic pain in prostatitis, the underlying cause of chronic prostatodynia maintenance in prostatitis patients remains unclear.
Learn More >Background and aims Chronic low back pain (chronic LBP) is the number one cause for years lived with disability among 301 diseases and injuries analyzed by The Global Burden of Disease study 2013. Insomnia is highly prevalent among people with chronic LBP. To explain the sleep-pain relationship, theoretical models propose that insomnia symptoms may be associated with increased basal inflammation, operationalized as c-reactive protein (CRP) and lead to further pain and disrupted sleep. We aimed to determine the associations between insomnia, chronic LBP, and inflammation (operationalized as CRP), whilst controlling for age, body mass index, smoking, physical activity, depression, anxiety and osteoarthritis. Methods A cross-sectional analysis of the third Nord-Trøndelag Health Study (2006-2008), a rural population survey of 50,666 participants in Norway aged 20-96 years. Insomnia (dichotomous) was defined according to the Diagnostic and Statistical Manual of Mental Disorders 5th Edition, and chronic LBP (dichotomous) as low back pain or stiffness lasting at least 3 months. Data for CRP were obtained from non-fasting serum samples and assessed via latex immunoassay methodology. We excluded participants with the following self-reported chronic somatic diseases: chronic heart failure, chronic obstructive pulmonary disease, rheumatoid arthritis, fibromyalgia or ankylosing spondylosis. Possible associations between presence of insomnia and presence of chronic LBP (dependent), and the level of CRP and presence of chronic LBP (dependent), were assessed using logistic regression models. The possible association between insomnia and CRP (dependent) was assessed using linear regression. Multivariable analyses were conducted adjusting for confounders stated in our aim that achieved p ≤ 0.2 in univariate regressions. We performed stratified analyses for participants with "Normal" (<3 mg/L) "Elevated" (3-10 mg/L) and "Very High" (>10 mg/L) levels of CRP. Results In our total included sample (n = 30,669, median age 52.6, 54% female), 6.1% had insomnia (n = 1,871), 21.4% had chronic LBP (n = 6,559), and 2.4% had both (n = 719). Twenty four thousand two hundred eighty-eight (79%) participants had "Normal" CRP, 5,275 (17%) had "Elevated" CRP, and 1,136 (4%) had "Very High" CRP. For participants with "Normal" levels of CRP, insomnia was associated with higher levels of CRP (adjusted B = 0.04, 95%CI [0.00-0.08], p = 0.046), but not for people with "Elevated" or "Very High" levels of CRP. There was an association between CRP and presence of chronic LBP in the total sample (adjusted OR = 1.01, [1.00-1.01], p = 0.013) and for people with "Normal" CRP (1.05, [1.00-1.10, p = 0.034]. Insomnia was associated with the presence of chronic LBP in the total sample (adjusted OR = 1.99, 95%CI [1.79-2.21], <0.001) and for people with "Normal", "Elevated" and "Very High". Conclusions Individuals with insomnia have twice the odds of reporting chronic LBP. Insomnia, CRP and chronic LBP appear to be linked but the role of CRP appears to be limited. Longitudinal studies may help further explore the causal inference between insomnia chronic LBP, and inflammation. Implications Given the strong relationship between insomnia and chronic LBP, screening and management of comorbid insomnia and chronic LBP should be considered in clinical practice. Further longitudinal studies are required to explore whether the presence of insomnia and increased inflammation affects the development of chronic LBP.
Learn More >Background and aims Chronic low back pain (CLBP) is a complex disorder where central and peripheral nociceptive processes are influenced by factors from multiple dimensions associated with CLBP (e.g. movement, pain sensitivity, psychological). To date, outcomes for treatments matched to unidimensional subgroups (e.g. psychologically-based) have been poor. Therefore, unidimensional subgrouping may not reflect the complexity of CLBP presentations at an individual level. The aim of this study was therefore to explore patterns of classification at an individual level across the three previously-published, data-driven, within-dimension subgrouping studies. Methods Cross-sectional, multidimensional data was collected in 294 people with CLBP. Statistical derivation of subgroups within each of three clinically-important dimensions (pain sensitivity, psychological profile, pain responses following repeated spinal bending) was briefly reviewed. Patterns of classification membership were subsequently tabulated across the three dimensions. Results Of 27 possible patterns across these dimensions, 26 were represented across the cohort. Conclusions This result highlights that while unidimensional subgrouping has been thought useful to guide treatment, it is unlikely to capture the full complexity of CLBP. The amount of complexity important for best patient outcomes is currently untested. Implications For clinicians this study highlights the high variability of presentations of people with CLBP at the level of the individual. For example, clinician's should not assume that those with high levels of pain sensitivity will also have high psychological distress and have pain summation following repeated spinal bending. A more flexible, multidimensional, clinically-reasoned approach to profile patient complexity may be required to inform individualised, patient-centred care. Such individualised care might improve treatment efficacy. This study also has implications for researchers; highlighting the inadequacy of unidimensional subgrouping processes and methodological difficulties in deriving subgroups across multidimensional data.
Learn More >Background and aims Patellofemoral pain (PFP) and patellofemoral joint osteoarthritis (PFJOA) are common non-self-limiting conditions causing significant pain and disability. The underlying pain pathologies lack consensus with evidence suggesting reduced pressure pain thresholds (PPTs) in adolescent females with PFP and individuals with knee osteoarthritis. A paucity of evidence exists for mixed-sex adults with PFP and PFJOA in isolation. Exploring if pain sensitisation is a dominant feature of PFP and PFJOA may have important implications for the delivery of a patient centred management approach. The primary aim was to measure local and remote PPTs in PFP and PFJOA patients compared to matched controls. Secondary aims were to evaluate the relationship between PPTs and (1) condition severity and (2) knee function. Methods 13 PFP patients plus 20 matched controls and 15 PFJOA patients plus 34 matched controls were recruited from a UK mixed-sex adult population. Controls were matched on age, sex and activity level. Demographic details, Tegner activity level score, symptom duration, condition severity (Kujala and KOOS-PF scores for PFP and PFJOA, respectively) and knee function (Modified Whatman score rating of five single leg squats) were recorded. PPTs were measured at six sites: five local around the knee, one remote on the contralateral leg. Between-group differences were tested using a two-way mixed model analysis of variance with repeated measures. Strength of association between PPTs and condition severity and knee function were tested using Spearman's rank order correlation. Results No statistically significant difference in PPTs were observed between the PFP patients [F(1,31) = 0.687, p = 0.413, η2 = 0.022] or PFJOA patients [F(1,47) = 0.237, p = 0.629, η2 = 0.005] and controls. Furthermore, no correlation was found between PPTs and condition severity or knee function in PFP or PFJOA (p > 0.05). Conclusions Results suggest mechanical pain sensitisation is not a dominant feature of UK mixed-sex adults with PFP or PFJOA. Implications PFP and PFJOA remain persistent pain complaints which may not be well explained by objective measures of sensitivity such as PPTs. The findings suggest that peripheral pain processing changes leading to pain sensitisation is not a key feature in PFP or PFJOA. Instead the underlying pain pathway is likely to remain primary nociceptive, possibly with a subgroup of patients who experience pain sensitisation and might benefit from a more targeted management approach.
Learn More >Background and aims There is high level evidence for physical activity (PA) improving outcomes in persistent pain disorders and one of the mechanisms proposed is the effect of exercise on central nociceptive modulation. Although laboratory studies and small field intervention studies suggest associations between physical activity and pain sensitivity, the association of objectively measured, habitual PA and sedentary behaviour (SB) with pain sensitivity requires further investigation. Current evidence suggests PA typically lowers pain sensitivity in people without pain or with single-site pain, whereas PA is frequently associated with an increase in pain sensitivity for those with multisite pain. The aim of this study was to explore the relationships of PA and SB with pain sensitivity measured by pressure pain thresholds and cold pain thresholds, considering the presence of single-site and multisite pain and controlling for potential confounders. Methods Participants from the Western Australian Pregnancy Cohort (Raine) Study (n = 714) provided data at age 22-years. PA and SB were measured via accelerometry over a 7-day period. Pain sensitivity was measured using pressure pain threshold (4 sites) and cold pain threshold (wrist). Participants were grouped by number of pain areas into "No pain areas" (n = 438), "Single-site pain" (n = 113) and "Multisite pain" (n = 163) groups. The association of PA and SB variables with pain sensitivity was tested separately within each pain group by multivariable regression, adjusting for potential confounders. Results For those with "Single-site pain", higher levels (>13 min/day) of moderate-vigorous PA in ≥10 min bouts was associated with more pressure pain sensitivity (p = 0.035). Those with "Multisite pain" displayed increased cold pain sensitivity with greater amounts of vigorous PA (p = 0.011). Those with "No pain areas" displayed increased cold pain sensitivity with decreasing breaks from sedentary time (p = 0.046). Conclusions This study was a comprehensive investigation of a community-based sample of young adults with "No pain areas", "Single-site pain" and "Multisite pain" and suggests some associations of measures of PA and SB with pain sensitivity. Implications The findings suggest that the pattern of accumulation of PA and SB may be important to inform improved clinical management of musculoskeletal pain disorders. This study provides a baseline for follow-up studies using the Raine Study cohort. Future research should consider temporal influences of PA and SB on pain sensitivity, pain experience and consider using a broader range of pain sensitivity measures.
Learn More >The transient receptor potential (TRP) channels superfamily are a large group of proteins that play crucial roles in cellular processes. For example, these cation channels act as sensors in the detection and transduction of stimuli of temperature, small molecules, voltage, pH, and mechanical constrains. Over the past decades, different members of the TRP channels have been identified in the human gastrointestinal (GI) tract playing multiple modulatory roles. Noteworthy, TRPs support critical functions related to the taste perception, mechanosensation, and pain. They also participate in the modulation of motility and secretions of the human gut. Last but not least, altered expression or activity and mutations in the TRP genes are often related to a wide range of disorders of the gut epithelium, including inflammatory bowel disease, fibrosis, visceral hyperalgesia, irritable bowel syndrome, and colorectal cancer. TRP channels could therefore be promising drug targets for the treatment of GI malignancies. This review aims at providing a comprehensive picture of the most recent advances highlighting the expression and function of TRP channels in the GI tract, and secondly, the description of the potential roles of TRPs in relevant disorders is discussed reporting our standpoint on GI tract-TRP channels interactions.
Learn More >Osteoarthritis (OA) is a leading cause of chronic pain and disability in older adults, which most commonly affects the joints of the knee, hip, and hand. To date, there are no established disease modifying interventions that can halt or reverse OA progression. Therefore, treatment is focused on alleviating pain and maintaining or improving physical and psychological function. Rehabilitation is widely recommended as first-line treatment for OA as, in many cases, it is safer and more effective than the best-established pharmacological interventions. In this article, we describe the presentation of OA pain and give an overview of its peripheral and central mechanisms. We then provide a state-of-the-art review of rehabilitation for OA pain-including self-management programs, exercise, weight loss, cognitive behavioral therapy, adjunct therapies, and the use of aids and devices. Next, we explore several promising directions for clinical practice, including novel education strategies to target unhelpful illness and treatment beliefs, methods to enhance the efficacy of exercise interventions, and innovative, brain-directed treatments. Finally, we discuss potential future research in areas, such as treatment adherence and personalized rehabilitation for OA pain.
Learn More >The neuroinflammatory response to peripheral nerve injury is associated with chronic pain and significant changes in the molecular expression profiles of mRNAs in neurons, glia and infiltrating immune cells. Chronic constriction injury (CCI) of the rat sciatic nerve provides an opportunity to mimic neuropathic injury and quantitatively assess behavior and differential gene expression in individual animals. Previously, we have shown that a single intravenous injection of nanoemulsion containing celecoxib (0.24 mg/kg) reduces inflammation of the sciatic nerve and relieves pain-like behavior for up to 6 days. Here, we use this targeted therapy to explore the impact on mRNA expression changes in both pain and pain-relieved states. Sciatic nerve tissue recovered from CCI animals is used to evaluate the mRNA expression profiles utilizing quantitative PCR. We observe mRNA changes consistent with the reduced recruitment of macrophages evident by a reduction in chemokine and cytokine expression. Furthermore, genes associated with adhesion of macrophages, as well as changes in the neuronal and glial mRNAs are observed. Moreover, genes associated with neuropathic pain including Maob, Grin2b/NMDAR2b, TrpV3, IL-6, Cacna1b/Ca2.2, Itgam/Cd11b, Scn9a/Na1.7, and Tac1 were all found to respond to the celecoxib loaded nanoemulsion during pain relief as compared to those animals that received drug-free vehicle. These results demonstrate that by targeting macrophage production of PGE at the site of injury, pain relief includes partial reversal of the gene expression profiles associated with chronic pain.
Learn More >Observing pain in others can enhance our own pain. Two aspects of this effect remain unknown or controversial: first, whether it depends on the 'painfulness' of the visual stimulus; second, whether it reflects a genuine bias in perception or rather a bias in the memory encoding of the percept. Pain ratings and vegetative skin responses were recorded while 21 healthy volunteers received electric nociceptive shocks under three experimental conditions: (i) observing a painful contact between the body and a harmful object; (ii) observing a non-painful body contact, (iii) observing a control scene where the body and the object are not in contact. Pain reports and vegetative responses were enhanced exclusively when the subjects observed a painful body contact. The effect on perception was immediate, abated 3 sec after the shock, and positively correlated with the magnitude of vegetative arousal. This suggests that (a) hyperalgesia during observation of painful scenes was induced by their pain-related nature, and not by the simple body contact, and (b) hyperalgesia emerged from a very rapid bias in the perceptual encoding of the stimulus, and was not the result of a retrospective bias in memory recollection. Observing pain-depicting scenes can modify the processing of concomitant somatic stimuli, increasing their arousal value and shifting perception toward more painful levels.
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