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Pain is a common problem among children, particularly those with pediatric chronic diseases. Multi-faceted assessment of pain can improve communication about pain and help clinicians characterize, differentiate, and treat a patient's unique experience of pain. Pain quality is an important domain of pain, describing the subjective sensory experiences associated with pain as well as the affective experiences of pain. The aim of the current study was to quantitatively evaluate the measurement properties of the 59 PROMIS pediatric pain quality candidate items developed as part of the NIH's PROMIS initiative with input from children and adolescents with chronic pain. Participants included N = 448 pediatric patients between 8 and 18 years of age with chronic health conditions with a prominent component of chronic, or recurrent pain, including juvenile fibromyalgia (JFM), juvenile idiopathic arthritis (JIA), and sickle cell disease (SCD). A confirmatory factor analysis revealed a unidimensional model fit the data best, with 56 of the 59 items demonstrating good psychometric properties for inclusion in the final measure. Additionally, a consensus-building method was used to establish two versions of a short form measure – one with 8 items focused primarily on the sensory pain qualities and one with 8 items focused on affective pain qualities. The final measure shows good reliability and validity and is recommended for use in research and clinical care with pediatric populations.
Learn More >Pain is an alarm mechanism to prevent body damage in response to noxious stimuli. The NGF/TrkA axis plays an essential role as pain mediator and several clinical trials using antibodies against NGF have been yielded promising results, but side effects have precluded their clinical approval. A better understanding of the mechanism of NGF/TrkA-mediated nociception is needed. Here, we find that ARMS/Kidins220, a scaffold protein for Trk receptors, is a modulator of nociception. Male mice, with ARMS/Kidins220 reduction exclusively in TrkA-expressing cells, displayed hyperalgesia to heat, inflammatory and capsaicin stimuli, but not to cold or mechanical stimuli. Simultaneous deletion of BDNF reversed the effects of ARMS/Kidins220 knock-down alone. Mechanistically, ARMS/Kidins220 levels are reduced in vitro and in vivo in response to capsaicin through calpains, and this reduction leads to enhanced regulated BDNF secretion from DRGs. Altogether, these data indicate that ARMS/Kidins220 protein levels have a role as a pain modulator in the NGF/TrkA axis regulating BDNF secretion.
Learn More >Human epidemiological studies suggest that chronic pain can increase mortality risk. We investigated whether this was true in mice, so that underlying mechanisms might be identified. At 10 weeks of age, C57BL/6 mice of both sexes received sham or spared nerve injury (SNI) surgeries producing neuropathic pain. Mice were weighed monthly, tested behaviorally for mechanical and cold sensitivity and guarding behavior every three months post-surgery, and otherwise left undisturbed in their cages until death by natural causes. Evidence of pain over the lifespan displayed a strikingly sex-specific pattern. Male mice displayed largely stable mechanical and cold hypersensitivity and guarding at 6-30 months post-SNI. In contrast, female mice displayed a biphasic temporal pattern of mechanical hypersensitivity and guarding behavior, with a complete resolution of SNI-induced pain behavior at 6-9 months post-SNI followed by the return of pain thereafter. Mouse lifespan was not significantly altered by SNI in either sex, nor was frailty as assessed by cage inspection in the last six months of life. However, in male mice with SNI, we observe a significant correlation between average lifetime mechanical hypersensitivity and lifespan, such that death occurred sooner in male mice exhibiting more evidence of chronic pain. This relationship was not observed in female SNI mice nor in sham-operated mice of either sex. This experiment is the first to investigate pain behavior over an entire lifetime, and suggests that biology of relevance to human chronic pain is being ignored by the very short timespans of most extant preclinical pain research.
Learn More >The potential consequences of the number of chronic pain sites (referred to multisite chronic pain) on the risk of cardiovascular diseases (CVDs) remain unclear. We attempted to investigate the causality of multisite chronic pain with CVDs and its possible causal mediators. Using summary genome-wide association statistics, two-sample Mendelian randomization (MR) analyses were undertaken to assess whether multisite chronic pain has a causal effect on the three CVDs including coronary artery disease, atrial fibrillation, and stroke. We then conducted MR mediation analyses to establish whether body mass index (BMI), smoking, and depression causally mediate any association. Genetic liability to multisite chronic pain was associated with increased risk of coronary artery disease (odds ratio [OR] 1.52, 95% confidence interval [CI] 1.19 to 1.95 per one increase in the number of pain locations), but not with atrial fibrillation or stroke. We also found positive causal effects of multisite chronic pain on BMI, smoking, and depression, and causal effects of BMI, smoking, and depression on coronary artery disease. In multivariable MR analyses, the excess risk of coronary artery disease was attenuated after adjusting for BMI (OR 1.43, 95% CI 1.05 to 1.93), smoking (OR 1.49, 95% CI 1.11 to 2.00), depression (OR 1.44, 95% CI 1.03 to 2.01), and three risk factors combined (OR 1.34, 95% CI 0.88 to 2.05). Our findings demonstrated that multisite chronic pain led to higher risk of coronary artery disease, which is partly mediated through BMI, smoking, and depression.
Learn More >The rostral anterior cingulate cortex (rACC) has been found to be an important brain region in mediating visceral hypersensitivity. However, the underlying mechanisms remain unclear. This study aimed to explore the role of astrocytes in the maintenance of visceral hypersensitivity induced by chronic water avoidance stress (WAS) as well as the potential signaling pathway that activates astrocytes in the rACC. We found that ACC-reactive astrogliosis resulted in the overexpression of c-fos, TSP-1, and BDNF in stress-related visceral hypersensitivity rats. Visceral hypersensitivity was reversed by pharmacological inhibition of astrocytic activation after WAS, as were the overexpression of c-fos, TSP-1 and BDNF. Activation of the astrocytic Gi-pathway increased the visceral sensitivity and expression of c-fos, TSP-1, and BDNF. Visceral hypersensitivity was also ameliorated by the pharmacological inhibition of ERK and STAT1 phosphorylation after WAS. Furthermore, inhibition of the ERK-STAT1 cascade reduced astrocytic activation. These findings suggest that astrocytic ERK/STAT1 signaling in the rACC contributes to the maintenance of stress-related visceral hypersensitivity. PERSPECTIVE: Visceral hypersensitivity is a key factor in the pathophysiology of irritable bowel syndrome. This study highlights the important role of astrocytic ERK/STAT1 signaling in activating astrocytes in the rostral anterior cingulate cortex, which contributes to visceral hypersensitivity.
Learn More >This systematic review, meta-analysis and meta-regression investigated the effects of individualized interventions, based on exercise alone or combined with psychological treatment, on pain intensity and disability in patients with chronic non-specific low-back-pain. Databases were searched up to 31 January 2022 and to retrieve respective randomized controlled trials of individualized/personalized/stratified exercise interventions with or without psychological treatment compared to any control. Fifty-eight studies (n = 10084) were included. At short-term follow-up (12 weeks), low-certainty evidence for pain intensity (SMD -0.28 [95%CI -0.42 to -0.14]) and very low-certainty evidence for disability (-0.17 [-0.31 to -0.02]) indicates effects of individualized versus active exercises, and very low-certainty evidence for pain intensity (-0.40; [-0.58 to -0.22])), but not (low-certainty evidence) for disability (-0.18; [-0.22 to 0.01]) compared to passive controls. At long-term follow-up (1 year), moderate-certainty evidence for pain intensity (-0.14 [-0.22 to -0.07]) and disability (-0.20 [-0.30 to -0.10]) indicates effects versus passive controls. Sensitivity analyses indicates that the effects on pain, but not on disability (always short-term and versus active treatments) were robust. Pain reduction caused by individualized exercise treatments in combination with psychological interventions (in particular behavioral-cognitive therapies) (-0.28 [-0.42 to -0.14], low certainty) is of clinical importance. Certainty of evidence was downgraded mainly due to evidence of risk of bias, publication bias and inconsistency that could not be explained. Individualized exercise can treat pain and disability in chronic non-specific low-back-pain. The effects at short term are of clinical importance (relative differences versus active 38% and versus passive interventions 77%), especially in regard to the little extra effort to individualize exercise. Sub-group analysis suggests a combination of individualized exercise (especially motor-control based treatments) with behavioral therapy interventions to booster effects. PROSPERO registration: CRD42021247331.
Learn More >Physical activity can improve function in patients with chronic pain, however, adherence is low, in part due to inconsistent activity patterns. Smart wearable activity trackers, such as Fitbits, may help promote activity. In our program for chronic pain, we examined: (1) Fitbit activity patterns (i.e., step count, moderate-to-vigorous physical activity (MVPA), sedentary behavior), and (2) whether achievement of weekly, individualized Fitbit step goals was associated with functional outcomes. We conducted a secondary analysis of Fitbit data from our 10-week mind-body activity program for chronic pain (GetActive-Fitbit arm, N = 41). Participants self-reported emotional and physical function and completed performance-based and accelerometer-based assessments. From week 1 to week 10, 30% of participants increased >800 steps; 32.5% increased MVPA; and 30% decreased sedentary behavior. Only step count significantly changed across time with mean steps peaking at week 8 (M = +1897.60, SE = 467.67). Fitbit step goal achievement was associated with improvements in anxiety (ß = -.35, CI [-2.80, -0.43]), self-reported physical function (ß = -.34, CI [-5.17, 8.05]), and performance-based physical function (ß = .29, CI [-71.93, 28.38]), but not accelerometer-based physical function or depression. Adhering to individualized Fitbit step goals in the context of a mind-body activity program may improve anxiety and self-reported and performance-based physical function. Perspective: We examine Fitbit activity patterns and the association between quota-based pacing and functional outcomes within a mind-body activity program for adults with chronic pain. Complementing quota-based pacing and coping skills with Fitbits may be a useful approach to promote activity engagement and behavior change among chronic pain populations.
Learn More >To describe the prevalence and characteristics of spinal cord injury (SCI) related pain during initial inpatient rehabilitation and to investigate relationships with demographic and lesion characteristics.
Learn More >Arginine vasopressin (AVP) is a hypothalamic neurosecretory hormone well known as an antidiuretic, and recently reported to be involved in pain modulation. The expression kinetics of AVP and its potential involvement in the descending pain modulation system (DPMS) in neuropathic pain (NP) remains unclear. We investigated AVP expression and its effects on mechanical and thermal nociceptive thresholds using a unilateral spinal nerve ligation (SNL) model. All rats with SNL developed NP. Intensities of enhanced green fluorescent protein (eGFP) in the supraoptic and paraventricular nuclei, median eminence, and posterior pituitary were significantly increased at 7 and 14 days post-SNL in AVP-eGFP rats. In situ hybridisation histochemistry revealed significantly increased AVP mRNA expression at 14 days post-SNL compared with the sham control group. The chemogenetic activation of AVP neurones significantly attenuated mechanical and thermal hyperalgesia with elevated plasma AVP concentration. These analgesic effects were suppressed by pre-administration with V1a receptor antagonist. AVP neurones increased the neuronal activity of serotonergic dorsal raphe, noradrenergic locus coeruleus, and inhibitory interneurones in the spinal dorsal horn. These results suggest that the hypothalamo-neurohypophysial system of AVP is upregulated in NP and activated endogenous AVP exerts analgesic effects via the V1a receptors. AVP neurones may activate the DPMS.
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