Chronic pain enhances excitability of corticotropin-releasing factor-expressing neurons in the oval part of the bed nucleus of the stria terminalis.

We previously reported that enhanced corticotropin-releasing factor (CRF) signaling in the bed nucleus of the stria terminalis (BNST) caused the aversive responses during acute pain and suppressed the brain reward system during chronic pain. However, it remains to be examined whether chronic pain alters the excitability of CRF neurons in the BNST. In this study we investigated the chronic pain-induced changes in excitability of CRF-expressing neurons in the oval part of the BNST (ovBNSTCRF neurons) by whole-cell patch-clamp electrophysiology. CRF-Cre; Ai14 mice were used to visualize CRF neurons by tdTomato. Electrophysiological recordings from brain slices prepared from a mouse model of neuropathic pain revealed that rheobase and firing threshold were significantly decreased in the chronic pain group compared with the sham-operated control group. Firing rate of the chronic pain group was higher than that of the control group. These data indicate that chronic pain elevated neuronal excitability of ovBNSTCRF neurons.

Chronic pain: Central role of the claustrum in pain processing.

Nociceptive stimuli are processed by the brain into an unpleasant sensation. Two new studies highlight an important role of the claustrum in the processing of pain-related information.

The effects of neck exercise in comparison to passive or no intervention on quantitative sensory testing measurements in adults with chronic neck pain: A systematic review.

BACKGROUND: Previous systematic reviews have identified the benefits of exercise for chronic neck pain on subjective reports of pain, but not with objective measures such as quantitative sensory testing (QST). A systematic review was conducted to identify the effects of neck specific exercise on QST measures in adults with chronic neck pain to synthesise existing literature and provide clinical recommendations. METHODS: The study protocol was registered prospectively with PROSPERO (PROSPERO CRD42021297383). For both randomised and non-randomised trials, the following databases and trial registries were searched: AMED, CINAHL, Embase, Google Scholar, Medline, PEDro, PubMed, Scopus, SPORTDiscus, Science Citation Index and Social Science Citation Index from Web of Science Core Collection, clinicaltrials.gov, GreyOpen, and ISRCTN registry. These searches were conducted from inception to February 2022 and were updated until September 2023. Reference lists of eligible studies were screened. Study selection was performed independently by two reviewers, with data extraction and quality appraisal completed by one reviewer and independently ratified by a second reviewer. Due to high heterogeneity, narrative synthesis was performed with results grouped by exercise type. FINDINGS: Three trials were included. Risk of bias was rated as moderate and the certainty of evidence as low or moderate for all studies. All exercise groups demonstrated statistically significant improvement at an intermediate-term follow-up, with progressive resistance training combined with graded physical training demonstrating the highest certainty of evidence. Fixed resistance training demonstrated statistically significant improvement in QST measures at a short-term assessment. INTERPRETATION: Fixed resistance training is effective for short-term changes in pain sensitivity based on low-quality evidence, whilst moderate-quality evidence supports progressive resistance training combined with graded physical training for intermediate-term changes in pain sensitivity.

Targeting Prefrontal Cortex Dysfunction in Pain.

The prefrontal cortex (PFC) has justifiably become a significant focus of chronic pain research. Collectively, decades of rodent and human research have provided strong rationale for studying the dysfunction of the PFC as a contributing factor in the development and persistence of chronic pain and as a key supraspinal mechanism for pain-induced comorbidities such as anxiety, depression, and cognitive decline. Chronic pain alters the structure, chemistry, and connectivity of PFC in both humans and rodents. In this review, we broadly summarize the complexities of reported changes within both rodent and human PFC caused by pain and offer insight into potential pharmacological and nonpharmacological approaches for targeting PFC to treat chronic pain and pain-associated comorbidities. SIGNIFICANCE STATEMENT: Chronic pain is a significant unresolved medical problem causing detrimental changes to physiological, psychological, and behavioral aspects of life. Drawbacks of currently approved pain therapeutics include incomplete efficacy and potential for abuse producing a critical need for novel approaches to treat pain and comorbid disorders. This review provides insight into how manipulation of prefrontal cortex circuits could address this unmet need of more efficacious and safer pain therapeutics.

Effect of a slump posture on pain, proprioception, and electrical activity of the muscles in office workers with chronic non-specific neck pain. A retrospective study.

BACKGROUND: The impact of computer typing in a slump posture on pain, proprioception and muscle recruitment has not been extensively investigated. Therefore, the purpose of this study was to evaluate the extent of pain, proprioception and muscle activity resulting from computer typing in a slump posture in women who already suffer from chronic neck pain. METHODS: This cross-sectional study was conducted between May 20 to July 10, 2021. A total of 15 female 42-(±4.96)-year-old office workers with chronic non-specific neck pain participated in this study. Before and after 60 min of computer typing in a slump posture, proprioception and pain were measured using an inclinometer and visual analog scale (VAS), respectively. The activity of the cervical erector spine (CES) and upper trapezius (UT) muscle was also measured before and after the slump-posture computer typing, in upright, forward, and slump postures. RESU: lts: Paired-samples t-tests showed that pain was increased and proprioception in all directions (flexion, extension, right and left lateral flexion, and right, and left rotation) was less accurate (P < 0.05) after 60 min computer typing. The CES and UT muscle activity were elevated more in the forward head and slump posture than in the upright posture (P < 0.05). CONCLUSION: Sixty minutes computer typing in a slump posture increased neck pain, resulted in a decreased proprioception in the neck and was accompanied by an increased activity of the neck musculature.

The relationship between the psoas major muscle morphology characteristics with disability index and pain in patients with chronic nonspecific low back pain.

BACKGROUND: Chronic nonspecific low back pain (CNLBP) is a common disorder in people of active ages and significantly affects their quality of life. Different structures in the lumbar area can cause LBP. The lumbar muscle disorders, including the psoas major (PM) muscles, have an essential role in LBP. Magnetic Resonance Imaging (MRI) has been introduced as a safe and useful instrument for investigating the morphological properties of skeletal muscle. In general, PM morphology changes may be one reason for the pain and disability experienced in CNLBP patients. Thus, this study aimed to assess the relationship among the PM's Cross-sectional area (CSA), medial-lateral (ML), and anterior-posterior (AP) diameters, with disability index and pain score in patients with CNLBP. METHOD: One hundred twenty patients with CNLBP (60 men and 60 women) participated in this cross-sectional study. Axial MRIs were obtained from L3/L4 and L4/L5 disc levels. Then, patients filled out Rolland Morris Disability Questionnaires, demographic data forms, and the Numeric Pain Rating Scale (NPRS). Image J software was used to analyze the images. Using Linear Regression and the Pearson test, the correlation between muscle CSA and diameters, as well as data obtained from questionnaires and NPRS, was analyzed. RESULTS: Results from the statistical analysis showed no statistically significant relationship among morphological characteristics of the psoas major muscle in L3/L4 and L4/L5 disc levels with disability index and pain score (p < 0.05). CONCLUSIONS: There is no significant relationship between the PM morphological characteristics and disability index and pain score. Therefore, muscle CSA and diameters are insufficient to determine the cause of CNLBP.

Effects of different treatments on pain, functional disability, position sense and range of motion in elite bodybuilders with chronic low back pain.

Back pain is one of the major global challenges and is one of the most prevalent musculoskeletal disorders occurring in 80% of people at least once in their lifetime. Therefore, the need to find appropriate treatment methods for this issue is very important. The objective is to examine the short-term and acute effects of a treatment session with dry needling, massage therapy, stretching exercises and Kinesio tape on pain, functional disability, position sense and range of motion in elite bodybuilders with non-specific chronic low back pain. The sample of this quasi-experimental study consisted of 48 bodybuilders with non-specific chronic low back pain (all male, mean age = 25.96 ± 2.18 years; mean weight = 74.45 ± 4.51 kg; mean height = 173.88 ± 3.74 cm; mean BMI = 24.60 ± 0.74 kg/m2) who randomly were placed in 4 dry needling, massage therapy, stretching exercises and Kinesio tape groups. The duration of each intervention was 30 min. The dependent variables in this study included the massage range of motion, position sense tests and visual pain scale that were taken separately from each subject in pretest, posttest (acute effect) and follow-up test (72 h after posttest; short-term effect). The results of a 4 (groups) × 3 (time) the mixed ANOVAs showed that pain in the short-term phase was significantly lower in the dry needling group than in the stretching and massage groups (P < 0.05). Also in the acute effect phase, the flexion range of motion was significantly lower in the dry needling group than in the massage group (P < 0.05). Furthermore, the two groups of stretching and massage exercises showed significantly greater range of motion (P < 0.05). Other comparisons were not significant (P > 0.05). The findings of the study showed that both massage and stretching treatment have higher acute effects, while dry needling treatment was more effective in follow up. On the other hand, these findings show that these treatment methods can have immediate and lasting positive effects in improving the performance in elite bodybuilders with non-specific chronic low back pain.

Changes in SLITRK1 Level in the Amygdala Mediate Chronic Neuropathic Pain-Induced Anxio-Depressive Behaviors in Mice.

BACKGROUND: Comorbid chronic neuropathic pain (NPP) and anxio-depressive disorders (ADD) have become a serious global public-health problem. The SLIT and NTRK-like 1 (SLITRK1) protein is important for synaptic remodeling and is highly expressed in the amygdala, an important brain region involved in various emotional behaviors. We examined whether SLITRK1 protein in the amygdala participates in NPP and comorbid ADD. METHODS: A chronic NPP mouse model was constructed by L5 spinal nerve ligation; changes in chronic pain and ADD-like behaviors were measured in behavioral tests. Changes in SLITRK1 protein and excitatory synaptic functional proteins in the amygdala were measured by immunofluorescence and Western blot. Adeno-associated virus was transfected into excitatory synaptic neurons in the amygdala to up-regulate the expression of SLITRK1. RESULTS: Chronic NPP-related ADD-like behavior was successfully produced in mice by L5 ligation. We found that chronic NPP and related ADD decreased amygdalar expression of SLITRK1 and proteins important for excitatory synaptic function, including Homer1, postsynaptic density protein 95 (PSD95), and synaptophysin. Virally-mediated SLITRK1 overexpression in the amygdala produced a significant easing of chronic NPP and ADD, and restored the expression levels of Homer1, PSD95, and synaptophysin. CONCLUSION: Our findings indicated that SLITRK1 in the amygdala plays an important role in chronic pain and related ADD, and may prove to be a potential therapeutic target for chronic NPP-ADD comorbidity.

Unveiling the link between chronic pain and misuse of opioids and cannabis.

Over 50 million Americans endure chronic pain where many do not receive adequate treatment and self-medicate to manage their pain by taking substances like opioids and cannabis. Research has shown high comorbidity between chronic pain and substance use disorders (SUD) and these disorders share many common neurobiological underpinnings, including hypodopaminergic transmission. Drugs commonly used for self-medication such as opioids and cannabis relieve emotional, bothersome components of pain as well as negative emotional affect that perpetuates misuse and increases the risk of progressing towards drug abuse. However, the causal effect between chronic pain and the development of SUDs has not been clearly established. In this review, we discuss evidence that affirms the proposition that chronic pain is a risk factor for the development of opioid and cannabis use disorders by outlining the clinical evidence and detailing neurobiological mechanisms that link pain and drug misuse. Central to the link between chronic pain and opioid and cannabis misuse is hypodopaminergic transmission and the modulation of dopamine signaling in the mesolimbic pathway by opioids and cannabis. Moreover, we discuss the role of kappa opioid receptor activation and neuroinflammation in the context of dopamine transmission, their contribution to opioid and cannabis withdrawal, along with potential new treatments.

Chronic pain in pediatric patients: epidemiology, pathophysiology, and mitigation strategies.

PURPOSE OF REVIEW: To provide an updated summary on the epidemiology, pathophysiology, and treatment strategies of chronic pain in pediatric patients and its differences with chronic pain in adults. RECENT FINDINGS: Chronic pain in children is common, can be debilitating and can progress into adulthood, thus it requires an interdisciplinary evaluation and management. Targeting interdisciplinary care, including psychology, physical, and/or occupational therapy, has been shown to improve pain and function. Recent decline in mental health post pandemic has correlated with increase in pediatric chronic pain thus the need to identify patients at risk and offer early interdisciplinary treatment. SUMMARY: Chronic pediatric pain should be addressed under the biopsychosocial model, where the biological, psychological, and social factors are evaluated on how they influence the pain perception, pain experience, functional ability, and treatment focus. Pain education to patients and their families is the crucial initial step towards a functional rehabilitation of pain.

Acute, Chronic, and Everyday Physical Pain in Borderline Personality Disorder.

PURPOSE OF REVIEW: Physical pain is an underrecognized area of dysregulation among those with borderline personality disorder (BPD). Disturbances are observed within the experience of acute, chronic, and everyday physical pain experiences for people with BPD. We aimed to synthesize research findings on multiple areas of dysregulation in BPD in order to highlight potential mechanisms underlying the association between BPD and physical pain dysregulation. RECENT FINDINGS: Potential biological mechanisms include altered neural responses to painful stimuli within cognitive-affective regions of the brain, as well as potentially low basal levels of endogenous opioids. Emotion dysregulation broadly mediates dysregulation of physical pain. Certain psychological experiences may attenuate acute physical pain, such as dissociation, whereas others, such as negative affect, may exacerbate it. Social challenges between patients with BPD and healthcare providers may hinder appropriate treatment of chronic pain. Dysregulated physical pain is common in BPD and important in shaping health outcomes including elevated BPD symptoms, chronic pain conditions, and risk for problematic substance use.

Pathological claustrum activity drives aberrant cognitive network processing in human chronic pain.

Aberrant cognitive network activity and cognitive deficits are established features of chronic pain. However, the nature of cognitive network alterations associated with chronic pain and their underlying mechanisms require elucidation. Here, we report that the claustrum, a subcortical nucleus implicated in cognitive network modulation, is activated by acute painful stimulation and pain-predictive cues in healthy participants. Moreover, we discover pathological activity of the claustrum and a region near the posterior inferior frontal sulcus of the right dorsolateral prefrontal cortex (piDLPFC) in migraine patients during acute pain and cognitive task performance. Dynamic causal modeling suggests a directional influence of the claustrum on activity in this piDLPFC region, and diffusion weighted imaging verifies their structural connectivity. These findings advance understanding of claustrum function during acute pain and provide evidence of a possible circuit mechanism driving cognitive impairments in chronic pain.

Repetitive Transcranial Magnetic Stimulation Combined with Sling Exercise Modulates the Motor Cortex in Patients with Chronic Low Back Pain.

The study aims to explore the effects of combining repetitive transcranial magnetic stimulation (rTMS) with sling exercise (SE) intervention in patients with chronic low back pain (CLBP). This approach aims to directly stimulate brain circuits and indirectly activate trunk muscles to influence motor cortex plasticity. However, the impact of this combined intervention on motor cortex organization and clinical symptom improvement is still unclear, as well as whether it is more effective than either intervention alone. To investigate this, patients with CLBP were randomly assigned to three groups: SE/rTMS, rTMS alone, and SE alone. Motor cortical organization, numerical pain rating scale (NPRS), Oswestry Disability Index (ODI), and postural balance stability were measured before and after a 2-week intervention. The results showed statistically significant differences in the representative location of multifidus on the left hemispheres, as well as in NPRS and ODI scores, in the combined SE/rTMS group after the intervention. When compared to the other two groups, the combined SE/rTMS group demonstrated significantly different motor cortical organization, sway area, and path range from the rTMS alone group, but not from the SE alone group. These findings highlight the potential benefits of a combined SE/rTMS intervention in terms of clinical outcomes and neuroadaptive changes compared to rTMS alone. However, there was no significant difference between the combined intervention and SE alone. Therefore, our research does not support the use of rTMS as a standalone treatment for CLBP. Our study contributed to optimizing treatment strategies for individuals suffering from CLBP.

The effect of different pain characteristics on jaw functional limitations in patients with temporomandibular disorders.

BACKGROUND: Patients with painful temporomandibular disorders (TMD) more often experience jaw functional limitations. The study of jaw functional limitations should be primarily focused on painful TMD. OBJECTIVES: The impact of TMD pain characteristics (source, chronicity and intensity) on jaw functional limitations were evaluated using Jaw Functional Limitation Scale (JFLS). METHODS: This cross-sectional study reviewed the dental records and self-report questionnaires of patients with painful TMD. The pain source, chronicity and intensity were evaluated to study the TMD pain characteristics. The jaw functional limitations were analysed using the Thai version of the JFLS. RESULTS: A total of 176 patients with painful TMD were included in this study. The jaw functional limitations were affected only by pain intensity. Patients with TMD with severe pain intensity had significantly higher jaw functional limitations than those with mild-to-moderate pain intensity (p < .05). A significant association was observed between pain intensity and jaw functional limitations (p < .05). Mastication was highly restricted by pain intensity (odd ratio = 1.39, 95% confidence interval = 1.16-1.67). CONCLUSION: The present study found a significant effect of TMD pain intensity on jaw functional limitations. Patients with severe TMD pain intensity were more likely to experience jaw functional limitations, particularly mastication limitation. Management focusing on reduction of pain intensity may improve jaw functions in patients with TMD.

Chronic Visceral Pain: New Peripheral Mechanistic Insights and Resulting Treatments.

Chronic visceral pain is one of the most common reasons for patients with gastrointestinal disorders, such as inflammatory bowel disease or disorders of brain-gut interaction, to seek medical attention. It represents a substantial burden to patients and is associated with anxiety, depression, reductions in quality of life, and impaired social functioning, as well as increased direct and indirect health care costs to society. Unfortunately, the diagnosis and treatment of chronic visceral pain is difficult, in part because our understanding of the underlying pathophysiologic basis is incomplete. In this review, we highlight recent advances in peripheral pain signaling and specific physiologic and pathophysiologic preclinical mechanisms that result in the sensitization of peripheral pain pathways. We focus on preclinical mechanisms that have been translated into treatment approaches and summarize the current evidence base for directing treatment toward these mechanisms of chronic visceral pain derived from clinical trials. The effective management of chronic visceral pain remains of critical importance for the quality of life of suffers. A deeper understanding of peripheral pain mechanisms is necessary and may provide the basis for novel therapeutic interventions.

The effects of virtual reality training on postural sway and physical function performance on older women with chronic low back pain: A double-blind randomized clinical trial.

BACKGROUND: Chronic low back pain (CLBP) is known as an important debilitating health condition among older women. OBJECTIVE: This study aimed to evaluate the effects of eight-week virtual reality training (VRT) exercises on postural sway and physical function performance (PFP) among older women suffering from CLBP. METHODS: Twenty-seven older women presenting with CLBP were randomized into experimental and control groups. The experimental group was instructed to perform 30-minute VRT exercises three times a week for eight weeks. Plantar pressure variables [sway velocity (SV) and anterior-posterior (AP) and medial-lateral (ML) fluctuations of the center of pressure (CoP)], 30-second chair stand test (30CST), and timed up and go (TUG) test were recorded. RESULTS: The VRT group exhibited significant decreases in SV (p= 0.002), AP (p= 0.008), and ML (p= 0.02) fluctuations. Also, the performance of the VRT group in the 30CST and TUG tests significantly improved after the exercises (P< 0.001). CONCLUSION: According to the results, VRT and the program used in this study should be used to enhance balance and PFP in older women with CLBP who mostly prefer activities that are accessible and feasible in low-risk environments.

A randomized controlled trial investigating the impact of a single flash cupping session on patients with chronic lower back pain using multichannel surface electromyographic assessment.

BACKGROUND: Chronic lower back pain (CLBP) is one of the most common disorders worldwide. Flash cupping has the ability to relieve CLBP; nevertheless, its impact on CLBP and the likely mechanism of action have not been studied. OBJECTIVE: The goal of this study was to assess the impact of a single, brief cupping session on CLBP and low back muscle activity using multichannel surface electromyography (sEMG). METHODS: In this randomized controlled trial, 24 patients with CLBP were enrolled and randomly assigned to the control group (treated by acupuncture) and cupping group (treated by acupuncture and flash cupping). Acupuncture was applied on the shen shu (BL23), dachang shu (BL25), and wei zhong (BL40) acupoints in both the groups. A brief cupping treatment was applied to the shen shu (BL23), qihai shu (BL24), dachang shu (BL25), guanyuan shu (BL26), and xiaochang shu (BL27) acupoints on both sides of the lower back in the cupping group. The numeric rating scale (NRS) was used to assess therapy efficacy for lower back pain (LBP) before and after treatment. Surface EMG data collected during symmetrical trunk flexion-extension movements were utilized to measure lower back muscle activity and the effectiveness of LBP therapy. RESULTS: There was no statistically significant difference (P= 0.63) in pain intensity between the two groups before and after treatment. There was a statistically significant difference (P= 0.04) between the control group and the cupping group in the sEMG topographic map parameter CoGx-To-Midline. CONCLUSION: This study established a connection between the action mechanism of flash cupping and enhanced horizontal synchronization of lower back muscular activity.

Mediators of the association between childhood trauma and pain sensitivity in adulthood: a Multidisciplinary Approach to the Study of Chronic Pelvic Pain Research Network analysis.

ABSTRACT: Urologic chronic pelvic pain syndrome (UCPPS) is a complex, debilitating condition in which patients often report nonpelvic pain in addition to localized pelvic pain. Understanding differential predictors of pelvic pain only vs widespread pain may provide novel pathways for intervention. This study leveraged baseline data from the Multidisciplinary Approach to the Study of Chronic Pelvic Pain (MAPP) Research Network's Symptom Pattern Study to investigate the impact of childhood sexual and nonsexual violent trauma on pelvic and nonpelvic pain sensitivity among adult patients with UCPPS, as well as potential mediators of this association. Study participants who met inclusion criteria for UCPPS completed questionnaires assessing childhood and recent trauma, affective distress, cognitive dysfunction, and generalized sensory sensitivity. Experimental pain sensitivity was also evaluated using standardized pressure pain applied to the pubic region and the arm. Bivariate analyses showed that childhood violent trauma was associated with more nonviolent childhood trauma, more recent trauma, poorer adult functioning, and greater pain sensitivity at the pubic region, but not pain sensitivity at the arm. Path analysis suggested that childhood violent trauma was indirectly associated with pain sensitivity at both sites and that this indirect association was primarily mediated by generalized sensory sensitivity. More experiences of recent trauma also contributed to these indirect effects. The findings suggest that, among participants with UCPPS, childhood violent trauma may be associated with heightened pain sensitivity to the extent that trauma history is associated with a subsequent increase in generalized sensory sensitivity.

Focal mu-opioid receptor activation promotes neuroinflammation and microglial activation in the mesocorticolimbic system: Alterations induced by inflammatory pain.

Microglia participates in the modulation of pain signaling. The activation of microglia is suggested to play an important role in affective disorders that are related to a dysfunction of the mesocorticolimbic system (MCLS) and are commonly associated with chronic pain. Moreover, there is evidence that mu-opioid receptors (MORs), expressed in the MCLS, are involved in neuroinflammatory events, although the way by which they do it remains to be elucidated. In this study, we propose that MOR pharmacological activation within the MCLS activates and triggers the local release of proinflammatory cytokines and this pattern of activation is impacted by the presence of systemic inflammatory pain. To test this hypothesis, we used in vivo microdialysis coupled with flow cytometry to measure cytokines release in the nucleus accumbens and immunofluorescence of IBA1 in areas of the MCLS on a rat model of inflammatory pain. Interestingly, the treatment with DAMGO, a MOR agonist locally in the nucleus accumbens, triggered the release of the IL1α, IL1ß, and IL6 proinflammatory cytokines. Furthermore, MOR pharmacological activation in the ventral tegmental area (VTA) modified the levels of IBA1-positive cells in the VTA, prefrontal cortex, the nucleus accumbens and the amygdala in a dose-dependent way, without impacting mechanical nociception. Additionally, MOR blockade in the VTA prevents DAMGO-induced effects. Finally, we observed that systemic inflammatory pain altered the IBA1 immunostaining derived from MOR activation in the MSCLS. Altogether, our results indicate that the microglia-MOR relationship could be pivotal to unravel some inflammatory pain-induced comorbidities related to MCLS dysfunction.