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.

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.

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.

Wearable Nanocomposite Sensor System for Motion Phenotyping Chronic Low Back Pain: A BACPAC Technology Research Site.

Chronic low back pain (cLBP) is a prevalent and multifactorial ailment. No single treatment has been shown to dramatically improve outcomes for all cLBP patients, and current techniques of linking a patient with their most effective treatment lack validation. It has long been recognized that spinal pathology alters motion. Therefore, one potential method to identify optimal treatments is to evaluate patient movement patterns (ie, motion-based phenotypes). Biomechanists, physical therapists, and surgeons each utilize a variety of tools and techniques to qualitatively assess movement as a critical element in their treatment paradigms. However, objectively characterizing and communicating this information is challenging due to the lack of economical, objective, and accurate clinical tools. In response to that need, we have developed a wearable array of nanocomposite stretch sensors that accurately capture the lumbar spinal kinematics, the SPINE Sense System. Data collected from this device are used to identify movement-based phenotypes and analyze correlations between spinal kinematics and patient-reported outcomes. The purpose of this paper is twofold: first, to describe the design and validity of the SPINE Sense System; and second, to describe the protocol and data analysis toward the application of this equipment to enhance understanding of the relationship between spinal movement patterns and patient metrics, which will facilitate the identification of optimal treatment paradigms for cLBP.

Motor cortex excitability in chronic low back pain.

Chronic pain is associated with dysfunctional cortical excitability. Research has identified altered intracortical motor cortex excitability in Chronic Lower Back Pain (CLBP). However, research identifying the specific intracortical changes underlying CLBP has been met with inconsistent findings. In the present case-control study, we examined intracortical excitability of the primary motor cortex using transcranial magnetic stimulation (TMS) in individuals with CLBP. Twenty participants with CLBP (Mage = 54.45 years, SDage = 15.89 years) and 18 age- and gender-matched, pain-free controls (M = 53.83, SD = 16.72) were included in this study. TMS was applied to the hand motor area of the right hemisphere and motor evoked potentials (MEPs) were recorded from the first dorsal interosseous muscle of the contralateral hand. Resting motor threshold (rMT) and MEP amplitude were measured using single-pulse stimulation. Short interval intracortical inhibition (SICI) and intracortical facilitation (ICF) were assessed using paired-pulse stimulation. Individuals with CLBP had significantly higher rMT (decreased corticospinal excitability) and lower ICF compared to controls. No significant differences were found in MEP amplitude and SICI. These findings add to the growing body of evidence that CLBP is associated with deficits in intracortical modulation involving glutamatergic mechanisms.

Neuropathic pain caused by miswiring and abnormal end organ targeting.

Nerve injury leads to chronic pain and exaggerated sensitivity to gentle touch (allodynia) as well as a loss of sensation in the areas in which injured and non-injured nerves come together1-3. The mechanisms that disambiguate these mixed and paradoxical symptoms are unknown. Here we longitudinally and non-invasively imaged genetically labelled populations of fibres that sense noxious stimuli (nociceptors) and gentle touch (low-threshold afferents) peripherally in the skin for longer than 10 months after nerve injury, while simultaneously tracking pain-related behaviour in the same mice. Fully denervated areas of skin initially lost sensation, gradually recovered normal sensitivity and developed marked allodynia and aversion to gentle touch several months after injury. This reinnervation-induced neuropathic pain involved nociceptors that sprouted into denervated territories precisely reproducing the initial pattern of innervation, were guided by blood vessels and showed irregular terminal connectivity in the skin and lowered activation thresholds mimicking low-threshold afferents. By contrast, low-threshold afferents-which normally mediate touch sensation as well as allodynia in intact nerve territories after injury4-7-did not reinnervate, leading to an aberrant innervation of tactile end organs such as Meissner corpuscles with nociceptors alone. Genetic ablation of nociceptors fully abrogated reinnervation allodynia. Our results thus reveal the emergence of a form of chronic neuropathic pain that is driven by structural plasticity, abnormal terminal connectivity and malfunction of nociceptors during reinnervation, and provide a mechanistic framework for the paradoxical sensory manifestations that are observed clinically and can impose a heavy burden on patients.

A spinal microglia population involved in remitting and relapsing neuropathic pain.

Neuropathic pain is often caused by injury and diseases that affect the somatosensory system. Although pain development has been well studied, pain recovery mechanisms remain largely unknown. Here, we found that CD11c-expressing spinal microglia appear after the development of behavioral pain hypersensitivity following nerve injury. Nerve-injured mice with spinal CD11c+ microglial depletion failed to recover spontaneously from this hypersensitivity. CD11c+ microglia expressed insulin-like growth factor-1 (IGF1), and interference with IGF1 signaling recapitulated the impairment in pain recovery. In pain-recovered mice, the depletion of CD11c+ microglia or the interruption of IGF1 signaling resulted in a relapse in pain hypersensitivity. Our findings reveal a mechanism for the remission and recurrence of neuropathic pain, providing potential targets for therapeutic strategies.

Presynaptic NMDARs on spinal nociceptor terminals state-dependently modulate synaptic transmission and pain.

Postsynaptic NMDARs at spinal synapses are required for postsynaptic long-term potentiation and chronic pain. However, how presynaptic NMDARs (PreNMDARs) in spinal nociceptor terminals control presynaptic plasticity and pain hypersensitivity has remained unclear. Here we report that PreNMDARs in spinal nociceptor terminals modulate synaptic transmission in a nociceptive tone-dependent manner. PreNMDARs depresses presynaptic transmission in basal state, while paradoxically causing presynaptic potentiation upon injury. This state-dependent modulation is dependent on Ca2+ influx via PreNMDARs. Small conductance Ca2+-activated K+ (SK) channels are responsible for PreNMDARs-mediated synaptic depression. Rather, tissue inflammation induces PreNMDARs-PKG-I-dependent BDNF secretion from spinal nociceptor terminals, leading to SK channels downregulation, which in turn converts presynaptic depression to potentiation. Our findings shed light on the state-dependent characteristics of PreNMDARs in spinal nociceptor terminals on modulating nociceptive transmission and revealed a mechanism underlying state-dependent transition. Moreover, we identify PreNMDARs in spinal nociceptor terminals as key constituents of activity-dependent pain sensitization.

Altered activity of pain processing brain regions in association with hip osteoarthritis.

Hip osteoarthritis (OA) is characterized by chronic pain, but there remains a mismatch between symptoms and radiological findings. Recently, brain connectivity has been implicated in the modulation of chronic peripheral pain, however its association with perceived pain in hip OA is not understood. We used resting-state functional magnetic resonance imaging (fMRI) to examine functional connectivity associated with pain in hip OA patients. Thirty participants with hip OA and 10 non-OA controls were recruited. Using the visual analogue scale (VAS), pain scores were obtained before and after performing a painful hip activity. All participants underwent 3.0 T resting-state fMRI, and functional connectivity of brain regions associated with pain was determined and compared between participants, and before and after hip activity. Relative to controls, functional connectivity between the secondary somatosensory cortex and left posterior insula was increased, and functional connectivity between the bilateral posterior insula and motor cortices was significantly decreased in hip OA participants. In response to painful hip activity, functional connectivity increased between the thalamus, periaqueductal grey matter and brainstem. Functional connections between brain regions associated with pain are altered in hip OA patients, and several connections are modulated by performing painful activity. Unique lateralization of left posterior insula and linked brain functional connectivity patterns allows assessment of pain perception in hip OA providing an unbiased method to evaluate pain perception and pain modulation strategies.

Temporomandibular disorders cases with high-impact pain are more likely to experience short-term pain fluctuations.

Temporomandibular disorders (TMD) patients can present clinically significant jaw pain fluctuations which can be debilitating and lead to poor global health. The Graded Chronic Pain Scale evaluates pain-related disability and its dichotomous grading (high/low impact pain) can determine patient care pathways and in general high-impact pain patients have worse treatment outcomes. Individuals with low-impact TMD pain are thought to have better psychosocial functioning, more favorable disease course, and better ability to control pain, while individuals with high-impact pain can present with higher levels of physical and psychological symptoms. Thereby, there is reason to believe that individuals with low- and high-impact TMD pain could experience different pain trajectories over time. Our primary objective was to determine if short-term jaw pain fluctuations serve as a clinical marker for the impact status of TMD pain. To this end, we estimated the association between high/low impact pain status and jaw pain fluctuations over three visits (≤ 21-day-period) in 30 TMD cases. Secondarily, we measured the association between jaw pain intensity and pressure pain thresholds (PPT) over the face and hand, the latter measurements compared to matched pain-free controls (n = 17). Jaw pain fluctuations were more frequent among high-impact pain cases (n = 15) than low-impact pain cases (n = 15) (OR 5.5; 95% CI 1.2, 26.4; p value = 0.033). Jaw pain ratings were not associated with PPT ratings (p value > 0.220), suggesting different mechanisms for clinical versus experimental pain. Results from this proof-of-concept study suggest that targeted treatments to reduce short-term pain fluctuations in high-impact TMD pain is a potential strategy to achieve improved patient perception of clinical pain management outcomes.

Effectiveness of Ultrasound-Guided Canal Adductor Blockade for Chronic Pain and Functioning in Knee Osteoarthritis: A Prospective Longitudinal Observational Study.

METHODS: Seventy-seven patients with chronic knee osteoarthritis pain received ultrasound-guided ACB with 14 ml 0.25% levobupivacaine and 100 mcg clonidine. At baseline and 1 month after the blockade, we assessed maximal and minimal pain intensity in the knee using a numeric rating scale (NRS) and the Knee Injury and Osteoarthritis Outcome Score (KOOS). The range of motion in extension and flexion (ROMext and ROMflex) and quadriceps muscle strength of both knees (QS), Timed Up and Go Test (TUG), and 30-Second Chair Stand Test (30CST) results were determined at baseline, 1 hour, 1 week, and 1 month after the blockade. RESULTS: ACB with levobupivacaine and clonidine appeared to decrease pain severity (NRSmax 8.13 to 4.2, p < 0.001 and NRSmin 3.32 to 1.40, p < 0.001). Similarly, knee ROMext decreased from 3.90 preintervention to 2.89 postintervention at 1 month, p < 0.001; ROMflex decreased from 5.70 to 3.29, p < 0.001; TUG time decreased from 3.22 to 2.93, <0.001; QS increased from 18.43 to 22.77, p < 0.001; CST increased from 8.23 to 10.74, p < 0.001. The KOOS for pain (36.40 to 58.34), symptoms (52.55 to 64.32), activities of daily living functions (ADLs, 36.36 to 60.77), and quality of life (QoL, 17.87 to 30.97) also increased, all p < 0.001. CONCLUSION: ACB appeared to decrease pain and increase ambulation. If our preliminary results are reproducible in a planned randomized controlled trial, ACB could be a useful adjunctive pain therapy in patients with disabling pain due to knee OA.

Suvorexant and mirtazapine improve chronic pain-related changes in parameters of sleep and voluntary physical performance in mice with sciatic nerve ligation.

Both chronic pain and sleep disorders are associated with a reduction in the quality of life. They can be both a cause and a consequence of each other, and should therefore be simultaneously treated. However, optimal treatments for chronic pain-related sleep disorders are not well established. Here, we aimed to investigate the effects of suvorexant, a novel sleep drug, and mirtazapine, a noradrenergic and specific serotonergic antidepressant, on pain-related changes in sleep parameters in a preclinical chronic pain mice model, by partial sciatic nerve ligation. We evaluated the quantity, duration, and depth of sleep by analyzing the electroencephalogram and voluntary activity by counting the number of wheel rotations to determine various symptoms of sleep disorders, including reduced total sleep time, fragmentation, low quality, and impaired activity in the daytime. Suvorexant and mirtazapine normalized the reduction in sleep time and fragmented sleep, further regaining the sleep depth at sleep onset in the chronic pain state in nerve-ligated mice. Mirtazapine also increased the percentage of rapid eye movement sleep in mice. Suvorexant decreased voluntary activity, which was prolonged after administration; however, mirtazapine did not decrease it. Although the effects of suvorexant and mirtazapine on sleep and activity are different, both suvorexant and mirtazapine could be potential therapeutic agents for chronic pain-related sleep disorders.

Motor alterations in the kinetic chain in individuals with chronic shoulder pain.

BACKGROUND: Shoulder pain may be related to biomechanical dysfunctions in the kinetic chain. OBJECTIVE: To compare the mobility and muscular endurance of thoracolumbar spine and hip, and the neuromuscular control of the lower extremity of individuals with and without shoulder pain and to determine the discriminative capacity between groups of these variables. DESIGN: A cross-sectional study. METHOD: One hundred and two individuals with and without shoulder pain were evaluated to range of motion (ROM) of the thoracolumbar spine and hips, the muscular endurance time of the thoracolumbar spine and hips muscles, and the neuromuscular control of the lower extremity, by the Star Excursion Balance Test (SEBT). RESULTS: Individuals with shoulder pain presented lower ROM and muscular endurance time in all tests evaluated (p < 0.01-p = 0.03), greater perception of pain during all ROM and muscle endurance (p < 0.01-p = 0.04) evaluations, and less neuromuscular control of the lower extremity in the compound reach (p < 0.01-p = 0.01), anterior and posteromedial (p < 0.01-p = 0.04) directions of the SEBT on both sides. The anterior reach direction of the SEBT of the contralateral limb to the shoulder pain (AUC=0.80, cut-off point=47.7%) presented excellent capacity to discriminate individuals with shoulder pain, while the other variables showed between acceptable and small capacity (AUC=0.58-0.76). CONCLUSION: Individuals with chronic shoulder pain presented alterations in joint mobility, muscular endurance time of the thoracolumbar spine and hips and neuromuscular control of the lower extremity. The anterior reach of the SEBT of the contralateral limb showed excellent discriminative capacity.

Altered effective connectivity within the cingulo-frontal-parietal cognitive attention networks in chronic low back pain: a dynamic causal modeling study.

Dysfunction of the cingulo-frontal-parietal (CFP) cognitive attention network has been associated with the pathophysiology of chronic low back pain (cLBP). However, the direction of information processing within this network remains largely unknown. We aimed to study the effective connectivity among the CFP regions in 36 cLBP patients and 36 healthy controls by dynamic causal modeling (DCM). Both the resting-state and task-related (Multi-Source Interference Task, MSIT) functional magnetic resonance imaging (fMRI) data were collected and analyzed. The relationship between the effective connectivity of the CFP regions and clinical measures was also examined. Our results suggested that cLBP had significantly altered resting-state effective connectivity of the prefrontal cortex (PFC)-to-mid-cingulate cortex (MCC) (increased) and MCC-to-left superior parietal cortex (LPC) (decreased) pathways as compared with healthy controls. MSIT-related DCM suggested that the interference task could significantly increase the effective connectivity of the right superior parietal cortex (RPC)-to-PFC and RPC-to-MCC pathways in cLBP than that in healthy controls. The control task could significantly decrease the effective connectivity of the MCC-to-LPC and MCC-to-RPC pathways in cLBP than that in healthy controls. The endogenous connectivity of the PFC-to-RPC pathway in cLBP was significantly lower than that in healthy controls. No significant correlations were found between the effective connectivity within CFP networks and pain/depression scores in patients with cLBP. In summary, our findings suggested altered effective connectivity in multiple pathways within the CFP network in both resting-state and performing attention-demanding tasks in patients with cLBP, which extends our understanding of attention dysfunction in patients with cLBP.

Leptin promoter methylation in female patients with painful multisomatoform disorder and chronic widespread pain.

BACKGROUND: Different functional somatic syndromes (FSS), fibromyalgia (FMS) and other unexplained painful conditions share many common clinical traits and are characterized by troubling and functionally disabling somatic symptoms. Chronic pain is most frequently reported and at the center of patients' level of disease burden. The construct of multisomatoform disorder (MSD) allows to subsume severely impaired patients suffering from FSS, FMS and other unexplained painful conditions to be examined for common underlying processes. Altered leptin levels and a pathological response of the HPA-axis as a result of chronic stress and childhood trauma have been suggested as one of the driving factors of disease development and severity. Previous studies have demonstrated that methylation of the leptin promoter can play a regulatory role in addiction. In this study, we hypothesized that methylation of the leptin promoter is influenced by the degree of childhood traumatization and differs between patients with MSD and controls. A cohort of 151 patients with MSD and 149 matched healthy volunteers were evaluated using clinical and psychometric assessment while methylation level analysis of the leptin promoter was performed using DNA isolated from whole blood. RESULTS: In female controls, we found CpG C-167 to be negatively correlated with leptin levels, whereas in female patients CpG C-289, C-255, C-193, C-167 and methylation cluster (C-291 to C-167) at putative bindings sites for transcription factors Sp1 and c/EBPalpha were negatively correlated with leptin levels. Methylation levels were significantly lower in female patients CpG C-289 compared with controls. When looking at female patients with chronic widespread pain methylation levels were significantly lower at CpG C-289, C-255 and methylation cluster (C-291 to C-167). CONCLUSION: Our findings support the hypothesis that epigenetic regulation of leptin plays a role in the regulation of leptin levels in patients with MSD. This effect is more pronounced in patients with chronic widespread pain.

Bladder-colon chronic cross-sensitization involves neuro-glial pathways in male mice.

BACKGROUND: Irritable bowel syndrome and bladder pain syndrome often overlap and are both characterized by visceral hypersensitivity. Since pelvic organs share common sensory pathways, it is likely that those syndromes involve a cross-sensitization of the bladder and the colon. The precise pathophysiology remains poorly understood. AIM: To develop a model of chronic bladder-colon cross-sensitization and to investigate the mech-anisms involved. METHODS: Chronic cross-organ visceral sensitization was obtained in C57BL/6 mice using ultrasound-guided intravesical injections of acetic acid under brief isoflurane anesthesia. Colorectal sensitivity was assessed in conscious mice by measuring intracolonic pressure during isobaric colorectal distensions. Myeloperoxidase, used as a marker of colorectal inflammation, was measured in the colon, and colorectal permeability was measured using chambers. c-Fos protein expression, used as a marker of neuronal activation, was assessed in the spinal cord (L6-S1 level) using immunohistochemistry. Green fluorescent protein on the fractalkine receptor-positive mice were used to identify and count microglia cells in the L6-S1 dorsal horn of the spinal cord. The expression of NK1 receptors and MAPK-p38 were quantified in the spinal cord using western blot. RESULTS: Visceral hypersensitivity to colorectal distension was observed after the intravesical injection of acetic acid vs saline (P < 0.0001). This effect started 1 h post-injection and lasted up to 7 d post-injection. No increased permeability or inflammation was shown in the bladder or colon 7 d post-injection. Visceral hypersensitivity was associated with the increased expression of c-Fos protein in the spinal cord (P < 0.0001). In green fluorescent protein on the fractalkine receptor-positive mice, intravesical acetic acid injection resulted in an increased number of microglia cells in the L6-S1 dorsal horn of the spinal cord (P < 0.0001). NK1 receptor and MAPK-p38 levels were increased in the spinal cord up to 7 d after injection (P = 0.007 and 0.023 respectively). Colorectal sensitization was prevented by intrathecal or intracerebroventricular injections of minocycline, a microglia inhibitor, by intracerebroventricular injection of CP-99994 dihydrochloride, a NK1 antagonist, and by intracerebroventricular injection of SB203580, a MAPK-p38 inhibitor. CONCLUSION: We describe a new model of cross-organ visceral sensitization between the bladder and the colon in mice. Intravesical injections of acetic acid induced a long-lasting colorectal hypersensitivity to distension, mediated by neuroglial interactions, MAPK-p38 phosphorylation and the NK1 receptor.

Dysregulated anterior insula reactivity as robust functional biomarker for chronic pain-Meta-analytic evidence from neuroimaging studies.

Neurobiological pain models propose that chronic pain is accompanied by neurofunctional changes that mediate pain processing dysfunctions. In contrast, meta-analyses of neuroimaging studies in chronic pain conditions have not revealed convergent evidence for robust alterations during experimental pain induction. Against this background, the present neuroimaging meta-analysis combined three different meta-analytic approaches with stringent study selection criteria for case-control functional magnetic resonance imaging experiments during acute pain processing with a focus on chronic pain disorders. Convergent neurofunctional dysregulations in chronic pain patients were observed in the left anterior insula cortex. Seed-based resting-state functional connectivity based on a large publicly available dataset combined with a meta-analytic task-based approach identified the anterior insular region as a key node of an extended bilateral insula-fronto-cingular network, resembling the salience network. Moreover, the meta-analytic decoding showed that this region presents a high probability to be specifically activated during pain-related processes, although we cannot exclude an involvement in autonomic processes. Together, the present findings indicate that dysregulated left anterior insular activity represents a robust neurofunctional maladaptation and potential treatment target in chronic pain disorders.

Battle of the Appraisals: Pain-Related Injustice Versus Catastrophizing as Mediators in the Relationship Between Pain Intensity and 3-Month Outcomes in Adolescents with Chronic Pain.

Pain appraisals are closely tied to pain and functional outcomes. Pain-related injustice and pain catastrophizing appraisals have both been identified as important cognitive-emotional factors in the pain experience of youth. Although pain-related injustice and catastrophizing have been linked to worse pain outcomes - as primary predictors and intermediary variables - little is known about whether they operate as independent or parallel mediators of the relationship between pain and functioning in youth. We tested pain-related injustice and catastrophizing appraisals as candidate mediators of the relationship between baseline pain intensity and 3-month functional outcomes in adolescents. Youth with chronic pain (N = 89, 76% female, 89% White, average age = 15 years) completed measures assessing pain intensity, pain-related injustice, and catastrophizing at baseline, as well as measures assessing functional disability and overall quality of life 3 months later. Multiple mediation analyses indicated that injustice mediated the relationship between pain intensity and 3 month quality of life. Exploratory analyses of specific quality of life domains indicated that injustice mediated the relationship between pain intensity and 3 month emotional functioning, whereas catastrophizing mediated the relationship between pain intensity and 3 month social functioning. The findings suggest these pain-related appraisals play different intermediary roles in the relationships among pain and future psychosocial outcomes. PERSPECTIVE: Pain-related injustice and catastrophizing appraisals play different intermediary roles in the relationships among pain and future psychosocial outcomes in youth with chronic pain. Treatments targeting pain-related injustice appraisals in pediatric populations are needed to complement existing treatments for catastrophizing.

Chronic Pain Severity and Sociodemographics: An Evaluation of the Neurobiological Interface.

Chronic pain is variably associated with brain structure. Phenotyping based on pain severity may address inconsistencies. Sociodemographic groups also differ in the experience of chronic pain severity. Whether differences by chronic pain severity and/or sociodemographic groups are indicated in pain-related areas of the brain is unknown. Relations between 2 measures of chronic pain severity and brain structure via T1-weighted MRI were investigated and sociodemographic group differences explored. The observational study included 142 community-dwelling (68 non-Hispanic Black [NHB] and 74 non-Hispanic White [NHW]) adults with/at risk for knee osteoarthritis. Relationships between chronic pain severity, sociodemographic groups, and a priori selected brain structures (postcentral gyrus, insula, medial orbitofrontal, anterior cingulate, rostral middle frontal gyrus, hippocampus, amygdala, thalamus) were explored. Chronic pain severity associated with cortical thickness. NHB participants reported lower sociodemographic protective factors and greater clinical pain compared to NHWs who reported higher sociodemographic protective factors and lower clinical pain. Greater chronic pain severity was associated with smaller amygdala volumes in the NHB group and larger amygdala volumes in the NHW group. Brain structure by chronic pain stage differed between and within sociodemographic groups. Overall, chronic pain severity and sociodemographic factors are associated with pain-related brain structures. Our findings highlight the importance of further investigating social and environmental contributions in the experience of chronic pain to unravel the complex array of factors contributing to disparities. PERSPECTIVE: The study presents data demonstrating structural brain relationships with clinical pain severity, characteristic pain intensity and chronic pain stage, differ by sociodemographic groups. Findings yield insights into potential sources of previous inconsistent pain-brain relationships and highlights the need for future investigations to address social and environmental factors in chronic pain disparities research.