Infliximab alleviates memory impairment in rats with chronic pain by suppressing neuroinflammation and restoring hippocampal neurogenesis.

Patients with chronic pain commonly report impaired memory. Increasing evidence has demonstrated that inhibition of neurogenesis by neuroinflammation plays a crucial role in chronic pain-associated memory impairments. There is currently a lack of treatment strategies for this condition. An increasing number of clinical trials have reported the therapeutic potential of anti-inflammatory therapies targeting tumour necrosis factor-α (TNF-α) for inflammatory diseases. The present study investigated whether infliximab alleviates chronic pain-associated memory impairments in rats with chronic constriction injury (CCI). We demonstrated that infliximab alleviated spatial memory impairment and hyperalgesia induced by CCI. Furthermore, infliximab inhibited the activation of hippocampal astrocytes and microglia and decreased the release of proinflammatory cytokines in CCI rats. Furthermore, infliximab reversed the decrease in the numbers of newborn neurons and mature neurons in the dentate gyrus (DG) caused by chronic pain. Our data provide evidence that infliximab alleviates chronic pain-associated memory impairments, suppresses neuroinflammation and restores hippocampal neurogenesis in a CCI model. These facts indicate that infliximab may be a potential therapeutic agent for the treatment of chronic pain and associated memory impairments.

[Chronic Pain and Allostasis: Role of Glial Cells].

Lesions or diseases affecting the somatosensory system cause neuropathic pain, a debilitating chronic pain condition. From our recent study using a mouse model of neuropathic pain, CD11c+ microglia that appear in the spinal cord after nerve injury are important cells required for the pain remission. In this article, we review the transition of microglial states after nerve injury and the allostatic control mechanisms of neuropathic pain by CD11c+ microglia.

Brain-predicted age difference estimated using DeepBrainNet is significantly associated with pain and function-a multi-institutional and multiscanner study.

ABSTRACT: Brain age predicted differences (brain-PAD: predicted brain age minus chronological age) have been reported to be significantly larger for individuals with chronic pain compared with those without. However, a debate remains after one article showed no significant differences. Using Gaussian Process Regression, an article provides evidence that these negative results might owe to the use of mixed samples by reporting a differential effect of chronic pain on brain-PAD across pain types. However, some remaining methodological issues regarding training sample size and sex-specific effects should be tackled before settling this controversy. Here, we explored differences in brain-PAD between musculoskeletal pain types and controls using a novel convolutional neural network for predicting brain-PADs, ie, DeepBrainNet. Based on a very large, multi-institutional, and heterogeneous training sample and requiring less magnetic resonance imaging preprocessing than other methods for brain age prediction, DeepBrainNet offers robust and reproducible brain-PADs, possibly highly sensitive to neuropathology. Controlling for scanner-related variability, we used a large sample (n = 660) with different scanners, ages (19-83 years), and musculoskeletal pain types (chronic low back [CBP] and osteoarthritis [OA] pain). Irrespective of sex, brain-PAD of OA pain participants was ∼3 to 4.7 years higher than that of CBP and controls, whereas brain-PAD did not significantly differ among controls and CBP. Moreover, brain-PAD was significantly related to multiple variables underlying the multidimensional pain experience. This comprehensive work adds evidence of pain type-specific effects of chronic pain on brain age. This could help in the clarification of the debate around possible relationships between brain aging mechanisms and pain.

Mitochondrial dysfunction and type I interferon signaling induce anxiodepressive-like behaviors in mice with neuropathic pain.

Clinical evidence indicates that major depression is a common comorbidity of chronic pain, including neuropathic pain; however, the cellular basis for chronic pain-mediated major depression remains unclear. Mitochondrial dysfunction induces neuroinflammation and has been implicated in various neurological diseases, including depression. Nevertheless, the relationship between mitochondrial dysfunction and anxiodepressive-like behaviors in the neuropathic pain state remains unclear. The current study examined whether hippocampal mitochondrial dysfunction and downstream neuroinflammation are involved in anxiodepressive-like behaviors in mice with neuropathic pain, which was induced by partial sciatic nerve ligation (PSNL). At 8 weeks after surgery, there was decreased levels of mitochondrial damage-associated molecular patterns, such as cytochrome c and mitochondrial transcription factor A, and increased level of cytosolic mitochondrial DNA in the contralateral hippocampus, suggesting the development of mitochondrial dysfunction. Type I interferon (IFN) mRNA expression in the hippocampus was also increased at 8 weeks after PSNL surgery. The restoration of mitochondrial function by curcumin blocked the increased cytosolic mitochondrial DNA and type I IFN expression in PSNL mice and improved anxiodepressive-like behaviors. Blockade of type I IFN signaling by anti-IFN alpha/beta receptor 1 antibody also improved anxiodepressive-like behaviors in PSNL mice. Together, these findings suggest that neuropathic pain induces hippocampal mitochondrial dysfunction followed by neuroinflammation, which may contribute to anxiodepressive-behaviors in the neuropathic pain state. Improving mitochondrial dysfunction and inhibiting type I IFN signaling in the hippocampus might be a novel approach to reducing comorbidities associated with neuropathic pain, such as depression and anxiety.

Engineering a multicompartment in vitro model for dorsal root ganglia phenotypic assessment.

Despite the significant global prevalence of chronic pain, current methods to identify pain therapeutics often fail translation to the clinic. Phenotypic screening platforms rely on modeling and assessing key pathologies relevant to chronic pain, improving predictive capability. Patients with chronic pain often present with sensitization of primary sensory neurons (that extend from dorsal root ganglia [DRG]). During neuronal sensitization, painful nociceptors display lowered stimulation thresholds. To model neuronal excitability, it is necessary to maintain three key anatomical features of DRGs to have a physiologically relevant platform: (1) isolation between DRG cell bodies and neurons, (2) 3D platform to preserve cell-cell and cell-matrix interactions, and (3) presence of native non-neuronal support cells, including Schwann cells and satellite glial cells. Currently, no culture platforms maintain the three anatomical features of DRGs. Herein, we demonstrate an engineered 3D multicompartment device that isolates DRG cell bodies and neurites and maintains native support cells. We observed neurite growth into isolated compartments from the DRG using two formulations of collagen, hyaluronic acid, and laminin-based hydrogels. Further, we characterized the rheological, gelation and diffusivity properties of the two hydrogel formulations and found the mechanical properties mimic native neuronal tissue. Importantly, we successfully limited fluidic diffusion between the DRG and neurite compartment for up to 72 h, suggesting physiological relevance. Lastly, we developed a platform with the capability of phenotypic assessment of neuronal excitability using calcium imaging. Ultimately, our culture platform can screen neuronal excitability, providing a more translational and predictive system to identify novel pain therapeutics to treat chronic pain.

[Remodeling of Neuronal Circuits in Chronic Pain].

Chronic pain is associated with various brain malfunctions, such as allodynia and anxiety. The underlying mechanism is a long-term alteration of neural circuits in the related brain regions. Here, we focus on the contribution of glial cells to build up pathological circuits. In addition, an attempt to enhance the neuronal plasticity of the pathological circuits to repair them to relieve abnormal pain will be introduced. The possible clinical applications will also be discussed.

Elevated dementia risk, cognitive decline, and hippocampal atrophy in multisite chronic pain.

Numerous studies have investigated the impacts of common types of chronic pain (CP) on patients' cognitive function and observed that CP was associated with later dementia. More recently, there is a growing recognition that CP conditions frequently coexist at multiple body sites and may bring more burdens on patients' overall health. However, whether and how multisite CP (MCP) contributes to an increased risk of dementia, compared to single-site CP (SCP) and pain-free (PF), is largely unclear. In the current study, utilizing the UK Biobank cohort, we first investigated dementia risk in individuals (n = 354,943) with different numbers of coexisting CP sites using Cox proportional hazards regression models. We then applied generalized additive models to investigate whether MCP leads to excessive deterioration of participants' (n = 19,116) cognition and brain structure. We found that individuals with MCP were associated with significantly higher dementia risk, broader and faster cognitive impairment, and greater hippocampal atrophy than both PF individuals and those with SCP. Moreover, the detrimental effects of MCP on dementia risk and hippocampal volume aggravated along with the number of coexisting CP sites. Mediation analyses further revealed that the decline of fluid intelligence in MCP individuals was partially mediated by hippocampal atrophy. Our results suggested that cognitive decline and hippocampal atrophy interact biologically and may underlie the increased risk of dementia associated with MCP.

Psychological and neurological predictors of acupuncture effect in patients with chronic pain: a randomized controlled neuroimaging trial.

ABSTRACT: Chronic pain has been one of the leading causes of disability. Acupuncture is globally used in chronic pain management. However, the efficacy of acupuncture treatment varies across patients. Identifying individual factors and developing approaches that predict medical benefits may promise important scientific and clinical applications. Here, we investigated the psychological and neurological factors collected before treatment that would determine acupuncture efficacy in knee osteoarthritis. In this neuroimaging-based randomized controlled trial, 52 patients completed a baseline assessment, 4-week acupuncture or sham-acupuncture treatment, and an assessment after treatment. The patients, magnetic resonance imaging operators, and outcome evaluators were blinded to treatment group assignment. First, we found that patients receiving acupuncture treatment showed larger pain intensity improvements compared with patients in the sham-acupuncture arm. Second, positive expectation, extraversion, and emotional attention were correlated with the magnitude of clinical improvements in the acupuncture group. Third, the identified neurological metrics encompassed striatal volumes, posterior cingulate cortex (PCC) cortical thickness, PCC/precuneus fractional amplitude of low-frequency fluctuation (fALFF), striatal fALFF, and graph-based small-worldness of the default mode network and striatum. Specifically, functional metrics predisposing patients to acupuncture improvement changed as a consequence of acupuncture treatment, whereas structural metrics remained stable. Furthermore, support vector machine models applied to the questionnaire and brain features could jointly predict acupuncture improvement with an accuracy of 81.48%. Besides, the correlations and models were not significant in the sham-acupuncture group. These results demonstrate the specific psychological, brain functional, and structural predictors of acupuncture improvement and may offer opportunities to aid clinical practices.

Size Reduction of the Right Amygdala in Chronic Pain Patients with Emotional Stress: A Systematic Review and Meta-Analysis.

The structural impact of chronic pain on amygdala in chronic pain (CP) patients remains unclear, although major depression and anxiety are known to be associated with its increase and decrease in size, respectively. This study aimed at examining the relationship between emotional stress and amygdala size in CP patients. The effects of mediating and moderating variables were also examined. The PubMed, Embase, and Web of Science databases were searched for English clinical trials from inception to February 2022 using the appropriate keyword strings. We compared the differences in amygdala size assessed with magnetic resonance imaging between CP patients with emotional stress and healthy counterparts. Of the 49 full-text articles identified, 13 studies enrolling 1,551 participants including 738 CP patients with emotional stress and 813 controls were analyzed. Emotional stress evaluated with questionnaires based on Beck depression inventory, Hamilton depression/anxiety scale, state-trait anxiety inventory, and hospital anxiety and depression scale revealed significant differences between CP patients with emotional stress and controls, indicating a subclinical but significant level of emotional stress in CP patients. The results demonstrated an amygdala shrinkage among CP patients with emotional stress compared to the controls, especially the right side (P = .02). Besides, pain from a single body region was more likely to impact the amygdala size compared to diffuse pain (P = .02). Regression analysis revealed no significant association between continuous variables (age, gender, pain duration/intensity) and amygdala size. Our findings demonstrated that emotional stress was associated with a reduced right amygdala size in CP patients.

Astrocytes in Chronic Pain: Cellular and Molecular Mechanisms.

Chronic pain is challenging to treat due to the limited therapeutic options and adverse side-effects of therapies. Astrocytes are the most abundant glial cells in the central nervous system and play important roles in different pathological conditions, including chronic pain. Astrocytes regulate nociceptive synaptic transmission and network function via neuron-glia and glia-glia interactions to exaggerate pain signals under chronic pain conditions. It is also becoming clear that astrocytes play active roles in brain regions important for the emotional and memory-related aspects of chronic pain. Therefore, this review presents our current understanding of the roles of astrocytes in chronic pain, how they regulate nociceptive responses, and their cellular and molecular mechanisms of action.

Mechanosensitive Ion Channel TMEM63A Gangs Up with Local Macrophages to Modulate Chronic Post-amputation Pain.

Post-amputation pain causes great suffering to amputees, but still no effective drugs are available due to its elusive mechanisms. Our previous clinical studies found that surgical removal or radiofrequency treatment of the neuroma at the axotomized nerve stump effectively relieves the phantom pain afflicting patients after amputation. This indicated an essential role of the residual nerve stump in the formation of chronic post-amputation pain (CPAP). However, the molecular mechanism by which the residual nerve stump or neuroma is involved and regulates CPAP is still a mystery. In this study, we found that nociceptors expressed the mechanosensitive ion channel TMEM63A and macrophages infiltrated into the dorsal root ganglion (DRG) neurons worked synergistically to promote CPAP. Histology and qRT-PCR showed that TMEM63A was mainly expressed in mechanical pain-producing non-peptidergic nociceptors in the DRG, and the expression of TMEM63A increased significantly both in the neuroma from amputated patients and the DRG in a mouse model of tibial nerve transfer (TNT). Behavioral tests showed that the mechanical, heat, and cold sensitivity were not affected in the Tmem63a-/- mice in the naïve state, suggesting the basal pain was not affected. In the inflammatory and post-amputation state, the mechanical allodynia but not the heat hyperalgesia or cold allodynia was significantly decreased in Tmem63a-/- mice. Further study showed that there was severe neuronal injury and macrophage infiltration in the DRG, tibial nerve, residual stump, and the neuroma-like structure of the TNT mouse model, Consistent with this, expression of the pro-inflammatory cytokines TNF-α, IL-6, and IL-1ß all increased dramatically in the DRG. Interestingly, the deletion of Tmem63a significantly reduced the macrophage infiltration in the DRG but not in the tibial nerve stump. Furthermore, the ablation of macrophages significantly reduced both the expression of Tmem63a and the mechanical allodynia in the TNT mouse model, indicating an interaction between nociceptors and macrophages, and that these two factors gang up together to regulate the formation of CPAP. This provides a new insight into the mechanisms underlying CPAP and potential drug targets its treatment.

Transient astrocytic mGluR5 expression drives synaptic plasticity and subsequent chronic pain in mice.

Activation of astrocytes has a profound effect on brain plasticity and is critical for the pathophysiology of several neurological disorders including neuropathic pain. Here, we show that metabotropic glutamate receptor 5 (mGluR5), which reemerges in astrocytes in a restricted time frame, is essential for these functions. Although mGluR5 is absent in healthy adult astrocytes, it transiently reemerges in astrocytes of the somatosensory cortex (S1). During a limited spatiotemporal time frame, astrocytic mGluR5 drives Ca2+ signals; upregulates multiple synaptogenic molecules such as Thrombospondin-1, Glypican-4, and Hevin; causes excess excitatory synaptogenesis; and produces persistent alteration of S1 neuronal activity, leading to mechanical allodynia. All of these events were abolished by the astrocyte-specific deletion of mGluR5. Astrocytes dynamically control synaptic plasticity by turning on and off a single molecule, mGluR5, which defines subsequent persistent brain functions, especially under pathological conditions.

Association between chronic low back pain and regional brain atrophy in a Japanese older population: the Hisayama Study.

ABSTRACT: Chronic low back pain (CLBP) is the leading cause of years lived with disability. Recently, it has been reported that CLBP is associated with alterations in the central nervous system. The present study aimed to investigate the association between CLBP and regional brain atrophy in an older Japanese population. A total of 1106 community-dwelling participants aged ≥65 years underwent brain magnetic resonance imaging scans and a health examination in 2017 to 2018. We used the FreeSurfer software for the analysis of brain magnetic resonance imaging. Chronic pain was defined as subjective pain for ≥3 months. Participants were divided into 3 groups according to the presence or absence of chronic pain and the body part that mainly suffered from pain: a "no chronic pain (NCP)" group (n = 541), "CLBP" group (n = 189), and "chronic pain in body parts other than the lower back (OCP)" group (n = 376). The brain volumes of the ventrolateral and dorsolateral prefrontal cortex, the posterior cingulate gyrus, and the amygdala were significantly lower in the CLBP group than in the NCP group after adjustment for sociodemographic, physical, and lifestyle factors and depressive symptoms. In addition, the left superior frontal gyrus was identified as a significant cluster by the Query, Design, Estimate, Contrast interface. There were no significant differences in the brain volumes of pain-related regions between the NCP and the OCP groups. The present study suggests that CLBP is associated with lower brain volumes of pain-related regions in a general older population of Japanese.

Organic anion transporter 1 is an HDAC4-regulated mediator of nociceptive hypersensitivity in mice.

Persistent pain is sustained by maladaptive changes in gene transcription resulting in altered function of the relevant circuits; therapies are still unsatisfactory. The epigenetic mechanisms and affected genes linking nociceptive activity to transcriptional changes and pathological sensitivity are unclear. Here, we found that, among several histone deacetylases (HDACs), synaptic activity specifically affects HDAC4 in murine spinal cord dorsal horn neurons. Noxious stimuli that induce long-lasting inflammatory hypersensitivity cause nuclear export and inactivation of HDAC4. The development of inflammation-associated mechanical hypersensitivity, but neither acute nor basal sensitivity, is impaired by the expression of a constitutively nuclear localized HDAC4 mutant. Next generation RNA-sequencing revealed an HDAC4-regulated gene program comprising mediators of sensitization including the organic anion transporter OAT1, known for its renal transport function. Using pharmacological and molecular tools to modulate OAT1 activity or expression, we causally link OAT1 to persistent inflammatory hypersensitivity in mice. Thus, HDAC4 is a key epigenetic regulator that translates nociceptive activity into sensitization by regulating OAT1, which is a potential target for pain-relieving therapies.

Gray Matter Abnormalities in Patients with Chronic Primary Pain: A Coordinate-Based Meta-Analysis.

BACKGROUND: Many structural magnetic resonance imaging (MRI) studies have used voxel-based morphometry (VBM) to identify gray matter abnormalities in patients with chronic primary pain (CPP), but the findings have been inconsistent. OBJECTIVES: To identify (a) gray matter differences between CPP patients or female patients and healthy individuals and (b) the effects of symptom duration and pain scores on gray matter. STUDY DESIGN: We conducted a meta-analysis. METHODS: VBM studies in PubMed, Cochrane Library, and Google Scholar, from November 2005 to June 2020, were thoroughly collected and carefully reviewed. Manual searches were performed using title and citation information. Gray matter VBM study comparing adult patients (18-65 years) with CPP to healthy controls was reviewed, and results, presented in Talairach or Montreal Neurological Institute coordinates, were included. The t value, peak coordinates, and basic clinical information of each study were reported in detail. Anisotropic effect-size signed differential mapping was used for voxel-based meta-analyses. RESULTS: Patients with CPP had decreased gray matter in the left anterior cingulate (z value = 2.950, P < 0.001), right median cingulate (z value = 1.858, P = 0.001), and the insula bilaterally (left: z value = 2.441, P < 0.001; right: z value = 2.113, P < 0.001 ), and increased gray matter in the right striatum (z value = 1.194, P < 0.001). Subgroup meta-analysis showed female patients with CPP also had decreased gray matter in the left anterior cingulate gyrus (z value = 2.622, P < 0.001). Meta-regression analyses revealed that pain symptom duration was positively associated with a large right brain region (z value = 2.110, P < 0.001), a negative association between pain symptom duration and gray matter was found in the right anterior cingulate (z value = 1.969, P < 0.001) and right middle frontal gyrus (z value = 1.849, P < 0.001). LIMITATIONS: Due to the lack of data from male patients, we were unable to perform a male subgroup analysis; therefore, we cannot thoroughly explore the difference in CPP from the perspective of gender. CONCLUSION: We identified gray matter changes in CPP patients and female patients, as well as a close relationship between CPP and mental disorders. With the chronicity of pain leads to changes in relevant brain regions, which makes treatment more challenging and may have synergistic effects with affective disorders. More prospective longitudinal structural MRI studies of CPP examining the associations between those variables and gray matter in a larger population should be conducted. Additional prospective longitudinal structural MRI studies of CPP with larger sample sizes to confirm the relationships between these variables and gray matter are needed as well as gender differences of CPP in brain structure and function.

TGF-ß1 in plasma and cerebrospinal fluid can be used as a biological indicator of chronic pain in patients with osteoarthritis.

INTRODUCTION: Previous studies have demonstrated that cytokines, transforming growth factor (TGF-ß1), and brain-derived neurotrophic factor (BDNF) can impact the intensity of pain in rodents. However, the roles of cytokines, TGF-ß1 and BDNF in humans with chronic pain in osteoarthritis remains unclear, and no comparison between plasma and central cerebral spinal fluid (CSF) has been conducted. METHODS: Patients with osteoarthritis who were scheduled to receive spinal anesthesia were enrolled. The intensity of pain was evaluated with a visual analogue scale (VAS). In addition, patients with genitourinary system (GU) diseases and without obvious pain (VAS 0-1) were included as a comparison (control) group. The levels of TGF-ß1, BDNF, tumor necrosis factor-α (TNF-α), and interleukin (IL)-8 within the CSF and plasma were collected and evaluated before surgery. RESULTS: The plasma and CSF TGF-ß1 levels were significantly lower in the osteoarthritis patients with pain (VAS ≥ 3) than in the GU control patients. Downregulation of plasma BDNF was also found in osteoarthritis patients with pain. The Spearman correlation analysis showed that the VAS pain scores were significantly negatively correlated with the levels of TGF-ß1 in the CSF of patients with osteoarthritis. However, there was no significant correlations between the pain scores and the levels of BDNF, TNF-α, and IL-8 in either the CSF or plasma. CONCLUSIONS: TGF-ß1 but not BDNF, TNF-α, or IL-8 may be an important biological indicator in the CSF of osteoarthritis patients with chronic pain.

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.

Musculoskeletal diseases among French military high-speed boat pilots.

In 2016, the French Navy acquired a new high-speed boat, called ECUME. It exposes crewmembers to significant Whole Body Vibrations. This work explores the musculoskeletal diseases among this population. We conducted a retrospective declarative epidemiologic study using anonymous questionnaires. Eighty-four sailors were included. Fifty-six (66.7%) report acute traumas during a nautical raid during the 12 months study period. Sixty (71.4%) report chronic pains, which they associate with their nautical activity. Among them, only 16 (26.7%) have consulted a doctor, but 32 (53.3%) report consuming medication, including 18 through selfmedication. More than half rely to alternatives medicine, especially osteopathy. The traumatic risk of ECUME riding is obvious. Many crewmembers minimize their symptoms, and consult rarely a physician. They give preference to selfmedication and alternative medicines.