Papers: 14 May 2022 - 20 May 2022

Neuroimaging is a powerful tool to investigate potential associations between chronic pain and brain structure. However, the proliferation of studies across diverse chronic pain syndromes and heterogeneous results challenges data integration and interpretation. We conducted a preregistered anatomic likelihood estimate meta-analysis on structural magnetic imaging studies comparing patients with chronic pain and healthy controls. Specifically, we investigated a broad range of measures of brain structure as well as specific alterations in gray matter and cortical thickness. A total of 7,849 abstracts of experiments published between January 1, 1990 and April 26, 2021 were identified from eight databases and evaluated by two independent reviewers. Overall, 103 experiments with a total of 5,075 participants met the pre-registered inclusion criteria. After correction for multiple comparisons using the gold standard family-wise error correction (p < .05), no significant differences associated with chronic pain were found. However, exploratory analyses using threshold-free cluster enhancement revealed several spatially distributed clusters showing structural alterations in chronic pain. The majority of clusters coincided with regions implicated in nociceptive processing including the amygdala, thalamus, hippocampus, insula, anterior cingulate cortex and inferior frontal gyrus. Taken together, these results suggest that chronic pain is associated with subtle, spatially distributed alterations of brain structure.

Identifying the genetic determinants of pain is a scientific imperative given the magnitude of the global health burden that pain causes. Here, we report a genetic screen for nociception, performed under the auspices of the International Mouse Phenotyping Consortium. A biased set of 110 single-gene knockout mouse strains was screened for 1 or more nociception and hypersensitivity assays, including chemical nociception (formalin) and mechanical and thermal nociception (von Frey filaments and Hargreaves tests, respectively), with or without an inflammatory agent (complete Freund's adjuvant). We identified 13 single-gene knockout strains with altered nocifensive behavior in 1 or more assays. All these novel mouse models are openly available to the scientific community to study gene function. Two of the 13 genes (Gria1 and Htr3a) have been previously reported with nociception-related phenotypes in genetically engineered mouse strains and represent useful benchmarking standards. One of the 13 genes (Cnrip1) is known from human studies to play a role in pain modulation and the knockout mouse reported herein can be used to explore this function further. The remaining 10 genes (Abhd13, Alg6, BC048562, Cgnl1, Cp, Mmp16, Oxa1l, Tecpr2, Trim14, and Trim2) reveal novel pathways involved in nociception and may provide new knowledge to better understand genetic mechanisms of inflammatory pain and to serve as models for therapeutic target validation and drug development.

It was not until the twentieth century that pain was considered a disease. Before that it was managed medically as a symptom. The motivations for declaring chronic pain a disease, whether of the body or of the brain, include increasing its legitimacy as clinical problem and research focus worthy of attention from healthcare and research organizations alike. But one problem with disease concepts is that having a disease favors medical solutions and tends to reduce patient participation. We argue that chronic pain, particularly chronic primary pain (recently designated a first tier pain diagnosis in ICD 11), is a learned state that is not intransigent even if it has biological correlates. Chronic pain is sometimes a symptom, and may sometimes be its own disease. But here we question the value of a disease focus for much of chronic pain for which patient involvement is essential, and which may need a much broader societal approach than is suggested by the disease designation. PERSPECTIVE: This article examines whether designating chronic pain a disease of the body or brain is helpful or harmful to patients. Can the disease designation help advance treatment, and is it needed to achieve future therapeutic breakthrough? Or does it make patients over-reliant on medical intervention and reduce their engagement in the process of recovery?

Previous studies have reported sex differences in irritable bowel syndrome (IBS) and inflammatory bowel disease (IBD) patients, including differences in visceral pain perception. Despite this, sex differences in behavioral manifestations of visceral pain and underlying pathology of the gastrointestinal tract have been largely understudied in preclinical research. In this study, we evaluated potential sex differences in spontaneous nociceptive responses, referred abdominal hypersensitivity, disease progression and bowel pathology in mouse models of acute and persistent colon inflammation. Our experiments show that females exhibit more nociceptive responses and referred abdominal hypersensitivity than males in the context of acute but not persistent colon inflammation. We further demonstrate that, following acute and persistent colon inflammation, pain-related behavioral responses in females and males are distinct, with increases in licking of the abdomen only observed in females and increases in abdominal contractions only seen in males. During persistent colon inflammation, males exhibit worse disease progression than females, which is manifested as worse physical appearance and higher weight loss. However, no measurable sex differences were observed in persistent inflammation-induced bowel pathology, stool consistency or fecal blood. Overall, our findings demonstrate sex differences in pain-related behaviors and disease progression in the context of acute and persistent colon inflammation, highlighting the importance of considering sex as a biological variable in future mechanistic studies of visceral pain as well as in the development of diagnostics and therapeutic options for chronic gastrointestinal diseases.

Predicting the development of chronic low back pain (LBP) at the time of an acute episode remains challenging. The Understanding persistent Pain Where it ResiDes (UPWaRD) study aimed to identify neurobiological and psychological risk factors for chronic LBP. Individuals with acute LBP (N=120) participated in a prospective cohort study with six-month follow-up. Candidate predictors were selected from the neurobiological (e.g. sensorimotor cortical excitability assessed by sensory and motor evoked potentials, Brain Derived Neurotrophic Factor genotype), psychological (e.g. depression and anxiety), symptom-related (e.g. LBP history) and demographic domains. Analyses involved multivariable linear regression models with pain intensity or disability degree as continuous variables. Secondary analyses involved a multivariable logistic model with presence of low back pain at six months (thresholding pain intensity and disability degree) as a dichotomous variable. Lower sensory cortex and corticomotor excitability, higher baseline pain intensity, higher depression, stress and pain catastrophizing were the strongest predictors (R2=0.47) of pain intensity at six months. Older age and higher pain catastrophizing were the strongest predictors (R2=0.30) of disability at six months. When LBP outcome was dichotomised, sensory cortex and corticomotor excitability, BDNF genotype, depression and anxiety, LBP history and baseline pain intensity, discriminated between those who did and did not report LBP at six months (c-statistic 0.91). This study identifies novel risk factors for the development of future LBP. Neurobiological risk factors, when added to a multivariable linear regression model, explained a further 15% of the variance in six-month pain intensity.

Nowadays, the success of spinal cord stimulation (SCS) is evaluated separately in patients who have previous experiences with standard SCS and in SCS-naïve patients. Nevertheless, it is yet to be evaluated whether both patient groups are effectively distinct patient groups. Therefore, the aims of this study are twofold: 1) Are there clusters in the data to distinguish between both patient groups? 2) Can we discriminate both patient groups based on routinely collected clinical parameters?

The aim of our study was (I) To compare back muscle oxygenation and perfusion as well as Biering-Sorensen muscle endurance (BSME) test holding times between chronic non-specific low back pain (CNSLBP) patients and asymptomatic controls matched for age, body mass index (BMI), sex and physical activity, and (II) to investigate factors associated with BSME holding times. Muscle perfusion (tHb) and oxygenation (SmO) were measured by near-infrared spectroscopy (NIRS) based oximetry in three back muscles during the BSME. Reliability of tHb and SmO was assessed in a separate sample. BSME holding time and SmO were compared between patients (n = 45) and controls (n = 45) and factors associated with BSME holding time were assessed using multiple linear regression. Reliability for SmO was excellent (ICC = 0.87-0.99). THb showed poor to moderate reliability and was not further used. Groups differed for BSME holding time (P = 0.03), pain intensity (P ≤ 0.0005) and subcutaneous tissue thickness (P = 0.01) but not for NIRS measures. Physical activity and BMI were associated with BSME holding times. Insufficient muscle oxygenation does not seem to be a major factor contributing to CNSLBP. Future investigation should evaluate other determinants of BSME holding times, such as motivation and recruitment of auxiliary muscles.

In rheumatoid arthritis, neck pain can be caused by inflammatory reactions or cervical lesions, but the prevalence and associated factors have not been well studied. This study aimed to investigate the prevalence of neck pain in patients with rheumatoid arthritis and elucidate the related factors.

Clonidine is a presynaptic alpha-2-adrenergic receptor agonist that has been used for many years to treat hypertension and other conditions, including chronic pain. Adverse events associated with systemic use of the drug have limited its application. Topical use of drugs has been gaining interest since the beginning of the century, as it may limit adverse events without loss of analgesic efficacy. Topical clonidine (TC) formulations have been investigated for almost 20 years in clinical trials. This is an update of the original Cochrane Review published in Issue 8, 2015.

Chronic postsurgical pain (CPSP) in children remains an important problem with no effective preventive or therapeutic strategies. Recently, genomic underpinnings explaining additional interindividual risk beyond psychological factors have been proposed.

The aim of this bibliometric research was to identify and analyze the top 100 cited publications in the field of temporomandibular disorders (TMD) in order to guide any professional level with interest in this topic by mapping the current trends in the field of TMD.

After an interpretation trajectory, the Dutch Quality of Healthcare Institute recommended that for five indications, spinal cord stimulation, dorsal root ganglion stimulation, or occipital nerve stimulation, together referred to as neurostimulation, can be considered effective and be reimbursed in the Netherlands. These five indications are the well and largely studied, accepted neurostimulation indications in scientific literature. As an extension of this, all the scientific societies involved in the Netherlands were required to reach a consensus about the diagnosis and treatment of these five formulated indications to describe the place of neurostimulation within the treatment algorithm. This article describes the development process and content of the consensus paper.

Development of chronic pain is related to aberrant neuroimmune signaling. Small extracellular vesicles (sEVs) are 30-150nm size particles of endosomal origin. They play an important role in neuroimmune crosstalk facilitating transfer of biomolecular cargo between cells. Our studies show that sEVs from RAW 264.7 macrophage cells can be therapeutic or prophylactic in mouse model of inflammatory pain. We investigated the mechanistic basis of how sEVs from lipopolysaccharide (LPS) stimulated (Exo+) and unstimulated (Exo-) cells impact primary glial cells, dendritic cells (DCs) and adaptive immune cells such as CD4 T cells. We hypothesize that macrophage derived sEVs can potentiate T cell activation directly, or indirectly by the upregulation of major histocompatibility complex-II (MHC-II) and co-stimulatory molecules on DCs, attenuating pain hypersensitivity. We will also test if sEVs confer protection to glial cells in the context of inflammation.

Pain induces metabolic stress in pain sensing neurons (nociceptors); alleviating this stress represents an avenue for treating pain. Liver kinase B1 (LKB1) is involved in maintaining energy homeostasis and is a key mediator of the cellular response to metabolic stress. If cellular energy modulation and pain relief is LKB1-dependent, then its removal could lead to metabolic imbalance and innocuous stimuli becoming painful (allodynia).

The immune and nervous systems co-evolved to direct and mount coordinated behaviors, reflexes and immune responses to protect the host. In the neuro-immune paradigm sensory nociceptor neurons, located in multiple peripheral ganglia, have been shown to be sensitive to pattern associated molecular patterns (PAMPs). Upon stimulation, these sensory nociceptors release the neurotransmitter calcitonin gene related peptide (CGRP) which acts as a cytokine to assist with the coordination of the innate immune response. However, it remains unclear which PAMPs are sensed by these sensory c-fiber nerves and what specific substances are released in response to the specific PAMPs. Additionally, how long does this stimulation by PAMPs last? These are critical knowledge gaps in our understanding of how sensory neurons shape the innate immune response. To answer these questions, we cultured immortalized F11 dorsal root ganglion (DRG) neurons and exposed them to lipopolysaccharide (LPS 500 ng/mL, Gram-negative PAMP), lipoteichoic acid (LTA 50 μg/mL, Gram-positive PAMP), tumor necrosis factor alpha (TNFα 500 ng/mL, inflammatory cytokine) and capsaicin (1 μM, known C-fiber agonist, serving as a positive control). The exposures to the stimuli lasted for 0.5, 1, 2, 4 or 8 hours. The experiments were run in triplicate on three separate days where a control condition was run on each day for each time point. We measured the release of CGRP with ELISA, known to be released by DRG neurons in response to LPS. We hypothesized that CGRP would be released early on as neural excitation occurs quickly. All conditions and time points were normalized to the average of respective controls for specific time points on respective days. In contrast to our hypothesis, no condition increased CGRP concentration at 0.5 hours. However, at 1-hour LPS, LTA, TNFα and capsaicin increased CGRP release significantly (p<0.05). At 2 hours, LPS and LTA retained their neural stimulation as CGRP was still increased in comparison to controls (P<0.01). Stimulation subsided at 4 and 8 hours as CGRP concentration returned close to control conditions at respective time points. Our data demonstrate that Gram-positive and Gram-negative PAMPs stimulate the release of a known neurotransmitter from sensory nociceptor cells. Additional experiments with fungal PAMPs will be run as well as identifying the complete secrotome of the neuronal culture in response to a variety of PAMPs. These data coincide with the notion that neurons are stimulated early during infection by PAMPs and inflammation directly, as indicated by TNFα stimulation, in order to quickly assist with the innate immune response.

The present study describes our continued efforts in the discovery and characterization of a series of 2-sulfonamidebenzamides as allosteric modulators of MrgX1. MrgX1 has been shown to be an attractive target as a nonopioid receptor for the potential treatment of chronic pain. Working from our original compound, ML382, and utilizing iterative medicinal chemistry, we have identified key halogen substituents that improve MrgX1 potency by ∼8-fold. In addition, we have evaluated the compounds in Tier 1 drug metabolism and pharmacokinetics assays and have identified key compounds that impart improved potency and microsomal stability.

Petasins are the pharmacologically active ingredients of butterbur and of therapeutic benefit in the treatment of migraine and tension headaches. Here, we summarize the pharmacology, safety and clinical efficacy of butterbur in the prevention of migraine attacks and present new data on its mode of action. We review published literature and study reports on the safety and clinical efficacy of the butterbur root extract Petadolex® and report new findings on petasins in dampening nociception by desensitizing calcium-conducting TRP ion channels of primary sensory neurons. Importantly, butterbur diminishes the production of inflammatory mediators by inhibiting activities of cyclooxygenases, lipoxygenases and phospholipase A2 and desensitizes nociception by acting on TRPA1 and TRPPV1 ion channels. It inhibits the release of calcitonin-gene related peptide (CGRP) of meningeal afferents during migraine attacks. We also evaluated the safety of a butterbur root extract in repeated dose studies for up to 6 months. A no-observable-adverse-effect-level at 15-fold of the maximal clinical dose (3 mg/kg/day MCD) was established for rats. At supratherapeutic doses, i.e., 45-90-fold MCD, we observed bile duct hyperplasia, and mechanistic studies revealed regulations of solute carriers to likely account for bile duct proliferations. Additionally, liver function tests were performed in cultures of primary human hepatocytes and did not evidence hepatotoxicity at therapeutic butterbur level and with migraine co-medications. Lastly, in randomized, double-blinded and placebo-controlled trials with Petadolex® migraine attack frequency was reduced significantly at 150 mg/day, and no relevant abnormal liver function was reported. Together, butterbur is effective in the prevention of migraine attacks by blocking CGRP signaling.

Because pharmacological therapies may play an important role in managing musculoskeletal pain, the appropriate use of medicines for common conditions like Low Back Pain (LBP) is critical. New evidence on the effects and safety of paracetamol, non-steroidal anti-inflammatory drugs (NSAIDs), opioid analgesics, muscle relaxants, antibiotics, and antidepressants for LBP warrants an updated overview for musculoskeletal clinicians on this topic.

Enhancer of zeste homolog 2 (EZH2) has been noted to contribute to the pathogenesis of autoimmune diseases. This study sought to investigate the mechanism of EZH2 in osteoclast (OCL) and osteoblast (OBL) differentiation (OCLD/OBLD) and bone destruction in RA. The animal model of collagen-induced arthritis (CIA) was established, followed by arthritis index (AI) scoring and histological staining, and measurements of inflammatory cytokines levels. The number of OCLs was detected via Tartrate-resistant acid phosphatase (TRAP) staining, and levels of OBL markers were determined by Western blot analysis. Trimethylated histone H3 at lysine 27 (H3K27me3) expression and its enrichment in the Ndrg2 promoter were detected. Collaborative experiments were performed with GSK-J1 or sh-Ndrg2 in CIA mice with EZH2 knockdown. EZH2 was upregulated while Ndrg2 was downregulated in knee joint tissues of CIA mice. Silencing EZH2 reduced AI scores, pathological injury of the knee joint, levels of inflammatory cytokines, and TRAP-positive cells, and increased protein levels of RUNX2 and BMP2. EZH2 promoted H3K27me3 level in the Ndrg2 promoter to inhibit Ndrg2 transcription. H3K27me3 upregulation or Ndrg2 downregulation reversed the role of silencing EZH2 in bone destruction. Overall, EZH2 repressed OBLD and promoted OCLD to aggravate bone destruction in CIA mice through H3K27me3/Ndrg2.

Atopic dermatitis is a chronic inflammatory skin disease. Patients with atopic dermatitis experience inflammatory lesions associated with intense itch and pain, which lead to sleep disturbance and poor mental health and quality of life. We review the molecular mechanisms underlying itch and pain symptoms in atopic dermatitis and discuss the current clinical development of treatments for moderate-to-severe atopic dermatitis. The molecular pathology of atopic dermatitis includes aberrant immune activation involving significant cross-talk among the skin and immune and neuronal cells. Exogenous and endogenous triggers modulate stimulation of mediators including cytokine/chemokine expression/release by the skin and immune cells, which causes inflammation, skin barrier disruption, activation and growth of sensory neurons, itch and pain. These complex interactions among cell types are mediated primarily by cytokines, but also involve chemokines, neurotransmitters, lipids, proteases, antimicrobial peptides, agonists of ion channels or various G protein-coupled receptors. Patients with atopic dermatitis have a cytokine profile characterised by abnormal levels of interleukins 4, 12, 13, 18, 22, 31 and 33; thymic stromal lymphopoietin; and interferon gamma. Cytokine receptors mainly signal through the Janus kinase/signal transducer and activator of transcription pathway. Among emerging novel therapeutics, several Janus kinase inhibitors are being developed for topical or systemic treatment of moderate-to-severe atopic dermatitis because of their potential to modulate cytokine expression and release. Janus kinase inhibitors lead to changes in gene expression that have favourable effects on local and systemic cytokine release, and probably other mediators, thus successfully modulating molecular mechanisms responsible for itch and pain in atopic dermatitis.

Developing effective strategies to manage perioperative pain remains a focus of cleft care. The present study's purpose was to systematically review perioperative pain control strategies for cleft lip and palate repair.

We predicted that chronic pain patients have a more negative stress mindset and a lower level of social identification than people without chronic pain and that this, in turn, influences well-being through less adaptive coping. 1240 participants (465 chronic pain patients; 775 people in the control group) completed a cross-sectional online-survey. Chronic pain patients had a more negative stress mindset and a lower level of social identification than people without chronic pain. However, a positive stress mindset was linked to better well-being and fewer depressive symptoms, through the use of the adaptive coping behaviors positive reframing and active coping. A higher level of social identification did not impact well-being or depression through the use of instrumental and emotional support coping, but through the more frequent use of positive reframing and active coping. For chronic pain therapy, we propose including modules that foster social identification and a positive stress mindset.

Excessive pelvic floor muscle activity has been suggested as a source of pain in chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS). Our objective was to determine whether men with CP/CPPS have changes in neural drive that impair their ability to relax pelvic floor muscles.

Low back pain is the most common health problem with a prevalence of over 80% worldwide and an estimated annual cost of $100 billion in the United States. Intervertebral disc degeneration accounts for a major cause of low back pain. However, there is still a lack of safe and effective treatment to tackle this devastating condition. In this study, we synthesized four functionalized trimetallic nitride endohedral metallofullerenes (carboxyl-f-ScN@C, carboxyl-f-GdN@C, amino-f-ScN@C, and amino-f-GdN@C) and characterized them with X-ray photoelectron spectroscopy, matrix-assisted laser desorption/ionization-time of flight mass spectrometry, and UV-vis. Via electron paramagnetic resonance, all four metallofullerene derivatives possessed dose-dependent radical scavenging capabilities (hydroxyl radicals and superoxide anions), with the most promising radical scavenging properties shown in the amine functionalized C metallofullerenes. Both amino-f-ScN@C and amino-f-GdN@C at 1 μM significantly reduced lipopolysaccharide induced reactive oxygen species production and mRNA expressions of pro-inflammatory mediators (, , , and ) in macrophages without apparent cytotoxicity through regulating activity of p38 MAPK, p65, and nuclear translocation of NF-κB. Furthermore, in an established mouse model of lumbar radiculopathy, amino-f-ScN@C and amino-f-GdN@C effectively alleviated ipsilateral mechanical hyperalgesia for up to 2 weeks. In dorsal root ganglia explant culture, we also showed that amino-f-ScN@C and amino-f-GdN@C ameliorated TNF-α elicited neuroinflammation. In summary, we presented results for a potent radical scavenging, anti-inflammatory and analgesic nanoparticle, amino-functionalized eighty-carbon metallofullerenes and . Our study provides important assets for developing pleiotropic treatment strategies to tackle the inflammation, a significant pathological hallmark in the intervertebral disc degeneration and associated pain.

Atopic dermatitis (AD) is a chronic, heterogenous, inflammatory skin disorder associated with a high skin-related health burden, typically starting in childhood and often persisting into adulthood. AD is characterized by a wide range of clinical phenotypes, reflecting multiple underlying pathophysiological mechanisms and interactions between genetics, immune system dysregulation, and environmental factors. In this review, we describe the diverse cellular and molecular mechanisms involved in AD, including the critical role of T cell-driven inflammation, primarily via T helper (Th) 2- and Th17-derived cytokines, many of which are mediated by the Janus kinase (JAK) signaling pathway. These local inflammatory processes interact with sensory neuronal pathways, contributing to the clinical manifestations of AD, including itch, pain, and sleep disturbance. The recent elucidation of the molecular pathways involved in AD has allowed treatment strategies to evolve from broad-acting systemic immunosuppressive therapies to more targeted agents, including JAK inhibitors and cytokine-specific biologic agents. Evidence from the clinical development of these targeted therapies has reinforced and expanded our understanding of the pathophysiological mechanisms underlying AD and holds promise for individualized treatment strategies tailored to specific AD subtypes.

Repetitive transcranial magnetic stimulation (rTMS) is a non-invasive brain stimulation technique which is now being used in psychiatry clinics across the world as a therapeutic tool for a variety of neural-circuit based disorders (e.g., major depression, obsessive compulsive disorder, substance use disorders, post-traumatic stress disorder, headache, pain). The higher volume of use and publication of multiple large-scale clinical trials has provided researchers with a unique opportunity to retrospectively evaluate factors influencing TMS treatment responses in large samples of patients. While many studies have focused on TMS protocol parameters as moderators of treatment efficacy, sex/gender is another critical, often overlooked factor influencing TMS treatment outcome. Women, especially during periods of high estradiol, appear to be particularly sensitive to the therapeutic effects of rTMS. This manuscript makes a case for three potential biological explanations for these findings. Drawing on literature from cranio-facial anatomy, neuroimaging, and neuroendocrine fields, we posit that observed increases in response rates of women in clinical rTMS trials may be related to: (1) Closer proximity of the brain to the scalp at the prefrontal cortex, leading to larger TMS induced electric fields especially at the medial prefrontal cortex, (2) Greater gray matter density and gyrification in the prefrontal cortex, and (3) High levels of estradiol which facilitate cortical excitability. These biological explanations are empirical ideas which have been evaluated in laboratory studies and lend themselves to prospective evaluation in multisite clinical rTMS trials. The existing literature on this topic and these three potential biological explanations all indicate that the TMS field should routinely evaluate sex/gender (and associated biological metrics like scalp-to-cortex distance, gray matter density, estradiol/progesterone levels) as a factor that may influence treatment outcome.

The cholecystokinin receptor system, specifically cholecystokinin 2 receptor (CCK2R) is a historic target for pain management that has shown limited success. However, new approaches to target CCK2R have incited fresh enthusiasm for this target. In this mini-review, we discuss what is known about CCK2R in peripheral and central circuits under naïve physiological conditions and under conditions of chronic pain, the interactions of CCK2Rs with opioids and briefly, recent efforts to develop new treatments targeting CCK2R for chronic pain.

Musculoskeletal pain is a condition that characterises several diseases and represents a constantly growing issue with enormous socio-economic burdens, highlighting the importance of developing treatment algorithms appropriate to the patient's needs and effective management strategies. Indeed, the algic condition must be assessed and treated independently of the underlying pathological process since it has an extremely negative impact on the emotional and psychic aspects of the individual, leading to isolation and depression. A full understanding of the pathophysiological mechanisms involved in nociceptive stimulation and central sensitization is an important step in improving approaches to musculoskeletal pain. In this context, the bidirectional relationship between immune cells and neurons involved in nociception could represent a key point in the understanding of these mechanisms. Therefore, we provide an updated overview of the magnitude of the musculoskeletal pain problem, in terms of prevalence and costs, and summarise the role of the most important molecular players involved in the development and maintenance of pain. Finally, based on the pathophysiological mechanisms, we propose a model, called the "musculoskeletal pain cycle", which could be a useful tool to counteract resignation to the algic condition and provide a starting point for developing a treatment algorithm for the patient with musculoskeletal pain.

The cytohesin proteins, consisting of four closely related members (cytohesins-1, -2, -3, and -4), are a subfamily of the Sec7 domain-containing guanine nucleotide exchange factors for ADP ribosylation factors (Arfs), which are critical regulators of membrane trafficking and actin cytoskeleton remodeling. Recent advances in molecular biological techniques and the development of a specific pharmacological inhibitor for cytohesins, SecinH3, have revealed the functional involvement of the cytohesin-Arf pathway in diverse neuronal functions from the formation of axons and dendrites, axonal pathfinding, and synaptic vesicle recycling, to pathophysiological processes including chronic pain and neurotoxicity induced by proteins related to neurodegenerative disorders, such as amyotrophic lateral sclerosis and Alzheimer's disease. Here, we review the physiological and pathological roles of the cytohesin-Arf pathway in neurons and discuss the future directions of this research field.

Recent scientific evidence suggests that chronic pain phenotypes are reflected in metabolomic changes. However, problems associated with chronic pain, such as sleep disorders or obesity, may complicate the metabolome pattern. Such a complex phenotype was investigated to identify common metabolomics markers at the interface of persistent pain, sleep, and obesity in 71 men and 122 women undergoing tertiary pain care. They were examined for patterns in d = 97 metabolomic markers that segregated patients with a relatively benign pain phenotype (low and little bothersome pain) from those with more severe clinical symptoms (high pain intensity, more bothersome pain, and co-occurring problems such as sleep disturbance). Two independent lines of data analysis were pursued. First, a data-driven supervised machine learning-based approach was used to identify the most informative metabolic markers for complex phenotype assignment. This pointed primarily at adenosine monophosphate (AMP), asparagine, deoxycytidine, glucuronic acid, and propionylcarnitine, and secondarily at cysteine and nicotinamide adenine dinucleotide (NAD) as informative for assigning patients to clinical pain phenotypes. After this, a hypothesis-driven analysis of metabolic pathways was performed, including sleep and obesity. In both the first and second line of analysis, three metabolic markers (NAD, AMP, and cysteine) were found to be relevant, including metabolic pathway analysis in obesity, associated with changes in amino acid metabolism, and sleep problems, associated with downregulated methionine metabolism. Taken together, present findings provide evidence that metabolomic changes associated with co-occurring problems may play a role in the development of severe pain. Co-occurring problems may influence each other at the metabolomic level. Because the methionine and glutathione metabolic pathways are physiologically linked, sleep problems appear to be associated with the first metabolic pathway, whereas obesity may be associated with the second.

Owing to the rapid aging of society, the numbers of patients with joint disease continue to increase. Accordingly, a large number of patients require appropriate treatment for osteoarthritis (OA), the most frequent bone and joint disease. Thought to be caused by the degeneration and destruction of articular cartilage following persistent and excessive mechanical stimulation of the joints, OA can significantly impair patient quality of life with symptoms such as knee pain, lower limb muscle weakness, or difficulty walking. Because articular cartilage has a low self-repair ability and an extremely low proliferative capacity, healing of damaged articular cartilage has not been achieved to date. The current pharmaceutical treatment of OA is limited to the slight alleviation of symptoms (e.g., local injection of hyaluronic acid or non-steroidal anti-inflammatory drugs); hence, the development of effective drugs and regenerative therapies for OA is highly desirable. This review article summarizes findings indicating that proteoglycan 4 ()/lubricin, which is specifically expressed in the superficial zone of articular cartilage and synovium, functions in a protective manner against OA, and covers the transcriptional regulation of in articular chondrocytes. We also focused on growth differentiation factor 5 (, which is specifically expressed on the surface layer of articular cartilage, particularly in the developmental stage, describing its regulatory mechanisms and functions in joint formation and OA pathogenesis. Because several genetic studies in humans and mice indicate the involvement of these genes in the maintenance of articular cartilage homeostasis and the presentation of OA, molecular targeting of and is expected to provide new insights into the aetiology, pathogenesis, and potential treatment of OA.

Joint pain is the hallmark symptom of osteoarthritis (OA) and the main reason for patients to seek medical assistance. OA pain greatly contributes to functional limitations of joints and reduced quality of life. Although several pain-relieving medications are available for OA treatment, the current intervention strategy for OA pain cannot provide satisfactory pain relief, and the chronic use of the drugs for pain management is often associated with significant side effects and toxicities. These observations suggest that the mechanisms of OA-related pain remain undefined. The current review mainly focuses on the characteristics and mechanisms of OA pain. We evaluate pathways associated with OA pain, such as nerve growth factor (NGF)/tropomyosin receptor kinase A (TrkA), calcitonin gene-related peptide (CGRP), C-C motif chemokine ligands 2 (CCL2)/chemokine receptor 2 (CCR2) and tumor necrosis factor alpha (TNF-α), interleukin-1beta (IL-1β), the NOD-like receptor (NLR) family, pyrin domain-containing protein 3 (NLRP3) inflammasome, and the Wnt/β-catenin signaling pathway. In addition, animal models currently used for OA pain studies and emerging preclinical studies are discussed. Understanding the multifactorial components contributing to OA pain could provide novel insights into the development of more specific and effective drugs for OA pain management.

Neuromodulation for pain has been successfully applied for decades, in that the goals and expectations that patients aim to achieve are clearly described. Nevertheless, the point of view of health care providers is less clear. Therefore, this study aimed to explore the goals, expectations, and definition of success for neuromodulation for pain according to health care providers.

Phospholipase C β (PLCβ) plays an important role in cardiovascular diseases and opioid analgesia. PLCβ catalyzes the hydrolysis of the inner membrane lipid phosphatidylinositol-4,5-bisphosphate (PIP ) to inositol-1,4,5-triphosphate (IP ) and diacylglycerol (DAG). IP and DAG are crucial secondary messengers that activate multiple signaling pathways and modulate gene expression to control responses to extracellular signals. PLCβ is a downstream effector of G-protein coupled receptors (GPCRs) and is activated by both the Gα and Gβγ subunits. Activation by Gα requires a unique 400 amino acid C-terminal region of the lipase, which is subdivided into the proximal and distal C-terminal domains (CTDs). These domains are required for allosteric activation by Gα and for membrane binding. Our lab and others have reported that PLCβ is more flexible in solution, as compared to crystal structures of the protein. In small angle X-ray scattering (SAXS) experiments, the solution structure of PLCβ had additional density that cannot be accounted by the crystal structure. Additionally, crosslinking the PH and EF hand domains decreased this density and the maximum particle diameter. We propose that this additional density corresponds to an open conformation, wherein the PH and EF hand domains are extended from the core of the lipase, and that this conformation of PLCβ represents an autoinhibited state. To test this hypothesis, we mutated residues in PLCβ3 at the interface between the PH and EF hand domains to disrupt their interaction, and then measured changes in PLCβ basal activity and Gβγ-stimulated activity. These mutations had no significant impact on basal activity, however in many of these mutants, there was a decrease in apparent Gβγ activation. Since these mutations should stabilize an open conformation of PLCβ, this suggests the open conformation has less ability to bind to or be activated by Gβγ. We are currently working to solve the structure of PLCβ3 in solution using single particle cryo-electron microscopy (cryo-EM), which will allow us to determine a solution structure of PLCβ to a higher resolution than SAXS studies. We hypothesize that PLCβ3 will exist in the open, autoinhibited conformation, and will also shed light on possible allosteric interactions between the distal CTD and the core.

Chronic visceral pain (CVP) is a prevalent and debilitating syndrome with limited treatments. Guanylyl cyclase C (GUCY2C) is the receptor for uroguanylin (GUCA2B) in small intestine and guanylin (GUCA2A) in colorectum. This hormone-receptor axis produces cyclic (c)GMP accumulation, inducing intestinal fluid secretion. This forms the basis for use of GUCY2C agonists linaclotide and plecanatide to treat constipation-type irritable bowel syndrome (IBS-C) and chronic idiopathic constipation (CIC). Unexpectedly, GUCY2C agonists relieve CVP in these patients, and in mouse models of visceral pain. Interestingly, these patients are deficient in uroguanylin, suggesting that constipation and CVP may reflect hormone insufficiency silencing GUCY2C. Indeed, eliminating GUCY2C in mice (GUCY2C ) produced CVP, evoked by cyclic rectal distension, quantified by the abdominal withdrawal reflex and by phospho-ERK signaling in the spinal cord dorsal horn. CVP severity in GUCY2C mice recapitulated TNBS-induced inflammatory bowel disease in wild type (GUCY2 ) mice. Oral linaclotide relieved TNBS-induced CVP in wild type mice, but was without effect on CVP in GUCY2C mice. The mechanistic basis of GUCY2C-dependent visceral analgesia remains obscure. While GUCY2C is expressed by all epithelial cells in intestine, a GUCY2C promoter-driven GFP reporter revealed a novel rare population of cells enriched in GUCY2C mRNA, protein, and activity. GUCY2C cells, concentrated in duodenum but rare in rectum, morphologically resemble enteroendocrine cells with a basal neuropod potentially synapsing on visceral afferents in the lamina propria, offering a cellular substrate for GUCY2C visceral nociceptive signaling. RNAseq analysis revealed that GUCY2C neuropod cells were deficient in gene products canonically associated with GUCY2C-driven secretion, including GUCA2A, GUCA2B, CFTR and NHE3. Rather, these cells were enriched in gene sets characteristic of neurons. Importantly, dorsal root ganglia (DRG) cells formed functional connections with GUCY2C neuropod cells in co-culture. Thus, DRG cells with GUCY2C neuropod cells alone (GUCA2B-deficient, GUCY2C silenced) were hyperexcitable following current injection, with a reduced rheobase and repetitive action potentials (APs). In contrast, adding linaclotide (hormone replete, GUCY2C activated) silenced DRG neuron excitability, raising the rheobase and eliminating repetitive APs. DRG neuron excitability was not affected by linaclotide in co-cultures with neuropod cells from GUCY2C mice. Moreover, the effects of linaclotide on DRG neuron excitability was not recapitulated by extracellular cGMP. These observations suggest that GUCY2C neuropod cells synapse with DRG visceral afferents and modulate their excitability. They support a model in which GUCA2B sufficiency activates GUCY2C to suppress DRG neuron excitability, while GUCA2B insufficiency silences GUCY2C to produce DRG hyperexcitability and CVP. Finally, they suggest that linaclotide relieves CVP by stimulating GUCY2C neuropod cells to inhibit DRG excitability and nociceptive signaling.

Chronic pain is a debilitating condition leading to impaired quality of life but has few efficacious therapeutic options. The use of opioids to treat chronic pain is associated with well-known drawbacks including drug dependence and addiction. The development of opioid alternatives to treat chronic pain is an urgent, yet unmet, need. Here we show the therapeutic potential of GPR171, a G-Protein Coupled Receptor that was recently identified to regulate morphine antinociception. Previously shown that systemic administration of the GPR171 agonist, MS15203, enhances morphine antinociception in acute pain tests in mice. Here, we show that once-daily systemic administration of MS15203 (10 mg/kg, i.p.) over the course of 1 week improved chronic pain outcomes in two different mouse pain models. Chemotherapy-induced peripheral neuropathy (CIPN) was induced by injecting Paclitaxel (16 mg/kg cumulative) and inflammatory pain was induced by injecting Complete Freund's Adjuvant (CFA) under the epidermis into the plantar surface of both hind paws (20 µl/paw). MS15203 improved mechanical allodynia caused by CIPN and reduced thermal hypersensitivity caused by CFA-induced inflammatory pain. The reduction of chronic pain duration was observed only in male mice, but not in female mice, indicating a sex-dependent effect at this particular dose of GPR171 agonist. Analysis of GPR171 protein levels in the midbrain Periaqueductal Gray showed that neuropathic pain decreased GPR171 receptor levels in males, but treatment by MS15203 rescued this decrease. Taken together, our findings show that GPR171 activity exhibits sexual dimorphism and can regulate multiple modalities of chronic pain.

Recent evidence implicates the gut microbiome in peripheral hypersensitivity in chronic opioid use models, and in chemotherapeutic-induced hypersensitivity in mice. An important constituent of the commensal microbiome are bacterial species that ferment fibers through complex enzymatic pathways and produce short chain fatty acids, acetate, propionate, and butyrate. Butyrate is known to improve the integrity of the epithelium and enhance antimicrobial peptides thus preventing colonization by pathogenic bacteria, as well as having an established role in reducing inflammation through the inhibition of histone deacetylase. Based on this, we hypothesized that sodium butyrate can relieve peripheral hypersensitivity as well as reduce primary nociceptor hyperexcitability in experimental models of peripheral hypersensitivity. We used both paclitaxel (PAC) and morphine (MOR) animal models, which were organized into the following treatment groups: PAC (8mg/kg i.p q.d, total 4 injections) ± Sodium Butyrate (10mg/kg i.p b.i.d), MOR (escalating from 20mg/kg i.p b.i.d on day 1 to 80mg/kg i.p b.i.d on day 4) ± Sodium Butyrate (10mg/kg i.p b.i.d). PAC animals were assessed for peripheral cold hypersensitivity using an acetone evaporation assay. MOR-treated animals were assayed using a hot-plate test for opioid-induced hyperalgesia. Primary nociceptors from L4-S1 dorsal root ganglia were collected from these mice for whole-cell patch clamp electrophysiological recordings to assess for enhanced excitability. PAC-treated mice developed significant cold hypersensitivity 7 days post PAC, when compared with vehicle (average time engaging stimulated paw 2.0s vs 8.6s respectively). Butyrate ameliorated this paclitaxel-induced hypersensitivity (average time reduced to 2.5s). Similarly, MOR induced thermal hypersensitivity (Hot-plate latency of 14.8s vs 28.16s saline), which was also reversed by sodium butyrate (Hot-plate latency of 24.84s). Whole-cell patch clamp recordings revealed that PAC and MOR-treated neurons fired a greater number of regenerating action potentials compared to respective controls (PAC: 4 vs 2; MOR: 3.8 vs 2.1), indicating enhanced excitability. In-vivo butyrate treatment attenuated this enhanced excitability. Hysteresis plots of hyperexcitable cells revealed a depolarizing shift in the membrane potential of regenerating action potentials. Sodium butyrate treatment recovered this shift in membrane potential within the repetitive action potentials. Therefore, similar to the in-vivo peripheral hypersensitivity, butyrate reversed enhanced excitability of PAC and MOR-treated DRG neurons. These findings demonstrate that the short chain fatty acid, butyrate, a major metabolite of the gut microbiome plays an important role in preventing the development of drug-induced peripheral hypersensitivity.

Chronic pain syndrome is a heterogeneous group of diseases characterized by several pathological mechanisms. One in five adults in Europe may experience chronic pain. In addition to the individual burden, chronic pain has a significant societal impact because of work and school absences, loss of work, early retirement, and high social and healthcare costs. Several anti-inflammatory treatments are available for patients with inflammatory or autoimmune diseases to control their symptoms, including pain. However, patients with degenerative chronic pain conditions, some with 10-fold or more elevated incidence relative to these manageable diseases, have few long-term pharmacological treatment options, limited mainly to non-steroidal anti-inflammatory drugs or opioids. For this review, we performed multiple PubMed searches using keywords such as "pain," "neurogenic inflammation," "NGF," "substance P," "nociception," "BDNF," "inflammation," "CGRP," "osteoarthritis," and "migraine." Many treatments, most with limited scientific evidence of efficacy, are available for the management of chronic pain through a trial-and-error approach. Although basic science and pre-clinical pain research have elucidated many biomolecular mechanisms of pain and identified promising novel targets, little of this work has translated into better clinical management of these conditions. This state-of-the-art review summarizes concepts of chronic pain syndromes and describes potential novel treatment strategies.

Clinical studies on neuromodulation intervention for trigeminal neuralgia have not yet shown promising results. This might be due to the fact that the pathophysiology of chronic trigeminal neuropathy is not yet fully understood. Chronic trigeminal neuropathy includes trigeminal autonomic neuropathy, painful trigeminal neuropathy, and persistent idiopathic facial pain. This disorder is caused by complex abnormalities in the pain processing system, which is comprised of the affective, emotional, and sensory components, rather than mere abnormal sensation. Therefore, integrative understanding of the pain system is necessary for appropriate neuromodulation of chronic trigeminal neuropathy. The possible neuromodulation targets that participate in complex pain processing are as follows: the ventral posterior medial, periaqueductal gray, motor cortex, nucleus accumbens, subthalamic nucleus, globus pallidus internus, anterior cingulate cortex, hypothalamus, sphenopalatine ganglion, and occipital nerve. In conclusion, neuromodulation interventions for trigeminal neuralgia is yet to be elucidated; future advancements in this area are required.

The negative emotions caused by persistent pain, called affective pain, are known to seriously affect human physical and mental health. The anterior cingulate cortex (ACC), especially the rostral ACC (rACC) plays a key role in the development of this affective pain. N-methyl-D-aspartate (NMDA) receptors, which are widely distributed in the ACC, are involved in the regulation of emotional behavior. It is well known that activation of opioid receptors can relieve pain, but whether it can alleviate affective pain is not clear. In the present study, conditioned place avoidance (CPA) responses induced by complete Freund's adjuvant (CFA) were used to represent the affective pain of place aversion. The behavioral measurements were synchronously combined with multichannel electrophysiological recordings of the discharge frequency of rACC pyramidal neurons to explore whether affective pain could be alleviated by the synthetic opioid [D-Ala2, D-Leu5]-Enkefalin (DADLE), an agonist of δ-opioid receptors. To further investigate this treatment as a mechanism for the relief of affective pain in CFA-treated animals, we used whole-cell patch recordings in slice preparations of the rACC region to determine the dose-dependent effects of DADLE on NMDA receptor-mediated currents. Then, western blot was used to determine levels of phosphorylated NMDA receptor subunits GluN1, GluN2 and GluN3 as affected by the δ-opioid receptor activation. The results showed that activation of δ-opioid receptors down-regulates the phosphorylation of NMDA receptor subunits, thereby inhibiting NMDA currents, decreasing the discharge frequency of rACC pyramidal neurons, and reversing the CPA response. Thus, δ-opioid receptor activation in the rACC region can alleviate affective pain.

Neurogenic inflammation and central sensitization play a role in chronic prostatitis/chronic pelvic pain syndrome. We explore the molecular effects of low-intensity shock wave therapy (Li-ESWT) on central sensitization in a capsaicin-induced prostatitis rat model. Male Sprague-Dawley rats underwent intraprostatic capsaicin (10 mM, 0.1 cm) injections. After injection, the prostate received Li-ESWT twice, one day apart. The L6 dorsal root ganglion (DRG)/spinal cord was harvested for histology and Western blotting on days 3 and 7. The brain blood oxygenation level-dependent (BOLD) functional images were evaluated using 9.4 T fMRI before the Li-ESWT and one day after. Intraprostatic capsaicin injection induced increased NGF-, BDNF-, and COX-2-positive neurons in the L6 DRG and increased COX-2, NGF, BDNF, receptor Trk-A, and TRPV1 protein expression in the L6 DRG and the dorsal horn of the L6 spinal cord, whose effects were significantly downregulated after Li-ESWT on the prostate. Intraprostatic capsaicin injection increased activity of BOLD fMRI responses in brain regions associated with pain-related responses, such as the caudate putamen, periaqueductal gray, and thalamus, whose BOLD signals were reduced after Li-ESWT. These findings suggest a potential mechanism of Li-ESWT on modulation of peripheral and central sensitization for treating CP/CPPS.

Low back pain (LBP) is a physiologically complex and highly disabling condition with poorly understood pathophysiology. Glial reactivity has been reported in patients with chronic LBP and astrocyte reactivity has been suggested as a potential contributor to LBP chronicity. Spinal mobilization (SM) is a non-pharmacological approach with mild to moderate efficacy in treating LBP but physiological mechanisms responsible are unknown.

Opioids are commonly prescribed for the treatment of neuropathic pain; however, their high rates of physical dependency and addiction raise concern. Given their adverse side effects, there is a need for new therapeutics that target non-opioid receptors. GPR183 (Epstein-Barr induced gene 2, EBI2) is a G-protein coupled receptor (GPCR) that plays a role in the transduction of neuropathic pain. SAE-14 is a novel molecule that is able to antagonize, or inhibit GPR183; thus, preventing the transmission of pain. To gain a better understanding of which substituents improve the binding between SAE-14 and GPR-183, it is necessary to synthesize several analogs of the molecule. We have developed a structure-activity-relationship for GPR183 antagonism and the results from this gives a better understanding of the functional groups that are necessary for GPR183 antagonism and improve to the compound's potential therapeutic for neuropathic pain treatment.