Pain Conditions Research Articles

Cytokines in cerebrospinal fluid and chronic pain in humans - past, present, and future.

Background That neuroimmune interaction occurs in chronic pain conditions has been established for over a centrury, since the discovery of neurogenic inflammation in the periphery. However, the central aspects of neuroimmune interaction have not been fully appreciated until the late 1900s, when a growing interest in how cytokines in the cerebrospinal fluid might be relevant in chronic pain conditions emerged. Since then, the field has evolved, and nowadays neuroinflammation is considered to be involved in the pathophysiology of chronic pain. Whether or not pain conditions can be called "neuroinflammatory" is a matter of debate. This review summarizes the results from studies investigating cytokines in the CSF in various pain conditions, and critically discusses neuroimmune aspects of pain conditions using previously proposed hallmarks of neuroinflammation as a framework. Summary Fifty-two papers were summarized and their results discretized according to a) the level of the measured cytokines in patients compared to controls, and b) the correlation between cytokine level and pain intensity. A subdivision based on pain type was also conducted for each of the 52 studies. A total of 49 proteins have been studied in at least 5 studies, 21 of which were upregulated in a majority of studies. IL8 was specifically upregulated in a majority of studies of nociceptive pain conditions. Regarding correlation to pain intensity, there is a scarcity of data but 31 proteins were upregulated and correlated with pain in at least one study. Of these, 24 proteins were negatively correlated with pain, and 7 were positively correlated. None of the most studied cytokines, such as TNF, IL1b, IL6, IL8, CCL2/MCP1, BDNF or bNGF, were consistently correlated to pain. Key messages There is sufficient evidence to say that chronic pain conditions come with an upregulation of several cytokines. However, the majority of correlations to symptomatology seem to be negative, indicating that the cytokines might play a protective role that has not been broadly considered. Calling chronic pain conditions neuroinflammatory seems wrong; instead, a more suitable term for depicting the findings would, perhaps, be to talk about neuroimmune activation.

Mechanisms Underlying Sex Differences in Temporomandibular Disorders and Their Comorbidity with Migraine

Sexual dimorphism in temporomandibular disorders (TMDs) and their comorbidity with migraine are important phenomena observed in clinics. TMDs are the most prevalent orofacial pain conditions with jaw joint and masseter muscle dysfunction. Migraine is the predominant headache commonly associated with TMDs. Women much more often suffer from this orofacial pain than men. However, currently, there is no gender-specific therapy for such pain conditions. Understanding the pathophysiological mechanisms behind sex differences in TMDs as well as their comorbidity with migraines is essential for developing novel approaches for gender-specific treatment of TMDs and related orofacial pain comorbidity. In this review, we summarize recent research progress regarding sex differences in TMDs, focusing on the underlying mechanisms including craniofacial anatomy, hormonal regulation, and roles of opioids, transient receptor potential channels, and endocannabinoid systems. We also discuss the mechanisms of comorbid TMDs and migraine. The information covered in this review will provide mechanistic insights into sex differences in TMDs and their comorbidity with migraine, which could aid in developing effective treatment strategies for the overlapping orofacial pain condition.

Incidence, diagnosis, and management of orofacial pain among new patients receiving tertiary care in Thailand: A 6-year retrospective study comparing before and during the COVID-19 outbreak.

There is insufficient data on orofacial pain related to the COVID-19 outbreak in Thailand. To investigate the incidence, diagnosis and management of orofacial pain among new patients over the last 6 years, before and during the COVID-19 outbreak. Medical records from new patients who first visited Chulalongkorn Dental Hospital between 2017 and 2022 were retrospectively investigated. The sample size was determined, and proportional stratified random sampling was employed to distribute the sample number proportionally across each year. The hospital number of each patient was randomised using online software as a sampling strategy. A data collection form was developed and used to gather information from the digital data system. At the first visit, 770 out of 1359 patients (56.7/100 people, 95% CI: 54.0-59.3) reported orofacial pain defined as acute, chronic and unclassified pain. The most common chief complaints based on the AAOP classification were odontogenic pain (90.00%) and temporomandibular disorders (6.10%). The top three provisional modified ICD-10-TM diagnoses among these patients were pulp diseases (21.95%), impacted teeth (20.65%) and dental caries (9.09%). 81.87% of dental students' provisional diagnoses matched the final diagnoses given by dental specialists. Only 63.38% of orofacial pain patients were completely managed during the COVID-19 pandemic with common procedures being surgical removal, extraction and root canal therapy. Half of Thai dental patients seeking tertiary care at a university dental hospital reported orofacial pain, which was not impacted by the COVID-19 pandemic. In contrast, dysfunction-related problems in the orofacial area significantly increased during the pandemic.

Post-COVID asthenia, sarcopenia and muscle weakness among geriatric patients

Sarcopenia, asthenia, and motor activity restriction are common among geriatric patients in the post-COVID period. The SARS-CoV-2 virus triggers a cytokine storm in the human body and induces a direct viral effect on skeletal muscles. Manifestations of post-acute sequelae of COVID-19 (PASC) can include organ and system dysfunction, asthenia, muscle weakness, dyspnea, chest pain, cognitive impairment, depression, anxiety, and sleep disorders. Hypoxemia, comorbidity, and prolonged inactivity contribute to changes in the structure and functionality of the muscular fibers. One of the recent studies is ALMI-index, which indicates that a decrease in muscle mass of the upper and lower extremities may cause functional limitations in patients with long-COVID conditions. Rehabilitation of patients with post-COVID syndrome involves daily exercise with weights, considering load tolerance; mandatory medication; and nutritional and psychological support.

Opioid prescribing requirements to minimize unused medications after an emergency department visit for acute pain: a prospective cohort study.

Unused opioid prescriptions can be a driver of opioid misuse. Our objective was to determine the optimal quantity of opioids to prescribe to patients with acute pain at emergency department discharge, in order to meet their analgesic needs while limiting the amount of unused opioids. In a prospective, multicentre cohort study, we included consecutive patients aged 18 years and older with an acute pain condition present for less than 2 weeks who were discharged from emergency department with an opioid prescription. Participants completed a pain medication diary for real-time recording of quantity, doses, and names of all analgesics consumed during a 14-day follow-up period. We included 2240 participants, who had a mean age of 51 years; 48% were female. Over 14 days, participants consumed a median of 5 (quartiles, 1-14) morphine 5 mg tablet equivalents, with significant variation across pain conditions (p < 0.001). Most opioid tablets prescribed (63%) were unused. To meet the opioid need of 80% of patients for 2 weeks, we found that those experiencing renal colic or abdominal pain required fewer opioid tablets (8 morphine 5 mg tablet equivalents) than patients who had fractures (24 tablets), back pain (21 tablets), neck pain (17 tablets), or other musculoskeletal pain (16 tablets). Two-thirds of opioid tablets prescribed at emergency department discharge for acute pain were unused, whereas opioid requirements varied significantly based on the cause of acute pain. Smaller, cause-specific opioid prescriptions could provide adequate pain management while reducing the risk of opioid misuse. ClinicalTrials.gov, no. NCT03953534.

Successful treatment of a Himalayan cat with feline orofacial pain syndrome

AbstractFeline orofacial pain syndrome is a neuropathic pain disorder in cats, characterised by oral discomfort and tongue self‐mutilation. The pathogenesis of feline orofacial pain syndrome remains unclear, but trigger factors such as dental disease and environmental stress have been described. Feline orofacial pain syndrome is a diagnosis of exclusion, and suggested treatment includes administration of non‐steroidal anti‐inflammatory agents, opioids and adjuvant drugs for analgesia. This case report describes a 4‐year‐old female Himalayan cat with anorexia, ranula and unilateral lesions of the tongue. Clinical signs ranged from pawing at the mouth to tongue self‐mutilation during severe pain attacks. Although no dental disease was present, a dominant and suppressive partner cat may have had a stressful influence. First‐line treatment with non‐steroidal anti‐inflammatory drugs and opioids could not prevent further pain attacks. Successful treatment was achieved with administration of pregabalin and minimisation of potential stress factors. No clinical signs of pain were observed in a follow‐up period of 2 years.

Genetic Variations in TrkB.T1 Isoform and Their Association with Somatic and Psychological Symptoms in Individuals with IBS

Irritable bowel syndrome (IBS), a disorder of gut-brain interaction, is often comorbid with somatic pain and psychological disorders. Dysregulated signaling of brain-derived neurotrophic factor (BDNF) and its receptor, tropomyosin-related kinase B (TrkB), has been implicated in somatic-psychological symptoms in individuals with IBS. We investigated the association of 10 single nucleotide polymorphisms (SNPs) in the regulatory 3' untranslated region (UTR) of NTRK2 (TrkB) kinase domain-deficient truncated isoform (TrkB.T1) and BDNF Val66Met SNP with somatic and psychological symptoms and quality of life in a cohort from the United States (U.S.) (IBS n=464; healthy controls n=156). We found that the homozygous recessive genotype (G/G) of rs2013566 in individuals with IBS is associated with worsened somatic symptoms, including headache, back pain, joint pain, muscle pain, and somatization as well as diminished sleep quality, energy level and overall quality of life. Validation using United Kingdom BioBank (UKBB) data confirmed the association of rs2013566 with increased likelihood of headache. Several SNPs (rs1627784, rs1624327, rs1147198) showed significant associations with muscle pain in our U.S. cohort. These 4 SNPs are predominantly located in H3K4Me1-enriched regions, suggesting their enhancer and/or transcription regulation potential. Our findings suggest that genetic variation within the 3'UTR region of the TrkB.T1 isoform may contribute to comorbid conditions in individuals with IBS, resulting in a spectrum of somatic and psychological symptoms impacting their quality of life. These findings advance our understanding of the genetic interaction between BDNF/TrkB pathways and somatic-psychological symptoms in IBS, highlighting the importance of further exploring this interaction for potential clinical applications. PerspectiveThis study aims to understand the genetic effects on IBS-related symptoms across somatic, psychological, and quality of life domains, validated by UKBB data. The rs2013566 homozygous recessive genotype correlates with worsened somatic symptoms and reduced quality of life, emphasizing its clinical significance.

Lifespan of Splints in a Sample of German Soldiers Hospitalised with Post-traumatic Stress Disorder (PTSD) in Combination with Sleep Bruxism and Painful Temporomandibular Disorder (TMD).

This cross-sectional longitudinal observational study aimed to clarify the question of whether painful temporomandibular disorders (TMD) in psychiatrically confirmed patients hospitalised for post-traumatic stress disorder (PTSD) therapy after using splint therapy (ST) show long-term therapeutic effects in the case of functional disorders. One hundred fifty-three (153) inpatients (123 male and 20 female soldiers, age 35.8 ± 9.2 years, 26.6 ± 2.2 teeth) with confirmed PTSD (Impact of Event Scale - Revised ≥33), grade 3 to 4 chronic pain according to von Korff's Chronic Pain Scale and the research diagnostic criteria of painful TMD (RDC-TMD) were recorded. All participants received a maxillary occlusal splint that was worn at night. Control check-ups of the therapeutic effect of the splint were conducted for up to 9 years during psychiatric follow-ups. TMD pain worsened in 22 (14.4%) patients within the first 6 weeks and led to the removal of the splint. The pain intensity (PI) at BL was reported to be a mean of VAS 7.7 ± 1.1. Six weeks after ST (n = 131), the average PI was recorded as VAS 2.6 ± 1.3. Based on the last examination date of all subjects, the average PI was recorded as 0.7 ± 0.9. Seventy-two (72) patients used a second stabilisation splint in the maxilla after 14.4 ± 15.7 months, and 38 patients used between 3 and 8 splints during their psychiatric and dental treatment time (33.7 ± 29.8 months). The presented data shows that therapeutic pain reduction remained valid in the long term despite continued PTSD. The lifespan of a splint seems to be dependent on individual factors. Long-term splint therapy appears to be accepted by the majority of patients with PTSD and painful TMD.

Divergent histopathological and molecular patterns in chemically induced interstitial cystitis/bladder pain syndrome rat models

Interstitial cystitis/bladder pain syndrome (IC/BPS) is a complex chronic pain disorder with an elusive etiology and nonspecific symptoms. Although numerous animal models with phenotypes similar to human disease have been established, no available regimen can consistently alleviate clinical symptoms. This dilemma led us to question whether current animal models adequately represent IC/BPS. We compared four commonly used IC/BPS rat models to determine their diverse histopathological and molecular patterns. Female rats were given single treatments with hydrochloric acid (HCL), acetic acid (AA), protamine sulfate plus lipopolysaccharide (PS + LPS), or cyclophosphamide (CYP) to induce IC/BPS. Bladder sections were stained for histopathologic evaluation, and mRNA expression profiles were examined using next-generation sequencing and gene set analyses. Mast cell counts were significantly higher in the HCL and AA groups than in the PS + LPS, CYP, and control groups, but only the AA group showed significant collagen accumulation. The models differed substantially in terms of their gene ontology and Kyoto encyclopedia of genes and genomes pathways. Our observations suggest that none of these rat models fully reflects the complexity of IC/BPS. We recommend that future studies apply and compare multiple models simultaneously to fully replicate the complicated features of IC/BPS.

Association Between Socioeconomic Inequalities in Pain and All-Cause Mortality in the China Health and Retirement Longitudinal Study: Longitudinal Cohort Study.

Few studies focus on the equality of pain, and the relationship between pain and death is inconclusive. Investigating the distribution of pain and potential mortality risks is crucial for ameliorating painful conditions and devising targeted intervention measures. Our study aimed to investigate the association between inequalities in pain and all-cause mortality in China. Longitudinal cohort data from waves 1 and 2 of the China Health and Retirement Longitudinal Study (2011-2013) were used in this study. Pain was self-reported at baseline, and death information was obtained from the 2013 follow-up survey. The concentration index and its decomposition were used to explain the inequality of pain, and the association between pain and death was analyzed with a Cox proportional risk model. A total of 16,747 participants were included, with an average age of 59.57 (SD 9.82) years. The prevalence of pain was 32.54% (8196/16,747). Among participants with pain, the main pain type was moderate pain (1973/5426, 36.36%), and the common pain locations were the waist (3232/16,747, 19.3%), legs (2476/16,747, 14.78%) and head (2250/16,747, 13.44%). We found that the prevalence of pain was concentrated in participants with low economic status (concentration index -0.066, 95% CI -0.078 to -0.054). Educational level (36.49%), location (36.87%), and economic status (25.05%) contributed significantly to the inequality of pain. In addition, Cox regression showed that pain was associated with an increased risk of all-cause mortality (hazard ratio 1.30, 95% CI 1.06-1.61). The prevalence of pain in Chinese adults is concentrated among participants with low economic status, and pain increases the risk of all-cause death. Our results highlight the importance of socioeconomic factors in reducing deaths due to pain inequalities by implementing targeted interventions.

Selection of DNA aptamer for label-free electrochemical aptasensor for the detection of rubella virus

The Rubella virus (RUBV) is a highly contagious pathogen classified within the rubivirus genus, primarily infecting humans and transmitted via airborne routes. RUBV infection generally manifests as a mild illness reminiscent of measles. However, when affecting pregnant women, it can lead to a severe condition known as congenital rubella syndrome (CRS). Rubella infection could be also associated with joint pain, arthritis, and neurological disorders. Determination of Rubella immunity and diagnosis conventionally involve the Hemagglutination Inhibition (HI) test or the Enzyme-Linked Immunosorbent Assay (ELISA). In this study, we describe the selection and characterization of specific aptamers targeting the Rubella virus by using the process of Systematic Evolution of Ligands by EXponantial enrichment (SELEX). The Binding affinity studies have shown that the two aptamers; R-7 and R-5 display the lowest dissociation constants (Kd) of 6.58 nM and 19.05 nM, respectively. Then, R-7 aptamer was modified with a thiol group to enable its immobilization on screen-printed gold electrodes for the Rubella virus aptasensing. The label-free electrochemical detection was achieved using square wave voltammetry (SWV). The designed aptasensor has shown an excellent performance in detecting the Rubella virus within the range of 0.0005 ng/ml to 1000 ng/ml antigen and a limit of detection (LOD) of 0.00015 ng/ml. Selectivity studies were also performed against other viral antigens and serum proteins. Finally, the biosensor applicability was successfully demonstrated in spiked serum samples.

Sodium-glucose transport protein 2 inhibitor use in the management of insulin dysregulation in ponies and horses.

Laminitis is a common and painful condition of the equine foot and approximately 90% of cases are associated with insulin dysregulation (ID) that is a central feature of the common endocrine disorder equine metabolic syndrome (EMS) and occurs in a subset of animals with pituitary pars intermedia dysfunction. Additional features of EMS include obesity, altered circulating concentrations of adipokines (particularly adiponectin and leptin) and hypertriglyceridaemia. Obesity, ID, hypoadiponectinaemia, hyperleptinaemia and an altered plasma lipid profile are also features of human metabolic syndrome (HMS) alongside hyperglycaemia. Sodium-glucose cotransporter 2 inhibitors (SGLT2i) are a novel class of oral hypoglycaemic agents used in combination with lifestyle changes in the management of HMS. SGLT2 receptors are responsible for 90% of the renal glucose reabsorption that occurs in the proximal convoluted tubule. Thus, these drugs increase urinary glucose excretion by suppressing glucose reabsorption from the glomerular filtrate resulting in urinary calorie loss with consequent weight loss and improvements in ID, hyperglycemia, hypoadiponectinaemia and hyperleptinaemia. There are no licenced veterinary drugs available for treating ID and preventing insulin-associated laminitis in horses. Thus, the use of SGLT2i for the control of equine hyperinsulinaemia with the goal of improving recovery from associated active laminitis or preventing future laminitis has recently been advocated. There are a small number of published studies reporting the use of the SGLT2i canagliflozin, ertugliflozin and velagliflozin to aid the management of equine ID. However, the doses used are largely extrapolated from human studies with limited consideration of species-specific variations. In addition, there is limited evaluation of the fundamental differences between ID in horses and humans, particularly the fact that most horses with ID remain hyperinsulinaemic but normoglycaemic such that increased urinary loss of glucose may not explain the beneficial effects of these drugs. Further study of the potential deleterious effects of treatment-associated hypertriglyceridaemia is required together with the effect of SGLT2i therapy on circulating concentrations of adipokines in horses.

Sodium-glucose transport protein 2 inhibitor use in the management of insulin dysregulation in ponies and horses.

Laminitis is a common and painful condition of the equine foot and approximately 90% of cases are associated with insulin dysregulation (ID) that is a central feature of the common endocrine disorder equine metabolic syndrome (EMS) and occurs in a subset of animals with pituitary pars intermedia dysfunction. Additional features of EMS include obesity, altered circulating concentrations of adipokines (particularly adiponectin and leptin) and hypertriglyceridaemia. Obesity, ID, hypoadiponectinaemia, hyperleptinaemia and an altered plasma lipid profile are also features of human metabolic syndrome (HMS) alongside hyperglycaemia. Sodium-glucose cotransporter 2 inhibitors (SGLT2i) are a novel class of oral hypoglycaemic agents used in combination with lifestyle changes in the management of HMS. SGLT2 receptors are responsible for 90% of the renal glucose reabsorption that occurs in the proximal convoluted tubule. Thus, these drugs increase urinary glucose excretion by suppressing glucose reabsorption from the glomerular filtrate resulting in urinary calorie loss with consequent weight loss and improvements in ID, hyperglycemia, hypoadiponectinaemia and hyperleptinaemia. There are no licenced veterinary drugs available for treating ID and preventing insulin-associated laminitis in horses. Thus, the use of SGLT2i for the control of equine hyperinsulinaemia with the goal of improving recovery from associated active laminitis or preventing future laminitis has recently been advocated. There are a small number of published studies reporting the use of the SGLT2i canagliflozin, ertugliflozin and velagliflozin to aid the management of equine ID. However, the doses used are largely extrapolated from human studies with limited consideration of species-specific variations. In addition, there is limited evaluation of the fundamental differences between ID in horses and humans, particularly the fact that most horses with ID remain hyperinsulinaemic but normoglycaemic such that increased urinary loss of glucose may not explain the beneficial effects of these drugs. Further study of the potential deleterious effects of treatment-associated hypertriglyceridaemia is required together with the effect of SGLT2i therapy on circulating concentrations of adipokines in horses.

S1P/S1PR1 signaling is involved in the development of nociceptive pain

BackgroundPain is a complex perception involving unpleasant somatosensory and emotional experiences. However, the underlying mechanisms that mediate its different components remain unclear. Sphingosine-1-phosphate (S1P), a metabolite of sphingomyelin and a potent lipid mediator, initiates signaling via G protein-coupled receptors (S1PRs) on cell surfaces. It serves as a second messenger in cellular processes such as proliferation and apoptosis. Nevertheless, the neuropharmacology of sphingolipid signaling in pain conditions within the central nervous system remains largely unexplored and controversial.MethodsChronic nociceptive pain models were induced in vivo by intraplantar injection of 20 μL complete Freund's adjuvant (CFA) into the left hind paws. We assessed S1P and S1PR1 expression in the spinal cords of CFA model mice. Functional antagonists of S1PR1 or S1PR1-specific siRNA were administered daily following CFA model establishment. Paw withdrawal response frequency (PWF) and paw withdrawal latency (PWL) were measured to evaluate mechanical allodynia and thermal hyperalgesia, respectively. RT-PCR assessed interleukin (IL)-1β, IL-6, and tumor necrosis factor (TNF)-α levels. Western blotting and immunofluorescence were used to analyze glial fibrillary acidic protein (GFAP), ionized calcium-binding adapter molecule (Iba1), STAT3, ERK, and p38 MAPK protein expression.ResultsIn the chronic nociceptive pain model induced by CFA, S1P and S1PR1 expression levels were significantly elevated, leading to activation of spinal cord glial cells. S1PR1 activation also promoted MMP2-mediated cleavage of mature IL-1β. Additionally, S1PR1 activation upregulated phosphorylation of STAT3, ERK, and p38 MAPK in glial cells, profoundly impacting downstream signaling pathways and contributing to chronic nociceptive pain.ConclusionThe S1P/S1PR1 axis plays a pivotal role in the cellular and molecular mechanisms underlying nociceptive pain. This signaling pathway modulates glial cell activation and the expression of pain-related genes (STAT3, ERK, p38 MAPK) and inflammatory factors in the spinal dorsal horn. These findings underscore the potential of targeting the S1P system for developing novel analgesic therapies.

Nucleus accumbens myocyte enhancer factor 2C mediates the maintenance of peripheral nerve injury-induced physiological and behavioral maladaptations.

Preclinical and clinical work has demonstrated altered plasticity and activity in the nucleus accumbens (NAc) under chronic pain states, highlighting critical therapeutic avenues for the management of chronic pain conditions. In this study, we demonstrate that myocyte enhancer factor 2C (MEF2C), a master regulator of neuronal activity and plasticity, is repressed in NAc neurons after prolonged spared nerve injury (SNI). Viral-mediated overexpression of Mef2c in NAc neurons partially ameliorated sensory hypersensitivity and emotional behaviors in mice with SNI, while also altering transcriptional pathways associated with synaptic signaling. Mef2c overexpression also reversed SNI-induced potentiation of phasic dopamine release and neuronal hyperexcitability in the NAc. Transcriptional changes induced by Mef2c overexpression were different than those observed after desipramine treatment, suggesting a mechanism of action different from antidepressants. Overall, we show that interventions in MEF2C-regulated mechanisms in the NAc are sufficient to disrupt the maintenance of chronic pain states, providing potential new treatment avenues for neuropathic pain.

Barriers and facilitators for physical activity in people living with chronic pain: a systematic review and combined analysis.

Chronic pain is a prevalent and complex health issue associated with physical, emotional, and social consequences. Management of pain is multifactorial and challenging; however, physical activity (PA) has consistently been shown to be beneficial. Despite this, PA levels among people with chronic pain are low. This study aimed to identify facilitators and barriers to PA among adults with chronic pain and analyse these using the structure of a validated behaviour change model: the capability, opportunity, and motivation behaviour change model (COM-B). We performed a systematic review of 6 databases and subsequent combined analysis including peer-reviewed primary research published in English up to November 15, 2023. Search terms consisted of 3 components: pain, PA, and facilitators/barriers. Quality appraisal of studies was conducted using appropriate tools. The systematic search yielded 40 eligible studies with a total of 2164 participants. The studies represented various chronic pain conditions, locations, and study designs. The key barriers to engagement in PA were the impact of pain severity, comorbidities, lack of knowledge about PA benefits, and time constraints. Key facilitators were a personalised approach, social support, and awareness of the benefits. The findings were categorised according to the COM-B model, allowing for the identification of modifiable factors. Person-centred approaches, education, and accessible environments were identified as important aspects to consider for successful PA promotion among people with chronic pain. Utilising the factors identified in the COM-B model is crucial for successful future interventions to increasing PA uptake and adherence in this population.

Nucleus accumbens myocyte enhancer factor 2C mediates the maintenance of peripheral nerve injury-induced physiological and behavioral maladaptations.

Preclinical and clinical work has demonstrated altered plasticity and activity in the nucleus accumbens (NAc) under chronic pain states, highlighting critical therapeutic avenues for the management of chronic pain conditions. In this study, we demonstrate that myocyte enhancer factor 2C (MEF2C), a master regulator of neuronal activity and plasticity, is repressed in NAc neurons after prolonged spared nerve injury (SNI). Viral-mediated overexpression of Mef2c in NAc neurons partially ameliorated sensory hypersensitivity and emotional behaviors in mice with SNI, while also altering transcriptional pathways associated with synaptic signaling. Mef2c overexpression also reversed SNI-induced potentiation of phasic dopamine release and neuronal hyperexcitability in the NAc. Transcriptional changes induced by Mef2c overexpression were different than those observed after desipramine treatment, suggesting a mechanism of action different from antidepressants. Overall, we show that interventions in MEF2C-regulated mechanisms in the NAc are sufficient to disrupt the maintenance of chronic pain states, providing potential new treatment avenues for neuropathic pain.

Barriers and facilitators for physical activity in people living with chronic pain: a systematic review and combined analysis.

Chronic pain is a prevalent and complex health issue associated with physical, emotional, and social consequences. Management of pain is multifactorial and challenging; however, physical activity (PA) has consistently been shown to be beneficial. Despite this, PA levels among people with chronic pain are low. This study aimed to identify facilitators and barriers to PA among adults with chronic pain and analyse these using the structure of a validated behaviour change model: the capability, opportunity, and motivation behaviour change model (COM-B). We performed a systematic review of 6 databases and subsequent combined analysis including peer-reviewed primary research published in English up to November 15, 2023. Search terms consisted of 3 components: pain, PA, and facilitators/barriers. Quality appraisal of studies was conducted using appropriate tools. The systematic search yielded 40 eligible studies with a total of 2164 participants. The studies represented various chronic pain conditions, locations, and study designs. The key barriers to engagement in PA were the impact of pain severity, comorbidities, lack of knowledge about PA benefits, and time constraints. Key facilitators were a personalised approach, social support, and awareness of the benefits. The findings were categorised according to the COM-B model, allowing for the identification of modifiable factors. Person-centred approaches, education, and accessible environments were identified as important aspects to consider for successful PA promotion among people with chronic pain. Utilising the factors identified in the COM-B model is crucial for successful future interventions to increasing PA uptake and adherence in this population.

Crisis in the gut: navigating gastrointestinal challenges in Gulf War Illness with bioengineering.

Gulf War Illness (GWI) is characterized by a wide range of symptoms that manifests largely as gastrointestinal symptoms. Among these gastrointestinal symptoms, motility disorders are highly prevalent, presenting as chronic constipation, stomach pain, indigestion, diarrhea, and other conditions that severely impact the quality of life of GWI veterans. However, despite a high prevalence of gastrointestinal impairments among these veterans, most research attention has focused on neurological disturbances. This perspective provides a comprehensive overview of current in vivo research advancements elucidating the underlying mechanisms contributing to gastrointestinal disorders in GWI. Generally, these in vivo and in vitro models propose that neuroinflammation alters gut motility and drives the gastrointestinal symptoms reported in GWI. Additionally, this perspective highlights the potential and challenges of in vitro bioengineering models, which could be a crucial contributor to understanding and treating the pathology of gastrointestinal related-GWI.

Trends in Utilization and Cost of Nonpharmacological Pain Therapies in the United States Under Medicare Part B, 2000-2022.

Background: Many clinical practice guidelines for management of pain disorders now favor first-line use of nonpharmacological therapies (NPT). However, Medicare coverage of NPT is limited. Methods: Using a serial cross-sectional design, we examined temporal trends in the utilization and cost of NPT procedures commonly used to treat pain under Medicare. Results: Utilization and costs for physical therapy increased while those for spinal and osteopathic manipulation declined. Discussion: Future research on NPT under Medicare should focus on equity of patient access and comparative outcomes.