NCBIGene:935261

The study investigates the functional differences between the two alleles of rs678849, a genetic variant in the delta-opioid receptor gene (OPRD1) associated with substance use disorder phenotypes, regional brain volume, addiction risk, and the efficacy of buprenorphine/naloxone in treating opioid use disorder. The research found that the C allele construct had significantly lower luciferase expression than the T allele construct. Proteomic analysis identified XRCC6 as a transcription factor specifically binding the C allele, whereas hnRNP D0 was found to specifically bind the T allele. These differences may explain the psychiatric and neurological phenotype differences predicted by rs678849 genotype.


NCBIGene:395767


PR:000008664


RXCUI:216284

The study aims to identify clinical and genetic factors that increase the risk of developing opioid use disorder (OUD) in individuals using prescription opioids (POs) for pain relief. The researchers are conducting a prospective observational study using an existing biobank that includes whole exome sequencing and array genotyping. The data capture includes self-report surveys measuring addiction severity, depression, anxiety, and nicotine use, as well as clinical, prescription, and brain imaging data extracted from electronic health records.


HP:5200333


MONDO:0012048


MONDO:0011918


PUBCHEM.COMPOUND:126961754

Total hip and knee arthroplasty (THA and TKA)

The study investigates the reasons for preoperative opioid use in patients undergoing total hip and knee arthroplasty (THA and TKA). It was found that patients who used opioids for combined reasons (surgical site pain and pain in other body areas) had greater odds of persistent use at 3 and 6 months postoperatively. This suggests that nonsurgical pain, in part, drives persistent opioid use after surgery. The study emphasizes the need for tailored postoperative opioid weaning plans that consider both pain and non-pain reasons for presurgical opioid use.


HP:0000735

The paper discusses the use of Pragmatic Clinical Trials (PCTs) to address the dual public health crises of chronic pain and opioid misuse, which have been exacerbated by the COVID-19 pandemic. The National Institutes of Health, Department of Defense, and Department of Veterans Affairs have formed an interagency research partnership, the Pain Management Collaboratory, to advance nonpharmacological approaches and integrated models of care for pain management and common co-occurring conditions. The partnership supports 11 large-scale, multisite PCTs in veteran and military health systems.


HP:0000735


MONDO:0100096


EFO:0011014


GO:0140976


CL:1000338


CHEBI:30879

associated with new persistent opioid use after

The study found that among patients not using opioids at the time of surgery, those with a history of opioid use were more likely to continue using opioids 3 months after surgery. This was particularly true for patients with a history of continuous opioid use. Moderate to high alcohol use was also associated with new persistent opioid use and opioid prescription refill 1 month after surgery.


MONDO:0100096

The study explores the impact of the COVID-19 pandemic on veterans with chronic pain who were part of a clinical trial focused on pain management. The pandemic disrupted pain management services, leading to changes in how veterans manage their pain symptoms. However, it also provided opportunities for resilience and personal growth as veterans reflected on their lives and personal goals. The pandemic also highlighted mental health issues among veterans, which should be addressed as part of a comprehensive pain management approach.


NCIT:C165593

The study found that patients who had been exposed to opioids before surgery consumed more opioids after surgery compared to those who had not been exposed. This increase in consumption was dose-dependent, with chronic users reporting the highest consumption. Among those receiving perioperative prescriptions, patients with prior opioid exposure had a higher likelihood of refill, number of refills, and average refill amount. The study suggests that existing guidelines may meet the postoperative needs of most patients with preoperative opioid exposure, but may need to be tailored for patients with chronic use.


RXCUI:1047755


PUBCHEM.COMPOUND:126961754

The study found that new persistent opioid use after benign hysterectomy was associated with several factors. These include younger age, southern geographic location, preoperative psychiatric and pain disorders, more than one perioperative prescription, mood disorder medication use, tobacco smoking, and surgical complications. The study also found that the total morphine milligram equivalent of ≥300 in the first perioperative prescription and dispensing of a first perioperative prescription before the surgery increased the likelihood of persistent use. However, minimally invasive hysterectomy and a more recent surgery year significantly decreased its likelihood.


PUBCHEM.COMPOUND:5288826


MONDO:0002025


HP:0012531


PUBCHEM.COMPOUND:44570765


HP:0032500


NCIT:C35019


NCIT:C60986


EFO:0010702

The study investigates the cause of death among West Virginia Medicaid enrollees discharged from hospitalization due to infective endocarditis (IE), with a focus on those diagnosed with opioid use disorder (OUD). The top three causes of death were accidental drug poisoning, mental and behavioral disorders due to polysubstance use, and cardiovascular diseases. The proportion of deaths among patients discharged after IE-related hospitalization increased seven times from 2016 to 2019 among the OUD deaths, and doubled among the non-OUD deaths. The increase was higher in those with an OUD diagnosis, indicating that OUD significantly impacts survival outcomes among IE patients.


MONDO:0029000


MONDO:0004630

Mental and behavioral disorders due to polysubstance use


MONDO:0004995


MESH:C513575


MONDO:0100096

increases the need for timely treatment in


CHEBI:35482

The study explores the beliefs about opioid risk, protective factors, and behavioral functions of opioid misuse among American Indian youth and young adults living on or near a reservation. The study found that family played a significant role in the initiation of opioid use, but also in treatment and recovery. The study also highlighted the need for upstream prevention methods, including increased employment and after-school activities.


PUBCHEM.COMPOUND:126961754

The study investigated the impact of prenatal opioid exposure on the global brain network connectivity in infants. Using resting-state functional MRI, the researchers found significant differences in the brain network connectivity of infants exposed to opioids prenatally compared to healthy control infants. Four network components were significantly different between the two groups, two of which were associated with maternal psychological factors. The study also found that prenatal opioid exposure was associated with alterations in intra-network graph metrics, including average flow coefficient, clustering coefficient, and transitivity. These network alterations were also associated with maternal comorbidity, particularly mental health.


PUBCHEM.COMPOUND:126961754


EFO:0009095


UBERON:0015838

The study investigates how adolescents manage pain after third molar dental extractions, with a focus on the use of opioid and non-opioid analgesics. The study found that most adolescents and their parents discussed pain management plans that included non-medication options, over-the-counter medications, and opioid medications to be taken as needed. All participants reported receiving an opioid prescription for post-extraction pain management, but most only took it on the day of the extraction and up to 2 days following. The study suggests that providers may have an opportunity to reduce the number of opioids prescribed, and should educate patients and their parents about safe disposal of opioids to mitigate the potential for diversion.


MONDO:0850461

Neonatal opioid withdrawal syndrome (NOWS)

The study investigates the impact of prenatal opioid exposure (POE) on neonatal opioid withdrawal syndrome (NOWS) severity. The researchers used resting-state functional magnetic resonance imaging (rs-fMRI) to assess alterations in thalamic functional connectivity in neonates with POE. The results showed significant alterations in thalamic to cortical functional connectivity in infants with POE compared to healthy infants. These alterations were found to correlate with the severity of NOWS. The study suggests that future research could use thalamocortical resting state functional connectivity to stratify the risk of long-term neurodevelopmental outcomes in infants with POE.


MONDO:0850461


UBERON:0011917


PUBCHEM.COMPOUND:126961754

The study aimed to estimate the prevalence of delayed dispensing of opioid prescriptions from surgeons and dentists, and to evaluate the impact of laws shortening the maximum period between prescription writing and dispensing. The data showed that in 2019, out of 20,858,413 opioid prescriptions, 194,452 (0.9%) had delayed dispensing. The study also found that a law enacted in Minnesota in July 2019, which precluded opioid prescription dispensing more than 30 days after writing, decreased delayed dispensing prevalence by 0.22 percentage points.


RXCUI:1724207

The study reveals a significant increase in infective endocarditis (IE) cases in West Virginia, primarily due to injection drug use. The study found that patients with drug use-associated IE (DU-IE) were younger, had longer hospital stays, and had a higher proportion of methicillin-resistant Staphylococcus aureus (MRSA) isolates, psychiatric disorders, cardiac surgeries, and discharges against medical advice compared to patients with non-DU-IE. Drug use was found to be an independent predictor of the combined outcome of discharge against medical advice/in-hospital mortality.


RXCUI:1724207


MONDO:0000565


NCIT:C146778

The study examined the association and trajectory of perioperative anxiety, pain, and opioid use following common surgical procedures. It was found that anxiety and surgical site pain were highest on the day of surgery and declined in the follow-up period. Patients with anxiety reported higher opioid use and an increase in patient-reported surgical pain compared to those without anxiety. However, anxiety did not significantly mediate the relationship between pain and opioid use. The study concluded that anxiety is an independent risk factor for increased pain and opioid use after surgery.


NCIT:C146778


NCIT:C143869


GO:0001798

The study aimed to develop a clinical tool to predict severe pain during dressing changes in patients with open skin wounds. The study identified three predictors that are most useful for a clinical prediction tool: type of dressing, resting wound pain, and expected pain. Algorithms based on these predictors can be used to predict patients likely to experience severe pain during a dressing change. This tool is important as it can help target patients for preventive pain control strategies.


NCIT:C119218


NCIT:C41333


CHEBI:35482

The study examined the frequency of coprescribing opioids with skeletal muscle relaxants or benzodiazepines after implant-based breast reconstruction. It was found that 86.7% of women who had this procedure filled an opioid prescription perioperatively. Of these, 27.7% filled prescriptions for opioids and benzodiazepines, 14.4% for opioids and skeletal muscle relaxants, and 2.4% for all three. Risk factors for coprescribing opioids and benzodiazepines included use of acellular dermal matrix, immediate reconstruction, and history of anxiety. Women who filled prescriptions for opioids and skeletal muscle relaxants, opioids and benzodiazepines, and opioids with skeletal muscle relaxants and benzodiazepines were significantly more likely to refill opioid prescriptions. The study suggests that coprescribing of opioids with skeletal muscle relaxants may potentiate opioid use after surgery and should be avoided due to the risks of sedation.


MESH:D024744


CHEBI:22720


MESH:D022282


MONDO:0011918


NCBIGene:7442

The study found that pain-sensing neurons, or nociceptors, play a role in regulating intestinal inflammation. In a mouse model of intestinal damage and inflammation, the silencing or removal of TRPV1+ nociceptors led to more severe inflammation and impaired tissue repair processes. This was associated with significant changes in the intestinal microbiota. The presence of Gram+Clostridium spp. in germ-free mice promoted intestinal tissue protection through a nociceptor-dependent pathway. The disruption of nociception resulted in decreased levels of substance P, a protein involved in pain perception. Therapeutic delivery of substance P promoted tissue-protective effects in a microbiota-dependent manner. Dysregulated nociceptor gene expression was also observed in intestinal biopsies from patients with inflammatory bowel diseases.


NCBIGene:7442


NCBITaxon:1485


GO:0052067


UniProtKB:B8Q0B2


NCBIGene:1027731


MONDO:0006680

The study examined the impact of a payment incentive by Blue Cross Blue Shield of Michigan (BCBSM) for opioid-sparing vasectomies on the percentage of patients who filled opioid prescriptions before and after the procedure. The results showed a significant reduction in the percentage of men who filled opioid prescriptions after vasectomy following the implementation of the incentive. There was a 19.9% absolute reduction and 61.0% relative reduction in opioid prescription fills after the incentive was introduced. No significant change was observed in the control group.


PUBCHEM.COMPOUND:126961754

The study discusses the treatment of Neonatal abstinence syndrome (NAS), a condition that infants develop after intrauterine maternal drug exposure. The Finnegan Score is used to monitor infants with opioid exposure, with a score of >8 suggesting exposure. Non-pharmacological approaches are the first line of treatment for all infants, regardless of initial symptoms. However, if symptoms persist despite supportive care, pharmacological treatment is recommended, which can be life-saving in severe cases.


NCBITaxon:1406245


MESH:D054316


MONDO:0009906

Neonatal opioid withdrawal syndrome (NOWS)

The study examined the variation in care for infants with neonatal opioid withdrawal syndrome (NOWS) across different sites. The study found significant variation in maternal-infant characteristics, infant management, and outcomes for infants with NOWS across 30 participating hospitals. The variation included the proportion of infants whose mothers received adequate prenatal care, medication-assisted treatment, and prenatal counseling. There was also variation in the proportion of infants with toxicology screening, receiving pharmacologic therapy, secondary medications, and nonpharmacologic interventions. The mean length of stay and the proportion of infants discharged with their parents also varied across sites. The study concluded that the observed variation makes it unlikely that all infants are receiving efficient and effective care for NOWS.


EFO:0004609


NCIT:C70920


MESH:D000085703


MONDO:0006964


RXCUI:1314626


UBERON:0001913


PUBCHEM.COMPOUND:4763

shortens hospital stay and duration of treatment

The study investigates the effectiveness of phenobarbital and clonidine as secondary medications for neonatal opioid withdrawal syndrome (NOWS) when first-line opioid medications fail. The study found that infants treated with phenobarbital had a shorter hospital stay and shorter duration of morphine treatment compared to those treated with clonidine. However, infants were more likely to be discharged from the hospital on phenobarbital than clonidine. The potential neurodevelopmental consequences of phenobarbital use in infants with NOWS need further investigation.


PUBCHEM.COMPOUND:2803

longer hospital stay and duration of treatment compared to Phenobarbital


PUBCHEM.COMPOUND:4763


EFO:0004609

Neonatal opioid withdrawal syndrome (NOWS) is a risk for newborns whose mothers consumed opioids during pregnancy. Nonpharmacologic treatment is usually the first line of management, with pharmacologic treatment added if necessary. Morphine and methadone are commonly used, but buprenorphine is emerging as a potential treatment option based on its pharmacologic profile and results from initial clinical trials. This report discusses the current state of knowledge and practical considerations regarding the use of buprenorphine for NOWS treatment.


PUBCHEM.COMPOUND:5288826


PUBCHEM.COMPOUND:4095


PUBCHEM.COMPOUND:644073


PUBCHEM.COMPOUND:45103600

The study investigates the effects of the cannabinoid receptor type 1 (CB 1) agonist CB-13 on pain in mice. Acute dosing of CB-13 reduced inflammation-induced pain in a peripheral CB 1-receptor-dependent manner and relieved thermal hyperalgesia. This was achieved by reducing TRPV1 sensitization and neuronal hyperexcitability induced by the inflammatory mediator prostaglandin E 2. However, repeated dosing led to analgesic tolerance and CB 1 receptor dependence, suggesting increased central nervous system (CNS) exposure and unwanted engagement of central CB 1 receptors.


PUBCHEM.COMPOUND:45103600


UBERON:0005061

The study developed an automated pipeline using convolutional neural networks to segment lumbar intervertebral discs and characterize their biochemical composition using voxel-based relaxometry. The method was used to establish local associations with clinical measures of disability, muscle changes, and other symptoms of lower back pain. The segmentation algorithm produced accurate, high-confidence segmentations of the lumbar discs. The imaging-based degenerative grades were strongly negatively correlated with T1ρ and T2, particularly in the nucleus. Stratifying patients by disability grades revealed significant differences in the relaxation maps between minimal/moderate versus severe disability.


MONDO:0001383


HP:0033695


HP:0003419

The study aimed to identify serum biomarkers that correlate with vertebral endplate bone marrow lesions, also known as Modic changes (MC), which are associated with chronic low back pain (cLBP). The researchers found that biomarkers related to the formation and degradation of type III and type IV collagen, which are key molecules in bone marrow fibrosis, correlated with the presence of MC. The bivariable model with the highest diagnostic value for MC in cLBP patients was PRO-C3 + C4M.


PR:000003328


PR:000003388


PR:000019177


NCBIGene:3403788


UBERON:0014386

The study used T2* mapping from ultrashort echo-time (UTE) magnetic resonance imaging (MRI) to evaluate the biochemical composition of the cartilage endplate (CEP) and its correlation with adjacent disc degeneration. The results showed that CEP T2* values were highest centrally and lowest posteriorly. In younger individuals with mild-to-moderate disc degeneration, low CEP T2* values were associated with more severe disc degeneration. However, in older individuals, CEP T2* values did not associate with disc degeneration. The study suggests that deficits in CEP composition, as indicated by low T2* values, associate with more severe disc degeneration during the mild-to-moderate stages.


PUBCHEM.COMPOUND:91398517


UBERON:0014386


MESH:D000085703

The study presents a protocol for a Sequential Multiple-Assignment Randomization Trial for Low Back Pain (SMART LBP) within the Military Health System (MHS). The trial aims to assess the effectiveness of nonpharmacologic treatments for chronic low back pain. The trial has two phases, with participants initially randomized to receive either physical therapy (PT) or the Move2Health (M2H) program. Nonresponders to phase I treatment are then randomized to receive either a combination of M2H and PT or the Mindfulness-Oriented Recovery Enhancement (MORE) program. The primary outcome is the Patient-Reported Outcomes Measurement Information System pain interference computer-adapted test score.


MGI:4948856


NCIT:C160918

Mindfulness-Oriented Recovery Enhancement (MORE) program


MONDO:0011321

Vertebral endplate bone marrow lesions (Modic changes, MC)

The study aimed to understand the composition of vertebral endplate bone marrow lesions (Modic changes, MC) in patients with chronic low back pain (CLBP) using water-fat MRI. The bone marrow fat fraction (BMF) was measured in 42 CLBP patients and 18 asymptomatic controls. The results showed that the presence of MC coincided with significantly altered BMF. In MC 1, BMF was lower than endplates without MC, while in MC 2, BMF was higher. The differences in BMF were larger in patients with greater disability and were not associated with pain.


UBERON:0000332

Vertebral endplate bone marrow lesions (Modic changes, MC)


UBERON:0000332

larger differences in patients with greater


UBERON:0000332


HP:5200423

The study presents a protocol for a trial evaluating the effectiveness of three forms of virtual reality (VR) for patients with chronic lower back pain (cLBP). The trial will randomize 360 patients into one of three arms: skills-based VR, distraction-based VR, and sham VR. The primary outcome will be the NIH Patient-Reported Outcomes Measurement Information System (PROMIS) Pain Interference scale. Secondary outcomes will include PROMIS Anxiety, PROMIS Sleep Disturbance, opioid prescription data, and Pain Catastrophizing Scale Short Form.


HP:5200423

NIH Patient-Reported Outcomes Measurement Information System (PROMIS) Pain Interference scale


HP:5200423


MONDO:0008450

The study developed a deep learning algorithm to automatically extract the vertebral midline for frontal and lateral radiographs, addressing the limitations of current measurement methods for spinal deformities. The algorithm was validated using 20,118 pairs of full spine radiographs from 15,378 patients. The resulting 3D dataset was used to describe global imbalance parameters in the patient population and to build a statistical shape model to describe global spine shape variations in preoperative deformity patients.


MONDO:0016225


UBERON:0007271

The study investigates the role of paraspinal musculature (PSM) in chronic low back pain (LBP) using standard MRI and chemical shift encoding-based water-fat MRI (CSE-MRI). The fat fraction (FF) of PSM, measured by CSE-MRI, showed excellent intra- and interreader agreement and was significantly associated with Goutallier classification (GC) at all spinal levels. The study suggests that CSE-MRI can detect early changes in PSM that are not detectable with GC. Both FF and GC were significantly associated with pain scores.


NCIT:C83492


NCIT:C139041


UBERON:8480060

The study used hierarchical multiple factor analysis (hMFA) to analyze MRI data of paraspinal muscles (PSM) in relation to low back pain (LBP). The analysis was applied to two unique cohorts: astronauts with pre- and post-spaceflight data and a group of chronic LBP subjects and asymptomatic controls. The study found complex relationships between pain intensity and specific muscles and spinal levels. Subjects with high asymmetry between left and right lean muscle composition and differences between spinal segments PSM quality and structure were more likely to experience increased pain after prolonged time in microgravity. Changes in PSM quality and structure between pre and post-spaceflight were also related to increased pain after prolonged microgravity. The study also confirmed previous research on the association of CEP damage and LBP diagnosis.


NCBIGene:10271074


UBERON:0014386

The study investigates the role of cartilage endplate (CEP) composition and vertebral bone marrow fat fraction (BMFF) in intervertebral disc degeneration in patients with chronic low back pain (cLBP). The study used MRI data from 60 patients and found that both CEP composition and vertebral BMFF were independently associated with disc degeneration. However, after adjusting for age, sex, and BMI, only CEP composition remained significantly associated with disc degeneration. The findings suggest that poor CEP composition plays a significant role in disc degeneration severity and can affect disc health both with and without deficits in vertebral perfusion.


NCIT:C77692

Vertebral bone marrow fat fraction (BMFF)


UBERON:0014386


NCIT:C77692


EFO:0020900

The study investigates the spatial distribution of fat infiltration (FI) in the paraspinal muscles (PSMs) in relation to chronic low back pain (cLBP) and degenerative intervertebral disc (IVD) pathology. Using MRI scans of 40 cLBP patients and 21 controls, the researchers found that the distribution of FI in the PSMs varies according to symptoms and the severity of adjacent degenerative IVD pathology. The region of the multifidus muscle closest to the disc center of rotation was found to be most susceptible to FI in the presence of symptomatic IVD degeneration. The findings suggest that the spatial distribution patterns of FI in the PSMs could serve as a potential diagnostic biomarker for cLBP.


EFO:0020900


EFO:0020900

Degenerative intervertebral disc (IVD) pathology


NCBITaxon:171895


HP:0004626

The study aims to investigate the effectiveness of a combined approach of physical therapy and mindfulness (MIND-PT) for post-surgical rehabilitation in patients with chronic low back pain (LBP) undergoing lumbar surgery. The study will compare an enriched pain management (EPM) pathway integrating physical therapy and mindfulness to usual care pain management (UC). The primary outcome will be the pain impact assessed with the Pain, Enjoyment and General Activity (PEG) scale, and the main secondary outcome will be the time to opioid discontinuation. The study is part of the National Institutes of Health, Helping to End Addiction Long-term (HEAL) initiative.


HP:0004626

Pain, Enjoyment and General Activity (PEG) scale


PUBCHEM.COMPOUND:126961754


NCIT:C146739

The Back Pain Consortium (BACPAC) Spine Imaging Working Group has developed standard operating procedures (SOPs) for spinal imaging protocols to be used in all BACPAC studies. These SOPs aim to standardize the collection, reading/grading, and storage of images for patients suffering from low back pain (LBP). The procedures are designed to improve understanding of pain mechanisms and facilitate patient phenotyping by providing standardized, non-invasive assessments of spinal pathologies.


PUBCHEM.COMPOUND:44449960


MONDO:0008450


PUBCHEM.COMPOUND:60835

The study discusses the development of a personalized medicine algorithm for chronic low back pain (cLBP) treatment. The Back Pain Research Consortium, part of the National Institutes of Health Helping to End Addiction Long-termSM (HEAL) Initiative, is conducting a clinical trial to optimize treatment selection for cLBP patients. Four leading, evidence-based treatments for cLBP were selected for the trial: duloxetine, acceptance and commitment therapy, a classification-based exercise and manual therapy intervention, and a self-management approach. These treatments were chosen based on their moderate to high level of evidence supporting a therapeutic effect and their belonging to different therapeutic classes.


MONDO:0006450


GO:0040002

Classification-based exercise and manual therapy intervention


HP:0025479


EFO:0007874

The paper reviews the potential connection between the gut microbiome and musculoskeletal pain. It discusses the role of various metabolites associated with inflammation and immune-metabolic response, which are known to contribute to musculoskeletal pain. The paper also explores modifiable factors like diet, lifestyle choices, exposure to prescription drugs, pollutants, and chemicals, and non-modifiable factors like gut architecture, genetics, age, birth history, and early feeding patterns that can influence the gut microbiome. The review suggests that the gut microbiome may play a crucial role in musculoskeletal health, and further research is needed to understand this connection.


MESH:D000094162


EFO:0008111


EFO:0010724


MESH:D055553


MESH:D014875


CHEBI:38824


GO:1902900


NCBITaxon:3049538


EFO:0000246


HP:0033623


HP:0011968


EFO:0007874


NCIT:C51220

The study aimed to test the effectiveness of Mindful Awareness in Body-oriented Therapy (MABT) as an additional treatment to buprenorphine for individuals with opioid use disorder (OUD). The results showed that the group that received MABT in addition to their usual treatment demonstrated an increase in interoceptive awareness skills, which was not observed in the control group. The study also found that MABT was well-received by the participants, indicating its potential as a feasible adjunct to medication treatment for OUD.


NCIT:C51220


NCIT:C160918

The study investigates the effects of Mindfulness-Oriented Recovery Enhancement (MORE) on opioid craving, pain, and positive affective state in individuals with opioid use disorder (OUD) and chronic pain undergoing methadone maintenance therapy (MMT). The results showed that participants who underwent MORE experienced significant improvements in craving, pain unpleasantness, stress, and positive affect compared to those who received treatment as usual (TAU). Furthermore, positive affect was associated with reduced craving, a relationship that was stronger in the MORE group than in the TAU group.


NCIT:C160918


HP:0012003


MONDO:0030859

The study aimed to assess the appropriateness of a Peer Recovery Coach (PRC)-delivered adapted behavioral activation (BA) intervention to reduce problematic substance use in a medically underserved community in Baltimore. The study found that 30% of clients reported past problematic substance use and 70% met criteria for current use, most commonly cocaine and opioids. The study concluded that PRC-delivered BA could be acceptable and appropriate with suggested adaptations, including adding peer-delivered case-management and linkage to care alongside BA, and tailoring BA to include activities that are accessible and feasible in the community.


NCIT:C55555


HP:4000076


NCBIGene:38540

The paper discusses the manipulation of interoceptive pathways to improve symptoms in various disorders. The primary focus is on the respiratory system, and the paper outlines different pathways that can be manipulated at neural, behavioral, and psychological levels. These manipulations can change the representation of and attention to interoceptive signals, which can alter interconnected physiological systems and improve functioning and adaptive behavior. Interventions can alter interoception via neuromodulation of the vagus nerve, slow breathing to change respiratory rate and depth, or awareness processes such as mindfulness-based interventions.


HP:0002136


HP:5200016

The paper presents a systematic review of peer-delivered services for substance use in low- and middle-income countries (LMICs). The study found that peer-delivered services, provided by individuals with lived experience of substance use, may be effective in expanding access to treatment, supporting outcomes, and reducing stigma. The review included articles that spanned four continents and used both quantitative and qualitative methodologies. The results showed that some articles demonstrated positive impacts of the peer-delivered services, including reductions in risk behaviors and increases in infectious disease knowledge scores. However, many others showed no significant difference in outcomes between peer intervention and control groups. The study concludes that peer-delivered services may be feasible for addressing substance use and reducing infectious disease risk behaviors in LMICs.


HP:5200016


PUBCHEM.COMPOUND:6321408

The study investigates the effects of therapy dose and therapeutic alliance on opioid abstinence in youth with opioid use disorder (OUD). The participants were divided into two groups: one receiving 12-weeks of treatment with Buprenorphine/Naloxone (Bup-Nal) and the other receiving up to 2 weeks of Bup/Nal detoxification. The results showed that participants in the Bup-Nal group attended more therapy sessions, had increased therapeutic alliance, and had less opioid use by week-12 compared to those in the detox group. The study found that therapy dose mediated the association between treatment arm and opioid abstinence, suggesting that extended Bup-Nal treatment may enhance abstinence, in part, through a mechanism of therapy facilitation, by increasing therapy dose during treatment.


EFO:0000428


PUBCHEM.COMPOUND:6321408


EFO:0010702

The study investigates the feasibility and acceptability of the Mindful Recovery Opioid Use Disorder Care Continuum (M-ROCC), a 24-week mindfulness-based intervention (MBI) for adults with Opioid Use Disorder (OUD) prescribed buprenorphine/naloxone (B/N) treatment. The results showed that M-ROCC was feasible and acceptable, with high retention rates and increased mindfulness levels from baseline to 24 weeks. The increase in mindfulness was correlated with the frequency of informal mindfulness practice.


NCIT:C160918

The study evaluated the effectiveness of Mindfulness-Oriented Recovery Enhancement (MORE) as an adjunct to methadone maintenance treatment (MMT) for individuals with opioid use disorder and chronic pain. The results showed that participants who received MORE in addition to their usual MMT showed significantly fewer days of illicit drug use, lower levels of craving, pain, physical and emotional limitations, depression, and anxiety through a 16-week follow-up compared to those who only received MMT. Participants in the MORE group also reported higher levels of well-being, vitality, and social functioning.


PUBCHEM.COMPOUND:6540411

Medication for opioid use disorder (MOUD)

The study investigates the role of peer recovery specialists (PRSs) in reducing stigma-related barriers to medication for opioid use disorder (MOUD) treatment retention. The research found that stigma, particularly within ethno-racial minority communities, is a significant barrier to MOUD retention. PRSs, who have shared experiences in substance use and recovery, can play a key role in decreasing these barriers. The study also found that reducing stigma surrounding substance use disorder (SUD) and methadone treatment (MT) is critical for improving MOUD outcomes.


PUBCHEM.COMPOUND:135036


PUBCHEM.COMPOUND:14760831

The study investigates the feasibility and acceptability of a mobile digital therapeutic, reSET-O, in treating opioid use disorder. reSET-O is a prescription digital therapeutic that delivers cognitive behavioral therapy modules and contingency management rewards. The study involved 15 individuals with opioid use disorder who were on buprenorphine treatment. Results showed that reSET-O was well accepted by both patients and providers, but adherence and retention in treatment remain areas for improvement.


PUBCHEM.COMPOUND:14760831


GO:0048480

The paper investigates the role of misinformation, stigma, and misconceptions in the low uptake of treatment for opioid use disorder among patients and providers. It was found that misinformation about opioids is prevalent among future healthcare providers, first responders, and pharmaceutical companies, which may affect treatment. Misconceptions about treatment efficacy and side effects, as well as stigma, have negatively impacted treatment uptake and adherence among individuals with opioid use disorder. The paper suggests that social media, education, and community involvement can help mitigate misinformation and address misconceptions about opioids and treatment options.


NCIT:C115206


HP:0000708

Peer recovery specialist-delivered behavioral activation and problem-solving approach

The study aimed to improve retention in methadone treatment for opioid use disorder (OUD) through a peer recovery specialist-delivered behavioral activation and problem-solving approach, called Peer Activate. The results showed high feasibility, acceptability, and fidelity of the intervention. The methadone retention rate was significantly higher in the Peer Activate group compared to a comparison cohort. There was also a significant reduction in substance use frequency and substance use-related problems among the Peer Activate participants.


HP:0000708


NCBITaxon:584942

The study investigates the effects of a 24-week trauma-informed program, Mindful Recovery OUD Care Continuum (M-ROCC), on patients undergoing office-based opioid treatment (OBOT) with buprenorphine. The program was found to reduce comorbid pain, anxiety, and substance use, including cocaine and benzodiazepines. It also increased mindfulness, interoceptive awareness, and self-compassion. The study suggests that M-ROCC could enhance retention and prevent overdose during OBOT. However, larger randomized controlled trials are needed to confirm these findings.


NCBITaxon:584942


MONDO:0030397

The study aimed to find an objective diagnostic sign for neuropathic corneal pain (NCP), a condition often difficult to differentiate from dry eye disease (DED). Using in vivo confocal microscopy (IVCM), the researchers found a decrease in total nerve density in both NCP and DED patients compared to healthy controls. However, the presence of microneuromas, terminal enlargements of subbasal corneal nerve, was observed in all NCP patients but not in DED patients, suggesting that microneuromas could serve as a specific biomarker for NCP. Dendritiform cell (DC) density was also significantly increased in both NCP and DED patients compared to controls.


MONDO:0005013


MONDO:0030397


MONDO:0001390

The study compared the clinical characteristics and in vivo confocal microscopy (IVCM) findings of patients with neuropathic corneal pain (NCP) due to refractive surgery (RS-NCP) and herpetic eye disease (H-NCP). The study found that the mean pain intensity score, quality of life scores, and alterations in DC density were similar in both groups. However, the mean total nerve density was lower in both RS-NCP and H-NCP groups compared to their respective controls.


MONDO:0004616


MONDO:0021667


PUBCHEM.COMPOUND:6741

The study investigates the effects of glucocorticoids (GC), specifically methylprednisolone (MP), on the immune response following major surgery. Using a high-dimensional mass cytometry approach, the researchers found that MP significantly altered immune cell signaling trajectories, particularly in the adaptive compartments of the immune system. However, key innate signaling responses associated with pain and recovery after surgery, such as STAT3 and CREB phosphorylation, were not affected by MP. This suggests that GCs have cell-specific and pathway-specific effects.


PUBCHEM.COMPOUND:6741

Adaptive compartments of the immune system


PUBCHEM.COMPOUND:6741


EFO:0006883

The PREDICT study aims to validate a novel biomarker signature, consisting of peak alpha frequency (PAF) and corticomotor excitability (CME), for predicting pain sensitivity. The study will use a human model of sustained myofascial temporomandibular pain, induced by intramuscular injection of nerve growth factor (NGF) into the right masseter muscle. The study will follow 150 healthy participants for 30 days as they develop and experience complete resolution of NGF-induced muscle pain. The primary outcome is pain sensitivity.


MESH:C015875


PR:000011194


PUBCHEM.COMPOUND:4543

The study investigates the effectiveness and tolerability of the tricyclic antidepressant, nortriptyline, in treating neuropathic corneal pain (NCP). The results showed that nortriptyline was effective in relieving NCP symptoms in patients who had a centralized component of pain and had not responded sufficiently to other systemic and topical therapies. However, some patients discontinued treatment due to persistent side effects.


PUBCHEM.COMPOUND:4543


PUBCHEM.COMPOUND:5360515

The study found that low-dose naltrexone (LDN) was effective in reducing pain and improving quality of life in patients with neuropathic corneal pain (NCP), a condition caused by damage or disease of the somatosensory nervous system that innervates the cornea. The treatment was well-tolerated, with common side effects including vivid dreams, headaches, and stomachache.


PUBCHEM.COMPOUND:5360515


MONDO:0015290

The study found that ocular pain can occur in patients with neurotrophic keratopathy (NK), a condition typically thought to lack discomfort symptoms. A subset of these patients may also present with neuropathic corneal pain (NCP). The study involved a retrospective case series of 7 stage 1 NK patients who presented with concurrent ocular pain. The findings showed a significant decrease in mean total, main and branch nerve densities in ranges consistent with NK as compared to normal controls. Increased dendritiform cell density was found in three patients and the presence of microneuromas in six of the patients. The study suggests that nerve damage and inflammation, which play a role in the development of NK, may result in the development of chronic ocular pain, such as NCP, leading to potential underdiagnosis of either disease.


MONDO:0015290


UBERON:0001021


NCIT:C3137


MONDO:0024317

The study developed a classification system for chronic pain using multidimensional patient-reported symptoms and clustering analysis. The system was validated using three different patient subsets and was found to be effective in predicting follow-up assessments based on initial cluster assignment. The system could potentially improve clinical care by providing markers for personalized diagnosis and prognosis.


GO:0045162


HP:0031467


NCIT:C111777


RXCUI:8375

The study investigates the effects of placebo administration on immune function and its relationship with the endogenous opioid neurotransmitter system. The study involved 37 healthy human volunteers who were exposed to a standardized pain challenge. The results showed that placebo administration reduced the levels of the pro-inflammatory cytokine IL-18 during pain, and this reduction correlated with a decrease in pain scores. Furthermore, the reduction in IL-18 levels was associated with placebo-induced endogenous opioid release in the left nucleus accumbens and left amygdala. These findings suggest that placebo administration can modulate the levels of a potent pro-inflammatory cytokine (IL-18) and its relationship with the endogenous opioid system.


RXCUI:8375


UniProtKB:X2D2W2


PR:000001497


PR:000011194

The study evaluated the reliability of peak alpha frequency (PAF) and corticomotor excitability (CME) as prospective cortical biomarkers for pain. Participants were given an injection of nerve growth factor (NGF) into the right masseter muscle, inducing sustained pain. PAF and CME were assessed using electroencephalography (EEG) and transcranial magnetic stimulation (TMS) respectively. The study found that PAF was reliable even in the presence of pain and that 80% of individuals exhibited either facilitation or depression of CME, with these changes being stable across sessions.


EFO:0006883


MESH:C015875

shows facilitation or depression in presence of


MONDO:0858950

The study found that clinical questionnaires completed after mild traumatic brain injury (mTBI) can effectively predict headache improvement at 3 and 6 months, as well as the progression of the headache over the first 3 months. The study also found that reducing the questionnaire battery to only three, which assess post-concussive symptom load and biopsychosocialecologic factors, can provide a reasonable prediction accuracy for headache improvement.


MONDO:0858950

can be predicted by clinical questionnaires


EFO:0005323


MONDO:0007598


NCBIGene:819869

The study investigates the safety and efficacy of the isolated enzymatic A1 domain of LT (LTA1) as an adjuvant in intranasal influenza vaccines. The research found that LTA1-treated mice showed no neurotoxicity, unlike those treated with cholera toxin. The use of LTA1 in vaccines enhanced immune responses to inactivated virus antigen and improved protection against H1N1 influenza in mice. This protection was also observed in μMT mice lacking B-cells, suggesting that the mechanism of action does not require B-cells.


UniProtKB:B5AAN5


NCBIGene:819869


PUBCHEM.COMPOUND:3345

The study presents the design and testing of a novel vaccine against fentanyl, an opioid. The vaccine is composed of a fentanyl hapten conjugated to tetanus toxoid (TT) and adjuvanted with liposomes containing monophosphoryl lipid A adsorbed on aluminum hydroxide. The vaccine induced high and robust antibody endpoint titers against the hapten in mice. The antisera bound fentanyl and its analogues in vitro, with no cross-reactivity to other opioids like naloxone, naltrexone, methadone, or buprenorphine. In vivo, the vaccine shifted the antinociceptive dose-response curve of fentanyl to higher doses, demonstrating its potential to combat fentanyl-induced effects.


UniProtKB:A0A379ZBZ8


MESH:D014612


UniProtKB:I3NBA6


MESH:D014612

shifts antinociceptive dose-response curve


PUBCHEM.COMPOUND:88949721

connected through a trityl-protected 3-mercaptopropanamide linker

The paper discusses the synthesis of a deuterated hapten, 6-AmHap, which is essential for a future study of residual hapten and stability of a hapten-protein conjugate. This hapten is chosen for a heroin vaccine that is now slated for a Phase 1 clinical trial. The vaccine, which connects the hapten 6-AmHap with an immunogenic carrier protein (tetanus toxoid, TT) through a trityl-protected 3-mercaptopropanamide linker, has been found to have activity against several opioids, including heroin and its metabolites, and importantly, does not affect alternate pain treatment medications such as methadone. The starting material for the synthesis of the deuterated 6-AmHap was Hydrocodone.


PUBCHEM.COMPOUND:5462328


PUBCHEM.COMPOUND:5284569


PUBCHEM.COMPOUND:3345

The study investigates the use of a vaccine targeting fentanyl, a major contributor to substance use disorder-related overdose deaths. The vaccine uses fentanyl-based haptens and is delivered with adjuvants derived from the heat-labile toxin of E. coli, including dmLT and LTA1. The vaccine was delivered via intramuscular, sublingual, or intranasal methods. The results showed that the vaccine produced anti-fentanyl serum antibodies and antibody-secreting cells in the bone marrow. The highest levels of these antibodies were observed when the vaccine was adjuvanted with LTA1 or dmLT. The most effective blockade of fentanyl-induced analgesia and CNS penetration was achieved with sublingual dmLT or intranasal LTA1, correlating strongly to anti-FEN IgA.


RXCUI:1159059


UNII:D9K3SN2LNY


CL:0000946


PR:000031945


PUBCHEM.COMPOUND:5282627

The study explores the synthesis of three novel opiate surrogates (6,14-AmidoHap, 14-AmidoMorHap, and 14-AmidoHerHap) as potential haptens for a heroin vaccine. These haptens were conjugated to the tetanus toxoid carrier protein and tested in mice for immunogenicity and efficacy. The results showed that none of the conjugates induced antibodies with broad enough selectivity to recognize and bind heroin, 6-AM, and morphine, resulting in little to no protection against the antinociceptive effects of heroin. Only the mice immunized with 14-AmidoHerHap were partially protected against heroin-induced antinociception.


PUBCHEM.COMPOUND:25125273


PUBCHEM.COMPOUND:5282627


UniProtKB:A0A379ZBZ8

The study investigates the impact of preexisting immunity to tetanus toxoid on the efficacy of a heroin vaccine (TT-6-AmHap) in mice. The vaccine is designed to generate high affinity antibodies to neutralize opioids before they reach the brain. The vaccine components include an opioid hapten (6-AmHap), a carrier protein (tetanus toxoid), and adjuvants (Army Liposome Formulation adsorbed to aluminum hydroxide-ALFA). The mice were first primed with a diphtheria, tetanus, and acellular pertussis (DTaP) vaccine, then immunized with the TT-6-AmHap vaccine. The results showed that preexisting immunity to tetanus toxoid did not affect the immunogenicity and efficacy of the TT-6-AmHap vaccine.


PUBCHEM.COMPOUND:453626

Army Liposome Formulation adsorbed to aluminum hydroxide-ALFA


MESH:D022681

Diphtheria, tetanus, and acellular pertussis (DTaP) vaccine


UniProtKB:G9KAG2

The study developed chimeric monoclonal antibodies (mAb) that can specifically bind with fentanyl and its analogs in the periphery, preventing them from reaching the central nervous system. This mAb-based passive immunotherapy does not interfere with other medications used to treat opioid use disorder (OUD). The study found that two mAb candidates with high binding affinities to fentanyl and its analogs were effective in engaging fentanyl in the periphery and blocking its effects in animals.


PUBCHEM.COMPOUND:3345


UniProtKB:G9KAG2


EFO:0009510

The study investigates the impact of peripheral nerve injury on neuropathic pain and sympathetic activity in two rat pain models: ligation of the L5 spinal nerve, and local inflammation of the L5 dorsal root ganglion (DRG). The results showed that both models led to neuroinflammatory changes in the sympathetic ganglia, characterized by macrophage responses, satellite glia activation, and increased numbers of T cells. There were also slight increases in sympathetic neuron excitability. The spinal nerve ligation model generally caused larger responses than DRG inflammation.


EFO:0009510


UBERON:0000962


UBERON:0002859


HP:0010854

Low-velocity variable-amplitude spinal manipulation (LVVA-SM)

The study aimed to understand the analgesic mechanisms of low-velocity variable-amplitude spinal manipulation (LVVA-SM) in treating peripheral neuropathic pain. An animal model was developed using adult male Sprague-Dawley rats. The sciatic nerve tibial and common peroneal branches were transected, sparing the sural branch. The rats were then subjected to LVVA-SM or control conditions. The results showed that LVVA-SM reduced mechanical hypersensitivity but not cold hypersensitivity in the rats.


HP:0010854


MONDO:0043797

The study investigates the role of immune responses in the development of neuropathic pain following spinal cord injury (SCI) and the potential of exercise in modulating these responses. The researchers found that rats with SCI-induced pain had greater microglial activation in the C7-C8 dorsal horn and an increased number of macrophages in the dorsal root ganglia (DRG). Early exercise post-SCI was found to reduce microglial activation and the number of macrophages in the DRG, suggesting that exercise may prevent pain by modulating the injury-induced macrophage response in the DRG.


MONDO:0043797


HP:0410139


PUBCHEM.COMPOUND:4829

The study investigates the role of sex in central neuropathic pain and its pharmacological inhibition in individuals with spinal cord injury (SCI). The analgesic efficacy of pioglitazone (PIO), a drug approved for diabetes treatment, and azithromycin (AZM), a commonly prescribed antibiotic with immunomodulatory properties, was tested in a mouse model of SCI pain. The results showed a sex-specific effect of PIO with significant antihyperalgesic effects in females, but not males. However, AZM was effective in both sexes. The findings support the use of PIO and AZM as novel therapies for SCI pain and emphasize the importance of considering sex as a biological variable in clinical and experimental SCI pain research.


PUBCHEM.COMPOUND:447043

has antihyperalgesic effects in both sexes


PUBCHEM.COMPOUND:4829


PUBCHEM.COMPOUND:447043

is a potential treatment for pain associated with


MONDO:0001230

The study investigates the role of calcium permeable (CP) α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptors (AMPARs) in chronic pain. The researchers found that acute inflammation triggers the accumulation of CP-AMPARs in the dorsal horn of the spinal cord, which contributes to acute inflammatory pain. The study also found that the CP-AMPAR antagonist IEM-1460 inhibited AMPAR-evoked Ca2+ transients after injury. The study concludes that CP-AMPAR inhibitors could be a promising class of agents for the treatment of chronic inflammatory pain.


PR:000005794


PUBCHEM.COMPOUND:6604954


MESH:C000718808


UniProtKB:A0A539E2E6

The study investigates the properties of the DOP-KOP heteromer agonist, 6'-guanidinonaltrindole (6'-GNTI), in comparison with agonists for DOP ([D-Pen2,5]-enkephalin [DPDPE]) and KOP (U50488) in peripheral sensory neurons. All three agonists inhibited PGE2-stimulated cAMP accumulation and activated ERK with similar efficacy. However, ERK activation by U50488 was Gi-protein mediated, while that by DPDPE or 6'-GNTI was Gi-protein independent. In vivo, all three agonists reduced thermal nociception. The study suggests that DOP-KOP heteromers exhibit unique signaling and functional regulation in peripheral sensory neurons and may be a promising therapeutic target for the treatment of pain.


UniProtKB:A0A6L6Y1H2


PR:000003959


PUBCHEM.COMPOUND:880

The study investigates the role of Methylglyoxal (MG) in Painful Diabetic Neuropathy (PDN) in type 2 diabetes using db/db mice and C57BL/6J mice. The study found that administration of a MG scavenger (GERP10) or a vector overexpressing glyoxalase 1, the enzyme that breaks down MG, reduced heat hypersensitivity in db/db mice. In C57BL/6J mice, MG administration resulted in signs of pain. The study concludes that MG and a spinal TRPA1-AC1-Epac signaling cascade facilitate PDN in db/db mice, suggesting potential treatments for PDN in type 2 diabetes.


NCBIGene:828226


NCBIGene:1403978


NCBIGene:4983711


PR:000030577

The study reveals the significant role of apolipoprotein A-I binding protein (AIBP) in regulating cholesterol efflux and lipid rafts, which are cholesterol-rich and sphingomyelin-rich membrane domains. AIBP mediates selective cholesterol efflux, particularly through binding to toll-like receptor-4 (TLR4) in activated macrophages and microglia, thereby reversing lipid raft increases in activated cells. AIBP also regulates the function of vascular endothelial growth factor receptor-2, Notch1, and TLR4. In animal models, AIBP deficiency leads to accelerated angiogenesis, increased inflammation, and exacerbated atherosclerosis. The administration of recombinant AIBP reduces inflammation and persistent pain in a mouse model of chemotherapy-induced polyneuropathy and reduces lipopolysaccharide-induced acute lung injury. These findings suggest potential therapeutic applications for AIBP in angiogenic and inflammatory diseases.


PR:000030577


PR:000030577

Lipopolysaccharide-induced acute lung injury


UniProtKB:A0A6G1R1G5

The study investigates the role of TWIK-related spinal cord K+ (TRESK) channel in trigeminal pain processing. The research used TRESK global knock-out mice as a model system and found that the loss of TRESK increased the intrinsic excitability of small-diameter nociceptors, especially those that do not bind to isolectin B4 (IB4-). This resulted in hyper-excitation of the small IB4- dural afferent neurons. Both male and female TRESK knock-out mice exhibited more robust trigeminal nociceptive behaviors, including headache-related behaviors. The study concludes that endogenous TRESK activity regulates trigeminal nociception, likely through controlling the intrinsic excitability of TG nociceptors, and that genetic loss of TRESK significantly increases the likelihood of developing a headache.


UniProtKB:A0A6G1R1G5


MESH:D063388

The paper discusses the role of endocannabinoids, a type of neurotransmitter system, in providing short-term pain relief following spinal manipulative therapy, a treatment used for chronic pain. The research suggests that endocannabinoids contribute to the analgesic effect of this therapy, and understanding their involvement could improve the clinical efficacy of the treatment.


MESH:D063388


MESH:D000085703


CHEBI:50803

The study presents a pH-responsive, soft polymeric nanoparticle designed to target acidified endosomes and inhibit endosomal signalling events that lead to chronic pain. In chronic pain, the substance P (SP) neurokinin 1 receptor (NK1R) moves from the plasma membrane to acidified endosomes, where it signals to maintain pain. The nanoparticles enter cells via clathrin- and dynamin-dependent endocytosis and accumulate in NK1R-containing endosomes. When injected into rodents, the nanoparticles, which contain the FDA-approved NK1R antagonist aprepitant, inhibit SP-induced activation of spinal neurons and thus prevent pain transmission. This treatment results in complete and persistent relief from nociceptive, inflammatory, and neuropathic nociception, providing a non-opioid treatment option for chronic pain.


CHEBI:50803


PUBCHEM.COMPOUND:135413536


CHEBI:50803

Nociceptive, inflammatory, and neuropathic nociception


UBERON:0025591

Central nucleus of the amygdala (GABACeA)

The study identifies a neural pathway that may be responsible for comorbid pain in depression (CP). This pathway involves GABAergic neurons from the central nucleus of the amygdala (GABACeA) projecting to glutamatergic neurons in the parafascicular nucleus (GluPF), which then relay directly to neurons in the second somatosensory cortex (S2). Enhanced inhibition of this pathway is found in mice exhibiting CP symptoms. Using chemogenetic or optogenetic approaches to reverse this pathway alleviates CP symptoms.


GO:0035249


UBERON:0025591


CHEBI:18059

The paper discusses the role of lipid rafts in glial cells and their contribution to neuroinflammatory sensitization of central pain signaling pathways. The authors introduce the concept of an "inflammaraft" (i-raft), which are enlarged lipid rafts that contain activated receptors and adaptor molecules, initiating inflammatory signaling and cellular response. The study highlights the involvement of inflammatory receptors, redox molecules, and ion channels in inflammaraft formation and the regulation of cholesterol and sphingolipid metabolism in inflammaraft maintenance and disruption. The paper suggests that targeting inflammarafts could lead to new therapies for neuropathic pain states and other neuroinflammatory conditions.


GO:0001765


PUBCHEM.COMPOUND:5997


CHEBI:26739


MONDO:0004466


EFO:0003843

The study found that short-term pain, induced by an injection of complete Freund's adjuvant (CFA), decreased voluntary morphine intake in rats. This decrease was blocked by pre-treatment with indomethacin, a non-opioid inhibitor of pain. In rats with steady morphine self-administration, the protein level of GluA1 subunits of glutamate AMPA receptors was increased in the central nucleus of the amygdala (CeA), while that of GluA2 was decreased. This resulted in an increased GluA1/GluA2 ratio. Pain decreased this ratio. Microinjection of NASPM, an inhibitor of GluA1-AMPARs, into CeA inhibited morphine intake. Overexpression of GluA1 protein in CeA maintained morphine intake at a higher level and reversed the pain-induced reduction in morphine intake. This suggests that CeA GluA1 promotes opioid use and its upregulation increases opioid consumption, counteracting the acute inhibitory effect of pain on opioid intake.


PUBCHEM.COMPOUND:3715


NCBIGene:4327027


NCBIGene:4348563


PUBCHEM.COMPOUND:16219727


NCBIGene:4897

The study investigates the role of alternative splicing of the Nrcam gene in neuropathic pain. Two splicing variants of Nrcam, Nrcam+10 and Nrcam-10, were found to be differentially expressed in the dorsal root ganglions (DRGs) after spinal nerve ligation (SNL) in mice. SNL increased the amount of Nrcam+10 and decreased the level of Nrcam-10. An antisense oligonucleotide (ASO) targeting exon 10 of Nrcam gene repressed Nrcam+10 expression and increased Nrcam-10 expression in DRG cell culture. Injections of Nrcam ASO attenuated SNL-induced pain hypersensitivities. The study concludes that the relative levels of alternatively spliced Nrcam variants are critical for neuropathic pain genesis.


NCBIGene:4897


MESH:C428115


MESH:C558606


UniProtKB:A0A3G2QWQ4

expression increased following nerve injury

The study found that the expression of the orphan GPCR Gpr160 and GPR160 increased in the rodent dorsal horn of the spinal cord following traumatic nerve injury. Inhibition of GPR160 in the spinal cord prevented and reversed neuropathic pain in rodents without altering normal pain response. The study also identified cocaine- and amphetamine-regulated transcript peptide (CARTp) as a GPR160 ligand. Inhibiting endogenous CARTp signaling in the spinal cord attenuated neuropathic pain, while exogenous intrathecal CARTp evoked painful hypersensitivity through GPR160-dependent ERK and cAMP response element-binding protein (CREB).


NCBIGene:460993


PR:000005046


PR:000004969

The study discusses the role of the neuropeptide calcitonin gene-related peptide (CGRP) in migraine pathophysiology. It highlights the development and clinical testing of drugs targeting CGRP or its receptor, which have been found to alleviate migraine symptoms in half of the patients. The study also suggests that a second CGRP receptor could be a new therapeutic target. The CGRP-targeting drugs have shown a remarkable safety profile, which may be due to the redundancy of peptides within the CGRP family and a second CGRP receptor that may compensate for reduced CGRP activity.


GTOPDB:681


UniProtKB:A0A9L0SH84


UniProtKB:Q7TUX1

The paper discusses the role of cytokines, a type of soluble mediator, in the development and maintenance of inflammatory and neuropathic pain. The study suggests that cytokines facilitate nociceptive processing at all levels of the neuraxis, including peripheral nociceptor termini, dorsal root ganglia, spinal cord, and supraspinal areas. This action of cytokines throughout the neuraxis is believed to play key roles in the induction of pain and the maintenance of the facilitated states of pain behavior generated by tissue injury/inflammation and nerve injury.


UniProtKB:Q7TUX1


GO:0035106

The study introduces a new method, the operant plantar thermal assay (OPTA), for measuring thermal pain tolerance in mice. The OPTA requires mice to make a decision to obtain a reward under thermally adverse conditions. The study found that female mice showed greater temperature-dependent tolerance than males. The study also found that neuropathic pain, induced by chronic constriction injury (CCI), increased thermal tolerance, while inflammation, induced by complete Freund's adjuvant (CFA), had no effect. The administration of clonidine increased thermal tolerance in both injured and sham animals, while the non-steroidal anti-inflammatory meloxicam reduced thermal pain tolerance.


MONDO:0019976


MESH:D005620


PUBCHEM.COMPOUND:2803


PUBCHEM.COMPOUND:54677470


EFO:0009510

The study found that peripheral nerve injury led to an increase in the expression of long noncoding RNA H19 in the injured dorsal root ganglion (DRG). The use of a specific H19 siRNA was found to alleviate symptoms of mechanical allodynia and thermal hyperalgesia, suggesting that H19 plays a role in the development and maintenance of neuropathic pain. Therefore, H19 could be a potential target for the treatment of neuropathic pain.


NCBIGene:14955


NCBIGene:14955

contributes to development and maintenance of


NCBIGene:4327027

The paper suggests that GluA1, a protein found in the central amygdala, has a dual role in pain perception and opioid withdrawal. It increases pain but inhibits the aversion typically associated with opioid withdrawal.


NCBIGene:4327027


GO:0007272

The paper discusses the sensitization of Group II metabotropic glutamate receptor expressing neurons in the anterior cingulate cortex following inflammatory and neuropathic pain.


HP:0012531


NCIT:C96210


UniProtKB:A0A1S2VQX2

The study investigates the effect of local sympathectomy on chemotherapy-induced neuropathic pain in mice. The procedure, which involves cutting the ipsilateral gray rami entering the spinal nerves near the L3 and L4 dorsal root ganglia, was performed on mice receiving intraperitoneal injections of the chemotherapeutic drug paclitaxel. The results showed that sympathectomy led to a fast recovery from mechanical allodynia and prevented the development of cold allodynia. The procedure also induced transcriptional increases in dorsal root ganglia of macrophage markers and anti-inflammatory cytokines, such as the transforming growth factor-β. Depletion of monocytes/macrophages and blockade of transforming growth factor-β signaling reversed the relief of mechanical allodynia by sympathectomy. Exogenous transforming growth factor-β was sufficient to relieve mechanical allodynia after paclitaxel, and transforming growth factor-β signaling regulated neuronal activity in dorsal root ganglia.


UniProtKB:A0A1S2VQX2


UBERON:0000979

The study found that tibia fractures can induce an adaptive autoimmune response, characterized by germinal center formation in popliteal lymph nodes and T follicular helper cell (Tfh) dependent B cell activation, leading to nociceptive sensitization within 3 weeks. This response was found to be dependent on the production of IgM. The study also found that treating fracture mice with the Tfh signaling inhibitor FK506 reduced germinal center reactions, IgM levels, and nociceptive sensitization.


UBERON:0010754


PR:000050257


PUBCHEM.COMPOUND:87059324


PUBCHEM.COMPOUND:71610929

The study found that general anesthesia (GA) can suppress pain by activating a specific group of GABAergic neurons in the central amygdala (CeAGA neurons) of mice. These neurons are activated by different GA drugs and have a basal activity that reflects the internal state of the animal. When these neurons were activated, they suppressed pain and abolished neuropathic pain-induced mechanical hypersensitivity. In contrast, inhibiting these neurons exacerbated pain and cancelled the analgesic effect of low-dose ketamine. The researchers suggest that CeAGA neurons could be a potential therapeutic target for chronic pain relief.


UBERON:0025591


PUBCHEM.COMPOUND:3821

analgesic effect cancelled when GABAergic neurons are inhibited


MONDO:0043797

The study investigates the effect of sex on neurodegeneration, locomotor impairment, and neuropathic pain following a spinal cord injury (SCI) in male and female C57BL/6 mice. The study found that while motor function was largely similar between sexes, all males and only half of the females recovered plantar stepping. The rostral-caudal lesion length was shorter in females than in males. However, there were no significant differences in behavioral signs of neuropathic pain between sexes.


MONDO:0043797


UniProtKB:A0A9L0SH84

The study used next-generation transcriptomics and imaging-based approaches to compare the expression of population markers in mouse and human dorsal root ganglion (DRG). The researchers found a large overlapping CGRP and P2X3R neuronal subpopulation in human lumbar DRG that was not present in mouse. They also found differential expression in a variety of mRNAs for transient receptor potential channels, cholinergic receptors, potassium channels, sodium channels, and other markers/targets. These findings suggest that sensory system organizational principles are likely different between both species.


UniProtKB:A0A8C2QET8


UniProtKB:A0A922ISJ9


UniProtKB:A0A3V0YXY6


UniProtKB:A0A8S5RBG4


UBERON:0011926

The study found that a localized sympathectomy, which involves cutting the gray rami containing sympathetic postganglionic axons, reduced mechanical hypersensitivity in two different rat neuropathic pain models. This procedure also reduced functional and anatomical measures of regeneration, as well as the expression of growth-associated protein 43 (GAP43), a protein related to regeneration. In addition, the sympathectomy reduced the formation of neuromas and the density of macrophages in the sensory ganglia and peripheral nerve. These findings suggest that sympathetic nerves may locally affect immune function and that managing pain in neuropathic conditions without inhibiting peripheral nerve regeneration is a challenge.


UBERON:0011926


PR:000004931

The study investigates the role of cyclin-dependent kinase 5 (Cdk5) in neuropathic pain. Cdk5 and its activators p35 and p39, which are expressed in spinal nerves, dorsal root ganglia, and the dorsal horn of the spinal cord, are found to have increased expression/activity in neuropathic pain conditions. Cdk5 is regulated through its own phosphorylation, through increasing p35's interaction with Cdk5, and through cleavage of p35 into p25. Cdk5 affects various proteins involved in pain signaling, including channels (eg, transient receptor potential cation channel and voltage-gated calcium channel), proteins involved in neurotransmitter release (eg, synaptophysin and collapsin response mediator protein 2), and receptors (eg, glutamate, purinergic, and opioid). Therefore, Cdk5 could be a potential target for treating neuropathic pain conditions.


UniProtKB:P0DJ01


NCBIGene:991039


PR:000004931

Transient receptor potential cation channel


PR:000004931


PR:000011387

The study provides insights into the role of spinal neuropeptide Y (NPY) in inhibiting chronic pain and itch. The research focuses on the Gi-coupled neuropeptide Y1 receptor (Y1), which is found in primary afferent neurons and a subpopulation of small, excitatory, glutamatergic/somatostatinergic interneurons (Y1-INs) in the dorsal horn. The selective removal of spinal Y1-INs with an NPY-conjugated saporin neurotoxin reduces peripheral nerve injury-induced hypersensitivity. On the other hand, reducing NPY expression or administering Y1 antagonists reinstates hypersensitivity in models of chronic latent pain sensitization. The study suggests that spinal NPY release and the subsequent inhibition of pain facilitatory Y1-INs is a significant mechanism of endogenous analgesia. This mechanism can be replicated with pharmacological approaches, such as the administration of Y1 agonists, to inhibit hypersensitivity and spinal neuron activity in rodent models of neuropathic, inflammatory, and postoperative pain. Activation of Y1 also inhibits mechanical- and histamine-induced itch. The findings suggest that Y1-INs could be a potential therapeutic target for the development of NPY-Y1 agonists to treat chronic pain and itch.


UniProtKB:Q5FVH5


MESH:C085696


PUBCHEM.COMPOUND:24800709

Neuropathic, inflammatory, and postoperative pain


PUBCHEM.COMPOUND:24800709


MESH:D008822

The study investigates the neuropathic phenotype of the K/BxN transgenic mouse, which develops spontaneous autoimmune arthritis. Both male and female mice display severe tactile allodynia, which is reduced by gabapentin but not by ketorolac. In the dorsal horn, both genders show increased GFAP+ astrocytic cells, but only males show an increase in Iba1+ microglia. In the dorsal root ganglia (DRG), there is an increase in CGRP+, TH+, and Iba1+ (macrophage) labeling, but no increase in ATF3+ cells. At the ankle, there is increased CGRP+, TH+, and GAP-43+ fiber synovial innervation. These findings suggest that the adult K/BxN transgenic arthritic mice display a neuropathic phenotype, which is consistent with the analgesic pharmacology seen in this animal model.


HP:0012533


MONDO:0002503


NCBITaxon:336296


UniProtKB:A0A9L0SH84


UniProtKB:A0A7R8D2W3


GO:1990622


GO:0060384


PR:000009780

The study found that legumain (Lgmn), a cysteine protease, cleaves protease-activated receptor-2 (PAR2) in the acidic microenvironment of oral squamous cell carcinoma (OSCC), causing pain. Lgmn was found to be activated in OSCC patient tumors compared to normal oral tissue. Lgmn evoked pain in wild-type female mice but not in mice lacking PAR2 in NaV1.8-positive neurons or in mice treated with a Lgmn inhibitor, LI-1. Lgmn caused PAR2-dependent hyperexcitability of trigeminal neurons and activated PAR2 by biased mechanisms to induce calcium mobilization, cAMP formation, and activation of protein kinase A (PKA) and protein kinase D (PKD), but not β-arrestin recruitment or PAR2 endocytosis.


PR:000009780


PR:000009780

does not recruit or induce endocytosis of


NCBIGene:12772

The study investigates the role of CCR2-expressing macrophages in a mouse model of low back pain and radiculopathy. The researchers found that local inflammation of the dorsal root ganglia (DRG) induced pain behaviors in mice, which were dominated by increases in CCR2+ macrophages. The primary endogenous ligand for CCR2, CCL2, was upregulated in inflamed DRG. Experimental manipulations that reduced the CCR2+ macrophage influx also reduced pain behaviors. These included global CCR2 knockout, systemic injection of INCB3344 (a specific CCR2 blocker), and intravenous injection of liposomal clodronate. The study suggests a key role for the CCR2/CCL2 system in establishing the pain state in this model of inflammatory low back pain and radiculopathy.


NCBIGene:102089721


NCBIGene:6347


PUBCHEM.COMPOUND:53419504


MESH:C506643


MONDO:0024317

The paper discusses the role of neuroimmune signaling in chronic pain conditions such as low back pain, arthritis, persistent post-surgical pain, fibromyalgia, and neuropathic pain disorders. It emphasizes that the interaction between immune cells, glia, and neurons is crucial for the onset and persistence of chronic pain. The paper also discusses recent advancements in understanding these neuroimmune signaling mechanisms and potential therapeutic targets in rodent models of chronic pain. Additionally, it mentions new technologies to study, diagnose, and quantify the neuroimmune contributions to chronic pain in patients.


MONDO:0024317


MONDO:0019369

The study suggests that complex regional pain syndrome (CRPS) may be a posttraumatic autoimmune disease. The research found that early CRPS patient IgM antibodies have pronociceptive effects in the skin and spinal cord of muMT fracture mice lacking B cells. The study also found that complement component C5a and its receptor expression increased in skin and spinal cord after fracture, predominantly on dermal macrophages and spinal microglia. The pronociceptive effects of IgM were blocked by a C5a receptor antagonist (PMX53) or a global cytokine inhibitor (pentoxifylline). Chronic CRPS patient IgM (but not IgG) caused nociceptive sensitization in muMT fracture mice. The researchers suggest that CRPS IgM antibodies bind to neoantigens in the fracture limb skin and corresponding spinal cord to activate C5a complement signaling in macrophages and microglia, leading to proinflammatory cytokine expression contributing to nociceptive sensitization in the injured limb.


PR:000050257


NCBIGene:728


MONDO:0019369


UniProtKB:A0A1T3C6T0

The paper discusses the role of G protein-coupled receptors (GPCRs) in chronic pain associated with digestive system disorders, inflammation, and cancer. The study suggests that GPCRs, when activated by mediators from injured tissues, can lead to sensitization of ion channels and acute hyperexcitability and nociception. Sustained agonist release can cause GPCR redistribution to endosomes, where persistent signaling regulates activity of channels and genes that control chronic hyperexcitability and nociception. The paper also discusses the potential of endosomally targeted GPCR antagonists, biased agonists of µ-opioid receptors (MOPrs), and allosteric modulators of GPCRs in providing superior pain relief. The study also highlights the potential of GPCR dimers as distinct therapeutic targets for nociception.


UniProtKB:E9FVN7


MESH:D011992

site of GPCR redistribution in chronic pain


UniProtKB:A0A3G2QWQ4

potential distinct therapeutic targets for


CL:0000134

Chemotherapy-induced peripheral neuropathy (CIPN)

The study demonstrates that nasal administration of mesenchymal stem cells (MSC) can completely reverse the signs of chemotherapy-induced peripheral neuropathy (CIPN), a common adverse effect of cancer treatment, in mice. This reversal includes mechanical allodynia, spontaneous pain, and loss of intraepidermal nerve fibers (IENF) in the paw. The resolution of CIPN is associated with the normalization of the cisplatin-induced decrease in mitochondrial bioenergetics in DRG neurons. The MSC enter the meninges of the brain, spinal cord, and peripheral lymph nodes to promote IL-10 production by macrophages. The reversal of CIPN symptoms critically depends on IL-10 production. MSC from IL-10 knockout animals are not capable of reversing the symptoms of CIPN. Moreover, wild type MSC do not reverse CIPN in mice lacking IL-10 receptors on peripheral sensory neurons.


CL:0000134


UniProtKB:A0A0B5H157


MONDO:0004820

The paper discusses neuropathic pain, a common clinical disorder that significantly impacts the quality of life of patients. The study focuses on the downregulation of opioid receptors in primary afferent neurons following peripheral nerve trauma, which limits the effectiveness of opioids in treating this disorder. The paper explores the molecular mechanisms behind this downregulation, including alterations in epigenetic modifications (DNA methylation, histone methylation, and microRNAs), expression of transcription factors, post-transcriptional modifications (RNA methylation), and protein translation initiation in the neurons of the dorsal root ganglion (DRG). The study suggests that understanding these mechanisms could provide new avenues for the prevention and treatment of neuropathic pain.


HGNC.FAMILY:245


MONDO:0004820


NCBIGene:9486897

The paper discusses the role of T cells in the suppression of pain, suggesting that they play a key role in resolving pain. The study also suggests that dysregulation of certain immune functions may lead to chronic pain. The paper proposes that stimulating the endogenous immune-mediated resolution pathways could be a potent approach to treat chronic pain.


MONDO:0003140


GO:0016064

Endogenous immune-mediated resolution pathways


UniProtKB:A0A1R4ABV0

The study investigates the role of non-SUMOylated collapsin response mediator protein 2 (CRMP2) in the functional expression of the voltage-gated sodium channel NaV1.7, which is crucial in neuronal excitability and pain signaling. The research found that non-SUMOylated CRMP2 forms a complex with endocytic proteins Numb, Eps15, and Nedd4-2 to promote the endocytosis of NaV1.7. Inhibiting clathrin assembly in nerve-injured mice precipitated mechanical allodynia, a type of neuropathic pain. The expression of Numb, Nedd4-2, and Eps15 was not modified in the dorsal root ganglia (DRG) of the mice. Silencing these proteins in DRG neurons restored the loss of sodium currents.


PR:000005580


NCBIGene:80036

The study investigates the role of Transient receptor potential melastatin 3 (TRPM3), a heat-activated ion channel in primary sensory neurons, in various pain modalities. The research used two inhibitors of TRPM3, isosakuranetin and primidone, in mice with nerve injury-induced neuropathic pain. The results showed that these inhibitors reduced heat hypersensitivity induced by chronic constriction injury (CCI) of the sciatic nerve in wild-type mice, but not in TRPM3-/- mice. The study also found that genetic deletion or inhibitors of TRPM3 reduced the increase in the levels of the early genes c-Fos and pERK in the spinal cord and dorsal root ganglia (DRGs) in CCI mice, suggesting spontaneous activity of the channel. The findings indicate a role for TRPM3 in heat hypersensitivity and spontaneous pain after nerve injury.


NCBIGene:80036


PUBCHEM.COMPOUND:160481


PUBCHEM.COMPOUND:4909


NCBIGene:101831721


NCBIGene:3767664


NCBIGene:445457

The study focuses on the role of Transient Receptor Potential (TRP) ion channels in orofacial pain, which includes temporomandibular joint disorders pain, trigeminal neuralgia, dental pain, and headaches. The research indicates that TRP ion channels, specifically TRPV1, TRPA1, TRPV4, and TRPM8, are expressed in the trigeminal sensory system and play a significant role in the transduction and pathogenesis of orofacial pain. The study also highlights the distinct peripheral and central pain processing and different sensitivities of the orofacial sensory system from the spinal sensory system.


NCBIGene:828226


NCBIGene:395427


PR:000030689


UBERON:0004132


CL:0009000


MESH:C038777

The study investigates the effects of a neurokinin 1 receptor (NK1R) antagonist, Spantide I (Span), conjugated to cholestanol (Span-Chol), on pain relief. The research found that Span-Chol accumulates in endosomes, inhibits endosomal NK1R signaling, and causes prolonged antinociception. Over time, Span-Chol increased local concentration at the plasma membrane, showed an increase in NK1R-binding affinity, and more potent inhibition of NK1R-mediated calcium signaling. Span-Chol also caused a persistent decrease in NK1R recruitment of β-arrestin and receptor internalization to early endosomes. In a preclinical model of pain, Span-Chol caused prolonged antinociception, which is attributable to a three-pronged mechanism of action: increased local concentration at membranes, a prolonged decrease in NK1R endocytosis, and persistent inhibition of signaling from endosomes.


MESH:C038777


NCBIGene:24498

The study investigates the role of interleukin 6 (IL-6) signaling in the development of adaptive immune responses and nociceptive sensitization in a murine tibia fracture model of complex regional pain syndrome (CRPS). The findings suggest that IL-6 signaling is necessary for the development of nociceptive sensitization, vascular changes, and IgM immune complex deposition in the skin of injured limbs. The study also found that the administration of anti-IL-6 antibodies reduced nociceptive and vascular changes after fracture and inhibited lymphadenopathy.


NCBIGene:24498

required for deposition in injured limbs


NCBIGene:24498


GO:0010161

The study reviews the mechanisms and pathways of pain modulation by light exposure, known as photobiomodulation. It was found that cutaneous application of red light (660 nm) can reduce pain in neuropathies and complex regional pain syndrome-I, but visual application of the same wavelength can exacerbate migraine headaches and cause functional pain in animal models. Conversely, visual exposure to green light can reduce pain in conditions like migraines and fibromyalgia. Both routes of exposure cause changes in the brainstem, spinal cord, dorsal root ganglia, and nociceptors.


GO:0010161


PUBCHEM.COMPOUND:21223


PR:000013429

The study found that intermittent parathyroid hormone (iPTH) can reduce osteoarthritis pain by inhibiting sensory innervation, deterioration of subchondral bone, and degeneration of articular cartilage in a mouse model. The iPTH treatment also reduced the level of prostaglandin E2 in the subchondral bone of the mice and regulated uncoupled subchondral bone remodeling caused by increased transforming growth factor β signaling. The effects of iPTH were found to be specifically through the PTH type 1 receptor in Nestin+ mesenchymal stromal cells.


PR:000013429


UniProtKB:A9JQD6

The study investigates the use of targeted epigenetic repression of NaV1.7, a sodium channel protein associated with pain signaling, as a potential treatment for chronic pain. The researchers used epigenome engineering approaches based on CRISPR-dCas9 and zinc finger proteins to repress NaV1.7 in primary afferents at the spinal level. The efficiency of NaV1.7 repression was first optimized in vitro in Neuro2A cells. The epigenome engineering platforms were then delivered via adeno-associated viruses (AAVs) to assess their effects in three mouse models of pain. The results showed effective repression of NaV1.7 in lumbar dorsal root ganglia, reduced thermal hyperalgesia in the inflammatory state, decreased tactile allodynia in the neuropathic state, and no changes in normal motor function in mice.


NCBITaxon:1520554


UniProtKB:A0A9P3PJS1


NCBITaxon:82300


UniProtKB:A9JQD6


NCBIGene:741390

Cocaine- and amphetamine-regulated transcript (Cartpt)

The peptide encoded by the cocaine- and amphetamine-regulated transcript (Cartpt) gene, known as CART peptide (CART), has been recognized since 1981. The gene encoding CART was identified in 1995. The CART peptide has been linked to ingestive behaviors, reward behaviors, and pain sensation. Despite the significance of CART, the full potential for this peptide or its analogs to be developed into therapeutic agents remained unrealized due to the absence of an identified receptor. Recently, the G protein-coupled receptor (GPCR), GPR160, has been identified as a receptor for CART, opening up potential for the development of pharmcotherapies targeting GPR160.


UniProtKB:A0A7L8Y656


NCIT:C158332

The study found that macrophages (MΦ) residing in the sciatic nerve play a significant role in cancer-induced pain. Depletion of these resident macrophages (rMΦ) in mice reduced pain sensitivity caused by the injection of melanoma or lung carcinoma cells. The study also found that MΦ-colony stimulating factor (M-CSF) was upregulated in the sciatic nerve trunk and contributed to cancer-induced pain through rMΦ expansion, activation of transient receptor potential ankyrin 1 (TRPA1), and oxidative stress. The deletion of Trpa1 revealed that Schwann cell TRPA1 is crucial for sciatic nerve rMΦ expansion and pain-like behaviors. The study concluded that a feed-forward pathway involving M-CSF, rMΦ, oxidative stress, and Schwann cell TRPA1 signals cancer-induced pain.


CL:0002573


PUBCHEM.COMPOUND:71605072

The study investigates the effectiveness of a fentanyl analogue, NFEPP, which preferentially activates the µ-opioid receptor (MOPr) in acidified diseased tissues, in treating pain in a preclinical model of inflammatory bowel disease (IBD) without side effects in healthy tissues. The results show that NFEPP inhibited pain responses in mice with colitis but not in control mice, consistent with acidification of the inflamed colon. Unlike fentanyl, NFEPP did not decrease defecation, cause respiratory depression, or induce hyperactivity in mice with colitis. The study concludes that NFEPP preferentially activates MOPr in acidified microenvironments of inflamed tissues to induce pain relief without causing respiratory depression, constipation, and hyperactivity.


PUBCHEM.COMPOUND:71605072


PUBCHEM.COMPOUND:3345


PR:000001379

The study investigates the effect of low-dose interleukin-2 (ld-IL2) and regulatory T (Treg) cells on mechanical allodynia, a condition of heightened sensitivity to pain, in a mouse model of sciatic nerve injury. The results show that treatment with ld-IL2 or adoptive transfer of Treg cells can significantly reduce the severity of allodynia. The study also found that ld-IL2 increased the frequency of Treg cells in the injured sciatic nerves, suggesting that the injured nerve is the site of action for ld-IL2.


HP:0020112


PR:000001379

increases frequency in injured sciatic nerves


UniProtKB:M4IRL4

The study investigates the effect of a localized "microsympathectomy" and the manipulation of CCL2 (monocyte chemoattractant protein 1) in a rat tibial nerve crush model of neuropathic pain. The results show that microsympathectomy and localized siRNA-mediated knockdown of CCL2 in the lumbar dorsal root ganglion led to partial improvement of mechanical hypersensitivity and guarding behavior, reduction of regeneration markers growth-associated protein 43 and activating transcription factor 3, and reduction of macrophage density in the sensory ganglia and regenerating nerve. The study suggests that local sympathetic effects on neuropathic pain may be mediated largely by the effects on expression of CCL2, which in turn regulates the regeneration process.


UniProtKB:M4IRL4


MONDO:0024317

The paper discusses the challenge of chronic pain, a disabling disease with limited treatment options. The authors propose a multi-institutional collaboration to better understand the cells and networks of pain in humans, which could potentially lead to improved therapeutic development.


MONDO:0024317


NCIT:C34338


PR:000032589

The study found that neuroinflammation, a major component in the transition to and perpetuation of neuropathic pain states, involves the activation of TLR4 in cholesterol-enriched lipid rafts, termed as inflammarafts. The deletion of cholesterol transporters ABCA1 and ABCG1 in microglia led to the formation of inflammarafts and induced tactile allodynia in naive mice. The apoA-I binding protein (AIBP) facilitated cholesterol depletion from inflammarafts and reversed neuropathic pain in a model of chemotherapy-induced peripheral neuropathy (CIPN) in wild-type mice. However, AIBP failed to reverse allodynia in mice with ABCA1/ABCG1-deficient microglia, suggesting a cholesterol-dependent mechanism. An AIBP mutant lacking the TLR4-binding domain did not bind microglia or reverse CIPN allodynia. The long-lasting therapeutic effect of a single AIBP dose in CIPN was associated with anti-inflammatory and cholesterol metabolism reprogramming and reduced accumulation of lipid droplets in microglia.


NCBIGene:9619


PR:000005046

The paper discusses the diverse pharmacological actions of the Cocaine- and amphetamine-regulated transcript peptide (CARTp) in the central and peripheral nervous systems and several endocrine organs, including the pancreas. The identification of a CARTp receptor, GPR160, has revealed the physiological importance and therapeutic potential of CARTp or its analogs. The CARTp-GPR160 interaction is essential for the circadian regulation of appetite and thirst and for the transmission of nerve injury-induced pain. Further molecular approaches are being used to uncover additional physiologically relevant actions of this ligand/receptor pair.


PR:000005046


NCIT:C26791

The study investigates the role of FTO (fat-mass and obesity-associated protein), an N6-methyladenosine demethylase, in hemorrhage-induced thalamic pain. The research found that FTO expression was increased in the thalamus after hemorrhage caused by microinjection of Coll IV (type IV collagenase). The administration of meclofenamic acid (an FTO inhibitor) or microinjection of adeno-associated virus 5 (AAV5) expressing Cre into the thalamus of Ftofl/fl mice reduced TLR4 (Toll-like receptor 4) upregulation and nociceptive hypersensitivity. Conversely, thalamic microinjection of AAV5 expressing FTO increased TLR4 expression and elicited hypersensitivities to various stimuli. The findings suggest that FTO stabilizes TLR4 upregulation in thalamic neurons, contributing to hemorrhage-induced thalamic pain.


NCBIGene:291905


UniProtKB:A0A7J7JTT2


GTOPDB:681

The CGRP system, part of the calcitonin family of peptides, is a significant target for migraine treatment. However, not all migraine sufferers respond to anti-CGRP treatments, indicating the need for additional targets. Other peptides in the calcitonin family, including calcitonin, amylin, adrenomedullin, and adrenomedullin 2, show pro-nociceptive and anti-nociceptive actions in primary headache conditions like migraine. These peptides and their receptors may be useful in treating migraine and other pain disorders.


UniProtKB:B2D2C1


UniProtKB:B8PQ42


PR:000003781


PR:000032782

The study investigates the role of mitochondrial calcium uniporter in painful diabetic neuropathy (PDN), a complication affecting 25% of diabetic patients. The researchers found that mitochondrial fission proteins were elevated in dorsal root ganglion (DRG) neurons in mice with PDN. They also observed increased calcium signaling in DRG nociceptors and fragmented mitochondrial morphology. By selectively deleting the mitochondrial calcium uniporter, they were able to restore normal mitochondrial morphology, prevent axonal degeneration, and reverse mechanical allodynia in the mouse model. The study suggests that targeting calcium entry into nociceptor mitochondria could be a potential therapeutic approach for PDN.


PR:000010366


PUBCHEM.COMPOUND:5460341


MESH:D008928


PR:000032782


NCBIGene:11535

The study investigates the pharmacology of the calcitonin (CT) receptor family in mice, which includes two receptors (the CT receptor [CTR] and the CTR-like receptor [CLR]), three accessory proteins (RAMPs), and multiple endogenous peptides. The researchers synthesized and characterized mouse adrenomedullin, adrenomedullin 2, and βCGRP, and mouse CTR with or without mouse RAMPs. They found that the pharmacology of these receptors in mice is subtly different from that in humans, with mouse receptors showing less discrimination between ligands. This finding poses challenges for translating findings from mice to humans and underscores the need for new ligands to differentiate between these complexes.


NCBIGene:11988


PUBCHEM.COMPOUND:5283119

The study found that the concentration of prostaglandin E2 (PGE2) was elevated in porous endplates, leading to spinal pain. High-dose treatment with the cyclooxygenase 2 inhibitor, celecoxib, decreased the PGE2 concentration and reduced spinal pain in mice with lumbar spine instability. However, this treatment also impaired bone formation in porous endplates, and spinal pain returned after discontinuing the treatment. Low-dose celecoxib treatment, on the other hand, led to a long-lasting reduction in spinal pain and significantly reduced endplate porosity, which was associated with decreased sensory nerve innervation and spinal pain.


PUBCHEM.COMPOUND:5283119


PUBCHEM.COMPOUND:2662


UBERON:0002481


HP:0003301


PR:000013246

The study identified genes that are exclusively expressed in different types of mouse ganglion neurons. The pituitary hormone genes prolactin (Prl), growth hormone (Gh), and proopiomelanocortin (Pomc) were found to be almost exclusively in trigeminal ganglion (TG) neurons. The study also found that growth hormone (GH) plays a significant role in pain responses in the trigeminal system, as it produced mechanical hypersensitivity when injected intrathecally and generated orofacial and headache-like periorbital mechanical hypersensitivity. This hypersensitivity was reversed by a GH receptor antagonist, pegvisomant.


PR:000007968


UniProtKB:Q9PWN1


PR:000007968

Orofacial and headache-like periorbital mechanical hypersensitivity


UNII:N824AOU5XV


PR:000001590

The study investigates the sex differences in protein kinase A (PKA) signaling of latent postoperative pain sensitization, which is controlled by kappa opioid receptors (KOR) in the spinal cord. The research found that both males and females have NMDA receptor (NMDAR)→adenylyl cyclase-1 (AC1)→PKA and Epac signaling pathways in the dorsal horn of the spinal cord that maintain latent sensitization. However, only males recruit a PKA-dependent mechanism. The study suggests that AC1, PKA, and Epac inhibitors could be developed into a new pharmacotherapy for chronic postoperative pain.


NCBIGene:22585712


NCBIGene:4983711


UBERON:0004132

The study identified nine distinct subtypes of trigeminal (TG) sensory neurons that innervate the masseter muscle (MM) fibers, fascia, tendons, and adjusted tissues. These neurons were identified using patch clamp electrophysiology and immunohistochemistry on TG neurons back-traced from a reporter mouse MM. The study found that 24% of these neurons belonged to non-peptidergic IB-4+/TRPA1- or IB-4+/TRPA1+ groups, while two TRPV1+ small-sized neuronal groups were classified as peptidergic/CGRP+. The study also found that masseteric muscle fibers, tendons and masseteric fascia in mice and the common marmoset were exclusively innervated by either CGRP+/NFH+ or CGRP-/NFH+ medium-to-large neurons.


UniProtKB:A0A6J8ELD2


NCBIGene:101720480


UniProtKB:A0A9L0SH84


UniProtKB:A0A0S7J0C3


MESH:C000606949

The study identifies nociceptor endocytosis as a potential target for local, specific, and long-lasting treatment of inflammatory pain. The researchers found that AP2α2, an α-subunit isoform of the AP2 complex, is preferentially expressed within CGRP+/IB4- nociceptors in rodents and in CGRP+ dorsal root ganglion neurons from a human donor. By using genetic and pharmacological approaches to inhibit nociceptor endocytosis, they demonstrated its role in the development and maintenance of acute and chronic inflammatory pain. A one-time injection of an AP2 inhibitor peptide significantly reduced acute and chronic pain-like behaviors and provided prolonged analgesia. The study also found sexually dimorphic recovery responses to this pharmacological approach, emphasizing the importance of sex differences in pain development and response to analgesics.


MESH:C000606949


PUBCHEM.COMPOUND:30668

The study investigates the role of the autonomic nervous system in regulating the adaptive immune system activation and nociceptive sensitization in a mouse model of chronic post-traumatic pain with features of complex regional pain syndrome (CRPS). The researchers used 6-hydroxydopamine (6-OHDA) or lofexidine to reduce sympathetic signaling and nicotine to augment parasympathetic signaling. The results showed that these treatments reduced fracture-induced hindpaw nociceptive sensitization and unweighting, prevented IgM deposition, hypertrophy of popliteal lymph nodes, and the development of pronociceptive serum transfer effects. This suggests that inhibiting sympathetic or augmenting parasympathetic signaling inhibits pro-nociceptive immunological changes accompanying limb fracture.


PUBCHEM.COMPOUND:89594


PUBCHEM.COMPOUND:30668


MESH:C039578

Large-diameter afferent fibers (Aβ-fibers)

The study found that astrocytes, a type of cell in the spinal cord, play a significant role in pain gating, a process that reduces the transmission of pain signals to the brain. The researchers discovered that electrical stimulation of large-diameter afferent fibers (Aβ-fibers) in mice activated astrocytes, which then induced long-term depression (LTD) in neurokinin 1 receptor–positive (NK1R+) neurons and reduced pain through the activation of endogenous adenosinergic mechanisms. When astrocyte activation was suppressed, the induction of LTD in NK1R+ neurons and pain inhibition by Aβ-fiber stimulation was blocked.


REACT:R-SSC-210439

reduces through activation of endogenous adenosinergic mechanisms


EFO:0009510

causes abnormal spontaneous activity (cluster firing)

The study discovered a unique form of abnormal spontaneous activity in dorsal root ganglion (DRG) neurons following peripheral nerve injury, termed as "cluster firing". This cluster firing was found to be directly correlated with nerve injury-induced spontaneous pain behaviors. The study also found that this cluster firing is triggered by the activity of sympathetic nerves, which sprout into DRGs after injury, and identified norepinephrine as a key neurotransmitter mediating this unique firing. The study suggests that blocking sympathetically mediated cluster firing could be a new approach for treating spontaneous pain.


CHEBI:33731


MONDO:0019198


PUBCHEM.COMPOUND:439260