Inna Belfer

University of Pittsburgh | Pitt · Department of Anesthesiology

Rheumatoid arthritis-associated joint pain is frequently observed independent of disease activity, suggesting unidentified pain mechanisms. We demonstrate that antibodies binding to cartilage, specific for collagen type II (CII) or cartilage oligomeric matrix protein (COMP), elicit mechanical hypersensitivity in mice, uncoupled from visual, histolo...

Objective: Heightened somatic symptoms are reported by a wide range of patients with chronic pain and have been associated with emotional distress and physical dysfunction. Despite their clinical significance, molecular mechanisms leading to their manifestation are not understood. Methods: We used an association study design based on a curated l...

Rheumatoid arthritis–associated joint pain is frequently observed independent of disease activity, suggesting unidentified pain mechanisms. We demonstrate that antibodies binding to cartilage, specific for collagen type II (CII) or cartilage oligomeric matrix protein (COMP), elicit mechanical hypersensitivity in mice, uncoupled from visual, histolo...

Painful temporomandibular disorders (TMDs) are the leading cause of chronic orofacial pain, but its underlying molecular mechanisms remain obscure. Although many environmental factors have been associated with higher risk of developing painful TMD, family and twin studies support a heritable genetic component as well. We performed a genome-wide ass...

Chronic postmastectomy pain (PMP) imposes a major burden on the quality of life of the ever-increasing number of long-term survivors of breast cancer. An earlier report by Nissenbaum et al. (2010) claimed that particular polymorphisms in the gene CACNG2 are associated with the risk of developing chronic PMP after breast surgery. This information is...

This review is aimed to summarize the latest data regarding pain and nutrition, which have emerged during the second edition of Feed Your Destiny (FYD). Theme presentations and interactive discussions were held at a workshop on March 30, 2017, in Florence, Italy, during the 9th Annual Meeting of Study in Multidisciplinary Pain Research, where an in...

Background Sickle cell disease (SCD) is an inherited disorder of the red blood cells and is associated with chronic multisystem involvement. While SCD has been associated with poorer health-related quality of life (HRQoL), there is a paucity of data on the relationship of psychological covariates other than anxiety and depression and quality of lif...

Background Vaso-occlusive pain episodes (VOEs) are the hallmark of sickle cell disease (SCD), and our current understanding of disease biology, treatment, and psychological covariates does not adequately explain the variability of pain in SCD. Functional variants in catechol-O-methyltransferase (COMT) gene contribute to variability in pain percepti...

Introduction Sickle cell disease (SCD) is an inherited blood disorder characterized by abnormally shaped sickle cells. The hallmark of this disease is intermittent, painful vaso-occlusive episodes (VOE), but a subset of individuals with SCD experience chronic pain. The mechanism of transition to chronic pain is not well understood in SCD, but there...

Background and aims: Pain is the hallmark of sickle cell anemia (SCA), presenting as recurrent acute events or chronic pain. Central sensitization, or enhanced excitability of the central nervous system, alters pain processing and contributes to the maintenance of chronic pain. Individuals with SCA demonstrate enhanced sensitivity to painful stimu...

Background: Mild traumatic brain injury (mTBI) often results in post-concussion symptoms, chronic pain, and sleepiness. Genetic factors are thought to play an important role in poor prognosis. Aims: The aims of this study are to (1) document the prevalence of pain and post-concussion symptoms in mTBI patients in acute and chronic phases (2) determi...

Nociception is protective and prevents tissue damage but can also facilitate chronic pain. Whether a general principle governs these two types of pain is unknown. Here we show that both basal mechanical and neuropathic pain are controlled by the microRNA-183 cluster in mice. This single cluster controls more than 80% of neuropathic pain-regulated g...

Sickle cell disease (SCD) is associated with episodes of severe vaso-occlusive pain beginning in infancy with a subset of patients with SCD transitioning to chronic pain. Response to experimental pain using quantitative sensory testing in these patients suggests altered pain processing. The objectives of this study were to characterize sensitivity...

Graphical Abstract Highlights d Expression quantitative trait loci (eQTLs) are mapped in a collection of human DRGs d Pain-related genetic association results can be explained by DRG eQTLs d eQTLs predict contribution of the human leukocyte antigen locus to pain phenotypes d The dataset is a tool for interpretation of human GWAS with a sensory comp...

Introduction Chronic pain is a common and debilitating complication following breast surgery. One of the most challenging for treatment is the neuropathic pain condition, postmastectomy pain syndrome (PMPS). Gabapentin is a pharmacotherapy for neuropathic pain disorders; however, its once-daily, gastroretentive formulation, Gralise, has not been ev...

The hallmark manifestation of homozygous sickle cell disease (SCD) is acute pain. The underlying etiology is unknown. It is believed that hypoxia induces changes in erythrocyte shape and produces microvasculature occlusion by sickled red cells. Vascular occlusion is believed to represent the event inducing tissue hypoxia, reperfusion injury and pai...

Recently, attention to the lifestyle of patients has been rapidly increasing in the field of pain therapy, particularly with regard to the role of nutrition in pain development and its management. In this review, we summarize the latest findings on the role of nutrition and nutraceuticals, microbiome, obesity, soy, omega-3 fatty acids, and curcumin...

Genetic research heralds a new therapeutic approach to pain management. Increasing literature demonstrates individual genetic vulnerabilities to specific pain types and mechanisms, partially explaining differing responses to similar pain stimuli. Furthermore, analgesics demonstrate great variability among carriers of different genotypes. Family his...

Unlabelled: High interindividual variability in postoperative opioid consumption is related to genetic and environmental factors. We tested the association between morphine consumption, postoperative pain, and single nucleotide polymorphisms (SNPs) within opioid receptor μ 1 (OPRM1), catechol-O-methyltransferase (COMT), uridine diphosphate glucose...

Background: Children with Sickle Cell Disease (SCD) have increased sensitivity to heat and cold pain (Brandow et al) during steady state. However, the role of psychological factors such as anxiety, depressive symptoms and catastrophizing on pain sensitivity is not known in SCD. Characterization of these factors may provide an insight into the study...

Description: Pain in patients with chronic pancreatitis (CP) remains the primary clinical complaint and source of poor quality of life. However, clear guidance on evaluation and treatment is lacking. Methods: Pancreatic Pain working groups reviewed information on pain mechanisms, clinical pain assessment and pain treatment in CP. Levels of evide...

In EBioMedicine Meng et al. (2015a) reported the results from their second genome-wide association study on neuropathic pain that aimed to identify novel genetic factors contributing to neuropathic pain in diabetic patients. The first study (Meng et al., 2015b) published earlier this year in the European Journal of Pain identified a cluster in the...

Chronic pain is a highly prevalent and poorly managed human health problem. We used microarray-based expression genomics in 25 inbred mouse strains to identify dorsal root ganglion (DRG)-expressed genetic contributors to mechanical allodynia, a prominent symptom of chronic pain. We identified expression levels of Chrna6, which encodes the α6 subuni...

Persistent postoperative pain is a well-established clinical problem with potential severe personal and socioeconomic implications. The prevalence of persistent pain varies across surgery types. Severe persistent pain and related impairment occur in 5% to 10% of patients after groin hernia repair. The substantial interindividual variability in pain...

Vaso-occlusive pain, the hallmark of sickle cell disease (SCD), is a major contributor to morbidity, poor health-related quality of life and healthcare utilization associated with this disease. There is wide variation in the burden, frequency and severity of pain experienced by patients with SCD. As compared to healthcare utilization for pain, a da...

Title: Feasibility and Tolerability of Quantitative Sensory Testing in Patients with Sickle Cell Disease at the End of a Vasocclusive Episode Background: Children with Sickle Cell Disease (SCD) have increased sensitivity to heat and cold pain (Brandow et al) during steady state. It is unknown if sensitivity to pain varies with a Vaso-Occlusive Epis...

SUMMARY Persistent pain after breast cancer surgery (PPBCS) is increasingly recognized as a potential problem facing a sizeable subset of the millions of women who undergo surgery as part of their treatment of breast cancer. Importantly, an increasing number of studies suggest that individual variation in psychosocial factors such as catastrophizin...

Breast cancer is the most common type of cancer among women worldwide. Short--term post--surgical recovery is complicated by many factors, including imbalanced inflammatory and immune response, acute pain associated with functional impairment, and chronic post--mastectomy pain (CPMP), developed by about 25--60% of patients. Opioids, most common dru...

Objective Total knee replacement (TKR) is the treatment option of choice for the millions of individuals whose osteoarthritis pain can no longer be managed through non-invasive methods. Over 500,000 TKRs are performed annually in the United States. Although most patients report improvement in pain and functioning following TKR, up to 30% report per...

Background: Resource-limited communities in Washington, D.C. have high rates of obesity-related cardiovascular disease in addition to inadequate physical activity (PA) facilities and limited Internet access. Engaging community members in the design and implementation of studies to address these health disparities is essential to the success of comm...

GTP cyclohydrolase (GCH1) is rate limiting for tetrahydrobiopterin (BH4) synthesis, where BH4 is a cofactor for nitric oxide (NO) synthases and aromatic hydroxylases. GCH1 polymorphisms are implicated in the pathophysiology of pain, but have not been investigated in African populations. We examined GCH1 and pain in sickle cell anemia where GCH1 rs8...

Pain Genetics: Basic to Translational Science is a timely synthesis of the key areas of research informing our understanding of the genetic basis of pain. The book opens with foundational information on basic genetic mechanisms underlying pain perception and progresses recently discovered complex concepts facing the field. The coverage is wide-rang...

Background Depression and catastrophizing are critically important variables in understanding the experience of pain in patients with several types of chronic pain. In the PiSCES study, negative correlations were observed between high catastrophizing scores with greater depression and lower quality of life in adult patients with sickle cell disease...

Preclinical studies suggest that endogenous opioids and/or opioid medications may contribute to tumor growth. However, endogenous and exogenous opioids have not been modulated over time in cancer patients, who often need opioids for pain control. Most of the analgesic effect of opioids occurs through the activation of the μ-opioid receptor. The mos...

Persistent postmastectomy pain (PPMP) is increasingly recognized as a major individual and public health problem. Although previous studies have investigated surgical, medical, and demographic risk factors, in this study we aimed to more clearly elucidate the relationship of psychosocial factors to PPMP. Postmastectomy patients (611) were queried a...

Unlabelled: In pain clinical trials, the rescue analgesic medication such as patient-controlled analgesia morphine is often made available for patients for breakthrough pain. The patient-controlled analgesia morphine usage decreases the study agent's effect on pain relative to placebo and introduces greater variability in attainment of pain scores...

The enzyme catechol-O-methyltransferase (COMT) metabolizes catecholamine neurotransmitters involved in a number of physiological functions, including pain perception. Both human and mouse COMT genes possess functional polymorphisms contributing to interindividual variability in pain phenotypes such as sensitivity to noxious stimuli, severity of cli...

Pain is considered to be an evolutionary-conserved trait and is employed as a necessary means to survival. Although this trait is common in all humans, it shows great variability among individuals. The underlying mechanisms of pain perception are not fully understood. Functional single nucleotide polymorphism and other types of genetic polymorphism...

Background Preoperative pain, type of operation and anesthesia, severity of acute postoperative pain, and psychosocial factors have been identified as risk factors for chronic postsurgical pain (CPP). Recently, it has been suggested that genetic factors also contribute to CPP. In this study, we aimed to determine whether the catechol-O-methyl trans...

Humans are very different when it comes to pain. Some get painful piercings and tattoos; others can not stand even a flu shot. Interindividual variability is one of the main characteristics of human pain on every level including the processing of nociceptive impulses at the periphery, modification of pain signal in the central nervous system, perce...

Basic behavioral analysis of PI3Kγ KO mice. PI3Kγ expressing control and PI3Kγ knock-out (KO) mice exhibit similar behavioral responses in multiple paradigms. (A) PI3Kγ KO mice exhibit intact accuracy in a test for skilled reaching and (B) a slight decrease in cages crosses over a 24 hour period; but this trend failed to reach statistical significa...

Predicted mammalian orthologs for Drosophila pain genes and binding partners. To identify orthologs between Drosophila and mouse or Drosophila and human, we used pre-computed orthology predictions obtained from Compara r49, Homologene (03/08), Inparanoid v6.1, Orthomcl v2 [39]. Both One-to-one and many to many mappings were observed between the Dro...

PI3Kγ KO mice show no difference in inflammatory pain responses. (A) PI3Kγ KO mice exhibit significant enhancement of baseline thermal nociception sensitivity but a comparable degree of thermal hyperalgesia following intraplantar CFA challenge. (B) A sensitization ratio (Baseline/CFA latency) shows similar CFA-induced sensitization in wild type (WT...

GO analysis for mammalian orthologs of Drosophila candidate pain genes. GO enrichment for all mouse and human orthologs corresponding to Drosophila candidate pain genes. Significant GO ids, corresponding GO terms, functional category, Biological Process (BP), Molecular Function (MF) and Cellular Component (CC), gene count, total gene count, and P v...

Flow charts for global bioinformatics analyses. (A) Flow chart indicating the steps in the conversion of Drosophila candidate thermal nociception genes into mouse and human orthologs. (B) Flow chart indicating KEGG and C2 gene set analysis in Drosophila, mice, and humans. Data from all three organisms were pooled to generate a global network map. S...

Conserved regulators of thermal nociception. GO enrichment analysis for human (A) and mouse (B) orthologs of Drosophila thermal nociception hits. GO terms were pooled into functional categories for data representation. Numbers indicate the counts of GO terms included in each functional category. These GO terms are grouped according to their parent...

A global network map of thermal nociception based on primary hits without binding partners. The systems network includes data from the significantly enriched Drosophila KEGG pathways and GO processes, mouse and human KEGG pathways and C2 gene sets based on analysis of primary screening hits without binding partners. Pathways, processes and gene set...

Drosophila candidate pain genes with known mammalian pain gene orthologs. Drosophila candidate pain genes were compared to known mouse pain genes, and overlap is shown. Unique Drosophila (CG number) and mouse (Entrez ID) identifiers are provided. In some cases, multiple independent transgenic RNAi fly lines targeting a particular Drosophila gene we...

Mammalian KEGG analysis. Enrichment of KEGG pathways for mouse and human orthologs corresponding to Drosophila candidate pain genes. The complete analysis for 202 mouse (top), and 209 human (bottom) KEGG pathways are shown. For each pathway, the KEGG database ID, pathway name, KEGG gene sets, CG/Entrez IDs for the mapped genes, numbers of genes ass...

Interactions between candidate pain genes and first degree binding partners. All interactions involving mammalian orthologs of Drosophila pain hit genes and their first degree binding partners are listed. Each row corresponds to a biological interaction between two proteins. Every interaction has two participating nodes: Source and Target. Gene sym...

Overlap of pain systems map with pain OMIM and microarray data. A comparison of genes in the global network map of thermal nociception with genes with a pain annotation in the OMIM database (http://www.ncbi.nlm.nih.gov/omim) and previous rat microarray expression profiling data generated from pain studies [28] showed the global network map of therm...

This file contains Detailed Materials and Methods and Supporting References. (DOCX)

Mammalian C2 gene set analysis. Analysis for 687 mouse (top) and 680 human (bottom) C2 gene sets found significant at 99% probability (hypergeometric test). For each gene set, the C2 gene set name, gene symbols, counts for the total number of genes, pain hit orthologs, and percentages of genes mapped among the total C2 gene sets are given. C2 gene...

Combined KEGG and C2 data for mammalian orthologs of Drosophila candidate pain genes and their binding partners. (A) The table represents a combined list of select significant GO terms, KEGG pathways and C2 gene sets from Drosophila, mouse, and human, used to construct the combined systems map shown in Figure 1. Selected significant KEGG pathways a...

Persistent postmastectomy pain (PPMP) is a major individual and public health problem. Increasingly, psychosocial factors such as anxiety and catastrophizing are being revealed as crucial contributors to individual differences in pain processing and outcomes. Furthermore, differences in patients' responses to standardized quantitative sensory testi...

The ability to perceive noxious stimuli is critical for an animal's survival in the face of environmental danger, and thus pain perception is likely to be under stringent evolutionary pressure. Using a neuronal-specific RNAi knock-down strategy in adult Drosophila, we recently completed a genome-wide functional annotation of heat nociception that a...

Context: Persistent pain is common after surgical treatment of breast cancer, but fairly little is known about the changes in sensory processing that accompany such pain syndromes. Objectives: This study used quantitative sensory testing to compare psychophysical responses to standardized noxious stimulation in two groups of women who had previo...

The enzyme catechol-O-methyltransferase (COMT) has been shown to play a critical role in pain perception by regulating levels of epinephrine (Epi) and norepinephrine (NE). Although the key contribution of catecholamines to the perception of pain has been recognized for a long time, there is a clear dichotomy of observations. More than a century of...

Preclinical studies suggest that opioids may promote tumor growth. Genetic polymorphisms have been shown to affect opioid receptor function and to modify the clinical effects of morphine. In this study we assessed the association between six common polymorphisms in the μ-opioid receptor gene, including the well known A118G polymorphism, and breast...

Quantitative trait locus mapping of chemical/inflammatory pain in the mouse identified the Avpr1a gene, which encodes the vasopressin-1A receptor (V1AR), as being responsible for strain-dependent pain sensitivity to formalin and capsaicin. A genetic association study in humans revealed the influence of a single nucleotide polymorphism (rs10877969)...

1075 Background Pain crisis is the hallmark of sickle cell disease (SCD) but varies in frequency and severity. Variation in pain sensitivity and perception among individuals is partially attributed to genetic factors. Catechol-O-methyltransferase (COMT) regulates neurotransmission and plays an important role in the perception of pain sensation. Th...

An estimated 15-50% of the population experiences pain at any given time, at great personal and societal cost. Pain is the most common reason patients seek medical attention, and there is a high degree of individual variability in reporting the incidence and severity of symptoms. Research suggests that pain sensitivity and risk for chronic pain are...

Catechol-O-methyltransferase (COMT) metabolizes catechol neurotransmitters dopamine, noradrenaline and adrenaline that are involved in various physiological functions including mood, cognition and stress response. Human pain is closely related to all these functions. The gene encoding the COMT enzyme (COMT) has functional polymorphisms that contrib...

Worldwide, acute, and chronic pain affects 20% of the adult population and represents an enormous financial and emotional burden. Using genome-wide neuronal-specific RNAi knockdown in Drosophila, we report a global screen for an innate behavior and identify hundreds of genes implicated in heat nociception, including the alpha2delta family calcium c...

Surgical treatment for lumbar degenerative disc disease (DDD) has been associated with highly variable results in terms of postoperative pain relief and functional improvement. Many experts believe that DDD should be considered a chronic pain disorder as opposed to a degenerative disease. Genetic variation of the catechol-O-methyltransferase (COMT)...