"Transcriptional profiling of individual sensory neurons reveals high priority candidate genes underlying pain following spinal cord injury"
Kyle M. Baumbauer, PhD - UConn School of Nursing
Spinal cord injury (SCI) can result in profound loss of function the majority of patients experience persistent pain that is difficult to manage. Most of what is known about the mechanisms underlying pain following SCI has focused on changes occurring within the spinal cord. However, recent work has shown that peripheral nociceptors also contribute to the initiation and maintenance of SCI-induced chronic pain. What is not known is how spinal cord injury recruits peripheral sensory neurons, particularly those that innervate uninjured tissue and that contribute to pain below the level of the spinal lesion. Using single cell qPCR to generate focused transcriptional profiles, we find that expression of a number of pain-relevant genes is increased in sensory neurons for 7 days following moderate and severe SCI, and that increased gene expression corresponds to injury-induced changes in neuronal firing properties. Of these targets, Acid Sensing Ion Channel Subunit 3 (ASIC3) and GDNF family receptor alpha 3 (GFRa-3) exhibit the most profound increases in expression following SCI, suggesting that increased expression of these transcripts may contribute to the onset and persistence of functional alterations in sensory neurons recruited by SCI, and ultimately, pathological pain.
"In a search for a pain gene"
Luda Diatchenko, MD, PhD - McGill University
Chronic pain conditions are multifactorial disorders with a high frequency in the population. Their pathophysiology is often unclear, and treatment is inefficient. During the last 20 years, genetic linkage analysis and association studies have made considerable strides toward identifying key molecular contributors to the onset and maintenance of chronic pain. Here, I will review the genetic variants that have been implicated in pain phenotypes. In rare familial monogenic pain conditions several strong-effect mutations have been identified. In contrast, the genetic landscape of common chronic pain conditions suggests minor contributions from a large number of single nucleotide polymorphisms (SNP) representing different functional pathways. I will analyze up-to-date genetic association results using the new Human Pain Genetics Database (HPGDB), a comprehensive SNP-focused inventory of genetic contributors to pain published to date. The analysis reveals that many reported genetic variants are associated with multiple pain phenotypes and the strength of their association correlates between many pairs of phenotypes. These genetic variants explain a considerable amount of the variance between different pairs of pain phenotypes, indicating a shared genetic basis among pain phenotypes. Additionally, we find that HPGDB variants show many pleiotropic associations, indicating that genetic-pathophysiological mechanisms are also shared among painful and non-painful conditions.
"Integrated precision chronic pain management: Ready or not?"
Robert D Kerns, PhD - Yale University
Both the National Academy of Medicine (formerly the Institute of Medicine) “Relieving pain in America” and the Department of Health and Human Services National Pain Strategy call for the delivery of integrated, patient-centered, evidence-based, multimodal and interdisciplinary care for persons with chronic pain. An important question is how this recommendation can be reconciled with a similar call for “precision pain medicine.” This presentation will define a biopsychosocially informed approach to chronic pain management that is both comprehensive and individually-tailored and “prescriptive.” Scientific knowledge and clinical practice gaps will be identified, and significant and innovative current research to address them will be briefly reviewed. In particular, an ambitious partnered research initiative, the NIH-DoD-VA Pain Management Collaboratory, will be presented.
"Advances in Translational Medicine: New Targets and New Ways of Diagnosing and Caring for the Complex Pain Patient"
William Maixner, DDS, PhD, Duke University
To become knowledgeable in current concepts associated with etiological pathways associated with common persistent pain conditions
To become knowledgeable in how to assess the biopsychosocial and molecular pathways that underlie heterogeneous common persistent pain conditions.
To become knowledgeable of the emerging concepts in the area of Translational Pain Medicine.
Common persistent pain conditions (CPPCs) are composed of aggregates of phenotypes (signs and symptoms) associated with peripheral and central nervous system dynamics, stress responsiveness and inflammatory states. Complex molecular networks underlie these heterogeneous phenotypes and these networks are shaped by intrinsic polygenetic factors and environmental events such as physical injury and psychological stressors. Dr. Maixner will discuss the recent outcomes and lessons learned from various cohort studies including OPPERA study. Findings from these studies are leading to novel ways of conceptualizing CPPCs.
He will present findings from recently completed and ongoing cross-sectional and prospective studies that examine the biopsychosocial and genetic factors that contribute to CPPCS. Finally, he will discuss emerging bioinformatic technologies that are proving useful in unraveling molecular networks that contribute to the clinical phenotypes observed in subpopulations of patients with persistent pain conditions. The outcomes of these studies are leading to new diagnostic tools and the identification of novel therapeutic targets that have implications for the future treatment of CPPCs.
"Mechanisms governing the transition to chronic pain"
Theodore Price, PhD - University of Texas-Dallas
Ted Price’s talk will focus on the growing evidence that acute and chronic pain mechanisms are distinct and that different classes of drugs are likely needed to treat these different types of pain. A major focus of the talk will be on how we are starting to discover that distinct neuronal circuits control chronic pain and that these circuits may hold the key for developing better pain treatments. Another key theme of the talk will be sex differences in pain mechanisms. Dr. Price will discuss evidence from his and other labs that male rodents rely heavily on immune pain mediators whereas females seem to rely more on neuronal intrinsic plasticity mechanisms. These mechanistic differences highlight some important new opportunities for development of sex-specific pain therapeutics.
"Risk Factors of the Transition from Acute to Chronic Low Back Pain"
Angela Starkweather, PhD, RN, ACNP-BC, CNRN, FAAN - UConn School of Nursing
Purpose: The aim of this study was to identify differential measures of somatosensory function and gene expression in patients with acute onset of low back pain who either had resolution of their pain within 6 weeks from onset (acute resolvers; AR group) or developed a chronic low back pain trajectory (chronic low back pain, CLBP group).
Methods: In this longitudinal descriptive study, 220 participants were enrolled during an acute low back pain episode and data was collected until the low back pain either resolved or every six weeks until the end of the study at six months. Of the sample, 42 participants had resolution of pain at or before 6 weeks from onset and 42 participants developed chronic LBP at 6 months from onset. Psychosocial factors, pain sensitivity as measured by quantitative sensory testing and blood samples were collected for gene expression profiles at each study visit.
Results: Participants in the CLBP group had a significantly lower threshold for painful cold stimuli (p<.010), mechanical stimuli (p<.021) and detection of allodynia (p<.018) of the low back region compared to the AR group. In addition, the CLBP group had significantly reduced threshold to cold (p<.012) and pressure stimuli (p<.041) at a remote site compared with the AR group. The CLBP had differential expression of several genes known to influence pain sensitivity compared to the AR group.
Conclusions: The study findings suggest there are genetic vulnerabilities to CLBP that may be identified at the onset of the low back pain episode. Along with changes in somatosensory function, gene expression profiles may be useful for prognostication of the low back pain episode and possibly used to predict response to treatments.
"Diet and Pain: Interactions and Interventions"
Robert E. Sorge, PhD - University of Alabama-Birmingham
Chronic pain affects millions of Americans each year and the American diet may contribute to the rise. Aside from the obesogenic effects and added weight, many aspects of the diet directly stimulate the immune system and may result in a low-grade inflammatory state that increases susceptibility to chronic pain. We show that our newly-developed Standard American Diet (SAD) changes the body composition of rats and mice, elevates pro-inflammatory cytokine levels, prolongs recovery from injury and results in enhanced activation of immune cells in the spinal cord. Conversely, our Anti-Inflammatory Diet (AID), that includes a variety of food additives with known anti-inflammatory properties, can promote recovery when it is substituted for the SAD at the time of injury. These data suggest that diet has a direct impact on the immune system and can prolong or promote recovery following injury, arguing for their use as interventions. To that end, our clinical trial in older adults with knee osteoarthritis demonstrated that a low-carbohydrate diet reduced functional pain more than a calorie-reduced diet, in spite of similar weight loss. These results illustrate that diet quality, and not weight loss, was the important factor. Together these data provide evidence that diet has a profound impact on pain and that diet interventions can be useful as safe and accessible alternatives to opioid treatment for chronic pain.
"Precision Healthcare for Abdominal Pain: Identifying novel targets to address pain at the source"
Erin Young, PhD - UConn School of Nursing
Irritable bowel syndrome (IBS) is a functional gastrointestinal pain disorder characterized by abdominal pain and altered bowel habits in the absence of bowel pathology. One of the primary Rome IV diagnostic criteria for IBS is persistent or recurrent pain lasting longer than 3 months, and, yet, there is a gap in the literature when it comes to the mechanisms contributing to pain burden in IBS patients. Genetic studies have primarily focused on the risk for IBS diagnosis and/or for associations with particular IBS subtypes defined by diarrhea or constipation predominance. However, IBS patients overwhelmingly report pain as the most distressing symptom with the greatest negative impact on their quality of life and this symptom is medically difficult to treat due to the gastrointestinal effects of many first line analgesics (NSAIDS, opiates). As a result, understanding the mechanisms involved in the induction and maintenance of abdominal pain in IBS could provide insight into novel precision healthcare interventions designed to treat pain at the mechanism level. Using genomewide and targeted candidate gene methods in mice followed by translation into patient populations, we have begun constructing a list of high priority candidate genes in which variation and/or expression differences correspond to pain burden.
"Chronic Pain in Sickle Cell Disease: From Bedside to Bench"
William T. Zempsky, MD, MPH - Connecticut Children's Medical Center