Pain is a national health crisis, as well as a devastating daily experience for millions of people. It is at this more personal level that we recognize that pain is highly subjective, unique to each person, and influenced by a spectrum of innate and environmental factors. The overarching goal of the Smith Lab is to understand and explain the variability underlying the individual experience of pain. Our work has largely focused on looking for genetic risk factors in humans through candidate and genome-wide association studies, genome sequencing, and gene expression experiments, as well as transgenic animal models including knockout mice. We are also interested in epigenetic modifications to the genome such as DNA methylation that modify gene activity in response to environmental pressures.
In order to better understand the experience and causes of chronic pain, we are conducting a number of research projects. Our goal is to identify patient characteristics, whether behavioral patterns or molecular biomarkers, that reveal the complex etiology of pain and suggest new therapeutic approaches for personalized treatment.
The Center for Translational Pain Medicine Biorepository
Since 2017, we have enrolled over 2400 patients seeking treatment for pain at the Duke Innovative Pain Therapies (DIPT) clinic into our biobank. The purpose of this study is to identify characteristics of patients with a pain disorder or reporting pain that may be diagnostically or prognostically meaningful. We focus particularly on biopsychosocial markers that influence the course of chronic pain during treatment, and which may be used to stratify patients into risk pools. Consenting patients provide a blood sample and are rigorously assessed for comorbid pain conditions and putative risk factors, including psychosocial profile and pressure pain sensitivity. We use these data to cluster subjects into three distinct groups (Adaptive, Pain Sensitive, and Global Distress) based on etiological factors, using a reliable and validated algorithm. Previous research has shown that patients in the Global Distress group are at greater risk for high impact pain and other health problems. Patients in our biorepository are followed to assess factors that influence treatment outcomes. We hope to use these data to identify mechanisms that correspond with symptom trajectory and treatment success. We are also looking for genetic variants and circulating blood factors that associate with cluster profile and outcomes.
TMD Mechanism Grants
Painful temporomandibular disorders (TMD) are a common set of multifactorial health conditions associated with the temporomandibular joint and its surrounding muscles and nerves. Injury or deterioration of the local tissues does not necessarily correspond with or explain the severity of the disorder, and patients and physicians have long dealt with challenges of diagnosis and proper care. The CTPM Biorepository furnishes participants for a number of NIH-funded studies of mechanisms underlying TMD. We are currently working on a study using recent advances in genomic and cellular profiling technologies to understand the inflammatory, neuroimmune, and nociplastic mechanisms that drive painful TMD at a deeper resolution than has previously been possible. These new techniques, such as single-cell transcriptomics, epigenomics, and spatial transcriptomics, will allow us to identify how changes in circulating and muscle-infiltrating immune cells contribute to TMD pain pathogenesis. In a separate project, we will identify drivers of pain that differ between men and women, using a novel reverse translational screening approach. We have observed that we can initiate a chronic pain state in healthy mice by transferring blood fractions from chronic pain patients. We will identify the critical cell types and soluble protein pain mediators in patients’ blood using proteomic and transcriptomic technologies. Finally, in a third project we will seek to define the properties of sensory neurons that innervate tissues which form the temporomandibular joint. This work will lead to an understanding of the neurological mechanisms that underlie chronic orofacial pain in patients with TMD, thereby facilitating the development of new therapeutic approaches.
DIG & Follow-Up of GWAS Findings
Genetic factors substantially affect one’s risk of developing a chronic pain disorder, with potentially hundreds of genes contributing to common pain syndromes. The lab investigates the genetic causes of chronic pain using genome-wide screens (known as GWAS) to identify novel risk factors for many such disorders in search of effective, non-addictive treatments for pain. Our previous work with the OPPERA study culminated in a GWAS of temporomandibular disorders (TMD) incorporating data from over 300,000 people. The principle finding from this study was a novel TMD risk gene MRAS, which codes for an important cellular signaling enzyme M-Ras. This gene was associated with healing and resilience against chronic pain via an undetermined mechanism that seems to be active in males only. The contribution of MRAS to pain-relevant pathways is an entirely unexplored area, making this a promising direction for target discovery, in addition to revealing a previously undetected sex dimorphism in nociception. We are conducting experiments to characterize the influence of M-Ras on neuronal pathways and establish a basis for future translational studies. The potential clinical utility of this discovery lies in determining the cellular mechanisms by which this gene promotes analgesia and/or healing in a patient who has suffered an injury or trauma--leveraging the body’s own potential to activate innate healing processes.
Clinical Research Coordinator
Dongshunyi Dora Li
BCTIP Intern 2016-2017
Nanjiang Amber Liu
BCTIP Intern 2017-2018
BCTIP Intern 2023-2024
BCTIP Intern 2023
BCTIP Intern 2023
In the News
- Smith SB, Marker CL, Perry C, Liao G, Sotocinal SG, Austin JS, Melmed K, Clark JD, Peltz G, Wickman K, Mogil JS. Quantitative trait locus and computational mapping identifies Kcnj9 (GIRK3) as a candidate gene affecting analgesia from multiple drug classes. Pharmacogenet Genomics, 18(3): 231-241, 2008.
- Tchivileva IE, Lim PF, Smith SB, Slade GD, Diatchenko L, McLean SA, Maixner W. Effect of catechol-O-methyltransferase polymorphism on response to propranol therapy in chronic musculoskeletal pain: a randomized, double-blind, placebo-controlled, crossover pilot study. Pharmacogenet Genomics, 20(4): 239-48, 2010. PMCID: PMC2876724
- Reimann F, Cox JJ, Belfer I, Diatchenko L, Zaykin DV, McHale DP, Drenth JP, Dai F, Wheeler J, Sanders F, Wood L, Wu TX, Karppinen J, Nikolajsen L, Männikkö M, Max MB, Kiselycznyk C, Poddar M, Te Morsche RH, Smith SB, Gibson D, Kelempisioti A, Maixner W, Gribble FM, Woods CG. Pain perception is altered by a nucleotide polymorphism in SCN9A. Proc Natl Acad Sci USA, 107(11):5148-53, 2010. PMCID: PMC2841869
- Costigan M, Belfer I, Griffin RS, Dai F, Barrett LB, Coppola G, Wu T, Kiselycznyk C, Poddar M, Lu Y, Diatchenko L, Smith SB, Cobos EJ, Zaykin D, Allchorne A, Shen P-H, Nikolajsen L, Karppinen J, Männikkö M, Kelempisioti A, Goldman D, Maixner W, Geschwind DH, Max MB, Seltzer Z, Woolf CJ. Multiple chronic pain states are associated with a common amino acid changing allele in KCNS1. Brain. 133(9):2519-27, 2010. PMCID: PMC2929335
- Neely GG, Hess A, Costigan M, Keene AC, Goulas S, Langeslag M, Griffin RS, Belfer I, Dai F, Smith SB, Diatchenko L, Gupta V, Xia CP, Amann S, Kreitz S, Heindl-Erdmann C, Wolz S, Ly CV, Arora S, Sarangi R, Dan D, Novatchkova M, Rosenzweig M, Gibson DG, Truong D, Schramek D, Zoranovic T, Cronin SJ, Angjeli B, Brune K, Dietzl G, Maixner W, Meixner A, Thomas W, Pospisilik JA, Alenius M, Kress M, Subramaniam S, Garrity PA, Bellen HJ, Woolf CJ, Penninger JM. A genome-wide Drosophila screen for heat nociception identifies α2δ3 as an evolutionarily conserved pain gene. Cell, 143(4):628-38, 2010. PMCID: PMC3040441
- Smith SB, Maixner DW, Greenspan JD, Dubner R, Fillingim RB, Ohrbach R, Knott C, Slade GD, Bair E, Gibson DG, Zaykin DV, Weir BS, Maixner W, Diatchenko L. Potential genetic risk factors for chronic TMD: genetic associations from the OPPERA case control study. J Pain, 12(11; Supplement):T92-T101, 2011. PMCID: PMC3268684
- Smith SB, Maixner DW, Fillingim RB, Slade G, Gracely RH, Ambrose K, Zaykin DV, Hyde C, John S, Tan K, Maixner W, Diatchenko L. Large candidate gene association study reveals genetic risk factors and therapeutic targets for fibromyalgia. Arthritis Rheum, 64(2):584-93, 2012. PMCID: PMC3237946
- Neely GG, Rao S, Costigan M, Mair N, Racz I, Milinkeviciute G, Meixner A, Nayanala S, Griffin RS, Belfer I, Dai F, Smith SB, Diatchenko L, Marengo S, Haubner BJ, Novatchkova M, Gibson D, Maixner W, Pospisilik JA, Hirsch E, Whishaw IQ, Zimmer A, Gupta V, Sasaki J, Kanaho Y, Sasaki T, Kress M, Woolf CJ, Penninger JM. Construction of a global pain systems network highlights phospholipid signaling as a regulator of heat nociception. PLoS Genet, 8(12):e1003071, 2012. PMCID: PMC3516557
- Slade GD, Smith SB, Zaykin D, Tchivileva I, Gibson D, Yuryev A, Mazo I, Bair E, Fillingim R, Ohrbach R, Maixner W, Diatchenko L. Facial pain with localized and widespread manifestations: separate pathways of vulnerability. Pain, 154(11):2335-43, 2013. PMCID: PMC3808468
- Smith SB, Mir E, Bair E, Slade GD, Dubner R, Fillingim RB, Greenspan JD, Ohrbach R, Knott C, Weir B, Maixner W, Diatchenko L. Genetic variants associated with development of TMD and its intermediate phenotypes: the genetic architecture of TMD in the OPPERA prospective cohort study. J Pain, 14(12, Supplement): T91-T101, 2013. PMCID: PMC3855664
- Slade GD, Fillingim RB, Sanders AE, Bair E, Greenspan JD, Ohrbach R, Dubner R, Diatchenko L, Smith SB, Knott C, Maixner W. Summary of findings from the OPPERA Prospective Cohort Study of incidence of first-onset temporomandibular disorder: Implications and future directions. J Pain 14(12, Supplement): T116-T124, 2013. PMCID: PMC3857103
- Diatchenko L, Fillingim RB, Smith SB, Maixner W. The phenotypic and genetic signatures of common musculoskeletal pain conditions. Nat Rev Rheumatol, 9(6):340-50, 2013. PMCID: PMC3991785.
- Smith SB, Reenilä I, Männistö PT, Slade GD, Maixner W, Diatchenko L, Nackley AG. Epistasis between polymorphisms in COMT, ESR1, and GCH1 influences COMT enzyme activity and pain. Pain, 2014. PMCID: PMC4253645
- Meloto CB, Bortsov AV, Bair E, Helgeson E, Ostrom C, Smith SB, Dubner R, Slade GD, Fillingim RB, Greenspan JD, Ohrbach R, Maixner W, McLean SA, Diatchenko L. Modification of COMT-dependent pain sensitivity by psychological stress and sex. Pain, 157(4):858-67, 2016. PMCID:PMC4794347.
- Bair E, Gaynor S, Slade GD, Ohrbach R, Fillingim RB, Greenspan JD, Dubner R, Smith SB, Diatchenko L, Maixner W. Identification of clusters of individuals relevant to temporomandibular disorders and other chronic pain conditions: The OPPERA Study. Pain, 157(6):1266-1278, 2016. PMCID: 4949303.
- Slade GD, Ohrbach R, Greenspan JD, Fillingim RB, Bair E, Sanders AE, Dubner R, Diatchenko L, Meloto CB, Smith SB, Maixner W. Painful temporomandibular disorder: Decade of discovery from OPPERA studies. J Dent Res, 95(10):1084-92, 2016. PMCID: PMC5004239
- Maixner W, Slade GD, Fillingim RB, Smith SB, Williams D. Overlapping chronic pain conditions: Implications for diagnosis and classification. J Pain, 17(9 Suppl):T93-T107, 2016. PMCID: N/A.
- Sanders AE, Jain D, Sofer T, Kerr KF, Laurie CC, Shaffer JR, Marazita ML, Kaste LM, Slade GD, Fillingim RB, Ohrbach R, Maixner W, Kocher T, Bernhardt O, Teumer A, Schwahn C, Sipilä K, Lähdesmäki R, Männikkö M, Pesonen P, Järvelin M, Rizzatti-Barbosa CM, Meloto CB, Ribeiro-Dasilva M, Diatchenko L, Serrano P, Smith SB. GWAS identifies new loci for painful temporomandibular disorder. J Dent Res, 96(3):277-284, 2017. PMCID: PMC5298397.
- Parisien M, Khoury S, Chabot-Dore A-J, Sotocinal SG, Slade GD, Smith SB, Fillingim RB, Ohrbach R, Greenspan JD, Maixner W, Mogil JS, Belfer I, Diatchenko L. Effect of human genetic variability on gene expression in dorsal root ganglia and association with pain phenotypes. Cell Rep, 19(9):1940-52, 2017. PMCID: PMC5524461.Martin LJ, Smith SB, Khoutorsky A, Magnussen CA, Samoshkin A, Sorge RE, Cho C, Yosfpour N, Sivaselvachandran S, Tohyama S, Cole T, Khuong TM, Mir E, Gibson DG, Wieskopf JS, Sotocinal SG, Austin J-S, Meloto CB, Gitt JH, Gkogkas C, Sonenberg N, Greenspan J, Fillingim RB, Ohrbach R, Slade GD, Knott C, Dubner R, Nackley AG, Ribeiro-da-Silva A, Neely GG, Maixner W, Zaykin DV, Mogil JS, Diatchenko L. Epiregulin and EGFR interactions are involved in pain processing. J Clin Inv, 127(9):3353-3366, 2017. PMCID: PMC5669538.
- Smith SB, Parisien M, Bair E, Belfer I, Chabot-Dore AJ, Gris P, Khoury S, Tansley S, Torosyan Y, Zaykin DV, Bernhardt O, de Oliveira Serrano P, Gracely RH, Jain D, Jarvelin MR, Kaste LM, Kerr KF, Kocher T, Lahdesmaki R, Laniado N, Laurie CC, Laurie CA, Mannikko M, Meloto CB, Nackley AG, Nelson SC, Pesonen P, Ribeiro-Dasilva MC, Rizzatti-Barbosa CM, Sanders AE, Schwahn C, Sipila K, Sofer T, Teumer A, Mogil JS, Fillingim RB, Greenspan JD, Ohrbach R, Slade GD, Maixner W, Diatchenko L. Genome-wide association reveals contribution of MRAS to painful temporomandibular disorder in males. Pain, 160(3):579-591, 2019. doi: 10.1097/j.pain.0000000000001438. PMCID: PMC6377338.
- Van Tilburg MAL, Parisien M, Boles RG, Drury GL, Smith-Voudouris J, Verma V, Khoury S, Chabot-Doré AJ, Nackley AG, Smith SB, Whitehead WE, Zolnoun DA, Slade GD, Tchivileva E, Maixner W, Diatchenko L. A genetic polymorphism that is associated with mitochondrial energy metabolism increases risk of fibromyalgia. Pain, 161(2):2860-2871, 2020. PMCID: PMC7669626.
- Gaynor SM, Bortsov A, Bair E, Fillingim RB, Greenspan JD, Ohrbach R, Diatchenko L, Nackley A, Tchivileva IE, Whitehead W, Alonso AA, Buchheit TE, Boortz-Marx RL, Liedtke W, Park JJ, Maixner W, Smith SB. Phenotypic profile clustering pragmatically identifies diagnostically and mechanistically informative subgroups of chronic pain patients. Pain, 162(5):1528-1538, 2021. doi: 10.1097/j.pain. 0000000000002153. PMCID: PMC8049946