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204. Carbonic anhydrase-8 gene therapy inhibits the ITPR1-cytosolic free calcium pathway producing analgesia and anti-hyperalgesia

Author

Levitt, Roy C, primary, Zhuang, Gerald Z, additional, Keeler, Benjamin, additional, Grant, Jeff, additional, Bianchi, Laura, additional, Fu, Eugene S, additional, Zhang, Yan Ping, additional, Erasso, Diana M, additional, Cui, Jian Guo, additional, Wiltshire, Tim, additional, Li, Qiongzhen, additional, Hao, Shuanglin, additional, Sarantopoulos, Konstantinos D, additional, Candiotti, Keith, additional, Smith, Shad B, additional, Maixner, William, additional, Diatchenko, Luda, additional, and Martin, Eden R, additional

Published
2014
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207. Facial pain with localized and widespread manifestations: Separate pathways of vulnerability

Author

Slade, Gary D., primary, Smith, Shad B., additional, Zaykin, Dmitri V., additional, Tchivileva, Inna E., additional, Gibson, Dustin G., additional, Yuryev, Anton, additional, Mazo, Ilya, additional, Bair, Eric, additional, Fillingim, Roger, additional, Ohrbach, Richard, additional, Greenspan, Joel, additional, Maixner, William, additional, and Diatchenko, Luda, additional

Published
2013
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208. A Genome-wide Drosophila Screen for Heat Nociception Identifies alpha 2 delta 3 as an Evolutionarily Conserved Pain Gene

Author

Neely, G Gregory, Hess, Andreas, Costigan, Michael, Keene, Alex C, Goulas, Spyros, Langeslag, Michiel, Griffin, Robert S, Belfer, Inna, Dai, Feng, Smith, Shad B, Diatchenko, Luda, Gupta, Vaijayanti, Xia, Cui-Ping, Amann, Sabina, Kreitz, Silke, Heindl-Erdmann, Cornelia, Wolz, Susanne, Ly, Cindy V, Sarangi, Rinku, Dan, Debasis, Novatchkova, Maria, Rosenzweig, Mark, Gibson, Dustin G, Truong, Darwin, Schramek, Daniel, Zoranovic, Tamara, Cronin, Shane J F, Angjeli, Belinda, Brune, Kay, Dietzl, Georg, Maixner, William, Meixner, Arabella, Thomas, Winston, Pospisilik, J Andrew, Alenius, Mattias, Kress, Michaela, Subramaniam, Sai, Garrity, Paul A, Bellen, Hugo J, Woolf, Clifford J, Penninger, Josef M, Neely, G Gregory, Hess, Andreas, Costigan, Michael, Keene, Alex C, Goulas, Spyros, Langeslag, Michiel, Griffin, Robert S, Belfer, Inna, Dai, Feng, Smith, Shad B, Diatchenko, Luda, Gupta, Vaijayanti, Xia, Cui-Ping, Amann, Sabina, Kreitz, Silke, Heindl-Erdmann, Cornelia, Wolz, Susanne, Ly, Cindy V, Sarangi, Rinku, Dan, Debasis, Novatchkova, Maria, Rosenzweig, Mark, Gibson, Dustin G, Truong, Darwin, Schramek, Daniel, Zoranovic, Tamara, Cronin, Shane J F, Angjeli, Belinda, Brune, Kay, Dietzl, Georg, Maixner, William, Meixner, Arabella, Thomas, Winston, Pospisilik, J Andrew, Alenius, Mattias, Kress, Michaela, Subramaniam, Sai, Garrity, Paul A, Bellen, Hugo J, Woolf, Clifford J, and Penninger, Josef M

Abstract

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 alpha 2 delta family calcium channel subunit straightjacket (stj). Mice mutant for the stj ortholog CACNA2D3 (alpha 2 delta 3) also exhibit impaired behavioral heat pain sensitivity. In addition, in humans, alpha 2 delta 3 SNP variants associate with reduced sensitivity to acute noxious heat and chronic back pain. Functional imaging in alpha 2 delta 3 mutant mice revealed impaired transmission of thermal pain-evoked signals from the thalamus to higher-order pain centers. Intriguingly, in alpha 2 delta 3 mutant mice, thermal pain and tactile stimulation triggered strong cross-activation, or synesthesia, of brain regions involved in vision, olfaction, and hearing.

Published
2010
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211. Pain modality- and sex-specific effects of COMT genetic functional variants

Author

Belfer, Inna, primary, Segall, Samantha K., additional, Lariviere, William R., additional, Smith, Shad B., additional, Dai, Feng, additional, Slade, Gary D., additional, Rashid, Naim U., additional, Mogil, Jeffrey S., additional, Campbell, Claudia M., additional, Edwards, Robert R., additional, Liu, Qian, additional, Bair, Eric, additional, Maixner, William, additional, and Diatchenko, Luda, additional

Published
2013
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212. Polymorphisms in the glucocorticoid receptor co-chaperone FKBP5 predict persistent musculoskeletal pain after traumatic stress exposure

Author

Bortsov, Andrey V., primary, Smith, Jennifer E., additional, Diatchenko, Luda, additional, Soward, April C., additional, Ulirsch, Jacob C., additional, Rossi, Catherine, additional, Swor, Robert A., additional, Hauda, William E., additional, Peak, David A., additional, Jones, Jeffrey S., additional, Holbrook, Debra, additional, Rathlev, Niels K., additional, Foley, Kelly A., additional, Lee, David C., additional, Collette, Renee, additional, Domeier, Robert M., additional, Hendry, Phyllis L., additional, and McLean, Samuel A., additional

Published
2013
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215. Human Genetic Variability Contributes to Postoperative Morphine Consumption.

Author

De Gregori, Manuela, Diatchenko, Luda, Ingelmo, Pablo M., Napolioni, Valerio, Klepstad, Pal, Belfer, Inna, Molinaro, Valeria, Garbin, Giulia, Ranzani, Guglielmina N., Alberio, Giovanni, Normanno, Marco, Lovisari, Federica, Somaini, Marta, Govoni, Stefano, Mura, Elisa, Bugada, Dario, Niebel, Thekla, Zorzetto, Michele, De Gregori, Simona, and Molinaro, Mariadelfina

Abstract

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-glucuronosyltransferase-2B7, and estrogen receptor (ESR1) gene loci to elucidate genetic prediction of opioid consumption. We analyzed 20 SNPs in 201 unrelated Caucasian patients who underwent abdominal surgery and who were receiving postoperative patient-controlled analgesia-administered morphine. Morphine consumption and pain intensity were dependent variables; age and sex were covariates. A haplotype of 7 SNPs in OPRM1 showed significant additive effects on opioid consumption (P = .007); a linear regression model including age and 9 SNPs in ESR1, OPRM1, and COMT explained the highest proportion of variance of morphine consumption (10.7%; P = .001). The minimal model including 3 SNPs in ESR1, OPRM1, and COMT explained 5% of variance (P = .007). We found a significant interaction between rs4680 in COMT and rs4986936 in ESR1 (P = .007) on opioid consumption. SNPs rs677830 and rs540825 of OPRM1 and rs9340799 of ESR1 were nominally associated with pain Numeric Rating Scale scores. Combinations of genetic variants within OPRM1, COMT, and ESR1 better explain variability in morphine consumption than single genetic variants. Our results contribute to the development of genetic markers and statistical models for future diagnostic tools for opioid consumption/efficacy.Perspective: This article presents the efforts dedicated to detect correlations between the genetic polymorphisms and the clinical morphine effect self-administered by patients using a patient-controlled analgesia pump after major surgery. The clinical effect is expressed in terms of morphine consumption and pain scores. REGISTERED ON CLINICALTRIALS.GOV: NCT01233752. [ABSTRACT FROM AUTHOR]

Published
2016
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216. Differences in the Antinociceptive Effects and Binding Properties of Propranolol and Bupranolol Enantiomers.

Author

Martin, Loren J., Piltonen, Marjo H., Gauthier, Josee, Convertino, Marino, Acland, Erinn L., Dokholyan, Nikolay V., Mogil, Jeffrey S., Diatchenko, Luda, and Maixner, William

Abstract

Unlabelled: Recent efforts have suggested that the β-adrenergic receptor (β-AR) system may be a novel and viable therapeutic target for pain reduction; however, most of the work to date has focused on the β(2)-adrenergic receptor (AR). Here, we compared the antinociceptive effects of enantiomeric configurations of propranolol and bupranolol, two structurally similar nonselective β-blocking drugs, against mouse models of inflammatory and chronic pain. In addition, we calculated in silico docking and measured the binding properties of propranolol and bupranolol for all 3 β-ARs. Of the agents examined, S-bupranolol is superior in terms of its antinociceptive effect and exhibited fewer side effects than propranolol or its associated enantiomers. In contrast to propranolol, S-bupranolol exhibited negligible β-AR intrinsic agonist activity and displayed a full competitive antagonist profile at β(1)/β(2)/β(3)-ARs, producing a unique blockade of β(3)-ARs. We have shown that S-bupranolol is an effective antinociceptive agent in mice without negative side effects. The distinctive profile of S-bupranolol is most likely mediated by its negligible β-AR intrinsic agonist activity and unique blockade of β(3)-AR. These findings suggest that S-bupranolol instead of propranolol may represent a new and effective treatment for a variety of painful conditions.Perspective: The S enantiomer of bupranolol, a β-receptor antagonist, shows greater antinociceptive efficacy and a superior preclinical safety profile and it should be considered as a unique β-adrenergic receptor compound to advance future clinical pain studies. [ABSTRACT FROM AUTHOR]

Published
2015
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217. Quantitative H2S-mediated protein sulfhydration reveals metabolic reprogramming during the Integrated Stress Response.

Author

Xing-Huang Gao, Krokowski, Dawid, Bo-Jhih Guan, Hatzoglou, Maria, Gerson, Stanton L., Bederman, Ilya, Majumder, Mithu, Hoppel, Charles L., Parisien, Marc, Diatchenko, Luda, Kabil, Omer, Banerjee, Ruma, Willard, Belinda, Wang, Benlian, Bebek, Gurkan, Evans, Charles R., Ming Liu, Arvan, Peter, and Fox, Paul L.

Subjects
CYSTEINE, ENDOPLASMIC reticulum, PANCREATIC acinar cells
Abstract

The sulfhydration of cysteine residues in proteins is an important mechanism involved in diverse biological processes. We have developed a proteomics approach to quantitatively profile the changes of sulfhydrated cysteines in biological systems. Bioinformatics analysis revealed that sulfhydrated cysteines are part of a wide range of biological functions. In pancreatic β cells exposed to endoplasmic reticulum (ER) stress, elevated H2S promotes the sulfhydration of enzymes in energy metabolism and stimulates glycolytic flux. We propose that transcriptional and translational reprogramming by the Integrated Stress Response (ISR) in pancreatic β cells is coupled to metabolic alternations triggered by sulfhydration of key enzymes in intermediary metabolism. [ABSTRACT FROM AUTHOR]

Published
2015
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218. Genome-wide association meta-analyses to identify common genetic variants associated with hallux valgus in Caucasian and African Americans.

Author

Yi-Hsiang Hsu, Youfang Liu, Hannan, Marian T., Maixner, William, Smith, Shad B., Diatchenko, Luda, Golightly, Yvonne M., Menz, Hylton B., Kraus, Virginia B., Doherty, Michael, Wilson, A. G., and Jordan, Joanne M.

Subjects
HUMAN genome, META-analysis, HALLUX valgus, CAUCASIAN race, AFRICAN Americans, PATHOLOGICAL physiology
Abstract

Objective Hallux valgus (HV) affects ~36% of Caucasian adults. Although considered highly heritable, the underlying genetic determinants are unclear. We conducted the first genome-wide association study (GWAS) aimed to identify genetic variants associated with HV. Methods HV was assessed in three Caucasian cohorts (n=2263, n=915 and n=1231 participants, respectively). In each cohort, a GWAS was conducted using 2.5 M imputed SNPs. Mixed-effect regression with the additive genetic model adjusted for age, sex, weight and within-family correlations was used for both sex-specific and combined analyses. To combine GWAS results across cohorts, fixed-effect inverse-variance meta-analyses were used. Following meta-analyses, top-associated findings were also examined in an African American cohort (n=327). Results The proportion of HV variance explained by genome-wide genotyped SNPs was 50% in men and 48% in women. A higher proportion of genetic determinants of HV were sex specific. The most significantly associated SNP in men was rs9675316 located on chr17q23-a24 near the AXIN2 gene (p=0.000000546×10-7); the most significantly associated SNP in women was rs7996797 located on chr13q14.1-q14.2 near the ESD gene (p=0.000000721×10-7). Genome-wide significant SNPby- sex interaction was found for SNP rs1563374 located on chr11p15.1 near the MRGPRX3 gene (interaction p value =0.0000000041×10-9). The association signals diminished when combining men and women. Conclusions The findings suggest that the potential pathophysiological mechanisms of HV are complex and strongly underlined by sex-specific interactions. The identified genetic variants imply contribution of biological pathways observed in osteoarthritis as well as new pathways, influencing skeletal development and inflammation. [ABSTRACT FROM AUTHOR]

Published
2015
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219. Construction of a Global Pain Systems Network Highlights Phospholipid Signaling as a Regulator of Heat Nociception

Author

Neely, G. Gregory, primary, Rao, Shuan, additional, Costigan, Michael, additional, Mair, Norbert, additional, Racz, Ildiko, additional, Milinkeviciute, Giedre, additional, Meixner, Arabella, additional, Nayanala, Swetha, additional, Griffin, Robert S., additional, Belfer, Inna, additional, Dai, Feng, additional, Smith, Shad, additional, Diatchenko, Luda, additional, Marengo, Stefano, additional, Haubner, Bernhard J., additional, Novatchkova, Maria, additional, Gibson, Dustin, additional, Maixner, William, additional, Pospisilik, J. Andrew, additional, Hirsch, Emilio, additional, Whishaw, Ian Q., additional, Zimmer, Andreas, additional, Gupta, Vaijayanti, additional, Sasaki, Junko, additional, Kanaho, Yasunori, additional, Sasaki, Takehiko, additional, Kress, Michaela, additional, Woolf, Clifford J., additional, and Penninger, Josef M., additional

Published
2012
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221. Genetically determined P2X7 receptor pore formation regulates variability in chronic pain sensitivity

Author

Sorge, Robert E, primary, Trang, Tuan, additional, Dorfman, Ruslan, additional, Smith, Shad B, additional, Beggs, Simon, additional, Ritchie, Jennifer, additional, Austin, Jean-Sebastien, additional, Zaykin, Dmitri V, additional, Meulen, Heather Vander, additional, Costigan, Michael, additional, Herbert, Teri A, additional, Yarkoni-Abitbul, Merav, additional, Tichauer, David, additional, Livneh, Jessica, additional, Gershon, Edith, additional, Zheng, Ming, additional, Tan, Keith, additional, John, Sally L, additional, Slade, Gary D, additional, Jordan, Joanne, additional, Woolf, Clifford J, additional, Peltz, Gary, additional, Maixner, William, additional, Diatchenko, Luda, additional, Seltzer, Ze'ev, additional, Salter, Michael W, additional, and Mogil, Jeffrey S, additional

Published
2012
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222. Catechol-O-Methyltransferase Genotype Predicts Pain Severity in Hospitalized Burn Patients

Author

Orrey, Danielle C., primary, Bortsov, Andrey V., additional, Hoskins, Janelle M., additional, Shupp, Jeffrey W., additional, Jones, Samuel W., additional, Cicuto, Bryan J., additional, Hwang, James, additional, Jordan, Marion H., additional, Holmes, James H., additional, Haith, Linwood R., additional, Roane, Brandon M., additional, Diatchenko, Luda, additional, Cairns, Bruce A., additional, and McLean, Samuel A., additional

Published
2012
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224. Tissue-Specific Regulation Of Microrna-374 Family And Its mRNA Targets Associated With Pain In Humans And Mice

Author

Hernandez, Nathaniel, Rawls, Ashleigh, Wang, Yaomin, Zhang, Xin, Chen, Jiegen, Pan, Yue, Dang, Hong, Slade, Gary, Linnstaedt, Sarah, Parisien, Marc, Diatchenko, Luda, and Nackley, Andrea

Abstract

MiRNAs are well known to negatively regulate the expression of pain-relevant genes. Previously, we identified miRNAs contributing to pain associated with high catecholamine tone in two cohorts: one with tempromandibular disorder (TMD; N=488) and one with pain following motor vehicle collision (MVC; N=167). We found that miR-374 was downregulated in the plasma of both sexes of patients with TMD and MVC-related pain compared to controls. This signature was replicated in our mouse model of acute stress and pain associated with high catecholamine tone (N=31), providing the first link between miR-374 and pain. The purpose of the present study was to measure expression of miR-374′s predicted mRNA targets in tissues collected from the same mice. We predicted an overexpression of pain-relevant mRNAs with complimentary sequences to miR-374 in sites of miRNA downregulation. For the initial screen, we measured the expression of miR-374 and 10 mRNAs associated with miR-374 expression in the TMD cohort in 5 tissues (intrascapular brown adipose, subcutaneous white adipose, muscle, dorsal root ganglion, and spinal cord) using qPCR and 2-∆∆Ct analysis. Results show negative correlations between miR-374 and its mRNA targets. In white adipose, miR-374 was downregulated in both sexes, while CRK was upregulated in males and HIF1A, NUMB, and TGFBR2 were upregulated in females. In spinal cord, miR-374 was downregulated in females, while ATXN7 and TGFBR2 were upregulated in females compared to males. These data provide a framework for future experiments to confirm miRNA-mRNA interactions and determine the causal role of miR-374 in pain. NIH R01 NS109541, R61 NS123753, and R56 DE025298 to A Nackley. NIH K01 AR071504 to S Linnstaedt.

Published
2023
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225. Cytokine biomarkers and chronic pain: Association of genes, transcription, and circulating proteins with temporomandibular disorders and widespread palpation tenderness

Author

Slade, Gary D., primary, Conrad, Mathew S., additional, Diatchenko, Luda, additional, Rashid, Naim U., additional, Zhong, Sheng, additional, Smith, Shad, additional, Rhodes, Jesse, additional, Medvedev, Alex, additional, Makarov, Sergei, additional, Maixner, William, additional, and Nackley, Andrea G., additional

Published
2011
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227. Potential Autonomic Risk Factors for Chronic TMD: Descriptive Data and Empirically Identified Domains from the OPPERA Case-Control Study

Author

Maixner, William, primary, Greenspan, Joel D., additional, Dubner, Ronald, additional, Bair, Eric, additional, Mulkey, Flora, additional, Miller, Vanessa, additional, Knott, Charles, additional, Slade, Gary D., additional, Ohrbach, Richard, additional, Diatchenko, Luda, additional, and Fillingim, Roger B., additional

Published
2011
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228. Study Methods, Recruitment, Sociodemographic Findings, and Demographic Representativeness in the OPPERA Study

Author

Slade, Gary D., primary, Bair, Eric, additional, By, Kunthel, additional, Mulkey, Flora, additional, Baraian, Cristina, additional, Rothwell, Rebecca, additional, Reynolds, Maria, additional, Miller, Vanessa, additional, Gonzalez, Yoly, additional, Gordon, Sharon, additional, Ribeiro-Dasilva, Margarete, additional, Lim, Pei Feng, additional, Greenspan, Joel D., additional, Dubner, Ron, additional, Fillingim, Roger B., additional, Diatchenko, Luda, additional, Maixner, William, additional, Dampier, Dawn, additional, Knott, Charles, additional, and Ohrbach, Richard, additional

Published
2011
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229. Potential Genetic Risk Factors for Chronic TMD: Genetic Associations from the OPPERA Case Control Study

Author

Smith, Shad B., primary, Maixner, Dylan W., additional, Greenspan, Joel D., additional, Dubner, Ronald, additional, Fillingim, Roger B., additional, Ohrbach, Richard, additional, Knott, Charles, additional, Slade, Gary D., additional, Bair, Eric, additional, Gibson, Dustin G., additional, Zaykin, Dmitri V., additional, Weir, Bruce S., additional, Maixner, William, additional, and Diatchenko, Luda, additional

Published
2011
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234. Catechol O-Methyltransferase Haplotype Predicts Immediate Musculoskeletal Neck Pain and Psychological Symptoms After Motor Vehicle Collision

Author

McLean, Samuel A., primary, Diatchenko, Luda, additional, Lee, Young M., additional, Swor, Robert A., additional, Domeier, Robert M., additional, Jones, Jeffrey S., additional, Jones, Christopher W., additional, Reed, Caroline, additional, Harris, Richard E., additional, Maixner, William, additional, Clauw, Daniel J., additional, and Liberzon, Israel, additional

Published
2011
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235. A Genome-wide Drosophila Screen for Heat Nociception Identifies α2δ3 as an Evolutionarily Conserved Pain Gene

Author

Neely, G. Gregory, primary, Hess, Andreas, additional, Costigan, Michael, additional, Keene, Alex C., additional, Goulas, Spyros, additional, Langeslag, Michiel, additional, Griffin, Robert S., additional, Belfer, Inna, additional, Dai, Feng, additional, Smith, Shad B., additional, Diatchenko, Luda, additional, Gupta, Vaijayanti, additional, Xia, Cui-ping, additional, Amann, Sabina, additional, Kreitz, Silke, additional, Heindl-Erdmann, Cornelia, additional, Wolz, Susanne, additional, Ly, Cindy V., additional, Arora, Suchir, additional, Sarangi, Rinku, additional, Dan, Debasis, additional, Novatchkova, Maria, additional, Rosenzweig, Mark, additional, Gibson, Dustin G., additional, Truong, Darwin, additional, Schramek, Daniel, additional, Zoranovic, Tamara, additional, Cronin, Shane J.F., additional, Angjeli, Belinda, additional, Brune, Kay, additional, Dietzl, Georg, additional, Maixner, William, additional, Meixner, Arabella, additional, Thomas, Winston, additional, Pospisilik, J. Andrew, additional, Alenius, Mattias, additional, Kress, Michaela, additional, Subramaniam, Sai, additional, Garrity, Paul A., additional, Bellen, Hugo J., additional, Woolf, Clifford J., additional, and Penninger, Josef M., additional

Published
2010
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237. Pain perception is altered by a nucleotide polymorphism in SCN9A

Author

Reimann, Frank, primary, Cox, James J., additional, Belfer, Inna, additional, Diatchenko, Luda, additional, Zaykin, Dmitri V., additional, McHale, Duncan P., additional, Drenth, Joost P. H., additional, Dai, Feng, additional, Wheeler, Jerry, additional, Sanders, Frances, additional, Wood, Linda, additional, Wu, Tian-Xia, additional, Karppinen, Jaro, additional, Nikolajsen, Lone, additional, Männikkö, Minna, additional, Max, Mitchell B., additional, Kiselycznyk, Carly, additional, Poddar, Minakshi, additional, te Morsche, Rene H.M., additional, Smith, Shad, additional, Gibson, Dustin, additional, Kelempisioti, Anthi, additional, Maixner, William, additional, Gribble, Fiona M., additional, and Woods, C. Geoffrey, additional

Published
2010
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242. Expansion of the human μ-opioid receptor gene architecture: novel functional variants

Author

Shabalina, Svetlana A., primary, Zaykin, Dmitri V., additional, Gris, Pavel, additional, Ogurtsov, Aleksey Y., additional, Gauthier, Josee, additional, Shibata, Kyoko, additional, Tchivileva, Inna E., additional, Belfer, Inna, additional, Mishra, Bikashkumar, additional, Kiselycznyk, Carly, additional, Wallace, Margaret R., additional, Staud, Roland, additional, Spiridonov, Nikolay A., additional, Max, Mitchell B., additional, Goldman, David, additional, Fillingim, Roger B., additional, Maixner, William, additional, and Diatchenko, Luda, additional

Published
2008
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250. Three major haplotypes of the β2 adrenergic receptor define psychological profile, blood pressure, and the risk for development of a common musculoskeletal pain disorder

Author

Diatchenko, Luda, primary, Anderson, Amy D., additional, Slade, Gary D., additional, Fillingim, Roger B., additional, Shabalina, Svetlana A., additional, Higgins, Tomas J., additional, Sama, Swetha, additional, Belfer, Inna, additional, Goldman, David, additional, Max, Mitchell B., additional, Weir, Bruce S., additional, and Maixner, William, additional

Published
2006
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