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Human Molecular Genetics Advance Access originally published online on November 10, 2004
Human Molecular Genetics 2005 14(1):135-143; doi:10.1093/hmg/ddi013
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Human Molecular Genetics, Vol. 14, No. 1 © Oxford University Press 2005; all rights reserved

Genetic basis for individual variations in pain perception and the development of a chronic pain condition

Luda Diatchenko1,8,*, Gary D. Slade2, Andrea G. Nackley1, Konakporn Bhalang3, Asgeir Sigurdsson1, Inna Belfer4,7, David Goldman4, Ke Xu4, Svetlana A. Shabalina5, Dmitry Shagin6, Mitchell B. Max7, Sergei S. Makarov8 and William Maixner1

1Comprehensive Center for Inflammatory Disorders, University of North Carolina at Chapel Hill, Columbia Street, CB#7455, Chapel Hill, NC 27599, USA, 2Australian Research Centre for Population Oral Health, University of Adelaide, Frome Road, SA 5005, Adelaide, Australia, 3Department of Oral Medicine, Chulalongkorn University, 254 Phyathai Road, Bangkok 10330, Thailand, 4Laboratory of Neurogenetics, NIAAA, NIH, 12420 Parklawn Drive, Park 5 Building, Rockville, MD 20852, USA, 5NCBI, NIH, 6404 Landon Lane, 8600 Rockville Pike, Bethesda, MD 20894, USA, 6Shemyakin and Ovchinnikov Institute of Bioorganic Chemistry RAS, Ul. Miklukho-Maklaya 16/10, 117997, Moscow, Russia, 7NIDCR, NIH, Pain and Neurosensory Mechanisms Branch, Building 10, Room 3C-405, Bethesda, MD 20892-1258, USA and 8Attagene, Inc., 7030 Kit Creek Road, Research Triangle Park, NC 27560, USA

* To whom correspondence should be addressed at: Comprehensive Center for Inflammatory Disorders, University of North Carolina at Chapel Hill, Columbia Street, CB#7455, 2190 Old Dental Building, Chapel Hill, NC 27599, USA. Tel: +1 9198432549; Fax: +1 9199663683; Email: lbdiatch{at}email.unc.edu

Received September 22, 2004; Accepted November 2, 2004

Pain sensitivity varies substantially among humans. A significant part of the human population develops chronic pain conditions that are characterized by heightened pain sensitivity. We identified three genetic variants (haplotypes) of the gene encoding catecholamine-O-methyltransferase (COMT) that we designated as low pain sensitivity (LPS), average pain sensitivity (APS) and high pain sensitivity (HPS). We show that these haplotypes encompass 96% of the human population, and five combinations of these haplotypes are strongly associated (P=0.0004) with variation in the sensitivity to experimental pain. The presence of even a single LPS haplotype diminishes, by as much as 2.3 times, the risk of developing myogenous temporomandibular joint disorder (TMD), a common musculoskeletal pain condition. The LPS haplotype produces much higher levels of COMT enzymatic activity when compared with the APS or HPS haplotypes. Inhibition of COMT in the rat results in a profound increase in pain sensitivity. Thus, COMT activity substantially influences pain sensitivity, and the three major haplotypes determine COMT activity in humans that inversely correlates with pain sensitivity and the risk of developing TMD.


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