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Review
. 2013 Jun;9(6):340-50.
doi: 10.1038/nrrheum.2013.43. Epub 2013 Apr 2.

The phenotypic and genetic signatures of common musculoskeletal pain conditions

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Review

The phenotypic and genetic signatures of common musculoskeletal pain conditions

Luda Diatchenko et al. Nat Rev Rheumatol. 2013 Jun.

Abstract

Musculoskeletal pain conditions, such as fibromyalgia and low back pain, tend to coexist in affected individuals and are characterized by a report of pain greater than expected based on the results of a standard physical evaluation. The pathophysiology of these conditions is largely unknown, we lack biological markers for accurate diagnosis, and conventional therapeutics have limited effectiveness. Growing evidence suggests that chronic pain conditions are associated with both physical and psychological triggers, which initiate pain amplification and psychological distress; thus, susceptibility is dictated by complex interactions between genetic and environmental factors. Herein, we review phenotypic and genetic markers of common musculoskeletal pain conditions, selected based on their association with musculoskeletal pain in previous research. The phenotypic markers of greatest interest include measures of pain amplification and 'psychological' measures (such as emotional distress, somatic awareness, psychosocial stress and catastrophizing). Genetic polymorphisms reproducibly linked with musculoskeletal pain are found in genes contributing to serotonergic and adrenergic pathways. Elucidation of the biological mechanisms by which these markers contribute to the perception of pain in these patients will enable the development of novel effective drugs and methodologies that permit better diagnoses and approaches to personalized medicine.

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Figures

Figure 1
Figure 1
The translational clock—a schematic representation of a novel and rapid approach to identification of new therapeutic targets in commonly observed persistent pain conditions. The identification of COMT as a therapeutic target in TMD is used as an example, to provide an idea of the timescales involved. Identification of common genetic variants associated with risk of developing a chronic pain condition can reveal putative causal biological pathways. In our example, in 2005, COMT haplotypes were associated with experimental pain and myogenous TMD. Subsequent in vitro and in vivo proof-of-principle studies should demonstrate that the pharmacological or genetic modification of the identified pathways can produce cellular phenotypes and animal behaviours consistent with the human pain condition. For example, in 2006, a cellular molecular study demonstrated that COMT levels and activity were associated with COMT haplotypes. In 2007, pharmacological inhibition of COMT in rats was shown to increase sensitivity to pain, a response abrogated by β23-adrenergic antagonists, thus, identifying β-adrenergic receptors as therapeutic targets. Following positive proof-of-principle studies, a clinical proof-of-concept trial can be initiated using either existing or novel pharmacological agents. In our example, the nonselective β-adrenergic antagonist propranolol was the subject of a 2010 clinical trial in patients with TMD. This reverse translational process results in the rapid discovery and testing of interventions that modify the identified biological pathways that determine susceptibility. Abbreviations: COMT, catechol O-methyltransferase, TMD, temporomandibular joint disorder.
Figure 2
Figure 2
The pathological chronic pain circle. Genetic and environment interactions contribute to the development of pain conditions. Allelic variation underlies functional differences in expression or activity of pain-related gene products and activation of associated biological pathways, leading to manifestation of related pain endophenotypes. In addition, pain endophenotypes are shaped by exposure to environmental factors, which result in alteration of DNA methylation patterns that, in turn, change the expression of pain-related genes and the activity of associated biological pathways. With prolonged exposure to environmental stimuli that induce long-term methylation patterns—that is, long-lasting changes in DNA methylation—on a background of genetic susceptibility, altered gene expression profiles enable the transition of an acute pain state to a chronic pain state. The biological processes that lead to the chronic pain state further increase sensitivity to painful stimuli and perceived levels of stress, which further modifies pain-related gene expression, creating a pathological pain cycle.

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