Genetic architecture of human pain perception

Center for Neurosensory Disorders, University of North Carolina, 2190 Old Dental Building, Chapel Hill, NC 27599, USA.
Trends in Genetics (Impact Factor: 11.6). 01/2008; 23(12):605-13. DOI: 10.1016/j.tig.2007.09.004
Source: PubMed

ABSTRACT Pain is emotionally detrimental and consciously avoided; however, it is absolutely crucial for our survival. Pain perception is one of the most complicated measurable traits because it is an aggregate of several phenotypes associated with peripheral and central nervous system dynamics, stress responsiveness and inflammatory state. As a complex trait, it is expected to have a polygenic nature shaped by environmental pressures. Here we discuss what is known about these contributing genetic variants, including recent discoveries that show a crucial role of voltage-gated sodium channel Nav1.7 in pain perception and how we can advance our understanding of the pain genetic network. We propose how both rare deleterious genetic variants and common genetic polymorphisms are mediators of human pain perception and clinical pain phenotypes.

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    • "cluster headache, post-traumatic headache, post-herpetic neuralgia ) (Cairns, 2007). Genetic variants and polymorphisms as well as environmental factors have been shown to affect the susceptibility to different pain conditions (Diatchenko et al., 2007). Still, pain symptoms in women with IBS, TMD, and migraine fluctuate with the menstrual cycle (Houghton et al., 2002; Johannes et al., 1995; LeResche et al., 2003) and increased estrogen levels also correlate with a higher risk of chronic lower back pain (Wijnhoven et al., 2006) and temporomandibular disorders (LeResche et al., 1997). "
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    ABSTRACT: Gonadal hormones not only play a pivotal role in reproductive behavior and sexual differentiation, they also contribute to thermoregulation, feeding, memory, neuronal survival, and the perception of somatosensory stimuli. Numerous studies on both animals and human subjects have also demonstrated the potential effects of gonadal hormones, such as estrogens, on pain transmission. These effects most likely involve multiple neuroanatomical circuits as well as diverse neurochemical systems and they therefore need to be evaluated specifically to determine the localization and intrinsic characteristics of the neurons engaged. The aim of this review is to summarize the morphological as well as biochemical evidence in support for gonadal hormone modulation of nociceptive processing, with particular focus on estrogens and spinal cord mechanisms.
    Frontiers in Neuroendocrinology 06/2013; DOI:10.1016/j.yfrne.2013.06.001 · 7.58 Impact Factor
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    • "It is well known that the degree of chronic pain differs considerably among individuals with seemingly similar types of injuries. It is also well established that there is wide variability in threshold sensitivity and tolerance level to noxious stimulation among human populations, which cannot be fully explained by environmental and cultural causes (Mogil, 1999; Diatchenko et al., 2007). Ample evidence demonstrates that this is also the case in a range of experimental pain models, including neuropathic pain models (Devor and Raber, 1990; Lacroix-Fralish et al., 2006b; Costigan et al., 2010). "
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    ABSTRACT: Chronic pain of neuropathic nature after spinal cord injury (SCI) is common and its underlying mechanisms are poorly understood. Genes, as well as sex, have been implicated, but not thoroughly investigated in experimental genetic models for complex traits. We have previously found that inbred Dark-Agouti (DA) rats develop more severe SCI pain-like behaviour than a major histocompatibility complex-congenic Piebald Virol Glaxo (PVG)-RT1(av1) strain in a model of photochemically induced SCI. In this study, a genome-wide linkage study in an F2 cross between the susceptible DA and resistant PVG-RT1(av1) strains was performed in order to explore the influence of genes and sex for SCI pain. A consistent finding was that female rats in parental, F1 and F2 generations displayed increased pain sensitivity at testing before injury and also developed mechanical hypersensitivity more rapidly and to a greater extent than male rats. In addition, we could identify three quantitative trait loci (QTLs) associated with pain-like behaviour: a sex-specific QTL on chromosome 2, one on chromosome 15 and on chromosome 6. Animals carrying DA alleles at each of these loci were more susceptible to development of mechanical hypersensitivity compared with rats with PVG alleles. This is the first whole genome QTL mapping of neuropathic pain-like behaviour in a model of SCI. The results provide strong support for a significant genetic and sex component in development of pain after SCI and provide the basis for further genetic dissection and positional cloning of the underlying genes.
    European journal of pain (London, England) 11/2012; 16(10):1368-77. DOI:10.1002/j.1532-2149.2012.00144.x · 3.22 Impact Factor
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    • "Rodent and human studies suggest that neuropathic pain susceptibility is genetically linked (Diatchenko et al., 2007; Lacroix-Fralish and Mogil, 2009; Costigan et al., 2009b). We used a convergent experimental approach that implicates KCNS1 as a gene marking the risk of developing neuropathic pain. "
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    ABSTRACT: Not all patients with nerve injury develop neuropathic pain. The extent of nerve damage and age at the time of injury are two of the few risk factors identified to date. In addition, preclinical studies show that neuropathic pain variance is heritable. To define such factors further, we performed a large-scale gene profiling experiment which plotted global expression changes in the rat dorsal root ganglion in three peripheral neuropathic pain models. This resulted in the discovery that the potassium channel alpha subunit KCNS1, involved in neuronal excitability, is constitutively expressed in sensory neurons and markedly downregulated following nerve injury. KCNS1 was then characterized by an unbiased network analysis as a putative pain gene, a result confirmed by single nucleotide polymorphism association studies in humans. A common amino acid changing allele, the 'valine risk allele', was significantly associated with higher pain scores in five of six independent patient cohorts assayed (total of 1359 subjects). Risk allele prevalence is high, with 18-22% of the population homozygous, and an additional 50% heterozygous. At lower levels of nerve damage (lumbar back pain with disc herniation) association with greater pain outcome in homozygote patients is P = 0.003, increasing to P = 0.0001 for higher levels of nerve injury (limb amputation). The combined P-value for pain association in all six cohorts tested is 1.14 E-08. The risk profile of this marker is additive: two copies confer the most, one intermediate and none the least risk. Relative degrees of enhanced risk vary between cohorts, but for patients with lumbar back pain, they range between 2- and 3-fold. Although work still remains to define the potential role of this protein in the pathogenic process, here we present the KCNS1 allele rs734784 as one of the first prognostic indicators of chronic pain risk. Screening for this allele could help define those individuals prone to a transition to persistent pain, and thus requiring therapeutic strategies or lifestyle changes that minimize nerve injury.
    Brain 09/2010; 133(9):2519-27. DOI:10.1093/brain/awq195 · 10.23 Impact Factor
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