Genetic components of human pain sensitivity: a protocol for a genome-wide association study of experimental pain in healthy volunteers

Introduction Pain constitutes a major component of the global burden of diseases. Recent studies suggest a strong genetic contribution to pain susceptibility and severity. Whereas most of the available evidence relies on candidate gene association or linkage studies, research on the genetic basis of pain sensitivity using genome-wide association studies (GWAS) is still in its infancy. This protocol describes a proposed GWAS on genetic contributions to baseline pain sensitivity and nociceptive sensitisation in a sample of unrelated healthy individuals of mixed Latin American ancestry. Methods and analysis A GWAS on genetic contributions to pain sensitivity in the naïve state and following nociceptive sensitisation will be conducted in unrelated healthy individuals of mixed ancestry. Mechanical and thermal pain sensitivity will be evaluated with a battery of quantitative sensory tests evaluating pain thresholds. In addition, variation in mechanical and thermal sensitisation following topical application of mustard oil to the skin will be evaluated. Ethics and dissemination This study received ethical approval from the University College London research ethics committee (3352/001) and from the bioethics committee of the Odontology Faculty at the University of Antioquia (CONCEPTO 01–2013). Findings will be disseminated to commissioners, clinicians and service users via papers and presentations at international conferences

NIVEL DE EVIDENCIA EN IMPLANTES: VERDADES A MEDIAS EN CONSTRUCCIÓN

A manera de cavilación se pretende hacer un llamado a la investigación y a la mesura que abra un espacio para el trabajo en equipo en el que se hace imprescindible la planeación y en donde el nivel de evidencia basado en estudios con diseños metodológicos adecuados hacen creíble y traducible la información que se ofrece sobre esta temática que sin duda es actual y polémica. Además de tratar en concreto lo que la evidencia muestra sobre las uniones diente-implante y que aun se considera un tópico controvertible, se profundiza en la limitación de estudios con buenos diseños metodológicos que permitan llegar a conclusiones importantes en esta área biomédica. Igualmente, el considerable desconocimiento en la mayoría de protocolos de carga inmediata y temprana con implantes orales vistos en diferentes situaciones de edentulismo no es contemplado por algunos programas de escuelas odontológicas y casas comerciales que los avalan y popularizan basándose en investigaciones muy lejanas a las adecuadas y con un buen nivel de evidencia. Abstract As a reflection this article intends to make a call for the research and for the restraint, while opening a space for teamwork in which planning is prevalent and where the level of evidence-based studies with adequate methodological designs make credible and translate the information on this subject that is current and certainly controversial. It deals specifically what the evidence shows about tooth-implant unions that are still considered a controversial topic, also, describes the limitation of studies with good methodological designs that will lead to important conclusions in this biomedical area. Similarly, considerable unawareness in most protocols for immediate and progressive implants loading in different edentulism situations is not pondered by some dental schools programs and commercial corporations that consider them very popular and based on research far from adequate with a good level of evidence

Sodium-calcium exchanger-3 regulates pain “wind-up”: From human psychophysics to spinal mechanisms

Repeated application of noxious stimuli leads to a progressively increased pain perception; this temporal summation is enhanced in and predictive of clinical pain disorders. Its electrophysiological correlate is “wind-up,” in which dorsal horn spinal neurons increase their response to repeated nociceptor stimulation. To understand the genetic basis of temporal summation, we undertook a GWAS of wind-up in healthy human volunteers and found significant association with SLC8A3 encoding sodium-calcium exchanger type 3 (NCX3). NCX3 was expressed in mouse dorsal horn neurons, and mice lacking NCX3 showed normal, acute pain but hypersensitivity to the second phase of the formalin test and chronic constriction injury. Dorsal horn neurons lacking NCX3 showed increased intracellular calcium following repetitive stimulation, slowed calcium clearance, and increased wind-up. Moreover, virally mediated enhanced spinal expression of NCX3 reduced central sensitization. Our study highlights Ca2+ efflux as a pathway underlying temporal summation and persistent pain, which may be amenable to therapeutic targeting

Sodium-calcium exchanger-3 regulates pain "wind-up": From human psychophysics to spinal mechanisms

Repeated application of noxious stimuli leads to a progressively increased pain perception; this temporal summation is enhanced in and predictive of clinical pain disorders. Its electrophysiological correlate is "wind-up," in which dorsal horn spinal neurons increase their response to repeated nociceptor stimulation. To understand the genetic basis of temporal summation, we undertook a GWAS of wind-up in healthy human volunteers and found significant association with SLC8A3 encoding sodium-calcium exchanger type 3 (NCX3). NCX3 was expressed in mouse dorsal horn neurons, and mice lacking NCX3 showed normal, acute pain but hypersensitivity to the second phase of the formalin test and chronic constriction injury. Dorsal horn neurons lacking NCX3 showed increased intracellular calcium following repetitive stimulation, slowed calcium clearance, and increased wind-up. Moreover, virally mediated enhanced spinal expression of NCX3 reduced central sensitization. Our study highlights Ca2+efflux as a pathway underlying temporal summation and persistent pain, which may be amenable to therapeutic targeting

Neanderthal introgression in SCN9A impacts mechanical pain sensitivity

The Nav1.7 voltage-gated sodium channel plays a key role in nociception. Three functional variants in the SCN9A gene (encoding M932L, V991L, and D1908G in Nav1.7), have recently been identified as stemming from Neanderthal introgression and to associate with pain symptomatology in UK BioBank data. In 1000 genomes data, these variants are absent in Europeans but common in Latin Americans. Analysing high-density genotype data from 7594 Latin Americans, we characterized Neanderthal introgression in SCN9A. We find that tracts of introgression occur on a Native American genomic background, have an average length of ~123 kb and overlap the M932L, V991L, and D1908G coding positions. Furthermore, we measured experimentally six pain thresholds in 1623 healthy Colombians. We found that Neanderthal ancestry in SCN9A is significantly associated with a lower mechanical pain threshold after sensitization with mustard oil and evidence of additivity of effects across Nav1.7 variants. Our findings support the reported association of Neanderthal Nav1.7 variants with clinical pain, define a specific sensory modality affected by archaic introgression in SCN9A and are consistent with independent effects of the Neanderthal variants on Nav1.7 function