While it has become clear in recent years that susceptibility to pain has a strong inherited component, very little is known about actual "pain genes" and how they work. In the November 12th issue of Cell, researchers at Children's Hospital Boston and their collaborators report on a novel human pain gene.
People with minor variations in this gene showed clear differences in susceptibility to acute heat pain and chronic back pain. Corroborating mouse studies give some clues as to how the gene controls pain sensitivity. The gene was uncovered in a genome-wide hunt for pain genes in fruit flies, which revealed hundreds of other candidate pain genes that await further study.
Understanding the genetic basis of pain will lead to the development of new analgesics, the identification of risk factors for chronic pain and improved decision-making about the suitability of surgical treatment for different patients, says Clifford Woolf, MB, BCh, PhD, the study's senior co-author and director of the F.M. Kirby Center and Program in Neurobiology at Children's.
Classic studies of twins indicate that about 50 percent of variance in pain sensitivity is inherited. "Across a number of different kinds of pain, genes seem to be at least half the driver of how much pain you experience," Woolf says. "Genes give us an amazing and powerful tool to begin to understand how pain is generated, and which functional pathways and specific proteins are involved."
The new gene, discovered in a collaboration with the Institute of Molecular Biotechnology of the Austrian Academy of Sciences and others, encodes part of a calcium channel called alpha 2 delta 3 (á2ä3). Calcium channels are pores in the cell membrane through which calcium ions pass, and are critical for the electrical excitability of nerve cells.
The study, co-led by Joseph Penninger, PhD, scientific director of the Institute of Molecular Biotechnology in Vienna, took advantage of the relative ease of conducting genetic screens in fruit flies. Nearly 12,000 genes were targeted for mutations specifically in nerve cells, using RNA interference (RNAi) technology. The team then exposed the different mutant flies to noxious heat, and identified the ones that failed to fly away. After eliminating flies with other complications, such as an inability to see or fly, they zeroed in on those with mutations that appeared to be specific to pain.
Of the nearly 600 candidate pain genes identified, á2ä3 was one chosen for further study, in part because calcium channels are a known target of some existing analgesics. (Another member of the á2ä family of calcium channels, á2ä1, is a target of gabapentin and pregablin, commonly prescribed for neuropathic pain.)
Studies of mice lacking á2ä3 demonstrated that this gene controls sensitivity to noxious heat in mammals as well as flies. Further, functional MRI imaging of the mutant mice revealed that á2ä3 controls the processing of thermal pain signals in the brain: the heat pain signal seems to arrive appropriately at the thalamus, an early processing center, but does not travel to higher order pain centers in the cortex. Instead, the MRI images showed a surprising cross-activation of vision, olfaction and hearing cortical areas. This cross-activation, or synesthesia, was noted with tactile stimulation in addition to the heat pain stimulus.
To determine the gene's role in human pain sensitivity, Michael Costigan, PhD, assistant professor at Children's, together with colleagues at the University of Pittsburgh and the University of North Carolina, looked at four single nucleotide polymorphisms (SNPs), or single-letter variations in the DNA code, within or close to the á2ä3 gene in 189 healthy volunteers. They found that certain less common SNPs were associated with reduced sensitivity to acute pain in a test administering a quick series of noxious heat pulses. Additional testing in 169 patients who had undergone surgery for pain caused by herniated vertebral discs revealed that patients with these less common SNPs were substantially less likely to have persisting chronic pain.
The international team plans further studies on the other pain genes identified in the fly screen. In a recent publication in the journal Brain, Costigan and Woolf identified the gene encoding the potassium ion channel subunit KCNS1 as another pain gene. Minor variations in KCNS1 accounted for differential sensitivity to chronic pain in five of six independent patient cohorts. These patients, 1359 in total, suffered from lumbar back pain, pain following limb amputation or sciatica. A SNP in KCNS1 also accounted for differences in acute pain sensitivity in healthy volunteers. Importantly, the SNP variant associated with a higher risk of pain is relatively common in the general population—present homozygously (in its strongest form) in about one in five people and heterozygously (in a less dominant form) in about one in two people.
In 2006, the Woolf laboratory identified the first pain sensitivity gene in humans, GCH1, which encodes an enzyme controlling the synthesis of a co-factor essential for production of certain neurotransmitters.
"We are trying now to use a panel of the pain genes we've found— á2ä3, KCNS1, GCH1 and others—to develop a genetic risk profile and then say, if you combine these polymorphisms you have a 60% chance of chronic pain after surgery, versus say, if you have another polymorphism mix, a 5% chance. This is another way to personalize medicine," Woolf says.
The study was funded by the National Institutes of Health, the Austrian Academy of Sciences, the European Research Council and other organizations. The co-first authors were G. Gregory Neely, PhD of the Institute of Molecular Biotechnology and Andreas Hess, PhD of the University of Erlangen-Nuremberg in Germany.
Children's Hospital Boston is home to the world's largest research enterprise based at a pediatric medical center, where its discoveries have benefited both children and adults since 1869. More than 1,100 scientists, including nine members of the National Academy of Sciences, 12 members of the Institute of Medicine and 13 members of the Howard Hughes Medical Institute comprise Children's research community. Founded as a 20-bed hospital for children, Children's Hospital Boston today is a 392-bed comprehensive center for pediatric and adolescent health care grounded in the values of excellence in patient care and sensitivity to the complex needs and diversity of children and families. Children's also is the primary pediatric teaching affiliate of Harvard Medical School. For more information about the hospital and its research visit: www.childrenshospital.org/newsroom.
Erin McColgan | EurekAlert!
Link Discovered between Immune System, Brain Structure and Memory
26.04.2017 | Universität Basel
Researchers develop eco-friendly, 4-in-1 catalyst
25.04.2017 | Brown University
More and more automobile companies are focusing on body parts made of carbon fiber reinforced plastics (CFRP). However, manufacturing and repair costs must be further reduced in order to make CFRP more economical in use. Together with the Volkswagen AG and five other partners in the project HolQueSt 3D, the Laser Zentrum Hannover e.V. (LZH) has developed laser processes for the automatic trimming, drilling and repair of three-dimensional components.
Automated manufacturing processes are the basis for ultimately establishing the series production of CFRP components. In the project HolQueSt 3D, the LZH has...
Reflecting the structure of composites found in nature and the ancient world, researchers at the University of Illinois at Urbana-Champaign have synthesized thin carbon nanotube (CNT) textiles that exhibit both high electrical conductivity and a level of toughness that is about fifty times higher than copper films, currently used in electronics.
"The structural robustness of thin metal films has significant importance for the reliable operation of smart skin and flexible electronics including...
The nearby, giant radio galaxy M87 hosts a supermassive black hole (BH) and is well-known for its bright jet dominating the spectrum over ten orders of magnitude in frequency. Due to its proximity, jet prominence, and the large black hole mass, M87 is the best laboratory for investigating the formation, acceleration, and collimation of relativistic jets. A research team led by Silke Britzen from the Max Planck Institute for Radio Astronomy in Bonn, Germany, has found strong indication for turbulent processes connecting the accretion disk and the jet of that galaxy providing insights into the longstanding problem of the origin of astrophysical jets.
Supermassive black holes form some of the most enigmatic phenomena in astrophysics. Their enormous energy output is supposed to be generated by the...
The probability to find a certain number of photons inside a laser pulse usually corresponds to a classical distribution of independent events, the so-called...
Microprocessors based on atomically thin materials hold the promise of the evolution of traditional processors as well as new applications in the field of flexible electronics. Now, a TU Wien research team led by Thomas Müller has made a breakthrough in this field as part of an ongoing research project.
Two-dimensional materials, or 2D materials for short, are extremely versatile, although – or often more precisely because – they are made up of just one or a...
20.04.2017 | Event News
18.04.2017 | Event News
03.04.2017 | Event News
26.04.2017 | Materials Sciences
26.04.2017 | Agricultural and Forestry Science
26.04.2017 | Physics and Astronomy