Review Pain Genes Tom Foulkes1, John N. Wood 2 * 1 Department of Stem Cell Biology and Developmental Genetics, National Institute for Medical Research, London, United Kingdom, 2 Molecular Nociception Group, University College London, London, United Kingdom Abstract: Pain, which afflicts up to 20% of the population at any time, provides both a massive therapeutic challenge and a route to understanding mechanisms in the nervous system. Specialised sensory neurons (noci- ceptors) signal the existence of tissue damage to the central nervous system (CNS), where pain is represented in a complex matrix involving many CNS structures. Genetic approaches to investigating pain pathways using model organisms have identified the molecular nature of the transducers, regulatory mechanisms involved in changing neuronal activity, as well as the critical role of immune system cells in driving pain pathways. In man, mapping of human pain mutants as well as twin studies and association studies of altered pain behaviour have identified important regulators of the pain system. In turn, new drug targets for chronic pain treatment have been validated in transgenic mouse studies. Thus, genetic studies of pain pathways have complemented the traditional neuroscience approaches of electrophysiology and pharmacology to give us fresh insights into the molecular basis of pain perception. Introduction Noxious environmental stimuli, tissue damage, and disease all evoke pain. The avoidance of painful stimuli, the protection of damaged tissue to promote healing, and the amelioration of disease-evoked pain (preferably through resolution of the disease itself) have obvious survival value. The evolutionary utility of pain- evoked behavioural responses is confirmed by apparent conserva- tion of some mechanisms in all animals with nervous systems. The existence of specialised mammalian sensory neurons that respond to tissue damage (nociceptors), first proposed by Sherrington a century ago, has been clearly demonstrated in humans and mice, where mutations leading to loss of responsiveness to the trophic factor nerve growth factor (NGF) result in the loss of nociceptive neurons and a pain-free phenotype [1]. In this review we focus on genetic approaches to the mechanisms involved in activating nociceptive neurons, human genetics of pain perception, and genetic validation of pain targets leading to new drugs. The application of molecular genetics to the problem of pain has provided some remarkable insights over the past 15 years [2]. Nonetheless, the scale of the clinical problem of dysfunctional chronic pain remains vast (see for example http:// www.europeanpainnetwork.com/). New drugs acting on targets validated in mouse and man by genetic studies show promise for many of the present clinical problems. This therapeutic challenge is complemented by the fact that pain also provides a wonderful model system to understand how the nervous system works. This area is perhaps the most exciting for geneticists who want to address mechanisms of perception and consciousness, neuronal signalling, synaptic plasticity, and integrative aspects of nervous system function. The Pain System Figure 1 summarises the basic wiring and defined genes involved in the pain system. Unlike other sensory modalities, such as vision, hearing, and smell, the brain regions associated with pain perception are complex and have been best described as a pain matrix [3]. Given the uncertainty about central representation of pain sensation, it is not surprising that most research activity has focused on genes expressed by specialised peripheral sensory neurons essential for pain. The mechanisms by which noxious stimuli activate sensory neurons are summarised in Box 1. Spinal cord plasticity and descending circuits that regulate noxious input to the thalamus and higher brain centres have been examined in detail at the systems level, but genetic approaches to understand- ing CNS pain pathways are still at an early stage. The relationship between CNS pain perception and the activation of damage sensing neurons is complex, but most studies have focused on the more tractable aspects of peripheral pain pathways. Peripheral Pain Pathway Neurotransmission Tissue damage depolarises sensory neurons, but the transmis- sion of information to the CNS requires the recruitment of voltage-gated sodium channels to propagate action potentials, and cause neurotransmitter release (mainly glutamate) into the CNS (Figure 1). In the absence of selective antagonists of ion channels, knock-out mouse studies have provided important insights into the genes that underlie this first stage in the induction of pain [4]. Three genes encoding sodium channels are selectively expressed in sensory neurons. One, SCN11A, is found in a subset of damage- sensing neurons, and is activated close to the resting membrane potential. Knock-out studies have confirmed that the encoded channel NaV1.9 does not support action potentials but plays a key role in setting pain thresholds, as it is regulated by inflammatory mediators [5]. The second, SCN9A, is essential for peripheral pain and had been analysed in mouse knock-outs [6] before the discovery of naturally occurring human mutants [7]. Global mouse knock-outs of SCN9A die, probably because they are unable to feed. However, nociceptor-specific mutants show a loss of acute mechanical and inflammatory pain [6]. Interestingly, loss of Citation: Foulkes T, Wood JN (2008) Pain Genes. PLoS Genet 4(7): e1000086. doi:10.1371/journal.pgen.1000086 Editor: Elizabeth M. C. Fisher, University College London, United Kingdom Published July 25, 2008 Copyright: 2008 Foulkes, Wood. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Funding: We thank the Biotechnology and Biological Science Research Council (BBSRC), the Medical Research Council (MRC), and the Wellcome Trust for generous support. Competing Interests: The authors have declared that no competing interests exist. * E-mail: J.Wood@ucl.ac.uk PLoS Genetics | www.plosgenetics.org 1 July 2008 | Volume 4 | Issue 7 | e1000086