A compendium of validated pain genes

Abstract

The development of novel pain therapeutics hinges on the identification and rigorous validation of potential targets. Model organisms provide a means to test the involvement of specific genes and regulatory elements in pain. Here we provide a list of genes linked to pain‐associated behaviors. We capitalize on results spanning over three decades to identify a set of 242 genes. They support a remarkable diversity of functions spanning action potential propagation, immune response, GPCR signaling, enzymatic catalysis, nucleic acid regulation, and intercellular signaling. Making use of existing tissue and single‐cell high‐throughput RNA sequencing datasets, we examine their patterns of expression. For each gene class, we discuss archetypal members, with an emphasis on opportunities for additional experimentation. Finally, we discuss how powerful and increasingly ubiquitous forward genetic screening approaches could be used to improve our ability to identify pain genes. This article is categorized under: Neurological Diseases > Genetics/Genomics/Epigenetics Neurological Diseases > Molecular and Cellular Physiology

SCN9A rs6746030 Polymorphism and Pain Perception in Combat Athletes and Non-Athletes

“…Ion channels, which are responsible for cell excitability and thus intercellular communication, play an important role in the biological mechanisms that generate and maintain neuropathic pain. Of the three voltage-gated channels (sodium, calcium, and potassium channels) directly involved in regulating membrane potentials, sodium channels appear to be the most important targets for pain [ 7 ]. Two genome-wide association studies (GWAS) performed in primary erythromelalgia patients in 2004 and 2005 revealed gain-of-function mutations in the SCN9A gene [ 26 , 27 ].…”

“…Additionally, it needs to be highlighted that pain phenotype is a polygenic trait. To date, about 252 genes have been linked to pain-associated behaviors [ 7 ]. It is more likely that several gene loci, each with a small but significant contribution, are responsible for this genetic component.…”

“…One of the underlying mechanisms for individual differences in pain perception is genetic susceptibility. Multiple genes, derived from human and animal studies, have been shown to be important in modulating pain perception [ 7 , 8 , 9 ]. Literature research conducted by Wistrom et al [ 7 ] allowed for the identification of 242 genes linked to pain-associated behaviors.…”

“…Multiple genes, derived from human and animal studies, have been shown to be important in modulating pain perception [ 7 , 8 , 9 ]. Literature research conducted by Wistrom et al [ 7 ] allowed for the identification of 242 genes linked to pain-associated behaviors. Due to the function of the pain gene products, they were divided into six functional groups: (1) voltage-gated and ligand-gated ion channels (e.g., sodium channel NaV1.7— SCN9A ); (2) G protein-coupled receptors—GPCRs (e.g., delta-opioid receptor— OPRD1 ); (3) neuropeptides, neurotransmitters, and neurotrophins (e.g., tachykinin 1— TAC1 ); (4) growth factors, hormones, and cytokines (e.g., interleukin 10— IL-10 ); (5) enzymes and enzyme-linked receptors (e.g., mitogen-activated protein kinase 1— MAPK1 ); and (6) transcriptional and translational control and mRNA processing (e.g., PR domain-containing protein 12— PRDM12 ) [ 7 , 9 , 10 , 11 , 12 ].…”

“…Recent studies have revealed that variations in voltage-gated sodium channel genes are key players in peripheral pain processing [ 6 , 7 , 8 ]. For example, inactivating mutations in SCN9A result in congenital insensitivity to pain, whereas gain-of-function mutations generate different pain syndromes such as inherited erythromelalgia, paroxysmal extreme pain disorder, and small-fiber neuropathy [ 13 ].…”