To investigate the association between three selected pain polymorphisms and clinical, functional, sensory-related, psychophysical, psychological or cognitive variables in a sample of women with fibromyalgia (FMS). One hundred twenty-three (n = 123) women with FMS completed demographic (age, height, weight), clinical (years with pain, intensity of pain at rest and during daily living activities), functional (quality of life, physical function), sensory-related (sensitization-associated and neuropathic-associated symptoms), psychophysical (pressure pain thresholds), psychological (sleep quality, depressive and anxiety level) and cognitive (pain catastrophizing, kinesiophobia) variables. Those three genotypes of the OPRM1 rs1799971, HTR1B rs6296 and COMT rs4680 single nucleotide polymorphisms were obtained by polymerase chain reactions from no-stimulated whole saliva collection. No significant differences in demographic, clinical, functional, sensory-related, psychophysical, psychological and cognitive variables according to OPRM1 rs1799971, HTR1B rs6296 or COMT rs4680 genotype were identified in our sample of women with FMS. A multilevel analysis did not either reveal any significant gene-to-gene interaction between OPRM1 rs1799971 x HTR1B rs6296, OPRM1 rs1799971 x COMT rs4680 and HTR1B rs6296 x COMT rs4680 for any of the investigated outcomes. This study revealed that three single nucleotide polymorphisms, OPRM1 rs1799971, HTR1B rs6296 or COMT rs4680, mostly associated with chronic pain were not involved in phenotyping features of FMS. Potential gene-to-gene interaction and their association with clinical phenotype in women with FMS should be further investigated in future studies including large sample sizes.

BACKGROUND: In almost half of patients suffering from small fiber neuropathies (SFN), the etiology remains elusive. For these patients with \"idiopathic SFN\", symptomatic analgesic therapy is the only option. Reports on a potential genetic background of neuropathic pain syndromes are increasing and particularly in SFN patients, several genetic variants were found mainly located in genes encoding voltage-gated sodium channels. Although up to 30% of SFN patients show genetic alterations, most of these remain of \"unknown pathogenic significance\" and little is known about \"genetic SFN\".
OBJECTIVE: The study aimed to determine clinical characteristics of SFN patients carrying a rare genetic variant of unknown significance in pain-associated genes.
METHODS: From 2015 to 2020, 66 patients with primarily idiopathic SFN were examined and rare gene variants of unknown significance detected in 13/66 (20%) of these. A detailed medical history with focus on pain was recorded and patients filled in standardized questionnaires to assess physical and emotional burden due to pain.
RESULTS: The authors found 13/66 (20%) patients with rare variants of unknown significance located in pain-associated genes who reported pain refractory to analgesic treatment, a higher number of external factors influencing clinical symptoms, and a higher level of physical impairment and emotional stress due to pain compared with patients without such genetic variants.
CONCLUSIONS: Early genetic assessment is recommended to optimize the management of patients with potentially hereditary SFN. Early access to rehabilitation and mental support as well as a consequent elimination of external triggering factors should be granted.
UNASSIGNED: HINTERGRUND: Bei etwa der Hälfte der PatientInnen mit Small-Fiber-Neuropathie (SFN) findet sich für die Schmerzsymptomatik keine erklärende und behandelbare Ätiologie. Es häufen sich Berichte zu genetisch-neuropathischen Schmerzsyndromen. Auch einige SFN-PatientInnen weisen Variationen in schmerzassoziierten Genen auf. Teils sind diese bereits als „pathogen“ bestätigt, andere haben eine „unklare pathogenetische Relevanz“. Trotz des hohen Anteils betroffener PatientInnen ist über die genetische SFN bislang wenig bekannt.
UNASSIGNED: In unserer Arbeit fokussierten wir uns auf diese Kohorte: Durch Sammlung klinischer Daten sollten Charakteristika der PatientInnen mit seltenen Varianten unklarer Signifikanz in schmerzassoziierten Genen gesammelt werden.
METHODS: Von 2015 bis 2020 untersuchten wir 66 PatientInnen mit initial „idiopathischer“ SFN. Bei 13/66 (20 %) wurden Varianten unklarer pathogenetischer Relevanz in schmerzassoziierten Genen detektiert. Alle rekrutierten PatientInnen unterzogen sich einer detaillierten Anamneseerhebung mit Fokus auf Schmerz und beantworteten Fragebögen zu Beschwerden und Belastung.
UNASSIGNED: Die Kohorte mit seltener Variante in schmerzassoziierten Genen zeigte gegenüber den anderen PatientInnen subtile klinische Unterschiede: Neben einer höheren physischen und psychischen Belastung konnten eine von außen beeinflussbare Symptomatik und eine herausfordernde Therapie nachgewiesen werden.
CONCLUSIONS: Wir sehen eine frühzeitige genetische Diagnostik bei SFN als essenziell: Durch weitere supportive Maßnahmen wie Vermeidung von Einflussfaktoren, Stärkung der Resilienz und eventuell künftig verfügbare zielgerichtete Therapeutika kann die Versorgung der PatientInnen mit seltener Variante in schmerzassoziierten Genen optimiert werden.

The detection and avoidance of harmful stimuli are essential animal capabilities. The molecular and cellular mechanisms controlling nociception and its plasticity are conserved, genetically controlled processes of broad biomedical interest given their relevance to understand and treat pain conditions that represent a major health burden. Recent genome-wide association studies (GWAS) have identified a rich set of polymorphisms related to different pain conditions and pointed to many human pain gene candidates, whose connection to the pain pathways is however often poorly understood. Here, we used a computer-assisted Caenorhabditis elegans thermal avoidance analysis pipeline to screen for behavioral defects in a set of 109 mutants for genes orthologous to human pain-related genes. We measured heat-evoked reversal thermosensitivity profiles, as well as spontaneous reversal rate, and compared naïve animals with adapted animals submitted to a series of repeated noxious heat stimuli, which in wild type causes a progressive habituation. Mutations affecting 28 genes displayed defects in at least one of the considered parameters and could be clustered based on specific phenotypic footprints, such as high-sensitivity mutants, nonadapting mutants, or mutants combining multiple defects. Collectively, our data reveal the functional architecture of a network of conserved pain-related genes in C. elegans and offer novel entry points for the characterization of poorly understood human pain genes in this genetic model.

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.

Congenital insensitivity to pain (CIP) is caused by extremely rare Mendelian genetic disorders. CIP individuals demonstrate the unexpectedly severe consequences of painlessness. Although only a small number of causative conditions and genes are known, most have led to profound insights into human nociception. CIP gene discovery is catalyzing the manufacture of completely new classes of analgesics, and these are needed as alternatives to synthetic highly potent opioids.
Pubmed.gov peer-reviewed journal articles and reviews.
The importance of nerve growth factor-tropomyosin receptor kinase A (NGF-TRKA) signalling for nociceptor genesis and subsequent pain sensing.New analgesics can be generated from knowledge of the NGF-TRKA nociceptor pathway.Increased susceptibility to Staphylococcus aureus infection is a consequence of deficient NGF-TRKA signalling.Mutations in the voltage-gated sodium channels SCN9A and SCN11A can cause congenital painlessness, and in contradistinction, other mutations can cause episodic neuropathic pain. SCN9A/Nav1.7 is an analgesic target. SCN11A/Nav1.9 is unlikely to be an analgesic target.There are further Mendelian causes of painlessness to be discovered.
Which NGF-TRKA intracellular signalling pathways operate in nociceptor development and which in post-natal pain sensing?Why have no clinically effective Nav1.7 antagonist been generated? SCN9A-CIP causes analgesia, at least in part, through endogenous opioids.Why do all CIP phenotypes involve a complete loss of all types of nociception?
PRDM12 as an analgesic target.Discovery of the function and analgesic potential of new CIP genes.Can NGF-TRKA be used in the treatment of S. aureus?

[This corrects the article DOI: 10.3389/fnmol.2019.00037.].

Sex differences in gene expression are important contributors to normal physiology and mechanisms of disease. This is increasingly apparent in understanding and potentially treating chronic pain where molecular mechanisms driving sex differences in neuronal plasticity are giving new insight into why certain chronic pain disorders preferentially affect women vs. men. Large transcriptomic resources are now available and can be used to mine for sex differences to gather insight from molecular profiles using donor cohorts. We performed in-depth analysis of 248 human tibial nerve (hTN) transcriptomes from the GTEx Consortium project to gain insight into sex-dependent gene expression in the peripheral nervous system (PNS). We discover 149 genes with sex differential gene expression. Many of the more abundant genes in men are associated with inflammation and appear to be primarily expressed by glia or immune cells, with some genes downstream of Notch signaling. In women, we find the differentially expressed transcription factor SP4 that is known to drive a regulatory program, and may impact sex differences in PNS physiology. Many of these 149 differentially expressed (DE) genes have some previous association with chronic pain but few of them have been explored thoroughly. Additionally, using clinical data in the GTEx database, we identify a subset of DE, sexually dimorphic genes in diseases associated with chronic pain: arthritis and Type II diabetes. Our work creates a unique resource that identifies sexually dimorphic gene expression in the human PNS with implications for discovery of sex-specific pain mechanisms.

BACKGROUND: The enzyme guanosine triphosphate-cyclohydrolase-1 (GCH-1) is a rate limiting step in the de novo synthesis of tetrahydrobiopterin (BH4) a co-factor in monoamine synthesis and nitric oxide production. GCH-1 is strongly implicated in chronic pain based on data generated using the selective GCH-1 inhibitor 2,4-diamino-6-hydroxypyrimidine (DAHP), and studies which have identified a pain protective GCH-1 haplotype associated with lower BH4 production and reduced pain.
METHODS: To investigate the role for GCH-1 in visceral pain we examined the effects of DAHP on pain behaviors elicited by colorectal injection of mustard oil in rats, and the pain protective GCH-1 haplotype in healthy volunteers characterized by esophageal pain sensitivity before and after acid injury, and assessed using depression and anxiety questionnaires.
RESULTS: In rodents pretreatment with DAHP produced a substantial dose related inhibition of pain behaviors from 10 to 180 mg/kg i.p. (p < 0.01 to 0.001). In healthy volunteers, no association was seen between the pain protective GCH-1 haplotype and the development of hypersensitivity following injury. However, a substantial increase in baseline pain thresholds was seen between first and second visits (26.6 ± 6.2 mA) in subjects who sensitized to esophageal injury and possessed the pain protective GCH-1 haplotype compared with all other groups (p < 0.05). Furthermore the same subjects who sensitized to acid and possessed the haplotype, also had significantly lower depression scores (p < 0.05).
CONCLUSIONS: The data generated indicate that GCH-1 plays a role in visceral pain processing that requires more detailed investigation.

Hundreds of genes are proposed to contribute to nociception and pain perception. Historically, most studies of pain-related genes have examined them in isolation or alongside a handful of other genes. More recently the use of systems biology techniques has enabled us to study genes in the context of the biological pathways and networks in which they operate. Here we describe a Web-based resource, available at http://www.PainNetworks.org. It integrates interaction data from various public databases with information on known pain genes taken from several sources (eg, The Pain Genes Database) and allows the user to examine a gene (or set of genes) of interest alongside known interaction partners. This information is displayed by the resource in the form of a network. The user can enrich these networks by using data from pain-focused gene expression studies to highlight genes that change expression in a given experiment or pairs of genes showing correlated expression patterns across different experiments. Genes in the networks are annotated in several ways including biological function and drug binding. The Web site can be used to find out more about a gene of interest by looking at the function of its interaction partners. It can also be used to interpret the results of a functional genomics experiment by revealing putative novel pain-related genes that have similar expression patterns to known pain-related genes and by ranking genes according to their network connections with known pain genes. We expect this resource to grow over time and become a valuable asset to the pain community.