Introduction or background 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. Sources of data Pubmed.gov peer-reviewed journal articles and reviews. Areas of agreement 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. Areas of controversy 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? Areas timely for developing research 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?

Ethanol (EtOH) induces cognitive impairment through modulation of synaptic plasticity notably in the hippocampus. The cellular mechanism(s) of these EtOH effects may range from synaptic signaling modulation to alterations of the epigenome. Previously, we reported that two binge-like exposures to EtOH (3 g/kg, ip, 9 h apart) in adolescent rats abolished long-term synaptic depression (LTD) in hippocampus slices, induced learning deficits, and increased N-methyl-D-aspartate (NMDA) receptor signaling through its GluN2B subunit after 48 hours. Here, we tested the hypothesis of EtOH-induced epigenetic alterations leading to modulation of GluN2B and GluN2A NMDA receptor subunits. Forty-two days old rats were treated with EtOH or the histone deacetylase inhibitor (HDACi) sodium butyrate (NaB, 600 mg/kg, ip) injected alone or 30 minutes before EtOH. After 48 hours, learning was tested with novel object recognition while synaptic plasticity and the role of GluN2A and GluN2B subunits in NMDA-fEPSP were measured in CA1 field of hippocampus slices. LTD and memory were impaired 48 hours after EtOH and NMDA-fEPSP analysis unraveled changes in the GluN2A/GluN2B balance. These results were associated with an increase in histone deacetylase (HDAC) activity and HDAC2 mRNA and protein while Ac-H4K12 labelling was decreased. EtOH increases expression of HDAC2 and mRNA level for GluN2B subunit (but not GluN2A), while HDAC2 modulates the promoter of the gene encoding GluN2B. Interestingly, NaB pretreatment prevented all the cellular and memory-impairing effects of EtOH. In conclusion, the memoryimpairing effects of two binge-like EtOH exposure involve NMDA receptordependent LTD deficits due to a GluN2A/GluN2B imbalance resulting from changes in GluN2B expression induced by HDAC2. KEYWORDS epigenetic, ethanol, long-term depression Catherine Vilpoux and Olivier Pierrefiche are co-last authors. I.D., C.D., and R.A. performed and analyzed electrophysiology and behavior experiments; G.F., I.M., and V.D. performed and analyzed cellular biology; P.G., H.S., and C.V. performed and analyzed immunohistochemistry; S.P., M.N., C.V., and O.P. wrote and edited the manuscript. /journal/adb 1 of 15 2 | MATERIAL AND METHODS Experiments were performed following the European Community guiding principles for the care and use of animals (2010/63/UE, CE Off.

Summary By studying healthy women who do not request analgesia during their first delivery, we investigate genetic effects on labor pain. Such women have normal sensory and psychometric test results, except for significantly higher cuff pressure pain. We find an excess of heterozygotes carrying the rare allele of SNP rs140124801 in KCNG4 . The rare variant K V 6.4-Met419 has a dominant-negative effect and cannot modulate the voltage dependence of K V 2.1 inactivation because it fails to traffic to the plasma membrane. In vivo , Kcng4 (K V 6.4) expression occurs in 40% of retrograde-labeled mouse uterine sensory neurons, all of which express K V 2.1, and over 90% express the nociceptor genes Trpv1 and Scn10a . In neurons overexpressing K V 6.4-Met419, the voltage dependence of inactivation for K V 2.1 is more depolarized compared with neurons overexpressing K V 6.4. Finally, K V 6.4-Met419-overexpressing neurons have a higher action potential threshold. We conclude that K V 6.4 can influence human labor pain by modulating the excitability of uterine nociceptors.