Targeted ubiquitination of Na 1.8 reduces sensory neuronal excitability.

Chronic pain and addiction are a significant global health challenge. Voltage-gated sodium channel Na 1.8, a pivotal driver of pain signaling, is a clinically validated target for the development of novel, non-addictive pain therapeutics.

TRPM8 Mutations Associated With Persistent Pain After Surgical Injury of Corneal Trigeminal Axons.

Background And Objectives: Despite extensive efforts, the mechanisms underlying pain after axonal injury remain incompletely understood. Pain following corneal refractive surgery offers a valuable human model for investigating trigeminal axonal injury because laser-assisted in situ keratomileusis (LASIK) severs axons of trigeminal ganglion neurons innervating the cornea. While the majority of patients are pain-free shortly after surgery, a minority endure persistent postoperative ocular pain.

Impacts of resident physician unionization on house staff compensation.

Background: Physicians-in-training in the United States work long hours for relatively low wages. In response to increased economic burden, the popularity of unionization in residency training programs has increased dramatically. In this study, we conducted a cross-sectional investigation of the association between unionization status and Internal Medicine PGY-1 compensation and benefits.

Nav1.8 in small dorsal root ganglion neurons contributes to vincristine-induced mechanical allodynia.

Vincristine-induced peripheral neuropathy is a common side effect of vincristine treatment, which is accompanied by pain and can be dose-limiting. The molecular mechanisms that underlie vincristine-induced pain are not well understood. We have established an animal model to investigate pathophysiological mechanisms of vincristine-induced pain.

Functionally-selective inhibition of threshold sodium currents and excitability in dorsal root ganglion neurons by cannabinol.

Cannabinol (CBN), an incompletely understood metabolite for ∆9-tetrahydrocannabinol, has been suggested as an analgesic. CBN interacts with endocannabinoid (CB) receptors, but is also reported to interact with non-CB targets, including various ion channels. We assessed CBN effects on voltage-dependent sodium (Nav) channels expressed heterologously and in native dorsal root ganglion (DRG) neurons.

Sodium currents in naïve mouse dorsal root ganglion neurons: No major differences between sexes.

Sexual dimorphism has been reported in multiple pre-clinical and clinical studies on pain. Previous investigations have suggested that in at least some states, rodent dorsal root ganglion (DRG) neurons display differential sex-dependent regulation and expression patterns of various proteins involved in the pain pathway. Our goal in this study was to determine whether sexual dimorphism in the biophysical properties of voltage-gated sodium (Nav) currents contributes to these observations in rodents.

Systemic Effects of Perineural Glucocorticoids on Fasting Serum Glucose, Potassium, and White Blood Cell Count in Total Hip Arthroplasty.

Purpose: Glucocorticoids are commonly used as regional anesthesia adjuvants to improve blockade quality and duration. There are limited data in the literature regarding the potential systemic effects and safety of perineural glucocorticoids. This study examines the effects of perineural glucocorticoids on serum glucose, potassium, and white blood cell count (WBC) in the immediate postoperative period after primary total hip arthroplasty (THA).

Nav1.7 P610T mutation in two siblings with persistent ocular pain after corneal axon transection: impaired slow inactivation and hyperexcitable trigeminal neurons.

Despite extensive study, the mechanisms underlying pain after axonal injury remain incompletely understood. Pain after corneal refractive surgery provides a model, in humans, of the effect of injury to trigeminal afferent nerves. Axons of trigeminal ganglion neurons that innervate the cornea are transected by laser-assisted in situ keratomileusis (LASIK).

Fibroblast growth factor homologous factor 2 attenuates excitability of DRG neurons.

Fibroblast growth factor homologous factors (FHFs) are cytosolic members of the superfamily of the FGF proteins. Four members of this subfamily (FHF1-4) are differentially expressed in multiple tissues in an isoform-dependent manner. Mutations in FHF proteins have been associated with multiple neurological disorders.

Stem cell-derived sensory neurons modelling inherited erythromelalgia: normalization of excitability.

Effective treatment of pain remains an unmet healthcare need that requires new and effective therapeutic approaches. NaV1.7 has been genetically and functionally validated as a mediator of pain.

Trigeminal Neuralgia TRPM8 Mutation: Enhanced Activation, Basal [Ca] and Menthol Response.

Objective: To assess the functional effects of a variant, c.89 G > A (p.Arg30Gln), in the transient receptor potential melastatin 8 (TRPM8) cold-sensing, nonselective cation channel, which we have previously identified in a patient with familial trigeminal neuralgia.

Status of peripheral sodium channel blockers for non-addictive pain treatment.

The effective and safe treatment of pain is an unmet health-care need. Current medications used for pain management are often only partially effective, carry dose-limiting adverse effects and are potentially addictive, highlighting the need for improved therapeutic agents. Most common pain conditions originate in the periphery, where dorsal root ganglion and trigeminal ganglion neurons feed pain information into the CNS.

Pharmacological characterization of a rat Nav1.7 loss-of-function model with insensitivity to pain.

Sodium channel Nav1.7, encoded by the SCN9A gene, is a well-validated target that plays a key role in controlling pain sensation. Loss-of-function mutations of Nav1.

Fibroblast growth factor homologous factor 2 (FGF-13) associates with Nav1.7 in DRG neurons and alters its current properties in an isoform-dependent manner.

Fibroblast Growth Factor Homologous Factors (FHF) constitute a subfamily of FGF proteins with four prototypes (FHF1-4; also known as FGF11-14). FHF proteins have been shown to bind directly to the membrane-proximal segment of the C-terminus in voltage-gated sodium channels (Nav), and regulate current density, availability, and frequency-dependent inhibition of sodium currents. Members of the FHF2 subfamily, FHF2A and FHF2B, differ in the length and sequence of their N-termini, and, importantly, differentially regulate Nav1.

Therapeutic potential of Pak1 inhibition for pain associated with cutaneous burn injury.

Painful burn injuries are among the most debilitating form of trauma, globally ranking in the top 15 leading causes of chronic disease burden. Despite its prevalence, however, chronic pain after burn injury is under-studied. We previously demonstrated the contribution of the Rac1-signaling pathway in several models of neuropathic pain, including burn injury.

Between fire and ice: refractory hypothermia and warmth-induced pain in inherited erythromelalgia.

Inherited erythromelalgia (IEM) is a well-described pain disorder caused by mutations of sodium channel Na1.7, a peripheral channel expressed within dorsal root ganglion and the sympathetic ganglion neurons. Clinically, IEM is characterised by paroxysmal attacks of severe pain, usually in the distal extremities, triggered by warmth or exercise.

Reverse pharmacogenomics: carbamazepine normalizes activation and attenuates thermal hyperexcitability of sensory neurons due to Na 1.7 mutation I234T.

Background And Purpose: Pharmacotherapy for pain currently involves trial and error. A previous study on inherited erythromelalgia (a genetic model of neuropathic pain due to mutations in the sodium channel, Na 1.7) used genomics, structural modelling and biophysical and pharmacological analyses to guide pharmacotherapy and showed that carbamazepine normalizes voltage dependence of activation of the Na 1.

The ribosome can discriminate the chirality of amino acids within its peptidyl-transferase center.

The cellular translational machinery (TM) synthesizes proteins using exclusively L- or achiral aminoacyl-tRNAs (aa-tRNAs), despite the presence of D-amino acids in nature and their ability to be aminoacylated onto tRNAs by aa-tRNA synthetases. The ubiquity of L-amino acids in proteins has led to the hypothesis that D-amino acids are not substrates for the TM. Supporting this view, protein engineering efforts to incorporate D-amino acids into proteins using the TM have thus far been unsuccessful.

Natural amino acids do not require their native tRNAs for efficient selection by the ribosome.

The involvement of tRNA structural elements beyond the anticodon in aminoacyl-tRNA (aa-tRNA) selection by the ribosome has revealed that substrate recognition is considerably more complex than originally envisioned in the adaptor hypothesis. By combining recent breakthroughs in aa-tRNA synthesis and mechanistic and structural studies of protein synthesis, we have investigated whether aa-tRNA recognition further extends to the amino acid, which would explain various translation disorders exhibited by misacylated tRNAs. Contrary to expectation, we find that natural amino acids misacylated onto natural but non-native tRNAs are selected with efficiencies very similar to those of their correctly acylated counterparts.