A Point Mutation at F1737 of the Human Nav1.7 Sodium Channel Decreases Inhibition by Local Anesthetics

Abstract: Voltage-gated sodium channels (VGSC) contribute to the initiation and propagation of action potentials within the nervous system. These channels are important targets for inhibition by several classes of drugs, including antiarrhythmics and local anesthetics. Structural and pharmacological studies have localized the binding of these drugs to a common site near the channel's intracellular pore region. Point mutations within this region disrupt local anesthetic inhibition of cardiac, CNS, and skeletal muscle VGSC subtypes. This study was designed to test whether a similar structural requirement for drug binding exists on the peripheral neuronal VGSC subtype; Na_v1.7. In support of this hypothesis, an alanine substitution for phenylalanine at position 1737 (F1737A) in the pore lining S6 segment of domain IV in human Na_v1.7 reduced both use- and state- dependent inhibition of the local anesthetics, lidocaine and tetracaine, by 8–21-fold. We also saw a 2–3-fold reduction in tonic inhibition with the F1737A mutant. The voltage dependence of both activation and inactivation were unaffected by the F1737A mutation, however, fast inactivation kinetics were impaired, such that a significant portion of inward current remained at the end of a 20-ms depolarization. These data suggest that F1737 forms a part of the high affinity binding of local anesthetics as well as mediating inactivation processes of neuronal Na_v1.7 channels.     

Effects of Extracorporeal Shock Wave-Mediated Transdermal Local Anesthetic Drug Delivery on Rat Caudal Nerves

Cavitation plays a substantial role in the clinical effects of extracorporeal shock wave therapy (ESWT). It is also generally accepted as a major mechanism in sonophoresis. To identify the enhancing effect of extracorporeal shock wave-mediated transdermal drug delivery, 24 Wistar rats were randomly assigned to four groups: (i) topical application of a eutectic mixture of local anesthetics (EMLA); (ii) 1-MHz ultrasound; (iii) ESWT pre-treatment combined with EMLA application; (iv) ESWT concurrent with EMLA application on rat tails. The degree of anesthesia was assessed using the amplitude and latency of sensory nerve action potentials within 5?min after a 60-min EMLA application. The results indicated that ESWT pre-treatment and concurrent ESWT accelerated the anesthetic effects of the EMLA cream on the tail nerve (p?<?0.05). This finding might indicate that shock wave-mediated transdermal drug delivery is possible during the ESWT period.     

How UK obstetric anaesthetists assess neuraxial anaesthesia for caesarean delivery: National surveys of practice conducted in 2004 and 2010

BackgroundThere is much interest in optimal methods of assessing neuraxial block before caesarean delivery. Although cold sensation is commonly used, some evidence suggests that the risk of intraoperative pain may be reduced by assessing light touch. We aimed to determine how neuraxial anaesthesia was managed perioperatively, and whether changes in clinical practice reflected the differing evidence in the literature over six years.MethodsA survey was sent to UK consultant OAA members in 2004, asking how neuraxial block was assessed before caesarean delivery, what was documented, what information was given to the patient, and postoperative follow-up. The survey was repeated in 2010.ResultsCompared to all other methods of assessing neuraxial block, ethyl chloride was the most popular in 2004 (71.8%, 95% CI 68.3–75.0, P < 0.0001) and 2010 (74.6%, 95% CI 70.8–78.3, P < 0.0001). There was a non-significant increase in light touch use from 54% to 60.1%. The upper level of block varied with the modality tested. There was a significant increase in respondents testing with light touch to T5.ConclusionsMethods of assessing neuraxial block differed from those recommended in the literature. The wide range of modalities, methods of testing and targeted sensory levels suggest that clearer recommendations on best practice for assessment and documentation of neuraxial block before caesarean delivery are required.     

Phenomenology of OCD: Lessons from a large multicenter study and implications for ICD-11

This study aimed to investigate the phenomenology of obsessive–compulsive disorder (OCD), addressing specific questions about the nature of obsessions and compulsions, and to contribute to the World Health Organization's (WHO) revision of OCD diagnostic guidelines. Data from 1001 patients from the Brazilian Research Consortium on Obsessive–Compulsive Spectrum Disorders were used. Patients were evaluated by trained clinicians using validated instruments, including the Dimensional Yale–Brown Obsessive–Compulsive Scale, the University of Sao Paulo Sensory Phenomena Scale, and the Brown Assessment of Beliefs Scale. The aims were to compare the types of sensory phenomena (SP, subjective experiences that precede or accompany compulsions) in OCD patients with and without tic disorders and to determine the frequency of mental compulsions, the co-occurrence of obsessions and compulsions, and the range of insight. SP were common in the whole sample, but patients with tic disorders were more likely to have physical sensations and urges only. Mental compulsions occurred in the majority of OCD patients. It was extremely rare for OCD patients to have obsessions without compulsions. A wide range of insight into OCD beliefs was observed, with a small subset presenting no insight. The data generated from this large sample will help practicing clinicians appreciate the full range of OCD symptoms and confirm prior studies in smaller samples the degree to which insight varies. These findings also support specific revisions to the WHO's diagnostic guidelines for OCD, such as describing sensory phenomena, mental compulsions and level of insight, so that the world-wide recognition of this disabling disorder is increased.