Inhibition of nociceptors by TRPV1-mediated entry of impermeant sodium channel blockers

Most local anaesthetics used clinically are relatively hydrophobic molecules that gain access to their blocking site on the sodium channel by diffusing into or through the cell membrane. These anaesthetics block sodium channels and thereby the excitability of all neurons, not just sensory neurons. We tested the possibility of selectively blocking the excitability of primary sensory nociceptor (pain-sensing) neurons by introducing the charged, membrane-impermeant lidocaine derivative QX-314 through the pore of the noxious-heat-sensitive TRPV1 channel. Here we show that charged sodium-channel blockers can be targeted into nociceptors by the application of TRPV1 agonists to produce a pain-specific local anaesthesia. QX-314 applied externally had no effect on the activity of sodium channels in small sensory neurons when applied alone, but when applied in the presence of the TRPV1 agonist capsaicin, QX-314 blocked sodium channels and inhibited excitability. Inhibition by co-applied QX-314 and capsaicin was restricted to neurons expressing TRPV1. Injection of QX-314 together with capsaicin into rat hindpaws produced a long-lasting (more than 2 h) increase in mechanical and thermal nociceptive thresholds. Long-lasting decreases in pain sensitivity were also seen with regional injection of QX-314 and capsaicin near the sciatic nerve; however, in contrast to the effect of lidocaine, the application of QX-314 and capsaicin together was not accompanied by motor or tactile deficits.     

Common variants at 12q14 and 12q24 are associated with hippocampal volume

Aging is associated with reductions in hippocampal volume that are accelerated by Alzheimer's disease and vascular risk factors. Our genome-wide association study (GWAS) of dementia-free persons (n = 9,232) identified 46 SNPs at four loci with P values of <4.0 × 10(-7). In two additional samples (n = 2,318), associations were replicated at 12q14 within MSRB3-WIF1 (discovery and replication; rs17178006; P = 5.3 × 10(-11)) and at 12q24 near HRK-FBXW8 (rs7294919; P = 2.9 × 10(-11)). Remaining associations included one SNP at 2q24 within DPP4 (rs6741949; P = 2.9 × 10(-7)) and nine SNPs at 9p33 within ASTN2 (rs7852872; P = 1.0 × 10(-7)); along with the chromosome 12 associations, these loci were also associated with hippocampal volume (P < 0.05) in a third younger, more heterogeneous sample (n = 7,794). The SNP in ASTN2 also showed suggestive association with decline in cognition in a largely independent sample (n = 1,563). These associations implicate genes related to apoptosis (HRK), development (WIF1), oxidative stress (MSR3B), ubiquitination (FBXW8) and neuronal migration (ASTN2), as well as enzymes targeted by new diabetes medications (DPP4), indicating new genetic influences on hippocampal size and possibly the risk of cognitive decline and dementia.     

The colour centre in the cerebral cortex of man

Anatomical and physiological studies have shown that there is an area specialized for the processing of colour (area V4) in the prestriate cortex of macaque monkey brain. Earlier this century, suggestive clinical evidence for a colour centre in the brain of man was dismissed because of the association of other visual defects with the defects in colour vision. However, since the demonstration of functional specialization in the macaque cortex, the question of a colour centre in man has been reinvestigated, based on patients with similar lesions in the visual cortex. In order to study the colour centre in normal human subjects, we used the technique of positron emission tomography (PET), which measures increases in blood flow resulting from increased activity in the cerebral cortex. A comparison of the results of PET scans of subjects viewing multi-coloured and black-and-white displays has identified a region of normal human cerebral cortex specialized for colour vision.     

Names and types in perennial Atriplex Linnaeus (Chenopodiaceae) in North America selectively exclusive of Mexico

Cited are names and combinations within the woody species of Atriplex as they occur in North America. Types and their repositories are included for all taxa except those for which that information could not be located. New nomenclatural proposals include Atriplex gardneri var. aptera (A. Nelson) Welsh & Crompton, comb. nov.; A. garrettii var. navajoensis (C. A. Hanson) Welsh & Crompton, comb. nov.; Atriplex acanthocarpa var. coahuilensis (Henrickson) Welsh & Crompton, comb. nov. A lectotype is designated for A. breweri S. Watson.     

Inhibin beta in central neural pathways involved in the control of oxytocin secretion

Inhibin (I) a gonadal hormone glycoprotein which suppresses follicle-stimulating hormone (FSH) secretion from the anterior pituitary, is a heterodimer consisting of an alpha subunit and one of two distinct beta subunits. S1 nuclease analysis has revealed that RNAs encoding all three subunits (alpha, beta A and beta B) are expressed in rat brain. We report here on the localization, and a potential function, of inhibin beta in the rat brain. A cell group centred in the nucleus of the solitary tract (NTS), a major recipient of visceral sensory information, was stained immunohistochemically with antisera against synthetic fragments of I beta, but not I alpha. The distribution of I beta-stained fibres is consistent with known NTS projections, and includes a prominent projection to oxytocinergic aspects of the magnocellular neurosecretory system.     

Further simplification of a supernatant flow system for tissue culture

Zusammenfassung In der Arbeit wird eine Einrichtung für kontinuierliche Flüssigkeitszufuhr beschrieben, wie sie für Gewebskulturen wertvoll sein kann. Durch eine feinporöse Membran kann die Menge der Flüssigkeit reguliert werden.

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This research was supported by a P.H.S. Grant H-2249 from the National Heart Institute, U.S. Public Health Service.